Symptoms:
In principle, on intoxication with Zaledor XR symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
Treatment:
The general emergency measures apply. Keep open the respiratory tract (aspiration!), maintain respiration and circulation depending on the symptoms.
The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intravenously.
In case of intoxication with oral formulations, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after Zaledor XR intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations.
Zaledor XR is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Zaledor XR drops with haemodialysis or haemofiltration alone is not suitable for detoxification.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
SymptomsSymptoms of overdosage with ULTRAM® are respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
TreatmentA single or multiple overdose with ULTRAM® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.
In treating an overdose of ULTRAM®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Seizures may be controlled with diazepam.
In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
Emptying of the gastric contents is useful to remove any unabsorbed drug.
Symptoms
Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, circulatory collapse, sedation and coma, seizures and respiratory depression. In severe cases tramadol overdose may result in a fatal outcome.
Management
A patent airway must be maintained. The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose induced by tramadol, though it will not antagonize tramadol's inhibitory effects on MAO reuptake or serotonin releasing effects. Other supportive measures should be employed as needed. Naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam. In case of oral intake of overdose, consider activated charcoal if the patient presents within one hour of ingestion of tramadol, provided the patient's airway can be protected.
Although it may seem reasonable to assume that later administration of activated charcoal may be beneficial for prolonged-release preparations and drugs that slow gastric emptying, there is no clinical trial evidence to support this.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.
Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation.
Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of Zaledor XR could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
SymptomsSymptoms of overdosage with Zaledor XR® are respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
TreatmentA single or multiple overdose with Zaledor XR® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.
In treating an overdose of Zaledor XR®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Seizures may be controlled with diazepam.
In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
Emptying of the gastric contents is useful to remove any unabsorbed drug.
Zaledor XR drops is contraindicated
- in hypersensitivity to Zaledor XR or any of the excipients ,
- in acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic medicinal products,
- in patients who are receiving MAO inhibitors or who have taken them within the last 14 days ,
- in patients with epilepsy not adequately controlled by treatment,
- for use in narcotic withdrawal treatment.
Tramadol must not be used for narcotic withdrawal treatment
Zaledor XR should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Zaledor XR is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Zaledor XR may worsen central nervous system and respiratory depression in these patients.
Not applicable.
The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10 % of patients.
The frequencies are defined as follows:
Very common: | >1/10 |
Common: | >1/100, <1/10 |
Uncommon: | >1/1000, <1/100 |
Rare: | >1/10 000, <1/1000 |
Very rare: | <1/10 000 |
Not known: | cannot be estimated from the available data |
Immune system disorders:
Uncommon: toxic epidermal necrolysis (TEN) and Stevens-Johnson-syndrome (SJS), and cross reactivity with non steroidal anti-inflammatory drugs
Cardiovascular disorders:
Uncommon: cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Rare: bradycardia, increase in blood pressure
Metabolism and nutrition disorders
Not known: hypoglycaemia, hyponatraemia
Nervous system disorders:
Very common: dizziness
Common: headache, drowsiness, somnolence
Rare: changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, hypertonia and dysgeusia. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly , respiratory depression may occur. Epileptiform convulsions occurred mainly after administration of high doses of Zaledor XR or after concomitant treatment with medicinal products which can lower the seizure threshold.
Not known: speech disorders
Psychiatric disorders:
Rare: delirium, hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Zaledor XR drops which vary individually in intensity and nature (depending on personality and duration of treatment). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders). Dependence may occur. Suicidal ideation, drug abuse and addiction.
Eye disorders:
Rare: miosis, blurred vision
Not known: mydriasis
Respiratory disorders:
Rare: dyspnoea. Worsening of asthma has been reported, though a causal relationship has not been established.
Gastrointestinal disorders:
Very common: nausea
Common: constipation, dry mouth, vomiting, dyspepsia, abdominal pain
Uncommon: anorexia, retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Skin and subcutaneous tissue disorders:
Common: sweating
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)
Musculo-skeletal disorders:
Rare: motorial weakness
Hepatobiliary disorders:
Very rare: In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of Zaledor XR.
Renal and urinary disorders:
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Reproductive system and breast disorders:
Common: menopausal symptoms
Rare: menstrual disorders
General disorders:
Common: fatigue, asthenia, malaise
Rare: weight loss, allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with Zaledor XR discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalization, derealization, paranoia).
Adverse Drug Reaction OverviewThe most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.
Clinical Trial Adverse Drug ReactionsBecause clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain (Non-titration Trials)ULTRAM® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM® group. In the tramadol treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.
Table 1.1: Cumulative Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain
| Percentage of Patients with Adverse Reaction N = 427 | |||
| Up to 7 Days | Up to 30 Days | Up to 90 Days | |
| Dizziness/Vertigo | 26% | 31% | 33% |
| Nausea | 24% | 34% | 40% |
| Constipation | 24% | 38% | 46% |
| Headache | 18% | 26% | 32% |
| Somnolence | 16% | 23% | 25% |
| Vomiting | 9% | 13% | 17% |
| Pruritus | 8% | 10% | 11% |
| “CNS Stimulation” a | 7% | 11% | 14% |
| Asthenia | 6% | 11% | 12% |
| Sweating | 6% | 7% | 9% |
| Dyspepsia | 5% | 9% | 13% |
| Dry Mouth | 5% | 9% | 10% |
| Diarrhea | 5% | 6% | 10% |
| a “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations |
Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.
Incidence of Adverse Reactions for ULTRAM® CAPSS-047 Titration TrialIn the double–blind phase of this pivotal trial, gastrointestinal complaints (primarily nausea and vomiting) and dizziness were the adverse events reported most frequently by tramadol-treated subjects, Table 1.2. Most of the adverse events were assessed as mild or moderate in intensity and resolved.
Table 1.2: Â Adverse Events in CAPSS-047 - Double-Blind Phase - Frequently Reported ( ≥ 2%a) Adverse Eventsb and Total Incidence of AEs Summarized by WHOART Body System, Treatment Group and Preferred Term
| AEs in CAPSS-047 Double-Blind Phase ≥ 2% of patients Tramadol Group/Titration Schedule | ||||||
| Body System | 10-days to 200 mg/day N =54 | 16-days to 200 mg/day N =59 | 13-days to 150 mg/day N =54 | |||
| Preferred Term | n | % | n | % | n | % |
| Any Adverse Event | 41 | 75.9 | 41 | 69.5 | 33 | 61.1 |
| Body as a Whole - General Disorders | ||||||
| Influenza-like symptoms | 0 | 0.0 | 2 | 3.4 | 0 | 0.0 |
| Pain | 1 | 1.9 | 2 | 3.4 | 0 | 0.0 |
| Fatigue | 0 | 0.0 | 0 | 0.0 | 2 | 3.7 |
| Central and Peripheral Nervous System Disorders | ||||||
| Dizziness | 4 | 7.4 | 4 | 6.8 | 4 | 7.4 |
| Headache | 10 | 18.5 | 9 | 15.3 | 7 | 13.0 |
| Gastrointestinal System Disorders | ||||||
| Mouth Dry | 0 | 0.0 | 1 | 1.7 | 3 | 5.6 |
| Constipation | 4 | 7.4 | 2 | 3.4 | 6 | 11.1 |
| Diarrhea | 4 | 7.4 | 3 | 5.1 | 1 | 1.9 |
| Vomiting | 10 | 18.5 | 7 | 11.9 | 4 | 7.4 |
| Nausea | 29 | 53.7 | 25 | 42.4 | 18 | 33.3 |
| Psychiatric Disorders | ||||||
| Insomnia | 1 | 1.9 | 2 | 3.4 | 2 | 3.7 |
| Somnolence | 5 | 9.3 | 4 | 6.8 | 0 | 0.0 |
| Reproductive Disorders, Female | ||||||
| Menstrual Disorder | 0 | 0.0 | 2 | 2.0 | 0 | 0.0 |
| Reproductive Disorders, Male | ||||||
| Epididymitis | 0 | 0.0 | 0 | 0.0 | 1 | 11.1 |
| Respiratory Systems Disorders | ||||||
| Coughing | 0 | 0.0 | 3 | 5.1 | 0 | 0.0 |
| Sinusitis | 1 | 1.9 | 2 | 3.4 | 2 | 3.7 |
| Upper Resp Tract Infection | 2 | 3.7 | 0 | 0.0 | 0 | 0.0 |
| Skin and Appendages Disorders | ||||||
| Pruritus | 2 | 3.7 | 1 | 1.7 | 4 | 7.4 |
| Rash | 0 | 0.0 | 2 | 3.4 | 2 | 3.7 |
| a Preferred terms reported by ≥ 2% of subjects in one or more treatment groups, intent-to-treat population. b Number of patients with adverse event; numbers shown are all events regardless of relationship to study drug. | ||||||
Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM® exists.
