Acute overdosage with Hydromorphone Hydrochlorideextended-Release can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.
Treatment Of OverdoseIn case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, naloxone and nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydromorphone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose.
Because the duration of reversal is expected to be less than the duration of action of hydromorphone in Hydromorphone Hydrochlorideextended-Release, carefully monitor the patient until spontaneous respiration is reliably reestablished. Hydromorphone Hydrochlorideextended-Release will continue to release hydromorphone and add to the hydromorphone load for up to 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experiences will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Hydromorphone Hydrochlorideextended-Release is contraindicated in:
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Hydromorphone Hydrochlorideextended-Release was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to Hydromorphone Hydrochlorideextended-Release for greater than 6 months and 141 exposed for greater than one year.
The most common adverse reactions leading to study discontinuation were nausea, vomiting, constipation, somnolence, and dizziness. The most common treatment-related serious adverse reactions from controlled and uncontrolled chronic pain studies were drug withdrawal syndrome, overdose, confusional state, and constipation.
The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients.
The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.
A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 2.
Table 2. Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term
| Preferred Term | Open-Label Titration Phase | Double-Blind Treatment Phase | |
| Hydromorphone Hydrochlorideextended-Release (N=447) | Hydromorphone Hydrochlorideextended-Release (N=134) | Placebo (N=134) | |
| Constipation | 69 (15) | 10 (7) | 5 (4) |
| Nausea | 53 (12) | 12 (9) | 10 (7) |
| Somnolence | 39 (9) | 1 (1) | 0 (0) |
| Headache | 35 (8) | 7 (5) | 10 (7) |
| Vomiting | 29 (6) | 8 (6) | 6 (4) |
| Pruritus | 21 (5) | 1 (1) | 0 (0) |
| Dizziness | 17 (4) | 3 (2) | 2 (1) |
| Insomnia | 13 (3) | 7 (5) | 5 (4) |
| Dry Mouth | 13 (3) | 2 (1) | 0 (0) |
| Edema Peripheral | 13 (3) | 3 (2) | 1 (1) |
| Hyperhidrosis | 13 (3) | 2 (1) | 2 (1) |
| Anorexia/Decreased Appetite | 10 (2) | 2 (1) | 0 (0) |
| Arthralgia | 9 (2) | 8 (6) | 3 (2) |
| Abdominal Pain | 9 (2) | 4 (3) | 3 (2) |
| Muscle Spasms | 5 (1) | 3 (2) | 1 (1) |
| Weight Decreased | 3 (1) | 4 (3) | 3 (2) |
The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 3.
Table 3.
Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Chronic Pain Receiving Hydromorphone Hydrochlorideextended-Release in 14 Clinical Studies by Preferred Term
| Preferred Term | All Patients (N=2,474) |
| Constipation | 765 (31) |
| Nausea | 684 (28) |
| Vomiting | 337 (14) |
| Somnolence | 367 (15) |
| Headache | 308 (12) |
| Asthenia/Fatigue | 272 (11) |
| Dizziness | 262 (11) |
| Diarrhea | 201 (8) |
| Pruritus | 193 (8) |
| Insomnia | 161 (7) |
| Hyperhidrosis | 143 (6) |
| Edema Peripheral | 135 (5) |
| Anorexia/Decreased Appetite | 139 (6) |
| Dry Mouth | 121 (5) |
| Abdominal Pain | 115 (5) |
| Anxiety | 95 (4) |
| Back Pain | 95 (4) |
| Dyspepsia* | 88 (4) |
| Depression | 81 (3) |
| Dyspnea | 76 (3) |
| Muscle Spasms | 74 (3) |
| Arthralgia | 72 (3) |
| Rash | 64 (3) |
| Pain in Extremity | 63 (3) |
| Pain | 58 (2) |
| Drug Withdrawal Syndrome | 55 (2) |
| Pyrexia | 52 (2) |
| Fall | 51 (2) |
| Chest pain | 51 (2) |
| * Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia |
The following Adverse Reactions occurred in patients with an overall frequency of < 2% and are listed in descending order within each System Organ Class:
Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles
Ear and labyrinth disorders: vertigo, tinnitus
Endocrine disorders: hypogonadism
Eye disorders: vision blurred, diplopia, dry eye, miosis
Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation
General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling of body temperature change, feeling jittery, hangover, gait disturbance, feeling drunk, body temperature decreased
Infections and infestations: gastroenteritis, diverticulitis
Injury, poisoning and procedural complications: contusion, overdose
Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased
Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia
Musculoskeletal and connective tissue disorders: myalgia
Nervous system disorders: tremor, sedation, hypoesthesia, paresthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, crying, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity
Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, suicide ideation, libido decreased, aggression
Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder
Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction
Respiratory, thoracic and mediastinal disorders: rhinorrhea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression
Skin and subcutaneous tissue disorders: erythema
Vascular disorders: flushing, hypertension, hypotension
Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of hydromorphone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in Hydromorphone Hydrochlorideextended-Release.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.
