Not applicable.
On repeated oral and parenteral administration of Tramadol Krka 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 Tramadol Krka 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, Tramadol Krka can be classified as non-mutagenic.
Studies on the tumorigenic potential of Tramadol Krka 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 Tramadol Krka 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.
Pharmacotherapeutic group: other opioids; ATC-code: N 02 AX02.
Tramadol Krka 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.
Tramadol Krka has an antitussive effect. In contrast to morphine, analgesic doses of Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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.
Tramadol Krka has a high tissue affinity (Vd,ß = 203 ± 40 l). It has a plasma protein binding of about 20 %.
Tramadol Krka 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 Tramadol Krka is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethylTramadol Krka 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-desmethylTramadol Krka 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 Tramadol Krka.
The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of Tramadol Krka may affect the plasma concentration of Tramadol Krka or its active metabolite. Up to now, clinically relevant interactions have not been reported.
Tramadol Krka 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 (Tramadol Krka) and 18.5 ± 9.4 h (O-desmethylTramadol Krka), 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.
Tramadol Krka 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 Tramadol Krka SR tablet.
Biotransformation
Following administration of one Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka is coadministered with a triptan. If concomitant treatment of Tramadol Krka 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 Tramadol Krka and carbamazepine is not recommended.
Use With QuinidineCoadministration of quinidine with Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka, 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 Tramadol Krka (see CONTRAINDICATIONS).
Respiratory DepressionAdminister Tramadol Krka 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) DepressantsTramadol Krka 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. Tramadol Krka increases the risk of CNS and respiratory depression in these patients.
Increased Intracranial Pressure Or Head TraumaTramadol Krka 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 PatientsTramadol Krka 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 Tramadol Krka with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Tramadol Krka with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
WithdrawalWithdrawal symptoms may occur if Tramadol Krka 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 Tramadol Krka.
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 Tramadol Krka in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Tramadol Krka 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 AddictionTramadol Krka (tramadol hydrochloride) Extended-Release Tablets are classified as a Schedule IV controlled substance.
Tramadol Krka 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. Tramadol Krka, 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.
Tramadol Krka 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 Tramadol Krka 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. Tramadol Krka 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 Tramadol Krka do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Krka 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 Tramadol Krka has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of Tramadol Krka do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Krka 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. Tramadol Krka 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 DeliveryTramadol Krka 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 Tramadol Krka, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing MothersTramadol Krka 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 Tramadol Krka in patients under 18 years of age have not been established. The use of Tramadol Krka in the pediatric population is not recommended.
Geriatric UseNine-hundred-one elderly (65 years of age or older) subjects were exposed to Tramadol Krka 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, Tramadol Krka 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 Tramadol Krka 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.
CONTRAINDICATIONSTramadol Krka should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. Tramadol Krka 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. Tramadol Krka may worsen central nervous system and respiratory depression in these patients.
Clinical Pharmacology CLINICAL PHARMACOLOGY Mechanism Of ActionTramadol Krka 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 Tramadol Krka 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. Tramadol Krka is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.
The pharmacokinetics of Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka administration. The mean peak plasma concentrations of tramadol and M1 after administration of Tramadol Krka 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 Tramadol Krka, 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 | ||
| Tramadol Krka 200-mg Tablet Once-Daily | ULTRAM 50-mg Tablet Every 6 Hours | Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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). Tramadol Krka has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of Tramadol Krka does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka 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 Tramadol Krka does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Krka 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 Tramadol Krka® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® is coadministered with a triptan. If concomitant treatment of Tramadol Krka® 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 Tramadol Krka® with food does not significantly affect its rate or extent of absorption; therefore, Tramadol Krka® 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 Tramadol Krka® above the recommended range. Concomitant use of Tramadol Krka® 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 Krka® 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 Tramadol Krka® tablets (see CONTRAINDICATIONS).
Drug Abuse, Addiction And DependenceTramadol Krka® 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 Tramadol Krka® have been reported. Tramadol Krka® tablets should not be used in opioid-dependent patients. Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® has been established. The following are considered to be the essential components of the Risk Management strategy:
Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® for patients who are suicidal or addiction-prone.
Tramadol Krka® 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 TraumaTramadol Krka® 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 Krka® 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 Tramadol Krka® (see Respiratory, Respiratory Depression below).
Respiratory Respiratory DepressionAdminister Tramadol Krka® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of Tramadol Krka® 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) DepressantsTramadol Krka® 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. Tramadol Krka® increases the risk of CNS and respiratory depression in these patients.
Tramadol Krka® 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 AlcoholTramadol Krka® should not be used concomitantly with alcohol consumption.
Use In Ambulatory PatientsTramadol Krka® 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 Tramadol Krka® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).
Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of Tramadol Krka® 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 Tramadol Krka® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of Tramadol Krka® 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 Tramadol Krka® may complicate the clinical assessment of patients with acute abdominal conditions.
Use In Drug And Alcohol AddictionTramadol Krka® 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. Tramadol Krka® 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.
Tramadol Krka® 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 Tramadol Krka®, if any, on the later growth, development, and functional maturation of the child is unknown.
Nursing WomenTramadol Krka® 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 Tramadol Krka® has not been studied in the pediatric population. Therefore, use of Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® 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 Tramadol Krka® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.
In treating an overdose of Tramadol Krka®, 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.
CONTRAINDICATIONSTramadol Krka® 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 Tramadol Krka®. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, Tramadol Krka® 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, Tramadol Krka® has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
PharmacokineticsThe analgesic activity of Tramadol Krka® 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 Tramadol Krka® 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 TrialsTramadol Krka® 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 StudiesTramadol Krka® 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
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
No special requirement.
