Label: HYDROMORPHONE HYDROCHLORIDE- hydromorphone hydrochloride tablet
- NDC Code(s): 51224-102-50
- Packager: TAGI Pharma, Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CII
- Marketing Status: Abbreviated New Drug Application
Updated November 22, 2017
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- BOXED WARNING(What is this?)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTSClose
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Hydromorphone Hydrochloride Tablets, USP safely and effectively. See full prescribing information for Hydromorphone Hydrochloride Tablets, USP.
Hydromorphone Hydrochloride Tablets, USP, for oral use, C-II
Initial U.S. Approval: 1984
See full prescribing information for complete boxed warning.
- Hydromorphone Hydrochloride Tablets, USP exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. (5.1)
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
- Accidental ingestion of Hydromorphone Hydrochloride Tablets, USP, especially by children, can result in a fatal overdose of hydromorphone. (5.2)
- Prolonged use of Hydromorphone Hydrochloride Tablets, USP during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)
- 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; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4, 7).
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Hydromorphone Hydrochloride Tablets, USP contain hydromorphone, an opioid agonist, and are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1)
Limitations of Use (1)
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Hydromorphone Hydrochloride Tablets, USP for use in patients for whom alternative treatment options [e.g., non-opioid analgesics opioid combination products]:
- Have not been tolerated, or are not expected to be tolerated,
- Have not provided adequate analgesia, or are not expected to provide adequate analgesia
DOSAGE AND ADMINISTRATION
- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
- Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
- Usual adult starting dose for Hydromorphone Hydrochloride Tablets, USP is 8 mg every 12 hours. Appropriate use of Hydromorphone Hydrochloride Tablets must be decided by careful evaluation of each clinical situation. (2.2)
- Hepatic Impairment: Initiate treatment with one-fourth to one-half the ususal starting dose, depending on degree of hepatic impairment. (2.3)
- Renal Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. (2.4)
- Do not stop Hydromorphone Hydrochloride Tablets, USP abruptly in a physicallydependent patient. (2.5)
DOSAGE FORMS AND STRENGTHS
- Hydromorphone Hydrochloride Tablets, USP: 8 mg (3)
- 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)
- Known hypersensitivity to hydromorphone, hydromorphone salts, or sulfite-containing medications (4)
WARNINGS AND PRECAUTIONS
- Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.5)
- Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.6)
- Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Hydromorphone Hydrochloride Tablets, USP in patients with circulatory shock. (5.7)
- Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Hydromorphone Hydrochloride Tablets, USP in patients with impaired consciousness or coma. (5.8)
Most common adverse reactions are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. (6)
To report Suspected Adverse Reactions, contact Elite Laboratories, Inc., at 1-888-852-6657 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Hydromorphone Hydrochloride Tablets if serotonin syndrome is suspeacted (7)
- Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of hydromorphone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. (7)
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Hydromorphone Hydrochloride because they may reduce analgesic effect of Hydromorphone Hydrochloride or precipitate withdrawal symptoms. (7)
USE IN SPECIFIC POPULATIONS
- Pregnancy: May cause fetal harm. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
- FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.8 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
Hydromorphone Hydrochloride Tablets, USP 8 mg are white to off white, bisected triangular tablets debossed with "EL 14" on the biscected side.Close
- 4 CONTRAINDICATIONS
Hydromorphone Hydrochloride Tablets, USP are contraindicated in patients with:
- Significant respiratory depression [see Warnings and Precautions (5.5)]
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)]
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.9)]
- Hypersensitivity to hydromorphone, hydromorphone salts, any other components of the product, or sulfite-containing medications (e.g., anaphylaxis) [see Warnings and Precautions (5.13) Adverse Reactions (6.1)]
- 5 WARNINGS AND PRECAUTIONS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.8 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
- 6 ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:
- 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 (5.3)]
- Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4)
- Adrenal Insufficiency [see Warnings and Precautions (5.6)]
- Severe Hypotension [see Warnings and Precautions (5.7)]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.9)]
- Seizures [see Warnings and Precautions (5.10)]
- Withdrawal [see Warnings and Precautions (5.11)]
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.
Serious adverse reactions associated with Hydromorphone Hydrochloride include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
The most common adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.
Less Frequently Observed Adverse Reactions
Cardiac disorders: tachycardia, bradycardia, palpitations
Eye disorders: vision blurred, diplopia, miosis, visual impairment
Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain
General disorders and administration site conditions: weakness, feeling abnormal, chills
Hepatobiliary disorders: biliary colic
Metabolism and nutrition disorders: decreased appetite
Musculoskeletal and connective tissue disorders: muscle rigidity
Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope
Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams
Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects
Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm
Skin and subcutaneous tissue disorders: urticaria, rash, hyperhidrosis
Vascular disorders: flushing, hypotension, hypertension
6.2 Postmarketing Experience
The 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.