Hydromorphone Hydrochlorideextended-Release is indicated for the management of pain in opioid-tolerant patients severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Patients considered opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
Limitations Of UseAdditive pharmacodynamic effects may be expected when Hydromorphone Hydrochlorideextended-Release is used in conjunction with alcohol, other opioids, legal or illicit drugs that cause central nervous system depression.
Effects On The Central Nervous SystemHydromorphone produces dose-related respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation.
Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis, rather than miosis, may be seen due to severe hypoxia in overdose situations.
Effects On The Gastrointestinal Tract And Other Smooth MuscleHydromorphone causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects On The Cardiovascular SystemHydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by hydromorphone and can contribute to opioid-induced hypotension. Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.
Effects On The Endocrine SystemOpioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.
Effects On The Immune SystemOpioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Efficacy RelationshipsThe minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydromorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.
Concentration–Adverse Reaction RelationshipsThere is a relationship between increasing hydromorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.
Hydromorphone Hydrochlorideextended-Release is an extended-release formulation of hydromorphone that produces a gradual increase in hydromorphone concentrations. Following a single-dose administration of Hydromorphone Hydrochlorideextended-Release, plasma concentrations gradually increase over 6 to 8 hours, and thereafter concentrations are sustained for approximately 18 to 24 hours post-dose. The median Tmax values ranged from 12 to 16 hours. The mean half-life was approximately 11 hours, ranging from 8 to 15 hours in most individual subjects. Linear pharmacokinetics has been demonstrated for Hydromorphone Hydrochlorideextended-Release over the dose range 8 to 64 mg, with a doseproportional increase in Cmax and overall exposure (AUC0-∞) (see Table 4). Steady-state plasma concentrations are approximately twice those observed following the first dose, and steady state is reached after 3 to 4 days of once-daily dosing of Hydromorphone Hydrochlorideextended-Release. At steady state, Hydromorphone Hydrochlorideextended-Release given once daily maintained hydromorphone plasma concentrations within the same concentration range as the immediate-release tablet given 4 times daily at the same total daily dose and diminished the fluctuations between peak and trough concentrations seen with the immediate-release tablet (see Figure 1). The bioavailability of Hydromorphone Hydrochlorideextended-Release once daily and immediate-release hydromorphone four times daily in adults is comparable, as presented in Table 4.
Figure 1. Mean Steady-State Plasma Concentration Profile
Table 5. Mean (±SD) Hydromorphone Hydrochlorideextended-Release Pharmacokinetic Parameters
| Regimen | Dosage | Tmax* (hrs) | Cmax (ng/mL) | AUC (ng·hr/mL) | T½ (hr) |
| Single Dose (N = 31) | 8 mg | 12 (4-30) | 0.93 (1.01) | 18.1 (5.8) | 10.6 (4.3) |
| 16 mg | 16 (6-30) | 1.69 (0.78) | 36.5 (11.3) | 10.3 (2.4) | |
| 32 mg | 16 (4-24) | 3.25 (1.37) | 72.2 (24.3) | 11.0 (3.2) | |
| 64 mg | 16 (6-30) | 6.61 (1.75) | 156.0 (30.6) | 10.9 (3.8) | |
| Multiple Dose† (N = 29) | 16 mg q24h | 12 (6-24) | 3.54 (0.96)‡ | 57.6 (16.3) | NA |
| IR 4 mg q6h | 0.75 (0.5-2) | 5.28 (1.37)§ | 54.8 (14.8) | NA | |
| NA = not applicable *Median (range) reported for Tmax † Steady-state results on Day 5 (0-24 hours) ‡ Cmin 2.15 (0.87) ng/mL § Cmin 1.47 (0.42) ng/mL |
Food Effect
The pharmacokinetics of Hydromorphone Hydrochlorideextended-Release are not affected by food as indicated by bioequivalence when administered under fed and fasting conditions. Therefore, Hydromorphone Hydrochlorideextended-Release may be administered without regard to meals. When a 16 mg dose of Hydromorphone Hydrochlorideextended-Release was administered to healthy volunteers immediately following a high-fat meal, the median time to Cmax (Tmax) was minimally affected by the high-fat meal occurring at 16 hours compared to 18 hours while fasting.
