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Hydromorphone Hydrochloride

FDA Drug Information • Also known as: Dilaudid, Hydromorphone Hydrochloride

Brand Names
Dilaudid, Hydromorphone Hydrochloride
Route
INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS
Dosage Form
INJECTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS Addiction, Abuse, and Misuse Because the use of hydromorphone hydrochloride extended-release tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone hydrochloride extended-release tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential. Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of hydromorphone [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions ( 5.2 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydromorphone hydrochloride extended-release tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS See full prescribing information for complete boxed warning.

  • Hydromorphone hydrochloride extended-release tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 )
  • Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential. Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of hydromorphone. ( 5.2 )
  • Accidental ingestion of hydromorphone hydrochloride extended-release tablets, especially by children, can result in fatal overdose of hydromorphone. ( 5.2 )
  • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.3 , 7 )
  • Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 )
  • Healthcare providers are strongly encouraged to complete a REMS compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 )

    • Description

    11 DESCRIPTION Hydromorphone hydrochloride extended-release tablets are for oral use and contain hydromorphone hydrochloride, an opioid agonist. Hydromorphone hydrochloride USP is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. Hydromorphone hydrochloride is a white or almost white crystalline powder that is freely soluble in water, very slightly soluble in ethanol (96%), and practically insoluble in methylene chloride. Its empirical formula is C 17 H 19 NO 3

  • HCl. The compound has the following structural formula: Hydromorphone hydrochloride extended-release tablets also contain the following inactive ingredients: ammonio methacrylate copolymer, colloidal silicon dioxide, ethylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, talc and triethyl citrate. The color coating of the tablets contains ferric oxide black, ferric oxide red (8, 16, and 32 mg only), ferric oxide yellow (8 and 16 mg only), hypromellose, polyethylene glycol, polysorbate 80 (12 mg only), propylene glycol, shellac, and titanium dioxide. structural formula

    • What Is Hydromorphone Hydrochloride Used For?

    1 INDICATIONS AND USAGE Hydromorphone hydrochloride extended-release tablets are indicated in opioid-tolerant patients for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. 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 Use

  • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including hydromorphone hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
  • Hydromorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. Hydromorphone hydrochloride extended-release tablets are an opioid agonist indicated in opioid-tolerant patients for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Patients considered opioid tolerant are those who are taking, 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. ( 1 ) Limitations of Use
  • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including hydromorphone hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )
  • Hydromorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic. ( 1 )

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1 )
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 )
  • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse ( 2.1 , 5.1 )
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments ( 2.1 , 5.2 )
  • For once daily administration IN OPIOID-TOLERANT PATIENTS. ( 2.1 )
  • Instruct patients to swallow hydromorphone hydrochloride extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets (risk of potentially fatal overdose). ( 2.1 , 5.1 )
  • Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with hydromorphone hydrochloride extended-release tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 )
  • Dose may be increased using increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia. ( 2.4 )
  • Periodically reassess patients receiving hydromorphone hydrochloride extended-release tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 )
  • Do not rapidly reduce or abruptly discontinue hydromorphone hydrochloride extended-release tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.13 )
  • Moderate Hepatic Impairment : Initiate treatment with 25% of the dose that would be prescribed for patients with normal hepatic function. Monitor closely for respiratory and central nervous system depression. ( 2.6 )
  • Moderate and Severe Renal Impairment : Initiate treatment in patients with moderate renal impairment with 50% and patients with severe renal impairment with 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling:

  • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )]
  • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )]
  • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )]
  • Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ( 5.3 )]
  • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.6 )]
  • Adrenal Insufficiency [see Warnings and Precautions ( 5.8 )]
  • Severe Hypotension [see Warnings and Precautions ( 5.9 )]
  • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.11 )]
  • Seizures [see Warnings and Precautions ( 5.12 )]
  • Withdrawal [see Warnings and Precautions ( 5.13 )] Most common adverse reactions (incidence >10%) are: constipation, nausea, vomiting, somnolence, headache, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience 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 hydrochloride extended-release tablets was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to hydromorphone hydrochloride extended-release tablets 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 [see Clinical Studies ( 14 )] . 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 Hydromorphone Hydrochloride Extended-Release Tablets (N = 447) Double-Blind Treatment Phase Hydromorphone Hydrochloride Extended-Release Tablets (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 ≥...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 4 includes clinically significant drug interactions with hydromorphone hydrochloride extended-release tablets. Table 4. Clinically Significant Drug Interactions with Hydromorphone Hydrochloride Extended-Release Tablets Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue hydromorphone hydrochloride extended-release tablets immediately if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.3 )]. Intervention: The use of hydromorphone hydrochloride extended-release tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of hydromorphone hydrochloride extended-release tablets and/or precipitate withdrawal symptoms [see Warnings and Precautions ( 5.13 )]. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle...

    Contraindications

    4 CONTRAINDICATIONS Hydromorphone hydrochloride extended-release tablets are contraindicated in:

  • Opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.
  • Patients with significant respiratory depression [see Warnings and Precautions ( 5.2 )] .
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.7 )] .
  • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.11 )] .
  • Patients who have had surgical procedures and/or underlying disease resulting in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction [see Warnings and Precautions ( 5.11 )] .
  • Patients with hypersensitivity (e.g., anaphylaxis) to hydromorphone [see Warnings and Precautions ( 5.14 )].
  • Opioid non-tolerant patients ( 4 )
  • Significant respiratory depression ( 4 )
  • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 )
  • Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 )
  • Narrowed or obstructed gastrointestinal tract ( 4 )
  • Known hypersensitivity to any components including hydromorphone hydrochloride and sulfites ( 4 , 5.14 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )]. 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 [see Data] . 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 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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...

    8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2 ), Nonclinical Toxicology ( 13.1 )] .

    Overdosage

    10 OVERDOSAGE Clinical Presentation Acute overdose with hydromorphone hydrochloride extended-release tablets 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, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In 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 and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of reversal is expected to be less than the duration of action of hydromorphone in hydromorphone hydrochloride extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Hydromorphone hydrochloride extended-release tablets 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 an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual...

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Hydromorphone Hydrochloride Extended-Release Tablet Strengths Strength Color Tablet Description Bottle Count NDC 8 mg Dark Beige Round, biconvex, imprinted with “P293” over “8” on one side 100 0574-0293-01 12 mg White Round, biconvex, imprinted with “P294” over “12” on one side 100 0574-0294-01 16 mg Light Beige Round, biconvex, imprinted with “P295” over “16” on one side 100 0574-0295-01 32 mg Pink Round, biconvex, imprinted with “P297” over “32” on one side 100 0574-0297-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store hydromorphone hydrochloride extended-release tablets securely and dispose of properly [see Patient Counseling Information ( 17 )] .

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.