Body as a Whole: Malaise.
Cardiovascular: Vasodilation.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.
Gastrointestinal: Abdominal pain, Anorexia, Flatulence.
Musculoskeletal: Hypertonia.
Skin: Rash.
Special Senses: Visual disturbance.
Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.
Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).
Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.
Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS AND PRECAUTIONS), Tremor.
Respiratory: Dyspnea.
Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.
Special Senses: Dysgeusia.
Urogenital: Dysuria, Menstrual disorder.
Other adverse experiences, causal relationship unknown
A variety of other adverse events were reported infrequently in patients taking ULTRAM® during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.
Central Nervous System: Migraine, Speech disorders.
Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.
Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.
Sensory: Cataracts, Deafness, Tinnitus.
Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol HydrochlorideAdverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.
Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Post-marketing experience with the use of tramadol-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.
Drug Abuse, Addiction And DependenceTramadol may induce psychic and physical dependence of the morphine-type (μ-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development.
A Risk Management program to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management program:
Withdrawal symptoms may occur if ULTRAM® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with ULTRAM® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
The following frequency categories form the basis for classification of the undesirable effects:
Very common (>1/10)>
Common (>1/100 to <1/10)>
Uncommon (>1/1,000 to <1/100)>
Rare (>1/10,000 to <1/1,000)>
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
| Very Common | Common | Uncommon | Rare | Very Rare | Not known | |
| Immune system disorders | Hyper-sensitivity Anaphylactic and anaphylactoid responses | |||||
| Metabolism and nutrition disorders | Decreased appetite | Hypoglycaemia | ||||
| Psychiatric disorders | Hallucinations Nightmare Mood altered Euphoric moodDysphoria Decreased activity Illusion Confusional state Drug dependence | |||||
| Nervous system disorders | Dizziness | Somnolence | Headache | Paraesthesia Psychomotor hyperactivity Cognitive disorder Sensory disturbance Judgment impaired Convulsions | ||
| Eye disorders | Blurred vision | |||||
| Cardiac disorders | Palpitations Tachycardia | Bradycardia | ||||
| Vascular disorders | Orthostatic hypotension Hypotension Circulatory collapse | Hypertension Flushing | ||||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea Worsening of asthma Respiratory depression Bronchospasm Wheezing | |||||
| Gastro-intestinal disorders | Nausea | Vomiting Dry mouth | Retching Constipation Abdominal discomfort | Diarrhoea | ||
| Hepatobiliary disorders | Hepatic enzyme increased | |||||
| Skin and subcutaneous tissue disorders | Hyperhi-drosis | Pruritus Rash Urticaria | Angioedema | |||
| Musculoskeletal and connective tissue disorders | Muscular weakness | |||||
| Renal and urinary disorders | Micturition disorder Dysuria Urinary retention | |||||
| General disorders and administration site conditions | Drug withdrawal syndrome which may include: - agitation; - anxiety - nervousness - insomnia - hyperkinesia - termor; Gastrointestinal symptoms | Asthenia |
As these tablets are made using an insoluble matrix from which the active ingredient is gradually released, the patient may notice the matrix in their faeces.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Zaledor XR was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic nonmalignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2).
Table 2: Incidence (%) of patients with adverse event rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).
| MedDRA Preferred Term | Zaledor XR | Placebo | |||
| 100 mg (N=403) n (%) | 200 mg (N=400) n (%) | 300 mg (N=400) n (%) | 400 mg (N=202) n (%) | (N=406) n (%) | |
| Dizziness (not vertigo) | 64 (15.9) | 81 (20.3) | 90 (22.5) | 57 (28.2) | 28 ( 6.9) |
| Nausea | 61 (15.1) | 90 (22.5) | 102 (25.5) | 53 (26.2) | 32 ( 7.9) |
| Constipation | 49 (12.2) | 68 (17.0) | 85 (21.3) | 60 (29.7) | 17 ( 4.2) |
| Headache | 49 (12.2) | 62 (15.5) | 46 (11.5) | 32 (15.8) | 43 (10.6) |
| Somnolence | 33 ( 8.2) | 45 (11.3) | 29 ( 7.3) | 41 (20.3) | 7 ( 1.7) |
| Flushing | 31 ( 7.7) | 40 (10.0) | 35 ( 8.8) | 32 (15.8) | 18 ( 4.4) |
| Pruritus | 25 ( 6.2) | 34 ( 8.5) | 30 ( 7.5) | 24 (11.9) | 4 ( 1.0) |
| Vomiting | 20 ( 5.0) | 29 ( 7.3) | 34 ( 8.5) | 19 ( 9.4) | 11 ( 2.7) |
| Insomnia | 26 ( 6.5) | 32 ( 8.0) | 36 ( 9.0) | 22 (10.9) | 13 ( 3.2) |
| Dry Mouth | 20 ( 5.0) | 29 ( 7.3) | 39 ( 9.8) | 18 ( 8.9) | 6 ( 1.5) |
| Diarrhea | 15 ( 3.7) | 27 ( 6.8) | 37 ( 8.5) | 10 ( 5.0) | 17 ( 4.2) |
| Asthenia | 14 ( 3.5) | 24 ( 6.0) | 26 ( 6.5) | 13 ( 6.4) | 7 ( 1.7) |
| Postural hypotension | 7 ( 1.7) | 17 ( 4.3) | 8 ( 2.0) | 11 ( 5.4) | 9 ( 2.2) |
| Sweating increased | 6 ( 1.5) | 8 ( 2.0) | 15 ( 3.8) | 13 ( 6.4) | 1 ( 0.2) |
| Anorexia | 3 ( 0.7) | 7 ( 1.8) | 21 ( 5.3) | 12 ( 5.9) | 1 ( 0.2) |
The following adverse events were reported from all the chronic pain studies (N=3108).
The lists below include adverse events not otherwise noted in Table 2.
Adverse events with incidence rates of 1.0% to < 5.0%
Eye disorders: vision blurred
Gastrointestinal disorders: abdominal pain upper, dyspepsia, abdominal pain, sore throat
General disorders: weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain
Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis
Investigations: blood creatine phosphokinase increased, weight decreased
Metabolism and nutrition disorders: appetite decreased
Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain, pain in limb, neck pain
Nervous system disorders: tremor, paresthesia, hypoesthesia
Psychiatric disorders: nervousness, anxiety, depression, restlessness
Respiratory, thoracic and mediastinal disorders: sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion
Skin and subcutaneous tissue disorders: sweating increased, dermatitis
Vascular disorders: hot flushes, vasodilatation
Adverse events with incidence rates of 0.5% to < 1.0% and serious adverse events reported in at least 2 patients.
Cardiac disorders: palpitations, myocardial infarction
Ear and labyrinth disorders: tinnitus, vertigo
Gastrointestinal disorders: flatulence, toothache, constipation aggravated, appendicitis, pancreatitis
General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling
Hepato-biliary disorders: cholelithiasis, cholecystitis
Infections and infestations: cellulitis, ear infection, gastroenteritis, pneumonia, viral infection
Injury and poisoning: joint sprain, muscle injury
Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal
Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated
Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated
Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams
Renal and urinary disorders: difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention
Respiratory, thoracic and mediastinal disorders: yawning
Skin and subcutaneous tissue disorders: contusion, piloerection, clamminess, night sweats, urticaria
Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia
Post-marketing ExperienceThe following adverse reactions, not noted above, have been identified during post approval use of tramadol-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Eye disorders: miosis, mydriasis
Metabolism and nutrition disorders: Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.
Nervous system disorders: movement disorder, speech disorder
Psychiatric disorders: delirium
Adverse Drug Reaction OverviewThe most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.
Clinical Trial Adverse Drug ReactionsBecause clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Incidence of Adverse Reactions for Zaledor XR® in Chronic Trials of Non-Malignant Pain (Non-titration Trials)Zaledor XR® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. The overall incidence rates of adverse experiences in these trials were similar for Zaledor XR® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the Zaledor XR® group. In the tramadol treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.