DistributionFollowing intravenous administration of hydromorphone to healthy volunteers, the mean volume of distribution was 2.9 (±1.3) L/kg, suggesting extensive tissue distribution. The mean extent of binding of hydromorphone to human plasma proteins was determined to be 27% in an in vitro study.
EliminationMetabolism
After oral administration of an immediate-release formulation, hydromorphone undergoes extensive firstpass metabolism and is metabolized primarily in the liver by glucuronidation to hydromorphone-3- glucuronide, which follows a similar time course to hydromorphone in plasma. Exposure to the glucuronide metabolite is 35 to 40 times higher than exposure to the parent drug. In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.
Excretion
Approximately 75% of the administered dose is excreted in urine. Most of the administered hydromorphone dose is excreted as metabolites. Approximately 7% and 1% of the dose are excreted as unchanged hydromorphone in urine and feces, respectively.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Addiction, Abuse, And MisuseHydromorphone Hydrochlorideextended-Release contains hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochlorideextended-Release exposes users to the risks of addiction, abuse, and misuse. As modified- release products such as Hydromorphone Hydrochlorideextended-Release deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hydrochlorideextended-Release and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hydrochlorideextended-Release, and monitor all patients receiving Hydromorphone Hydrochlorideextended-Release for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Hydromorphone Hydrochlorideextended-Release for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Hydromorphone Hydrochlorideextended-Release, but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochlorideextended-Release along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of Hydromorphone Hydrochlorideextended-Release by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydromorphone Hydrochlorideextended-Release. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory DepressionSerious, life-threatening, or fatal respiratory depression has been reported with the use of modifiedrelease opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydromorphone Hydrochlorideextended-Release, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with Hydromorphone Hydrochlorideextended-Release and following dosage increases.
To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochlorideextended-Release are essential. Overestimating the Hydromorphone Hydrochlorideextended-Release dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of Hydromorphone Hydrochlorideextended-Release, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.
Neonatal Opioid Withdrawal SyndromeProlonged use of Hydromorphone Hydrochlorideextended-Release during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Risks From Concomitant Use With Benzodiazepines Or Other CNS DepressantsProfound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydromorphone Hydrochlorideextended-Release with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydromorphone Hydrochlorideextended-Release is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated PatientsThe use of Hydromorphone Hydrochlorideextended-Release in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients With Chronic Pulmonary DiseaseHydromorphone Hydrochlorideextended-Release treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydromorphone Hydrochlorideextended-Release.
Elderly, Cachectic, Or Debilitated PatientsLife-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating Hydromorphone Hydrochlorideextended-Release and when Hydromorphone Hydrochlorideextended-Release is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal InsufficiencyCases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Severe HypotensionHydromorphone Hydrochlorideextended-Release may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydromorphone Hydrochlorideextended-Release. In patients with circulatory shock, Hydromorphone Hydrochlorideextended-Release may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hydrochlorideextended-Release in patients with circulatory shock.
Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired ConsciousnessIn patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hydromorphone Hydrochlorideextended-Release may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hydromorphone Hydrochlorideextended-Release.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydromorphone Hydrochlorideextended-Release in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal ConditionsHydromorphone Hydrochlorideextended-Release is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Avoid the use of Hydromorphone Hydrochlorideextended-Release in patients with other GI obstruction.
Because the Hydromorphone Hydrochlorideextended-Release tablet is nondeformable and does not appreciably change in shape in the GI tract, Hydromorphone Hydrochlorideextended-Release is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.
It is possible that Hydromorphone Hydrochlorideextended-Release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.
The hydromorphone in Hydromorphone Hydrochlorideextended-Release may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Increased Risk Of Seizures In Patients With Seizure DisordersThe hydromorphone in Hydromorphone Hydrochlorideextended-Release may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hydromorphone Hydrochlorideextended-Release therapy.
WithdrawalAvoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydromorphone Hydrochlorideextended-Release. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
When discontinuing Hydromorphone Hydrochlorideextended-Release, gradually taper the dose. Do not abruptly discontinue Hydromorphone Hydrochlorideextended-Release.
SulfitesHydromorphone Hydrochlorideextended-Release contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Risks Of Driving And Operating MachineryHydromorphone Hydrochlorideextended-Release may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydromorphone Hydrochlorideextended-Release and know how they will react to the medication.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide)
Addiction, Abuse, And MisuseInform patients that the use of Hydromorphone Hydrochlorideextended-Release, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share Hydromorphone Hydrochlorideextended-Release with others and to take steps to protect Hydromorphone Hydrochlorideextended-Release from theft or misuse.
Life-threatening Respiratory DepressionInform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydromorphone Hydrochlorideextended-Release or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental IngestionInform patients that accidental ingestion, especially by children, may result in respiratory depression or death. Instruct patients to take steps to store Hydromorphone Hydrochlorideextended-Release securely and to dispose of unused Hydromorphone Hydrochlorideextended-Release by flushing the tablets down the toilet.
Interactions With Benzodiazepines And Other CNS DepressantsInform patients and caregivers that potentially fatal additive effects may occur if Hydromorphone Hydrochlorideextended-Release is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.
Serotonin SyndromeInform patients that Hydromorphone Hydrochlorideextended-Release could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications.
MAOI InteractionInform patients to avoid taking Hydromorphone Hydrochlorideextended-Release while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydromorphone Hydrochlorideextended-Release.
Adrenal InsufficiencyInform patients that Hydromorphone Hydrochlorideextended-Release could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.
Important Administration InstructionsInstruct patients how to properly take Hydromorphone Hydrochlorideextended-Release, including the following:
Advise patients that people with certain stomach or intestinal problems such as narrowing of the intestines or previous surgery may be at higher risk of developing a blockage. Symptoms include abdominal distension, abdominal pain, severe constipation, or vomiting. Instruct patients to contact their healthcare provider immediately if they develop these symptoms.
HypotensionInform patients that Hydromorphone Hydrochlorideextended-Release may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
AnaphylaxisInform patients that anaphylaxis has been reported with ingredients contained in Hydromorphone Hydrochlorideextended-Release. Advise patients how to recognize such a reaction and when to seek medical attention.
PregnancyNeonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Hydromorphone Hydrochlorideextended-Release during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that Hydromorphone Hydrochlorideextended-Release can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.
LactationAdvise patients that breastfeeding is not recommended during treatment with Hydromorphone Hydrochlorideextended-Release
InfertilityInform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
Driving Or Operating Heavy MachineryInform patients that Hydromorphone Hydrochlorideextended-Release may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
ConstipationAdvise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Disposal Of Unused Hydromorphone Hydrochlorideextended-ReleaseAdvise patients to flush the unused tablets down the toilet when Hydromorphone Hydrochlorideextended-Release is no longer needed.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisLong-term studies to evaluate the carcinogenic potential of hydromorphone hydrochloride were completed in both Han-Wistar rats and Crl:CD1®(ICR) mice. Hydromorphone HCl was administered to Han-Wistar rats (2, 5, and 15 mg/kg/day for males, and 8, 25 and 75 mg/kg/day for females) for 2 years by oral gavage. In female rats, incidences of hibernoma (tumor of brown fat) were increased at 10.5 times the maximum recommended daily exposure based on AUC at the mid dose (2 tumor, 25 mg/kg/day) and 53.7 times the maximum recommended human daily exposure based on AUC at the maximum dose (4 tumors, 75 mg/kg/day). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in male rats. The systemic drug exposure (AUC, ng•h/mL) at the 15 mg/kg/day in male rats was 7.6 times greater than the human exposure at a single dose of 32 mg/day of Hydromorphone Hydrochlorideextended-Release. There was no evidence of carcinogenic potential in Crl:CD1®(ICR) mice administered hydromorphone HCl at doses up to 15 mg/kg/day for 2 years by oral gavage. The systemic drug exposure (AUC, ng•h/mL) at the 15 mg/kg/day in mice was 1.1 (in males) and 1.2 (in females) times greater than the human exposure at a single dose of 32 mg/day of Hydromorphone Hydrochlorideextended-Release.
MutagenesisHydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.
