Highlights of prescribing information, Lecture notes of Pharmacology

Download Highlights of prescribing information and more Lecture notes Pharmacology in PDF only on Docsity! 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DILAUDID® ORAL SOLUTION and DILAUDID® TABLETS safely and effectively. See full prescribing information for DILAUDID® ORAL SOLUTION and DILAUDID® TABLETS. DILAUDID® (hydromorphone hydrochloride) oral solution DILAUDID® (hydromorphone hydrochloride) tablets, for oral use, C-II Initial U.S. Approval: January 1984 -------------------------------RECENT MAJOR CHANGES--------------------------- Boxed Warning 12/2016 Indications and Usage (1) 12/2016 Dosage and Administration (2) 12/2016 Warnings and Precautions (5) 12/2016 -------------------------------INDICATIONS AND USAGE---------------------------- DILAUDID Oral Solution and DILAUDID Tablets 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 DILAUDID Oral Solution or DILAUDID Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or 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 dosage of DILAUDID Oral Solution is one-half (2.5 mL) to two teaspoonsful (10 mL) (2.5 mg - 10 mg) every 3 to 6 hours. (2.2) • Usual adult starting dose for DILAUDID Tablets is 2 mg to 4 mg, orally, every 4 to 6 hours. (2.2) • Hepatic Impairment: Initiate treatment with one-fourth to one-half the usual 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 DILAUDID Oral Solution or DILAUDID Tablets abruptly in a physically-dependent patient. (2.5) ------------------------DOSAGE FORMS AND STRENGTHS----------------------- • DILAUDID Oral Solution: 5 mg/5 mL (1 mg/mL) • DILAUDID Tablets: 2 mg, 4 mg, 8 mg (3) ----------------------------------CONTRAINDICATIONS------------------------------ • 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. (5.6) • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.7) • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of DILAUDID Oral Solution or DILAUDID Tablets in patients with circulatory shock. (5.8) • 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 DILAUDID Oral Solution or DILAUDID Tablets in patients with impaired consciousness or coma. (5.9) ----------------------------------ADVERSE REACTIONS------------------------------- 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 Purdue Pharma L.P. at 1- 888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------------DRUG INTERACTIONS------------------------------- • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue DILAUDID Oral Solution or DILAUDID Tablets. if serotonin syndrome is suspected. (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 DILAUDID because they may reduce analgesic effect of DILAUDID 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. Revised:12/2016 WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • Ensure accuracy when prescribing, dispensing, and administering DILAUDID Oral Solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death. (2.1, 5.1) • DILAUDID Oral Solution or DILAUDID Tablets 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. (5.2) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.3) • Accidental ingestion of DILAUDID Oral Solution or DILAUDID Tablets, especially by children, can result in a fatal overdose of hydromorphone. (5.3) • Prolonged use of DILAUDID Oral Solution or DILAUDID Tablets 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. (5.4) •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. (5.5, 7). Reference ID: 4028086 2 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENTING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Initial Dosage 2.3 Dosage Modifications in Patients with Hepatic Impairment 2.4 Dosage Modifications in Patients with Renal Impairment 2.4 Titration and Maintenance of Therapy 2.5 Discontinuation of DILAUDID Oral Solution and DILAUDID TABLETS 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Accidental Overdose and Death due to Medication Errors 5.2 Addiction, Abuse, and Misuse 5.3 Life-Threatening Respiratory Depression 5.4 Neonatal Opioid Withdrawal Syndrome 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients 5.7 Adrenal Insufficiency 5.8 Severe Hypotension 5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 5.10 Risks of Use in Patients with Gastrointestinal Conditions 5.11 Increased Risk of Seizures in Patients Seizure Disorders 5.12 Withdrawal 5.13 Risks of Driving and Operating Machinery 5.14 Sulfites 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINCAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. ____________________________________________________________________________________________________________ Reference ID: 4028086 5 Conversion from Other Opioids to DILAUDID Oral Solution or DILAUDID Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of DILAUDID Oral Solution or DILAUDID Tablets. It is safer to underestimate a patient’s 24-hour DILAUDID dosage than to overestimate the 24-hour dosage and manage an adverse reaction due to overdose. In general, it is safest to start DILAUDID therapy by administering half of the usual starting dose every 3-6 hours for DILAUDID Oral Solution; and every 4-6 hours for DILAUDID Tablets. The dose of DILAUDID can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved [See Dosage and Administration (2.4)]. Conversion from DILAUDID Oral Solution or DILAUDID Tablets to Extended-Release Hydromorphone Hydrochloride The relative bioavailability of DILAUDID Oral Solution and DILAUDID Tablets compared to extended-release hydromorphone hydrochloride is unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive sedation and respiratory depression. 