Table 1.1: Cumulative Incidence of Adverse Reactions for Zaledor XR® in Chronic Trials of Non-Malignant Pain
| Percentage of Patients with Adverse Reaction N = 427 | |||
| Up to 7 Days | Up to 30 Days | Up to 90 Days | |
| Dizziness/Vertigo | 26% | 31% | 33% |
| Nausea | 24% | 34% | 40% |
| Constipation | 24% | 38% | 46% |
| Headache | 18% | 26% | 32% |
| Somnolence | 16% | 23% | 25% |
| Vomiting | 9% | 13% | 17% |
| Pruritus | 8% | 10% | 11% |
| “CNS Stimulation” a | 7% | 11% | 14% |
| Asthenia | 6% | 11% | 12% |
| Sweating | 6% | 7% | 9% |
| Dyspepsia | 5% | 9% | 13% |
| Dry Mouth | 5% | 9% | 10% |
| Diarrhea | 5% | 6% | 10% |
| a “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations |
Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.
Incidence of Adverse Reactions for Zaledor XR® CAPSS-047 Titration TrialIn the double–blind phase of this pivotal trial, gastrointestinal complaints (primarily nausea and vomiting) and dizziness were the adverse events reported most frequently by tramadol-treated subjects, Table 1.2. Most of the adverse events were assessed as mild or moderate in intensity and resolved.
Table 1.2: Â Adverse Events in CAPSS-047 - Double-Blind Phase - Frequently Reported ( ≥ 2%a) Adverse Eventsb and Total Incidence of AEs Summarized by WHOART Body System, Treatment Group and Preferred Term
| AEs in CAPSS-047 Double-Blind Phase ≥ 2% of patients Tramadol Group/Titration Schedule | ||||||
| Body System | 10-days to 200 mg/day N =54 | 16-days to 200 mg/day N =59 | 13-days to 150 mg/day N =54 | |||
| Preferred Term | n | % | n | % | n | % |
| Any Adverse Event | 41 | 75.9 | 41 | 69.5 | 33 | 61.1 |
| Body as a Whole - General Disorders | ||||||
| Influenza-like symptoms | 0 | 0.0 | 2 | 3.4 | 0 | 0.0 |
| Pain | 1 | 1.9 | 2 | 3.4 | 0 | 0.0 |
| Fatigue | 0 | 0.0 | 0 | 0.0 | 2 | 3.7 |
| Central and Peripheral Nervous System Disorders | ||||||
| Dizziness | 4 | 7.4 | 4 | 6.8 | 4 | 7.4 |
| Headache | 10 | 18.5 | 9 | 15.3 | 7 | 13.0 |
| Gastrointestinal System Disorders | ||||||
| Mouth Dry | 0 | 0.0 | 1 | 1.7 | 3 | 5.6 |
| Constipation | 4 | 7.4 | 2 | 3.4 | 6 | 11.1 |
| Diarrhea | 4 | 7.4 | 3 | 5.1 | 1 | 1.9 |
| Vomiting | 10 | 18.5 | 7 | 11.9 | 4 | 7.4 |
| Nausea | 29 | 53.7 | 25 | 42.4 | 18 | 33.3 |
| Psychiatric Disorders | ||||||
| Insomnia | 1 | 1.9 | 2 | 3.4 | 2 | 3.7 |
| Somnolence | 5 | 9.3 | 4 | 6.8 | 0 | 0.0 |
| Reproductive Disorders, Female | ||||||
| Menstrual Disorder | 0 | 0.0 | 2 | 2.0 | 0 | 0.0 |
| Reproductive Disorders, Male | ||||||
| Epididymitis | 0 | 0.0 | 0 | 0.0 | 1 | 11.1 |
| Respiratory Systems Disorders | ||||||
| Coughing | 0 | 0.0 | 3 | 5.1 | 0 | 0.0 |
| Sinusitis | 1 | 1.9 | 2 | 3.4 | 2 | 3.7 |
| Upper Resp Tract Infection | 2 | 3.7 | 0 | 0.0 | 0 | 0.0 |
| Skin and Appendages Disorders | ||||||
| Pruritus | 2 | 3.7 | 1 | 1.7 | 4 | 7.4 |
| Rash | 0 | 0.0 | 2 | 3.4 | 2 | 3.7 |
| a Preferred terms reported by ≥ 2% of subjects in one or more treatment groups, intent-to-treat population. b Number of patients with adverse event; numbers shown are all events regardless of relationship to study drug. | ||||||
Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with Zaledor XR® exists.
Body as a Whole: Malaise.
Cardiovascular: Vasodilation.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.
Gastrointestinal: Abdominal pain, Anorexia, Flatulence.
Musculoskeletal: Hypertonia.
Skin: Rash.
Special Senses: Visual disturbance.
Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.
Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).
Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.
Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS AND PRECAUTIONS), Tremor.
Respiratory: Dyspnea.
Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.
Special Senses: Dysgeusia.
Urogenital: Dysuria, Menstrual disorder.
Other adverse experiences, causal relationship unknown
A variety of other adverse events were reported infrequently in patients taking Zaledor XR® during clinical trials and/or reported in post-marketing experience. A causal relationship between Zaledor XR® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.
Central Nervous System: Migraine, Speech disorders.
Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.
Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.
Sensory: Cataracts, Deafness, Tinnitus.
Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol HydrochlorideAdverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.
Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Post-marketing experience with the use of tramadol-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.
Drug Abuse, Addiction And DependenceTramadol may induce psychic and physical dependence of the morphine-type (μ-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development.
A Risk Management program to support the safe and effective use of Zaledor XR® has been established. The following are considered to be the essential components of the Risk Management program:
Withdrawal symptoms may occur if Zaledor XR® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with Zaledor XR® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
On repeated oral and parenteral administration of Zaledor XR for 6 - 26 weeks in rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats Zaledor XR dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.
In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far, Zaledor XR can be classified as non-mutagenic.
Studies on the tumorigenic potential of Zaledor XR hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.
Reproductive and developmental toxicity
No effects of tramadol have been observed on male or female fertility in rats. Fetal malformations occurred in a rat developmental study in the presence of maternal toxicity and mortality. No developmental effects were observed in the rat at 20 mg/kg/day when plasma concentrations of tramadol and O-desmethyltramadol were 2.3x and 2.2x the estimated mean clinical Cmax and 1.1x and 1.5x the estimated mean clinical AUCt at the maximum recommended dose of Zaledor XR SR 200 mg twice daily. When female rats were treated during gestation and lactation there was increased pup mortality and decreased body weights during lactation for the offspring at maternally toxic dose levels of 60 mg/kg/day.
Treatment of moderate to severe pain.
AdultsULTRAM® (tramadol hydrochloride) is indicated for the management of moderate to moderately severe pain in adults.
Geriatrics ( > 65 Years of Age)Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. ULTRAM® should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).
Pediatrics ( < 18 Years of Age)The safety and effectiveness of ULTRAM® have not been studied in the pediatric population. Therefore, use of ULTRAM® tablets is not recommended in patients under 18 years of age.
Treatment of moderate to severe pain.
These tablets are indicated in adults and adolescents aged 12 years and above.
Zaledor XR is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.
AdultsZaledor XR® (tramadol hydrochloride) is indicated for the management of moderate to moderately severe pain in adults.
Geriatrics ( > 65 Years of Age)Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. Zaledor XR® should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).
Pediatrics ( < 18 Years of Age)The safety and effectiveness of Zaledor XR® have not been studied in the pediatric population. Therefore, use of Zaledor XR® tablets is not recommended in patients under 18 years of age.
Pharmacotherapeutic group: other opioids; ATC-code: N 02 AX02.
Zaledor XR is a centrally-acting opioid analgesic. It is a non-selective pure agonist at µ, δ and κ opioid receptors with a higher affinity for the µ receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and enhancement of serotonin release.
Zaledor XR has an antitussive effect. In contrast to morphine, analgesic doses of Zaledor XR over a wide range have no respiratory-depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of Zaledor XR is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.
Pharmacotherapeutic group: Analgesic, Other opioids. ATC code: N02A X02
Mechanism of action
Tramadol is a centrally acting analgesic It is a non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms that may contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and an increased serotonin release.
Paediatric population
Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000 paediatric patients ranging in age from neonate to 17 years of age. The indications for pain treatment studied in those trials included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as other painful conditions likely to require analgesic treatment for at least 7 days.
At single doses of up to 2 mg/kg or multiple doses of up to 8 mg/kg per day (to a maximum of 400 mg per day) efficacy of tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose morphine. The conducted trials confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and paediatric patients older than 1 year.
