HYDROCODONE BITARTRATE AND HOMATROPINE METHYLBROMIDE (Page 4 of 10)

5.14 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.15 Drug/Laboratory Test Interactions

Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of hydrocodone bitartrate and homatropine methylbromide oral solution.

6 ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, call Torrent Pharma, Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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), Drug Abuse and Dependence (9.3)]
• Life-threatening respiratory depression [see Warnings and Precautions (5.2, 5.3, 5.4, 5.8) and Overdosage (10)]
• Accidental overdose and death due to medication errors [see Warnings and Precautions (5.5)]
• Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6)]
• Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.5)]
• Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions (5.9)]
• Increased intracranial pressure [see Warnings and Precautions (5.10)]
• Obscured clinical course in patients with head injuries [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Severe hypotension [see Warnings and Precautions (5.12)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.13)]
• Adrenal insufficiency [see Warnings and Precautions (5.14)]

The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone and/or homatropine. Because these reactions may be 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.

The most common adverse reactions to hydrocodone bitartrate and homatropine methylbromide oral solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation.

Other reactions include:
Anaphylaxis: Anaphylaxis has been reported with hydrocodone, one of the ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution.

Body as a whole: Coma, death, fatigue, falling injuries, lethargy.

Cardiovascular: Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush.

Central Nervous System: Facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor.

Dermatologic: Flushing, hyperhidrosis, pruritus, rash.

Endocrine/Metabolic: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids.

Gastrointestinal: Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi).

Genitourinary: Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention.

Laboratory: Increases in serum amylase.

Musculoskeletal: Arthralgia, backache, muscle spasm.

Ophthalmic: Miosis (constricted pupils), visual disturbances.

Psychiatric: Agitation, anxiety, confusion, fear, dysphoria, depression.

Reproductive: Hypogonadism, infertility.

Respiratory: Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection.

Other: Drug abuse, drug dependence, opioid withdrawal syndrome.

7 DRUG INTERACTIONS

No specific drug interaction studies have been conducted with hydrocodone bitartrate and homatropine methylbromide oral solution.

7.1 Alcohol

Concomitant use of alcohol with hydrocodone bitartrate and homatropine methylbromide oral solution can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on hydrocodone bitartrate and homatropine methylbromide oral solution therapy [ see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ].

7.2 Inhibitors of CYP3A4 and CYP2D6

The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and homatropine methylbromide oral solution is achieved [ see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [ see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.3 CYP3A4 Inducers

The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [ see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [ see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [ see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Benzodiazepines, and Other CNS Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking benzodiazepines or other CNS depressants [ see Warnings and Precautions (5.8) ], and instruct patients to avoid consumption of alcohol while on hydrocodone bitartrate and homatropine methylbromide oral solution [ see Drug Interactions (7.1), Patient Counseling Information (17) ].

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