Impairment Of FertilityReduced implantation sites and viable fetuses were noted at 2.1 times the human daily dose of 32 mg/day in a study in which female rats were treated orally with 1.75, 3.5, or 7 mg/kg/day hydromorphone hydrochloride (0.7, 1.4, or 2.8 times a human daily dose of 24 mg/day (HDD) based on body surface area) beginning 14 days prior to mating through Gestation Day 7 and male rats were treated with the same hydromorphone hydrochloride doses beginning 28 days prior to and throughout mating.
Use In Specific Populations Pregnancy Risk SummaryProlonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. There are no adequate and well-controlled studies in pregnant women. Based on animal data, advise pregnant women of the potential risk to a fetus.
In animal reproduction studies, reduced postnatal survival of pups, developmental delays, and altered behavioral responses were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 2.1 times the human daily dose of 32 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 4.8 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 2.3 times the HDD to pregnant mice. No malformations were noted at 2.1 or 17 times the HDD in pregnant rats or rabbits, respectively. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsFetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, and manage accordingly.
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone Hydrochlorideextended-Release is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Hydromorphone Hydrochlorideextended-Release can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
DataAnimal Data
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day based on body surface area, respectively). Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in the two highest dose groups). There was no evidence of malformations or embryotoxicity reported.
Pregnant rabbits were treated with hydromorphone hydrochloride from Gestation Day 6 to 20 via oral gavage doses of 10, 25, or 50 mg/kg/day (4.3, 8.5, or 17 times the HDD of 32 mg/day based on body surface area, respectively). Maternal toxicity was noted in the highest dose group (reduced food consumption and body weights). There was no evidence of malformations or embryotoxicity reported.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (4.8 to 65.4 times the HDD of 32 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (3.5 times the human daily dose of 32 mg/day). In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.1, 2.3, or 4.6 times the human daily dose of 32 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 2.3 times the human dose of 32 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to Lactation Day 21 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day based on body surface area, respectively). Reduced pup weights were noted at 1.1 and 2.1 times the human daily dose of 32 mg/day and increased pup deaths, delayed ear opening, reduced auditory startle reflex, and reduced open-field activity were also noted at 2.1 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups) and decreased maternal care in the high dose group.
Lactation Risk SummaryBecause of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Hydromorphone Hydrochlorideextended-Release. Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving Hydromorphone Hydrochlorideextended-Release since hydromorphone is excreted in the milk.
Clinical ConsiderationsMonitor infants exposed to Hydromorphone Hydrochlorideextended-Release through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
Females And Males Of Reproductive Potential InfertilityChronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
Pediatric UseThe safety and effectiveness of Hydromorphone Hydrochlorideextended-Release in patients 17 years of age and younger have not been established.
Geriatric UseElderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were coadministered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochlorideextended-Release slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.
Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Hepatic ImpairmentIn a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold Increases in plasma levels of hydromorphone (Cmax and AUC0-∞) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on 25% of the Hydromorphone Hydrochlorideextended-Release dose that would be used in patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with Hydromorphone Hydrochlorideextended-Release and during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. As further increases in Cmax and AUC0-∞ of hydromorphone in this group are expected, use of alternate analgesics is recommended.
Renal ImpairmentAdministration of a single 4 mg dose of immediate-release hydromorphone tablets resulted in two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life. Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the Hydromorphone Hydrochlorideextended-Release dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with Hydromorphone Hydrochlorideextended-Release and during dose titration. As Hydromorphone Hydrochlorideextended-Release is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment.
To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.
Hydromorphone Hydrochlorideextended-Release should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Due to the risk of respiratory depression, Hydromorphone Hydrochlorideextended-Release is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning Hydromorphone Hydrochlorideextended-Release therapy. As Hydromorphone Hydrochlorideextended-Release is only for use in opioid-tolerant patients, do not begin any patient on Hydromorphone Hydrochlorideextended-Release as the first opioid.
Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
Instruct patients to swallow Hydromorphone Hydrochlorideextended-Release tablets whole. Crushing, chewing, or dissolving Hydromorphone Hydrochlorideextended-Release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death.
Initial Dosage Conversion From Other Oral Hydromorphone Formulations To Hydromorphone Hydrochlorideextended-ReleasePatients receiving oral immediate-release hydromorphone may be converted to Hydromorphone Hydrochlorideextended-Release by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.