More than 90% of Zaledor XR drops is absorbed after oral administration. The mean absolute bioavailability is approximately 70 %, irrespective of the concomitant intake of food. The difference between absorbed and non-metabolised available Zaledor XR is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30 %. Maximal serum concentrations are reached after 1 hour.
Zaledor XR has a high tissue affinity (Vd,ß = 203 ± 40 l). It has a plasma protein binding of about 20 %.
Zaledor XR passes the blood-brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1 % and 0.02 % respectively of the applied dose).
Elimination half-life t1/2,ß is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4.
In humans Zaledor XR is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethylZaledor XR is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethylZaledor XR is more potent than the parent substance by the factor 2 - 4. Its half-life t1/2,ß (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of Zaledor XR.
The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of Zaledor XR may affect the plasma concentration of Zaledor XR or its active metabolite. Up to now, clinically relevant interactions have not been reported.
Zaledor XR and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90 % of the total radioactivity of the administered dose. In case of impaired hepatic or renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (Zaledor XR) and 18.5 ± 9.4 h (O-desmethylZaledor XR), in an extreme case 22.3 h and 36 h respectively, have been determined. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h respectively.
Zaledor XR has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100 - 300 ng/ml is usually effective.
), such as quinidine, fluoxetine, paroxetine, amitriptyline (CYP2D6 inhibitors), ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome. Use with CimetidineConcomitant administration of ULTRAM® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM® dosage regimen is recommended.
Use with DigoxinPost-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Use with Warfarin-like CompoundsPost-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Periodic evaluation of prothrombin time should be performed when ULTRAM® tablets and warfarin-like compounds are administered concurrently.
TriptansBased on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM® is coadministered with a triptan. If concomitant treatment of ULTRAM® with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Drug-Food InteractionsOral administration of ULTRAM® with food does not significantly affect its rate or extent of absorption; therefore, ULTRAM® can be administered without regard to food.
Warnings & Precautions WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM® above the recommended range. Concomitant use of ULTRAM® increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In ULTRAM® overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid ReactionsSerious and rarely, fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRAM® tablets (see CONTRAINDICATIONS).
Drug Abuse, Addiction And DependenceULTRAM® has the potential to cause psychic and physical dependence of the morphine-type (μ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on ULTRAM® have been reported. ULTRAM® tablets should not be used in opioid-dependent patients. ULTRAM® can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids, treatment with ULTRAM® is not recommended.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
A Risk Management strategy to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management strategy:
ULTRAM® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.
Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Withdrawal SymptomsWithdrawal symptoms may occur if ULTRAM® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with ULTRAM® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Risk Of OverdosageSerious potential consequences of overdosage with ULTRAM® are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.
ULTRAM® should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Intracranial Pressure Or Head TraumaULTRAM® should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from ULTRAM® may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM® (see Respiratory, Respiratory Depression below).
Respiratory Respiratory DepressionAdminister ULTRAM® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of ULTRAM® are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsULTRAM® should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ULTRAM® increases the risk of CNS and respiratory depression in these patients.
ULTRAM® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Use With AlcoholULTRAM® should not be used concomitantly with alcohol consumption.
Use In Ambulatory PatientsULTRAM® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO InhibitorsConcomitant use of ULTRAM® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).
Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of ULTRAM® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.
Use With Serotonin Reuptake InhibitorsConcomitant use of ULTRAM® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of ULTRAM® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Gastrointestinal Acute Abdominal ConditionsThe administration of ULTRAM® may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Drug And Alcohol AddictionULTRAM® is an opioid with no approved use in the management of addictive disorders.
Carcinogenesis And MutagenesisSee Product Monograph PART II, Toxicology.
Special Populations Use in Renal and Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Pregnant WomenThere are no adequate and well-controlled studies in pregnant women. ULTRAM® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing.
ULTRAM® should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction and Dependence). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing WomenULTRAM® is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatrics ( < 18 years of age)The safety and effectiveness of ULTRAM® has not been studied in the pediatric population. Therefore, use of ULTRAM® tablets is not recommended in patients under 18 years of age.
Geriatrics ( > 65 years of age)In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
Overdosage & Contraindications OVERDOSEFor management of a suspected drug overdose, contact your regional Poison Control Centre.
SymptomsSymptoms of overdosage with ULTRAM® are respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
TreatmentA single or multiple overdose with ULTRAM® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.
In treating an overdose of ULTRAM®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Seizures may be controlled with diazepam.
In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
Emptying of the gastric contents is useful to remove any unabsorbed drug.
CONTRAINDICATIONSULTRAM® is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of ULTRAM®. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, ULTRAM® administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, ULTRAM® has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
PharmacokineticsThe analgesic activity of ULTRAM® is due to both parent drug and the M1 metabolite (see Mechanism of Action). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.
AbsorptionRacemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.
Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1.1 and Table 1.4 below).
Figure 1.1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl Given q.i.d.
Table 1.4: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
| Population/ Dosage Regimena | Parent Drug/ Metabolite | Cmax (ng/mL) | Time to Peak (hrs) | Clearance/Fb (mL/min/kg) | t½ (hrs) |
| Healthy Adults, 100 mg q.i.d., MD p.o. | Tramadol | 592 (30) | 2.3 (61) | 5.90 (25) | 6.7 (15) |
| M1 | 110 (29) | 2.4 (46) | c | 7.0 (14) | |
| Healthy Adults, 100 mg SD p.o. | Tramadol | 308 (25) | 1.6 (63) | 8.50 (31) | 5.6 (20) |
| M1 | 55.0 (36) | 3.0 (51) | c | 6.7 (16) | |
| Geriatric, ( > 75 yrs) 50 mg SD p.o. | Tramadol | 208 (31) | 2.1 (19) | 6.89 (25) | 7.0 (23) |
| M1 | d | d | c | d | |
| Hepatic Impaired, 50 mg SD p.o | Tramadol | 217 (11) | 1.9 (16) | 4.23 (56) | 13.3 (11) |
| M1 | 19.4 (12) | 9.8 (20) | c | 18.5 (15) | |
| Renal Impaired, CLcr10-30 mL/min 100 mg SD i.v. | Tramadol | c | c | 4.23 (54) | 10.6 (31) |
| M1 | c | c | c | 11.5 (40) | |
| Renal Impaired, CLcr < 5 mL/min 100 mg SD i.v. | Tramadol | c | c | 3.73 (17) | 11.0 (29) |
| M1 | c | c | c | 16.9 (18) | |
| a SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily b F represents the oral bioavailability of tramadol c Not applicable d Not measured |
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
MetabolismFollowing oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers”, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of serotonin reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure (see WARNINGS AND PRECAUTIONS) and serotonin syndrome.
ExcretionTramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.
Special Populations and Conditions PediatricsPharmacokinetics of ULTRAM® tablets have not been studied in pediatric patients below 18 years of age.
GeriatricsHealthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).
GenderThe absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg i.v. dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.
Hepatic InsufficiencyMetabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs for tramadol and 19 hrs for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal InsufficiencyExcretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen in this patient population is recommended. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Clinical TrialsULTRAM® was evaluated in single-dose trials (dental and surgery), multiple-dose, [short-term trials (dental and surgery), long-term trials (chronic malignant and non-malignant pain), and trials evaluating the impact of dose titration on tolerability]. Clinical trials in non-malignant pain included patients with osteoarthritis, low back pain, diabetic neuropathy and fibromyalgia. These trials included a randomized, double-blind, parallel group design, and in each of the single-dose and short-term multiple-dose trials tramadol was compared to a standard reference analgesic (either codeine, ASA/codeine or APAP/propoxyphene), placebo or to both. The active controls were included to establish model sensitivity. The efficacy of tramadol in these trials was established based on Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and time to remedication.
Collectively, a total of 2549 patients with dental pain, 1940 patients with surgical pain, 170 patients with chronic malignant pain, 119 patients with sub-acute low back pain, and 2046 patients with chronic non-malignant pain were enrolled into the 28 efficacy trials. Of the 6824 total patients enrolled into these trials, 4075 were randomized to a tramadol treatment arm.
Study Results Acute Pain, Single- and Multiple-Dose StudiesULTRAM® has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).
Results of these trials demonstrated statistically superior pain relief for tramadol compared to placebo. Data from these key trials provide information regarding the optimal analgesic dosage range of tramadol.