Confusional state, convulsions, drowsiness, dyskinesia, dyspnea, erectile dysfunction, fatigue, hepatic enzymes increased, hyperalgesia, hypersensitivity reaction, lethargy, myoclonus, oropharyngeal swelling, peripheral edema, and somnolence.
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: Anaphylaxis has been reported with ingredients contained in Hydromorphone Hydrochloride Tablets, USP
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2).
- 7 DRUG INTERACTIONS
Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride.
Table 1: Clinically Significant Drug Interactions with Hydromorphone Hydrochloride 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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydromorphone Hydrochloride Tablets, USP 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), 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 (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of Hydromorphone Hydrochloride Tablets, USP 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 Tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydromorphone Hydrochloride Tablets, USP and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Hydromorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
- 8 USE IN SPECIFIC POPULATIONS
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Hydromorphone Hydrochloride in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies, reduced postnatal survival of pups, and decreased were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 0.8 times the human daily dose of 24 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No malformations were noted at 4 or 40.5 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 2-4% and 15-20%, respectively.
Fetal/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 [see Warnings and Precautions (5.3)].
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 Hydrochloride Tablets, USP is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydromorphone Hydrochloride Tablets, USP, 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.
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1, 5, or 10 mg/kg/day (0.4, 2, or 4 times the HDD of 24 mg 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 7 to 19 via oral gavage doses of 10, 25, or 50 mg/kg/day (8.1, 20.3, or 40.5 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in the two highest dose groups (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 (6.4 to 87.2 times the HDD of 24 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 (4.7 times the human daily dose of 24 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 (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Softtissue 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 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
Increased pup mortality and decreased pup body weights were noted at 0.8 and 2 times the human daily dose of 24 mg in a study in which pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 7 to Lactation Day 20 via oral gavage doses of 0, 0.5, 2, or 5 mg/kg/day (0.2, 0.8, or 2 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity (decreased food consumption and body weight gain) was also noted at the two highest doses tested.
Low levels of opioid analgesics have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Hydromorphone Hydrochloride Tablets, USP and any potential adverse effects on the breastfed infant from Hydromorphone Hydrochloride Tablets, USP or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
The safety and effectiveness of Hydromorphone Hydrochloride in pediatric patients have not been established.
8.5 Geriatric Use
Elderly 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 Hydrochloride slowly in geriatric patients and montior closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].
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.
8.6 Hepatic Impairment
The pharmacokinetics of hydromorphone is affected by hepatic impairment. Due to increased exposure of hydromorphone, patients with hepatic impairment should be started at one-fourth to one-half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
The pharmacokinetics of hydromorphone is affected by renal impairment. In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life. Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Clinical Pharmacology (12.3)].
- 9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Hydromorphone Hydrochloride Tablets contain hydromorphone, a Schedule II controlled substance.
Hydromorphone Hydrochloride Tablets contain hydromorphone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, oxycodone, methadone, morphine, oxymorphone and tapentadol. Hydromorphone Hydrochloride Tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
"Drug-seeking" behavior is very common in persons with substance use disorders. 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 healthcare provider (s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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.
Hydromorphone Hydrochloride, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, 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.
Risks Specific to Abuse of Hydromorphone Hydrochloride
Hydromorphone Hydrochloride Tablets are for oral use only. Abuse of Hydromorphone Hydrochloride Tablets poses a risk of overdose and death. The risk is increased with concurrent abuse of Hydromorphone Hydrochloride Tablets with alcohol and other central nervous system depressants.
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g. pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Hydromorphone Hydrochloride Tablets, USP should not be abruptly discontinued in a physicallydependent patient [see Dosage and Administration (2.6)]. If Hydromorphone Hydrochloride Tablets, USP are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
- 10 OVERDOSAGE
Acute overdose with Hydromorphone Hydrochloride Tablets, USP 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 [see Clinical Pharmacology (12.2)].
Treatment of Overdose
In case of overdose, priorities are the reestablishment 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 techniques.
The opioid antagonists, naloxone or 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 opioid reversal is expected to be less than the duration of action of hydromorphone in Hydromorphone Hydrochloride Tablets, USP, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an 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 experienced 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.
- 11 DESCRIPTION
Hydromorphone Hydrochloride, a hydrogenated ketone of morphine, is an opioid agonist.
Hydromorphone Hydrochloride Tablets are supplied as 8 mg tablets for oral administration. The tablet strength describes the amount of hydromorphone hydrochloride in each tablet.
The chemical name is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The molecular Weight is 321.80. Its molecular formula is C17H19NO3∙HCl, and it has the following chemical structure:
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.