Conversion From Other Oral Opioids To Hydromorphone Hydrochlorideextended-ReleaseDiscontinue all other around-the-clock opioid drugs when Hydromorphone Hydrochlorideextended-Release therapy is initiated.
There is substantial inter-patient variability in the relative potency of different opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydromorphone Hydrochlorideextended-Release. It is safer to underestimate a patient’s 24-hour oral hydromorphone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone dosage and manage an adverse reaction due to overdose.
In an Hydromorphone Hydrochlorideextended-Release clinical trial with an open-label titration period, patients were converted from their prior opioid to Hydromorphone Hydrochlorideextended-Release using the Table 1 as a guide for the initial Hydromorphone Hydrochlorideextended-Release dose. The recommended starting dose of Hydromorphone Hydrochlorideextended-Release is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.
Consider the following when using the information in Table 1:
Table 1. Conversion Factors to Hydromorphone Hydrochlorideextended-Release
| Prior Oral Opioid | Approximate Oral Conversion Factor |
| Hydromorphone | 1 |
| Codeine | 0.06 |
| Hydrocodone | 0.4 |
| Methadone | 0.6 |
| Morphine | 0.2 |
| Oxycodone | 0.4 |
| Oxymorphone | 0.6 |
To calculate the estimated Hydromorphone Hydrochlorideextended-Release dose using Table 1:
Always round the dose down, if necessary, to the appropriate Hydromorphone Hydrochlorideextended-Release strength(s) available.
Example conversion from a single opioid to Hydromorphone Hydrochlorideextended-Release:
Step 1: Sum the total daily dose of the opioid
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
Step 3: Calculate the approximate starting dose of Hydromorphone Hydrochlorideextended-Release to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate Hydromorphone Hydrochlorideextended-Release tablet strengths available.
Close observation and frequent titration are warranted until pain management is stable on the new opioid.
Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Hydromorphone Hydrochlorideextended-Release.
Conversion From Transdermal Fentanyl To Hydromorphone Hydrochlorideextended-ReleaseEighteen hours following the removal of the transdermal fentanyl patch, Hydromorphone Hydrochlorideextended-Release treatment can be initiated. To calculate the 24-hour Hydromorphone Hydrochlorideextended-Release dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Hydromorphone Hydrochlorideextended-Release. Then reduce the Hydromorphone Hydrochlorideextended-Release dose by 50%.
For example:
Step 1: Identify the dose of transdermal fentanyl.
Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Hydromorphone Hydrochlorideextended-Release.
Step 3: Calculate the approximate starting dose of Hydromorphone Hydrochlorideextended-Release to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate Hydromorphone Hydrochlorideextended-Release tablet strengths available.
Close monitoring is of particular importance when converting from methadone to other opioid agonists.
The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.
Titration And Maintenance Of TherapyIndividually titrate Hydromorphone Hydrochlorideextended-Release to a dose that provides adequate analgesia and minimizes adverse reactions.
Continually reevaluate patients receiving Hydromorphone Hydrochlorideextended-Release to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.
Plasma levels of Hydromorphone Hydrochlorideextended-Release are sustained for 18 to 24 hours. Dosage adjustments of Hydromorphone Hydrochlorideextended-Release may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.
Patients who experience breakthrough pain may require a dose increase of Hydromorphone Hydrochlorideextended-Release, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Hydromorphone Hydrochlorideextended-Release dose.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
Discontinuation Of Hydromorphone Hydrochlorideextended-ReleaseWhen a patient no longer requires therapy with Hydromorphone Hydrochlorideextended-Release, taper doses gradually, by 25% to 50% every 2 to 3 days while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Hydromorphone Hydrochlorideextended-Release.
To dispose of unused Hydromorphone Hydrochlorideextended-Release flush all remaining tablets down the toilet or remit to authorities at a certified drug take-back program.
Dosage Modifications In Patients With Moderate Hepatic ImpairmentStart patients with moderate hepatic impairment on 25% of the Hydromorphone Hydrochlorideextended-Release dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with Hydromorphone Hydrochlorideextended-Release and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment.
Dosage Modifications In Patients With Renal ImpairmentStart patients with moderate renal impairment on 50% of the Hydromorphone Hydrochlorideextended-Release dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with Hydromorphone Hydrochlorideextended-Release and during dose titration. As Hydromorphone Hydrochlorideextended-Release is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment.