In single-dose dental trials, tramadol was superior to placebo at doses of 100 mg or greater (p ≤ 0.05). In addition, tramadol at doses of 100mg or greater were equivalent to or statistically superior to the reference analgesics for Total Pain Relief (TOTPAR) and Sum of Pain Intensity Difference (SPID) across the entire evaluation interval. The results of the multiple-dose short-term trials in acute pain also provide evidence for efficacy of tramadol in the management of acute pain.
Tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painf
Absorption
Following oral administration of a single dose, tramadol is almost completely absorbed and the absolute bioavailability is approximately 70% following administration of a single dose. Tramadol is metabolised to O desmethyltramadol, which has been shown to have analgesic activity in rodents. The elimination half life of tramadol is around 6 hours, although this is extended to around 12 hours following prolonged absorption from the Zaledor XR SR tablet.
Biotransformation
Following administration of one Zaledor XR SR tablet 75 mg in the fasting state, a mean peak plasma concentration (Cmax) of 80 ng.ml-1 was attained. This was associated with a median tmax of 5 hours (range 3-7 hours). In the presence of food, the availability and controlled release properties of Zaledor XR SR tablets were maintained, with no evidence of dose-dumping.
Elimination
A single dose-proportionality study has confirmed a linear pharmacokinetic response (in relation to tramadol and O-desmethyltramadol) following administration of the 75 mg, 100 mg, 150 mg and 200 mg tablets. A steady state study has confirmed the dose adjusted bioequivalence of the 75 mg, 100 mg and 150 mg tablets administered twice-daily.
The pharmacokinetics of tramadol are non-linear. Faster-releasing formulations are associated with an accumulation of the drug substance which is greater than would be anticipated from single dose data, a consequence of a saturated first-pass effect. The controlled delivery of tramadol from the range of Zaledor XR SR tablets minimises the non-linearity associated with faster-releasing preparations and consequently, single dose and steady state studies have demonstrated that, when compared with immediate release preparations, the mean availability of tramadol from the Zaledor XR SR tablet 75 mg was approximately 82%. On this basis it is recommended that patients receiving immediate release tramadol should be transferred initially to the nearest daily dose of Zaledor XR SR tablets. It may be necessary to titrate the dose thereafter. The more predictable plasma concentrations may lead to a more manageable dose titration process.
Paediatric population
The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple-dose oral administration to subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight, but with a higher between-subject variability in children aged 8 years and below.
In children below 1 year of age, the pharmacokinetics of tramadol and O-desmethyltramadol have been investigated, but have not been fully characterized. Information from studies including this age group indicates that the formation rate of O-desmethyltramadol via CYP2D6 increases continuously in neonates, and adult levels of CYP2D6 activity are assumed to be reached at about 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow elimination and accumulation of O-desmethyltramadol in children under 1 year of age.
), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome. Serotonergic DrugsThere have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when Zaledor XR is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of Zaledor XR with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome Risk).
TriptansBased on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when Zaledor XR is coadministered with a triptan. If concomitant treatment of Zaledor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome Risk).
Use With CarbamazepinePatients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Zaledor XR and carbamazepine is not recommended.
Use With QuinidineCoadministration of quinidine with Zaledor XR resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY, Drug Interactions). The clinical consequences of these findings are unknown.
Use With Digoxin and WarfarinPost-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Potential for Other Drugs to Affect TramadolIn vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with Zaledor XR may affect the metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadol to Affect Other DrugsIn vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Warnings & Precautions WARNINGS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.
Suicide RiskThe development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including Zaledor XR, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.
Anaphylactoid ReactionsSerious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Zaledor XR (see CONTRAINDICATIONS).
Respiratory DepressionAdminister Zaledor XR cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsZaledor XR should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Zaledor XR increases the risk of CNS and respiratory depression in these patients.
Increased Intracranial Pressure Or Head TraumaZaledor XR should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM ER (see WARNINGS, Respiratory Depression).
Use In Ambulatory PatientsZaledor XR may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO Inhibitors And Serotonin Re-uptake InhibitorsUse Zaledor XR with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Zaledor XR with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
WithdrawalWithdrawal symptoms may occur if Zaledor XR is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering Zaledor XR.
Misuse, Abuse And Diversion Of OpioidsTramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Zaledor XR in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Zaledor XR could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and Drug Abuse And Addiction).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions With Alcohol And Drugs of AbuseTramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Drug Abuse And AddictionZaledor XR (tramadol hydrochloride) Extended-Release Tablets are classified as a Schedule IV controlled substance.
Zaledor XR is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Zaledor XR, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Zaledor XR is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Risk of OverdosageSerious potential consequences of overdosage with ULTRAM ER are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
PRECAUTIONS Acute Abdominal ConditionThe administration of Zaledor XR may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Renal And Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Zaledor XR has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of Zaledor XR do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Zaledor XR should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of Zaledor XR has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of Zaledor XR do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Zaledor XR should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis, Impairment Of FertilityNo carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.
Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (approximately equivalent to MDHD).
Pregnancy Teratogenic EffectsPregnancy Category C
Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD).
Non-teratogenic EffectsTramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period.
There are no adequate and well-controlled studies in pregnant women. Zaledor XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products.
Labor And DeliveryZaledor XR should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse And Addiction). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol HCl during labor.
The effect of Zaledor XR, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing MothersZaledor XR is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100-mg dose of tramadol, the cumulative excretion in breast milk within sixteen hours postdose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatric UseThe safety and efficacy of Zaledor XR in patients under 18 years of age have not been established. The use of Zaledor XR in the pediatric population is not recommended.
Geriatric UseNine-hundred-one elderly (65 years of age or older) subjects were exposed to Zaledor XR in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Zaledor XR should be used with great caution in patients older than 75 years of age (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Overdosage & Contraindications OVERDOSEAcute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation.
Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of Zaledor XR could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
CONTRAINDICATIONSZaledor XR should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Zaledor XR is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Zaledor XR may worsen central nervous system and respiratory depression in these patients.
Clinical Pharmacology CLINICAL PHARMACOLOGY Mechanism Of ActionZaledor XR is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the Zaledor XR clinical studies.
Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
PharmacokineticsThe analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Zaledor XR is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.
The pharmacokinetics of Zaledor XR are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known.
AbsorptionIn healthy subjects, the bioavailability of a Zaledor XR 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following Zaledor XR administration. The mean peak plasma concentrations of tramadol and M1 after administration of Zaledor XR tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration of the Zaledor XR, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing.
The mean (%CV) pharmacokinetic parameter values for ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours are provided in Table 1.
Table 1: Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32)
| Pharmacokinetic Parameter | Tramadol | M1 Metabolite | ||
| Zaledor XR 200-mg Tablet Once-Daily | ULTRAM 50-mg Tablet Every 6 Hours | Zaledor XR 200-mg Tablet Once-Daily | ULTRAM 50-mg Tablet Every 6 Hours | |
| AUC0-24 (ngh/mL) | 5975 (34) | 6613 (27) | 1890 (25) | 2095 (26) |
| Cmax (ng/mL) | 335 (35) | 383 (21) | 95 (24) | 104 (24) |
| Cmin (ng/mL) | 187 (37) | 228 (32) | 69 (30) | 82 (27) |
| Tmax (h) | 12 (27) | 1.5 (42) | 15 (27) | 1.9 (57) |
| % Fluctuation | 61 (57) | 59 (35) | 34 (72) | 26 (47) |
| AUC0-24: Area Under the Curve in a 24-hour dosing interval; Cmax: Peak Concentration in a 24-hour dosing interval; Cmin: Trough Concentration in a 24-hour dosing interval; Tmax: Time to Peak Concentration |
Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours.
After a single dose administration of 200 mg Zaledor XR tablet with a high fat meal, the Cmax and AUC0-∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While Zaledor XR may be taken without regard to food, it is recommended that it be taken in a consistent manner.
DistributionThe volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
MetabolismTramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS: DRUG INTERACTIONS).
EliminationTramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Zaledor XR are approximately 7.9 and 8.8 hours, respectively.
Special Populations RenalImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of Zaledor XR 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). Zaledor XR has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of Zaledor XR does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Zaledor XR should not be used in patients with severe renal impairment (see PRECAUTIONS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
HepaticPharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of Zaledor XR 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol after the administration of Zaledor XR has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of Zaledor XR does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Zaledor XR should not be used in patients with severe hepatic impairment (see PRECAUTIONS, Use in
), such as quinidine, fluoxetine, paroxetine, amitriptyline (CYP2D6 inhibitors), ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome. Use with CimetidineConcomitant administration of Zaledor XR® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the Zaledor XR® dosage regimen is recommended.