2.3 Dosage Modifications in Patients with Hepatic Impairment Initiate treatment with one-fourth to one-half the usual DILAUDID starting dose depending on the degree of impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 2.4 Dosage Modifications in Patients with Renal Impairment Initiate treatment with one-fourth to one-half the usual DILAUDID starting dose depending on the degree of impairment [see Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 2.5 Titration and Maintenance of Therapy Individually titrate DILAUDID Oral Solution or DILAUDID Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DILAUDID Oral Solution or DILAUDID Tablets 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 [see Warnings and Precautions (5.2]. 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. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the DILAUDID Oral Solution or DILAUDID Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Reference ID: 4028086 6 For chronic pain, doses should be administered around-the-clock. A supplemental dose of 5-15% of the total daily usage may be administered every two hours on an as-needed basis. 2.6 Discontinuation of DILAUDID Oral Solution or DILAUDID Tablets When a patient who has been taking DILAUDID Oral Solution or DILAUDID Tablets regularly and may be physically dependent no longer requires therapy with DILAUDID, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs and 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 DILAUDID Oral Solution or DILAUDID Tablets in a physically dependent patient. [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)]. 3 DOSAGE FORMS AND STRENGTHS DILAUDID Oral Solution: 5 mg/5 mL (1 mg/mL) of hydromorphone hydrochloride in a clear, colorless to pale yellow, slightly viscous liquid. DILAUDID Tablets: • 2 mg tablets (light orange, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “2” on the opposite side) • 4 mg tablets (light yellow, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “4” on the opposite side) • 8 mg tablets (white, triangular shaped tablets, debossed with a “P” and an inverted “P” separated with a bisect on one side of the tablet and debossed with the number “8” on the other side of the tablet) 4 CONTRAINDICATIONS DILAUDID Oral Solution and DILAUDID Tablets are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.6)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)] • Hypersensitivity to hydromorphone, hydromorphone salts, any other components of the product, or sulfite-containing medications (e.g., anaphylaxis) [see Warnings and Precautions (5.15;) Adverse Reactions (6.1)] Reference ID: 4028086 7 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Ensure that the dose is communicated clearly and dispensed accurately. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, the enclosed measuring device should be used or a calibrated measuring device obtained from the pharmacist. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage. 5.2 Addiction, Abuse, and Misuse DILAUDID Oral Solution and DILAUDID Tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, DILAUDID exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DILAUDID Oral Solution or DILAUDID Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DILAUDID Oral Solution or DILAUDID Tablets, and monitor all patients receiving DILAUDID Oral Solution or DILAUDID Tablets 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DILAUDID Oral Solution or DILAUDID Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of DILAUDID Oral Solution and DILAUDID Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing DILAUDID Oral Solution or DILAUDID Tablets. 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 [see Patient Counseling Information (17)]. 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. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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, Reference ID: 4028086 10 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. 5.8 Severe Hypotension DILAUDID Oral Solution or DILAUDID Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of DILAUDID Oral Solution or DILAUDID Tablets. In patients with circulatory shock, DILAUDID may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DILAUDID Oral Solution or DILAUDID Tablets in patients with circulatory shock. 5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DILAUDID Oral Solution or DILAUDID Tablets 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 DILAUDID Oral Solution or DILAUDID Tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DILAUDID in patients with impaired consciousness or coma. 5.10 Risks of Use in Patients with Gastrointestinal Conditions DILAUDID Oral Solution or DILAUDID Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydromorphone in DILAUDID Oral Solution or DILAUDID Tablets 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. 