Each tablet for oral administration contains 8 mg hydromorphone hydrochloride. In addition, the tablets contain the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and silicon dioxide.Close
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Hydromorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of hydromorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Effects on the Central Nervous System
Hydromorphone produces 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 pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Hydromorphone causes a reduction in motility associated with an increase in smooth muscle 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 may be 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 System
Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. 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 [see Adverse Reactions (6.2)].
Effects on the Immune System
Opioids 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.
The 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 [see Dosage and Administration (2.1, 2.5)].
Concentration–Adverse Reaction Relationships
There 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 [see Dosage and Administration (2.2, 2.3, 2.5)].
The analgesic activity of Hydromorphone Hydrochloride is due to the parent drug, hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract after oral administration and undergoes extensive first-pass metabolism. Exposure of hydromorphone (Cmax and AUC ) is dose-proportional at a dose range of 2 and 8 mg. In vivo bioavailability following singledose administration of the 8 mg tablet is approximately 24% (coefficient of variation 21%). Bioequivalence between the Hydromorphone Hydrochloride 8 mg TABLET and an equivalent dose of Hydromorphone Hydrochloride Oral Solution has been demonstrated.
After oral administration of Hydromorphone Hydrochloride, peak plasma hydromorphone concentrations are generally attained within ½ to 1-hour.
Mean (%cv) Dosage Form Cmax
8 mg Tablet 5.5 (33%) 0.74 (34%) 23.7 (28%) 2.6 (18%) 8 mg Oral Liquid 5.7 (31%) 0.73 (71%) 24.6 (29%) 2.8 (20%)
At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. Afte an intravenous bolus dose, the steady state of volume distribution [mean (% cv)] is 302.9 (32%) liters.
The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.
Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.
After oral administration of a single 4 mg dose (2 mg hydromorphone immediate-release tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4-fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at a lower dose and closely monitored during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose should be even more conservative [see Use in Specific Populations (8.6)].
After oral administration of a single 4 mg dose (2 mg hydromorphone immediate-release tablets), exposure to hydromorphone ( C and AUC0-48) is increased in patients with impaired renal function by 2-fold in moderate (CLcr = 40 - 60 mL/min) and 3-fold in severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients with severe renal impairment should be even lower. Patients with renal impairment should be closely monitored during dose titration [see Use in Specific Populations (8.7)].
Age: Geriatric Population
In the geriatric population, age has no effect on the pharmacokinetics of hydromorphone.
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals to evaluate the carcinogenic potential of hydromorphone have not been conducted.
Hydromorphone was positive in the mouse lymphoma assay in the presence of metabolic activation, but was negative in the mouse lymphoma assay in the absence of metabolic activation. Hydromorphone 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 Fertility
Reduced 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 (0.5, 1.1, or 2.1 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.
- 14 CLINICAL STUDIES
Analgesic effects of single doses of Hydromorphone Hydrochloride Oral Solution administered to patients with postsurgical pain have been studied in double-blind controlled trials. In one study, both 5 mg and 10 mg of Hydromorphone Hydrochloride Oral Solution provided significantly more analgesia than placebo. In another trial, 5 mg and 10 mg of Hydromorphone Hydrochloride Oral Solution were compared to 30 mg and 60 mg of morphine sulfate oral liquid. The pain relief provided by 5 mg and 10 mg Hydromorphone Hydrochloride Oral Solution was comparable to 30 mg and 60 mg oral morphine sulfate, respectively.Close
- 16 HOW SUPPLIED/STORAGE AND HANDLING
Protect from light.
Hydromorphone Hydrochloride Tablets, USP 8 mg are white to off white, bisected, triangular tablets debossed with "EL14" on the bisected side. They are available in: Bottles of 100 - NDC# 51224-102-50
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
- 17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of Hydromorphone Hydrochloride Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share Hydromorphone Hydrochloride Tablets with others and to take steps to protect Hydromorphone Hydrochloride Tablets from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydromorphone Hydrochloride Tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store Hydromorphone Hydrochloride Tablets securely and to dispose of unused Hydromorphone Hydrochloride Tablets. When Hydromorphone Hydrochloride Tablets are no longer needed, the unused medication should be destroyed by flushing it down the toilet.
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Hydromorphone Hydrochloride Tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.3), Drug Interactions (7)].
Inform patients that Hydromorphone Hydrochloride 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. [see Drug Interactions 7].
Inform patients to avoid taking Hydromorphone Hydrochloride Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydromorphone Hydrochloride Tablets [see Dug Interactions (7)].
Inform patients that opioids 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 [see Warnings and Precautions (5.6)].
Important Administration Instructions
Instruct patients how to properly take Hydromorphone Hydrochloride.
- Advise patients not to adjust the dose of Hydromorphone Hydrochloride Tablets, USP without consulting with a physician or other healthcare professional.
- If patients have been receiving treatment with Hydromorphone Hydrochloride Tablets, USP for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see Dosage and Administration (2.5, 2.6)].