Use with DigoxinPost-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Use with Warfarin-like CompoundsPost-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Periodic evaluation of prothrombin time should be performed when Zaledor XR® tablets and warfarin-like compounds are administered concurrently.
TriptansBased on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when Zaledor XR® is coadministered with a triptan. If concomitant treatment of Zaledor XR® with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Drug-Food InteractionsOral administration of Zaledor XR® with food does not significantly affect its rate or extent of absorption; therefore, Zaledor XR® can be administered without regard to food.
Warnings & Precautions WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of Zaledor XR® above the recommended range. Concomitant use of Zaledor XR® increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In Zaledor XR® overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid ReactionsSerious and rarely, fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Zaledor XR® tablets (see CONTRAINDICATIONS).
Drug Abuse, Addiction And DependenceZaledor XR® has the potential to cause psychic and physical dependence of the morphine-type (μ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on Zaledor XR® have been reported. Zaledor XR® tablets should not be used in opioid-dependent patients. Zaledor XR® can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids, treatment with Zaledor XR® is not recommended.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
A Risk Management strategy to support the safe and effective use of Zaledor XR® has been established. The following are considered to be the essential components of the Risk Management strategy:
Zaledor XR® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.
Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Withdrawal SymptomsWithdrawal symptoms may occur if Zaledor XR® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with Zaledor XR® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Risk Of OverdosageSerious potential consequences of overdosage with Zaledor XR® are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Do not prescribe Zaledor XR® for patients who are suicidal or addiction-prone.
Zaledor XR® should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Intracranial Pressure Or Head TraumaZaledor XR® should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from Zaledor XR® may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving Zaledor XR® (see Respiratory, Respiratory Depression below).
Respiratory Respiratory DepressionAdminister Zaledor XR® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of Zaledor XR® are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsZaledor XR® should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Zaledor XR® increases the risk of CNS and respiratory depression in these patients.
Zaledor XR® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Use With AlcoholZaledor XR® should not be used concomitantly with alcohol consumption.
Use In Ambulatory PatientsZaledor XR® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO InhibitorsConcomitant use of Zaledor XR® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).
Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of Zaledor XR® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.
Use With Serotonin Reuptake InhibitorsConcomitant use of Zaledor XR® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of Zaledor XR® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Gastrointestinal Acute Abdominal ConditionsThe administration of Zaledor XR® may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Drug And Alcohol AddictionZaledor XR® is an opioid with no approved use in the management of addictive disorders.
Carcinogenesis And MutagenesisSee Product Monograph PART II, Toxicology.
Special Populations Use in Renal and Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Pregnant WomenThere are no adequate and well-controlled studies in pregnant women. Zaledor XR® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing.
Zaledor XR® should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction and Dependence). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of Zaledor XR®, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing WomenZaledor XR® is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatrics ( < 18 years of age)The safety and effectiveness of Zaledor XR® has not been studied in the pediatric population. Therefore, use of Zaledor XR® tablets is not recommended in patients under 18 years of age.
Geriatrics ( > 65 years of age)In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
A total of 455 elderly (65 years of age or older) subjects were exposed to Zaledor XR® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
Overdosage & Contraindications OVERDOSEFor management of a suspected drug overdose, contact your regional Poison Control Centre.
SymptomsSymptoms of overdosage with Zaledor XR® are respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
TreatmentA single or multiple overdose with Zaledor XR® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.
In treating an overdose of Zaledor XR®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Seizures may be controlled with diazepam.
In animals, convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
Emptying of the gastric contents is useful to remove any unabsorbed drug.
CONTRAINDICATIONSZaledor XR® is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of Zaledor XR®. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, Zaledor XR® administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, Zaledor XR® has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
PharmacokineticsThe analgesic activity of Zaledor XR® is due to both parent drug and the M1 metabolite (see Mechanism of Action). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.
AbsorptionRacemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.
Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1.1 and Table 1.4 below).
Figure 1.1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl Given q.i.d.
Table 1.4: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
| Population/ Dosage Regimena | Parent Drug/ Metabolite | Cmax (ng/mL) | Time to Peak (hrs) | Clearance/Fb (mL/min/kg) | t½ (hrs) |
| Healthy Adults, 100 mg q.i.d., MD p.o. | Tramadol | 592 (30) | 2.3 (61) | 5.90 (25) | 6.7 (15) |
| M1 | 110 (29) | 2.4 (46) | c | 7.0 (14) | |
| Healthy Adults, 100 mg SD p.o. | Tramadol | 308 (25) | 1.6 (63) | 8.50 (31) | 5.6 (20) |
| M1 | 55.0 (36) | 3.0 (51) | c | 6.7 (16) | |
| Geriatric, ( > 75 yrs) 50 mg SD p.o. | Tramadol | 208 (31) | 2.1 (19) | 6.89 (25) | 7.0 (23) |
| M1 | d | d | c | d | |
| Hepatic Impaired, 50 mg SD p.o | Tramadol | 217 (11) | 1.9 (16) | 4.23 (56) | 13.3 (11) |
| M1 | 19.4 (12) | 9.8 (20) | c | 18.5 (15) | |
| Renal Impaired, CLcr10-30 mL/min 100 mg SD i.v. | Tramadol | c | c | 4.23 (54) | 10.6 (31) |
| M1 | c | c | c | 11.5 (40) | |
| Renal Impaired, CLcr < 5 mL/min 100 mg SD i.v. | Tramadol | c | c | 3.73 (17) | 11.0 (29) |
| M1 | c | c | c | 16.9 (18) | |
| a SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily b F represents the oral bioavailability of tramadol c Not applicable d Not measured |
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
MetabolismFollowing oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers”, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of serotonin reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure (see WARNINGS AND PRECAUTIONS) and serotonin syndrome.
ExcretionTramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.
Special Populations and Conditions PediatricsPharmacokinetics of Zaledor XR® tablets have not been studied in pediatric patients below 18 years of age.
GeriatricsHealthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).
GenderThe absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg i.v. dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.
Hepatic InsufficiencyMetabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs for tramadol and 19 hrs for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal InsufficiencyExcretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen in this patient population is recommended. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Clinical TrialsZaledor XR® was evaluated in single-dose trials (dental and surgery), multiple-dose, [short-term trials (dental and surgery), long-term trials (chronic malignant and non-malignant pain), and trials evaluating the impact of dose titration on tolerability]. Clinical trials in non-malignant pain included patients with osteoarthritis, low back pain, diabetic neuropathy and fibromyalgia. These trials included a randomized, double-blind, parallel group design, and in each of the single-dose and short-term multiple-dose trials tramadol was compared to a standard reference analgesic (either codeine, ASA/codeine or APAP/propoxyphene), placebo or to both. The active controls were included to establish model sensitivity. The efficacy of tramadol in these trials was established based on Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and time to remedication.
Collectively, a total of 2549 patients with dental pain, 1940 patients with surgical pain, 170 patients with chronic malignant pain, 119 patients with sub-acute low back pain, and 2046 patients with chronic non-malignant pain were enrolled into the 28 efficacy trials. Of the 6824 total patients enrolled into these trials, 4075 were randomized to a tramadol treatment arm.
Study Results Acute Pain, Single- and Multiple-Dose StudiesZaledor XR® has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).
Results of these trials demonstrated statistically superior pain relief for tramadol compared to placebo. Data from these key trials provide information regarding the optimal analgesic dosage range of tramadol.
In single-dose dental trials, tramadol was superior to placebo at doses of 100 mg or greater (p ≤ 0.05). In addition, tramadol at doses of 100mg or greater were equivalent to or statistically superior to the reference analgesics for Total Pain Relief (TOTPAR) and Sum of Pain Intensity Difference (SPID) across the entire evaluation interval. The results of the multiple-dose short-term trials in acute pain also provide evidence for efficacy of tramadol in the management of acute pain.
Tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painf
Zaledor XR drops may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.
In patients sensitive to opiates Zaledor XR drops should only be used with caution.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered , or if the recommended dosage is significantly exceeded as the possibility of respiratory depression cannot be excluded in these situations.
Convulsions have been reported in patients receiving Zaledor XR at the recommended dose levels. The risk may be increased when doses of Zaledor XR hydrochloride exceed the recommended upper daily dose limit (400 mg). In addition, Zaledor XR may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold. Patients with epilepsy or those susceptible to seizures should only be treated with Zaledor XR if there are compelling circumstances.