5.11 Increased Risk of Seizures in Patients with Seizure Disorders The hydromorphone in DILAUDID Oral Solution or DILAUDID Tablets 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 DILAUDID Oral Solution or DILAUDID Tablets therapy. Reference ID: 4028086 11 5.12 Withdrawal Avoid 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 DILAUDID Oral Solution or DILAUDID Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)]. When discontinuing DILAUDID Oral Solution or DILAUDID Tablets in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue DILAUDID Oral Solution or DILAUDID Tablets in these patients. [see Drug Abuse and Dependence (9.3)]. 5.13 Risks of Driving and Operating Machinery DILAUDID Oral Solution or DILAUDID Tablets may impair the mental 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 DILAUDID Oral Solution or DILAUDID Tablets and know how they will react to the medication. 5.14 Sulfites DILAUDID Oral Solution and DILAUDID Tablets contain 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. Use of DILAUDID Oral Solution and DILAUDID Tablets is contraindicated in patients with hypersensitivity to sulfite-containing medications. 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 (5.2)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.5) • Adrenal Insufficiency [see Warnings and Precautions (5.7)] • Severe Hypotension [see Warnings and Precautions (5.8)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Withdrawal [see Warnings and Precautions (5.12] Reference ID: 4028086 12 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 DILAUDID 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 Reference ID: 4028086 15 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. Clinical Considerations 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 (5.4)]. 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. DILAUDID Oral Solution or DILAUDID Tablets is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DILAUDID Oral Solution or DILAUDID Tablets, 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. Data Animal Data 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. Reference ID: 4028086 16 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). 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 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. 8.2 Lactation Risk Summary 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 DILAUDID Oral Solution or DILAUDID Tablets and any potential adverse effects on the breastfed infant from DILAUDID Oral Solution or DILAUDID Tablets or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to DILAUDID through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphone is stopped, or when breast-feeding is stopped. Reference ID: 4028086 17 8.3 Females and Males of Reproductive Potential Infertility Chronic 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 [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of DILAUDID 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 co-administered with other agents that depress respiration. Titrate the dosage of DILAUDID slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)]. 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)]. Reference ID: 4028086 20 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 DILAUDID Oral Solution or DILAUDID Tablets, 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 DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid agonist. DILAUDID Tablets are supplied in 2 mg, 4 mg, and 8 mg tablets for oral administration. The tablet strengths describe the amount of hydromorphone hydrochloride in each tablet. DILAUDID Oral Solution is supplied as 5mg/ 5 mL (1 mg/mL) viscous liquid. 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: Reference ID: 4028086 21 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. The 2 mg, 4 mg, and 8 mg tablets contain the following inactive ingredients: lactose anhydrous and magnesium stearate. DILAUDID Tablets may also contain traces of sodium metabisulfite. The 2 mg tablets also contain D&C red #30 Lake dye, and D&C yellow #10 Lake dye. The 4 mg tablets also contain D&C yellow #10 Lake dye. Each 5 mL (1 teaspoon) of DILAUDID Oral Solution contains 5 mg of hydromorphone hydrochloride. The inactive ingredients are purified water, methylparaben, propylparaben, sucrose, and glycerin. DILAUDID Oral Solution may contain traces of sodium metabisulfite. 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. 