Inform patients that Hydromorphone Hydrochloride Tablets, USP 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) [see Warnings and Precautions (5.7)].
Inform patients that anaphylaxis has been reported with ingredients contained in Hydromorphone Hydrochloride Tablets, USP. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Hydromorphone Hydrochloride Tablets, USP during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Population (8.3)].
Driving or Operating Heavy Machinery
Inform patients that Hydromorphone Hydrochloride Tablets, USP 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 [see Warnings and Precautions (5.12)].
Disposal of Unused Hydromorphone Hydrochloride Tablets, USP Advise patients to flush unused Hydromorphone Hydrochloride Tablets, USP down the toilet.
Healthcare professionals can telephone Elite Laboratories, Inc., at 1-888-852-6657 for information on this product.
- SPL UNCLASSIFIED SECTION
A Schedule CII Narcotic DEA Order Form is required.
Elite Laboratories, Inc.
Northvale, NJ 07647
South Beloit, IL 61080
- Medication Guide Hydromorphone Hydrochloride Tablets, USP CII
Hydromorphone Hydrochloride Tablets, USP are:
- Strong prescription pain medicines that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid analgesic, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
- Opioid pain medicines that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
Important information about Hydromorphone Hydrochloride:
- Get emergency help right away if you take too much Hydromorphone Hydrochloride Tablets, USP (overdose). When you first start taking Hydromorphone Hydrochloride Tablets, USP, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
- Taking Hydromorphone Hydrochloride Tablets, USP with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
- Never give anyone else your Hydromorphone Hydrochloride Tablets, USP. They could die from taking it. Store Hydromorphone Hydrochloride Tablets, USP away from children and in a safe place to prevent stealing or abuse. Selling or giving away Hydromorphone Hydrochloride Tablets, USP is against the law.
Do not take Hydromorphone Hydrochloride Tablets, USP if you have:
- severe asthma, trouble breathing, or other lung problems.
- a bowel blockage or have narrowing of the stomach or intestines.
Before taking Hydromorphone Hydrochloride Tablets, USP, tell your healthcare provider if you have a history of:
- head injury, seizures
- problems urinating
- abuse of street or prescription drugs, alcohol addiction, or mental health problems.
- liver, kidney, thyroid problems
- pancreas or gallbladder problems
Tell your healthcare provider if you are:
- pregnant or planning to become pregnant. Prolonged use of Hydromorphone Hydrochloride Tablets, USP during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
- breastfeeding. Hydromorphone Hydrochloride Tablets, USP pass into breast milk and may harm your baby.
- taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Hydromorphone Hydrochloride with certain other medicines can cause serious side effects that could lead to death.
When taking Hydromorphone Hydrochloride:
- Do not change your dose. Take Hydromorphone Hydrochloride exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
- Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
- Call your healthcare provider if the dose you are taking does not control your pain.
- If you have been taking Hydromorphone Hydrochloride Tablets, USP regularly, do not stop taking Hydromorphone Hydrochloride Tablets, USP without talking to your healthcare provider.
- After you stop taking Hydromorphone Hydrochloride Tablets, USP flush any unused tablets or liquid down the toilet.
While taking Hydromorphone Hydrochloride DO NOT:
- Drive or operate heavy machinery, until you know how Hydromorphone Hydrochloride Tablets, USP affects you. Hydromorphone Hydrochloride can make you sleepy, dizzy, or lightheaded.
- Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Hydromorphone Hydrochloride Tablets, USP may cause you to overdose and die.
The possible side effects of Hydromorphone Hydrochloride Tablets, USP:
- constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These are not all the possible side effects of Hydromorphone Hydrochloride Tablets, USP. Call your doctor for medical advice about side effects. You may report side effects to Elite Laboratories, Inc., at 1-888-852-6657 or to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
Distributed by: Tagi Pharma, South Beloit, IL 61080
This Medication Guide has been approved by the U.S. Food and Drug Administration.
- PRINCIPAL DISPLAY PANEL - 8 mg Tablet Bottle Label
White to off-white,
with "EL 14" on the
- INGREDIENTS AND APPEARANCE
hydromorphone hydrochloride tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51224-102 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Hydromorphone Hydrochloride (UNII: L960UP2KRW) (Hydromorphone - UNII:Q812464R06) Hydromorphone Hydrochloride 8 mg Inactive Ingredients Ingredient Name Strength anhydrous lactose (UNII: 3SY5LH9PMK) magnesium stearate (UNII: 70097M6I30) microcrystalline cellulose (UNII: OP1R32D61U) silicon dioxide (UNII: ETJ7Z6XBU4) Product Characteristics Color WHITE Score 2 pieces Shape TRIANGLE Size 7mm Flavor Imprint Code EL;14 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51224-102-50 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/09/2012 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076723 03/09/2012 Labeler - TAGI Pharma, Inc. (963322560)