Zaledor XR has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment with Zaledor XR drops should only be carried out for short periods under strict medical supervision.
Zaledor XR is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, Zaledor XR cannot suppress morphine withdrawal symptoms.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM® above the recommended range. Concomitant use of ULTRAM® increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In ULTRAM® overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid ReactionsSerious and rarely, fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRAM® tablets (see CONTRAINDICATIONS).
Drug Abuse, Addiction And DependenceULTRAM® has the potential to cause psychic and physical dependence of the morphine-type (μ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on ULTRAM® have been reported. ULTRAM® tablets should not be used in opioid-dependent patients. ULTRAM® can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids, treatment with ULTRAM® is not recommended.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
A Risk Management strategy to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management strategy:
ULTRAM® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.
Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Withdrawal SymptomsWithdrawal symptoms may occur if ULTRAM® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with ULTRAM® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Risk Of OverdosageSerious potential consequences of overdosage with ULTRAM® are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.
ULTRAM® should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Intracranial Pressure Or Head TraumaULTRAM® should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from ULTRAM® may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM® (see Respiratory, Respiratory Depression below).
Respiratory Respiratory DepressionAdminister ULTRAM® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of ULTRAM® are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsULTRAM® should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ULTRAM® increases the risk of CNS and respiratory depression in these patients.
ULTRAM® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Use With AlcoholULTRAM® should not be used concomitantly with alcohol consumption.
Use In Ambulatory PatientsULTRAM® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO InhibitorsConcomitant use of ULTRAM® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).
Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of ULTRAM® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.
Use With Serotonin Reuptake InhibitorsConcomitant use of ULTRAM® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of ULTRAM® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Gastrointestinal Acute Abdominal ConditionsThe administration of ULTRAM® may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Drug And Alcohol AddictionULTRAM® is an opioid with no approved use in the management of addictive disorders.
Carcinogenesis And MutagenesisSee Product Monograph PART II, Toxicology.
Special Populations Use in Renal and Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Pregnant WomenThere are no adequate and well-controlled studies in pregnant women. ULTRAM® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing.
ULTRAM® should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction and Dependence). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing WomenULTRAM® is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatrics ( < 18 years of age)The safety and effectiveness of ULTRAM® has not been studied in the pediatric population. Therefore, use of ULTRAM® tablets is not recommended in patients under 18 years of age.
Geriatrics ( > 65 years of age)In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
The patient may develop tolerance to the medicinal product with chronic use and require progressively higher doses to maintain pain control. Prolonged use may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of drug withdrawal syndrome.
There is potential for abuse and development of psychological dependence to opioid analgesics, including tramadol , thereforethe clinical need for continued analgesic treatment should be reviewed regularly. Treatment should be for short periods and under strict medical supervision. These tablets should be used with particular care in patients with a history of alcohol and drug abuse.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold.. Tramadol should therefore be used with caution in patients prone to convulsive disorders.
Tramadol should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients in shock.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses respiratory depression has infrequently been reported.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicinal product.
WARNINGS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.
Suicide RiskThe development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including Zaledor XR, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.
Anaphylactoid ReactionsSerious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Zaledor XR (see CONTRAINDICATIONS).
Respiratory DepressionAdminister Zaledor XR cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsZaledor XR should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Zaledor XR increases the risk of CNS and respiratory depression in these patients.
Increased Intracranial Pressure Or Head TraumaZaledor XR should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM ER (see WARNINGS, Respiratory Depression).
Use In Ambulatory PatientsZaledor XR may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO Inhibitors And Serotonin Re-uptake InhibitorsUse Zaledor XR with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Zaledor XR with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
WithdrawalWithdrawal symptoms may occur if Zaledor XR is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering Zaledor XR.
Misuse, Abuse And Diversion Of OpioidsTramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Zaledor XR in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Zaledor XR could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and Drug Abuse And Addiction).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions With Alcohol And Drugs of AbuseTramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Drug Abuse And AddictionZaledor XR (tramadol hydrochloride) Extended-Release Tablets are classified as a Schedule IV controlled substance.
Zaledor XR is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Zaledor XR, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Zaledor XR is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Risk of OverdosageSerious potential consequences of overdosage with ULTRAM ER are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
PRECAUTIONS Acute Abdominal ConditionThe administration of Zaledor XR may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Renal And Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Zaledor XR has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of Zaledor XR do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Zaledor XR should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of Zaledor XR has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of Zaledor XR do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Zaledor XR should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis, Impairment Of FertilityNo carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.
Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (approximately equivalent to MDHD).
Pregnancy Teratogenic EffectsPregnancy Category C
Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD).
Non-teratogenic EffectsTramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period.
There are no adequate and well-controlled studies in pregnant women. Zaledor XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products.
Labor And DeliveryZaledor XR should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse And Addiction). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol HCl during labor.
The effect of Zaledor XR, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing MothersZaledor XR is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100-mg dose of tramadol, the cumulative excretion in breast milk within sixteen hours postdose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatric UseThe safety and efficacy of Zaledor XR in patients under 18 years of age have not been established. The use of Zaledor XR in the pediatric population is not recommended.
Geriatric UseNine-hundred-one elderly (65 years of age or older) subjects were exposed to Zaledor XR in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Zaledor XR should be used with great caution in patients older than 75 years of age (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS Seizure RiskSeizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of Zaledor XR® above the recommended range. Concomitant use of Zaledor XR® increases the seizure risk in patients taking:
Administration of tramadol may enhance the seizure risk in patients taking:
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In Zaledor XR® overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid ReactionsSerious and rarely, fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur, it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Zaledor XR® tablets (see CONTRAINDICATIONS).
Drug Abuse, Addiction And DependenceZaledor XR® has the potential to cause psychic and physical dependence of the morphine-type (μ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on Zaledor XR® have been reported. Zaledor XR® tablets should not be used in opioid-dependent patients. Zaledor XR® can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids, treatment with Zaledor XR® is not recommended.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
A Risk Management strategy to support the safe and effective use of Zaledor XR® has been established. The following are considered to be the essential components of the Risk Management strategy:
Zaledor XR® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.
Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Withdrawal SymptomsWithdrawal symptoms may occur if Zaledor XR® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with Zaledor XR® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Risk Of OverdosageSerious potential consequences of overdosage with Zaledor XR® are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Do not prescribe Zaledor XR® for patients who are suicidal or addiction-prone.
Zaledor XR® should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Intracranial Pressure Or Head TraumaZaledor XR® should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from Zaledor XR® may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving Zaledor XR® (see Respiratory, Respiratory Depression below).
Respiratory Respiratory DepressionAdminister Zaledor XR® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of Zaledor XR® are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) DepressantsZaledor XR® should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Zaledor XR® increases the risk of CNS and respiratory depression in these patients.
Zaledor XR® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Use With AlcoholZaledor XR® should not be used concomitantly with alcohol consumption.
Use In Ambulatory PatientsZaledor XR® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use With MAO InhibitorsConcomitant use of Zaledor XR® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).
Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of Zaledor XR® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.
Use With Serotonin Reuptake InhibitorsConcomitant use of Zaledor XR® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of Zaledor XR® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Gastrointestinal Acute Abdominal ConditionsThe administration of Zaledor XR® may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Drug And Alcohol AddictionZaledor XR® is an opioid with no approved use in the management of addictive disorders.
Carcinogenesis And MutagenesisSee Product Monograph PART II, Toxicology.
Special Populations Use in Renal and Hepatic DiseaseImpaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).
With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
Pregnant WomenThere are no adequate and well-controlled studies in pregnant women. Zaledor XR® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing.
Zaledor XR® should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction and Dependence). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of Zaledor XR®, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing WomenZaledor XR® is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
Pediatrics ( < 18 years of age)The safety and effectiveness of Zaledor XR® has not been studied in the pediatric population. Therefore, use of Zaledor XR® tablets is not recommended in patients under 18 years of age.
Geriatrics ( > 65 years of age)In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
A total of 455 elderly (65 years of age or older) subjects were exposed to Zaledor XR® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.
Even when taken according to instructions, Zaledor XR drops may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with alcohol and other psychotropic substances.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive
- Do not drive until you know how the medicine affects you
- It is an offence to drive while under the influence of this medicine
- However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely
Tramadol may cause drowsiness, blurred vision and dizziness which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive.