12.2 Pharmacodynamics 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 Reference ID: 4028086 22 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. Concentration–Efficacy Relationships 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)]. Reference ID: 4028086 25 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 DILAUDID Oral Solution administered to patients with post-surgical pain have been studied in double-blind controlled trials. In one study, both 5 mg and 10 mg of DILAUDID Oral Solution provided significantly more analgesia than placebo. In another trial, 5 mg and 10 mg of DILAUDID 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 DILAUDID Oral Solution was comparable to 30 mg and 60 mg oral morphine sulfate, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING Protect from light. DILAUDID Oral Solution is a clear, colorless to pale yellow, slightly viscous liquid. It is available in: Bottles of 1 pint (473 mL) – NDC# 59011-451-01. DILAUDID 2 mg Tablets are light orange, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “2” on the opposite side. They are available in: Bottles of 100 - NDC # 59011-452-10 Unit Dose Packages of 100 (4x25) - NDC # 59011-452-01 DILAUDID 4 mg Tablets are light yellow, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “4” on the opposite side. They are available in: Bottles of 100 - NDC # 59011-454-10 Unit Dose Packages of 100 (4x25) - NDC # 59011-454-01 Bottles of 500 - NDC # 59011-454-05 DILAUDID 8 mg Tablets are white, triangular shaped tablets debossed with a “P” and an inverted “P” separated with a bisect on one side of the tablet and debossed with the number “8” on the other side of the tablet. They are available in: Bottles of 100 - NDC# 59011-458-10 Reference ID: 4028086 26 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Reference ID: 4028086 27 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Medication Errors Instruct patients how to measure and take the correct dose of DILAUDID, and to always use the enclosed cup when administering DILAUDID Oral Solution to ensure the dose is measured and administered accurately [see Warnings and Precautions (5.1)]. If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse Inform patients that the use of DILAUDID Oral Solution or DILAUDUD Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)]. Instruct patients not to share DILAUDID Oral Solution or DILAUDUD Tablets with others and to take steps to protect DILAUDID Oral Solution or DILAUDUD 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 DILAUDID Oral Solution or DILAUDUD Tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)]. Instruct patients to take steps to store DILAUDID Oral Solution or DILAUDUD Tablets securely and to dispose of unused DILAUDID Oral Solution or DILAUDUD Tablets. When DILAUDID Oral Solution or DILAUDUD 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 DILAUDID Oral Solution or DILAUDUD 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 (5.4), Drug Interactions (7)]. Serotonin Syndrome Inform patients that DILAUDID 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]. Reference ID: 4028086 30 Medication Guide DILAUDID® (dī-law-did) ([hydromorphone hydrochloride) Tablets and Oral Solution , CII DILAUDID Tablets and DILAUDID Oral Solution 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 DILAUDID: • Get emergency help right away if you take too much DILAUDID Tablets or DILAUDID Oral Solution (overdose). When you first start taking DILAUDID Tablets or DILAUDID Oral Solution, 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 DILAUDID Tablets or DILAUDID Oral Solution 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 DILAUDID Tablets or DILAUDID Oral Solution. They could die from taking it. Store DILAUDID Tablets or DILAUDID Oral Solution away from children and in a safe place to prevent stealing or abuse. Selling or giving away DILAUDID Tablets or DILAUDID Oral Solution is against the law. Do not take DILAUDID Tablets or DILAUDID Oral Solution if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. Before taking DILAUDID Tablets or DILAUDID Oral Solution, tell your healthcare provider if you have a history of: • head injury, seizures ● liver, kidney, thyroid problems • problems urinating ● pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, or mental health problems. Tell your healthcare provider if you are: • pregnant or planning to become pregnant. Prolonged use of DILAUDID Tablets and DILAUDID Oral Solution during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. • breastfeeding. DILAUDID Tablets or DILAUDID Oral Solution pass into breast milk and may harm your baby. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking DILAUDID with certain other medicines can cause serious side effects that could lead to death. When taking DILAUDID: • Do not change your dose. Take DILAUDID 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 DILAUDID Tablets or DILAUDID Oral Solution regularly, do not stop taking DILAUDID Tablets or DILAUDID Oral Solution without talking to your healthcare provider. • After you stop taking DILAUDID Tablets or DILAUDID Oral Solution flush any unused tablets or liquid down the toilet. While taking DILAUDID DO NOT: • Drive or operate heavy machinery, until you know how DILAUDID Tablets or DILAUDID Oral Solution affects you. DILAUDID 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 DILAUDID Tablets or DILAUDID Oral Solution may cause you to overdose and die. The possible side effects of DILAUDID Tablets and DILAUDID Oral Solution: • 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: Reference ID: 4028086 31 • 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 DILAUDID Tablets and DILAUDID Oral Solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431, www.purduepharma.com or call 1-888-726-7535 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 12/2016 Reference ID: 4028086