Hydromorphone Hydrochloride 3 mg Suppository, 6 suppositories — NDC 0574-7224-06 (Billing 00574-7224-06)

5 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 suppositories 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 suppositories in patients with impaired consciousness or coma.

( 5.8 )

5.1Addiction, Abuse, and Misuse Hydromorphone hydrochloride suppositories contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride suppositories expose 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 hydromorphone hydrochloride suppositories.

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 hydromorphone hydrochloride suppositories, and monitor all patients receiving hydromorphone hydrochloride suppositories 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 hydromorphone hydrochloride suppositories, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride suppositories along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydromorphone hydrochloride suppositories. 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.

5.2Life-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, depending on the patient’s clinical status [see Overdosage ( 10 )] .

Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydromorphone hydrochloride suppositories, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of hydromorphone hydrochloride suppositories.

To reduce the risk o… [Excerpted — this section continues on DailyMed.]

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 )] 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 Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials 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

6.2Postmarketing 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 suppositories Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of op… [Excerpted — this section continues on DailyMed.]

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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 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 suppositories if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )] . 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 suppositories 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 suppositories 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 suppositories and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )]. 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… [Excerpted — this section continues on DailyMed.]

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance Hydromorphone hydrochloride suppositories contain hydromorphone, a Schedule II controlled substance.

9.2Abuse Hydromorphone hydrochloride suppositories 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 suppositories 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 suppositories are for rectal use only. Abuse of hydromorphone hydrochloride suppositories poses a risk of overdose and death. The risk is increased with concurrent abuse of hydromorphone hydrochloride suppositories with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3Dependence 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 is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting 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, nal… [Excerpted — this section continues on DailyMed.]

9.1Controlled Substance Hydromorphone hydrochloride suppositories contain hydromorphone, a Schedule II controlled substance.