- Do not drive until you know how the medicine affects you.
- It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').
- This defence applies when:
o The medicine has been prescribed to treat a medical or dental problem; and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.
- Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law.
Posology
The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.
Unless otherwise prescribed, Zaledor XR drops should be administered as follows:
Adults and adolescents above the age of 12 years:
The usual daily dose is 50 to 100 mg (20 to 40 drops), 3 to 4 times a day. In children from 12 to 14 years, it is recommended to use the lowest dose.
For acute pain an initial dose of 100 mg is usually necessary. In case Zaledor XR Drops is used for acute pain, it should be stressed that its activity is somewhat delayed in comparison to that of other analgesics.
For pain associated with chronic conditions an initial dose of 50 mg is advised. It is recommended, when possible in case of chronic treatment, to slowly increase Zaledor XR dosage to its final recommended dose (with increments every 2 to 3 days) in order to reduce the incidence of adverse events.
Paediatric population:
Zaledor XR drops is not suitable for children below the age of 12 years.
Geriatric patients:
A dose adjustment is not usually necessary in elderly patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary, the dosage interval is to be extended according to the patient's requirements.
Renal insufficiency/dialysis and hepatic impairment:
In patients with renal and/or hepatic insufficiency the elimination of Zaledor XR is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patients requirements. In cases of severe renal and/or severe hepatic insufficiency Zaledor XR drops are not recommended.
Method of administration
The drops should be administered orally and be diluted with water before administration, independent of meals.
The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances.
Zaledor XR drops should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Zaledor XR drops is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Dosing ConsiderationsULTRAM® is not recommended for minor pain that may be treated adequately through lesser means where benefit does not outweigh the possible opioid-related side effects.
ULTRAM® can be administered without regard to food.
Do not co-administer ULTRAM® tablets with other tramadol-containing products.
Due to the differences in pharmacokinetic properties, ULTRAM® tablets are not interchangeable with tramadol extended-release formulations.
The maximum recommended dose of ULTRAM® should not be exceeded.
Recommended Dose And Dosage AdjustmentGood pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.
Adults (18 Years of Age and Over)For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of ULTRAM® can be improved by initiating therapy with the following titration regimen: ULTRAM® should be started at 25 mg/day (half ULTRAM® scored tablet) qAM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.) as shown in Table 1.3 below.
Table 1.3: Initiation Titration Dose of ULTRAM® by Days
| Days 1 to 3 | Days 4 to 6 | Days 7 to 9 | Days 10 to 12 | Days 13 to 15 | Days 16 to 18 |
| Initiate at 25 mg (AM) (half ULTRAM® scored tablet) | 25 mg b.i.d. | 25 mg t.i.d. | 25 mg q.i.d. | 50 mg t.i.d. | 50 mg q.i.d. |
After titration, ULTRAM® 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.
For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, ULTRAM® 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg per day.
Use in Renal ImpairmentIn all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of ULTRAM® be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.
Use in Hepatic ImpairmentThe recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.
Elderly Patients ( > 65 years old)In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.
Pediatric Patients ( < 18 years old)The safety and effectiveness of ULTRAM® has not been studied in the pediatric population. Therefore, use of ULTRAM® tablets is not recommended in patients under 18 years of age.
Management of Patients Requiring Rescue MedicationIf ULTRAM® is used as rescue medication in conjunction with extended-release tramadol tablets, the total daily dose of tramadol should not exceed 400 mg. Fentanyl products should not be used as rescue medication in patients taking ULTRAM®.
Missed DoseIf a patient misses a dose, they should take their next dose as soon as they remember. If it is almost time for their next dose, they should not take the missed dose. Instead, they should take the next scheduled dose. They should not make up for the missed dose by taking a double dose.
DiscontinuationWithdrawal symptoms may occur if ULTRAM® is discontinued abruptly (see Drug Abuse, Addiction and Dependence). These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with ULTRAM® discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRAM® at the time of discontinuation.
Route of administration
Oral use
Posology
The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected. The correct dosage per individual patient is that which controls the pain with no or tolerable side effects for a full 12 hours. Patients transferring from immediate release tramadol preparations should have their total daily dose calculated, and start on the nearest dose in the Zaledor XR SR range. It is recommended that patients are slowly titrated to higher doses to minimise transient side effects. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported.. A total daily dose of 400 mg should not be exceeded except in special clinical circumstances.
Adults and children over 12 years:
The usual initial dose is one 75 mg tablet twice daily. If pain relief is not achieved, the dosage should be titrated upwards until pain relief is achieved.
Geriatric patients:
A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.
Renal insufficiency/dialysis and hepatic impairment:
In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements.
As tramadol is only removed very slowly by haemodialysis or by haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.
Paediatric population under 12 years of age:
Zaledor XR SR has not been studied in children. The safety and efficacy of Zaledor XR SR has not been established and the product should not be used in children.
Method of administration
These tablets should be taken at 12-hourly intervals and must be swallowed whole and not broken, crushed or chewed.
Zaledor XR should not be used in patients with:
Zaledor XR must be swallowed whole and must not be chewed, crushed, or split (see WARNINGS, Misuse, Abuse and Diversion of Opioids and Drug Abuse And Addiction).
Adults (18 years of age and over) Patients Not Currently on Tramadol Immediate-Release ProductsFor patients not currently treated with tramadol immediate-release (IR) products, Zaledor XR should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100-mg increments every five days to relief of pain and depending upon tolerability. Zaledor XR should not be administered at a dose exceeding 300 mg per day.
Patients Currently on Tramadol Immediate-Release ProductsFor patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose and initiate a total daily dose of Zaledor XR rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with Zaledor XR, some patients maintained on tramadol IR products may not be able to convert to Zaledor XR. Zaledor XR should not be administered at a dose exceeding 300 mg per day. The concomitant use of Zaledor XR with other tramadol products is not recommended (see WARNINGS).
Individualization Of DoseGood pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of Zaledor XR have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg.
In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Zaledor XR should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.
Dosing ConsiderationsZaledor XR® is not recommended for minor pain that may be treated adequately through lesser means where benefit does not outweigh the possible opioid-related side effects.
Zaledor XR® can be administered without regard to food.
Do not co-administer Zaledor XR® tablets with other tramadol-containing products.
Due to the differences in pharmacokinetic properties, Zaledor XR® tablets are not interchangeable with tramadol extended-release formulations.
The maximum recommended dose of Zaledor XR® should not be exceeded.
Recommended Dose And Dosage AdjustmentGood pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.
Adults (18 Years of Age and Over)For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of Zaledor XR® can be improved by initiating therapy with the following titration regimen: Zaledor XR® should be started at 25 mg/day (half Zaledor XR® scored tablet) qAM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.) as shown in Table 1.3 below.
Table 1.3: Initiation Titration Dose of Zaledor XR® by Days
| Days 1 to 3 | Days 4 to 6 | Days 7 to 9 | Days 10 to 12 | Days 13 to 15 | Days 16 to 18 |
| Initiate at 25 mg (AM) (half Zaledor XR® scored tablet) | 25 mg b.i.d. | 25 mg t.i.d. | 25 mg q.i.d. | 50 mg t.i.d. | 50 mg q.i.d. |
After titration, Zaledor XR® 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.
For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, Zaledor XR® 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg per day.
Use in Renal ImpairmentIn all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of Zaledor XR® be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.
Use in Hepatic ImpairmentThe recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.
Elderly Patients ( > 65 years old)In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.
Pediatric Patients ( < 18 years old)The safety and effectiveness of Zaledor XR® has not been studied in the pediatric population. Therefore, use of Zaledor XR® tablets is not recommended in patients under 18 years of age.
Management of Patients Requiring Rescue MedicationIf Zaledor XR® is used as rescue medication in conjunction with extended-release tramadol tablets, the total daily dose of tramadol should not exceed 400 mg. Fentanyl products should not be used as rescue medication in patients taking Zaledor XR®.
Missed DoseIf a patient misses a dose, they should take their next dose as soon as they remember. If it is almost time for their next dose, they should not take the missed dose. Instead, they should take the next scheduled dose. They should not make up for the missed dose by taking a double dose.
DiscontinuationWithdrawal symptoms may occur if Zaledor XR® is discontinued abruptly (see Drug Abuse, Addiction and Dependence). These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with Zaledor XR® discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering Zaledor XR® at the time of discontinuation.
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
No special requirement.
