Hydrocodone Bitartrate and Acetaminophen

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROCODONE BITARTRATE AND ACETAMINOPHEN TABLETS Addiction, Abuse, and Misuse Because the use of Hydrocodone Bitartrate and Acetaminophen Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see WARNINGS ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Hydrocodone Bitartrate and Acetaminophen Tablets, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate and Acetaminophen Tablets are essential [see WARNINGS ] . Accidental Ingestion Accidental ingestion of even one dose of Hydrocodone Bitartrate and Acetaminophen Tablets, especially by children, can result in a fatal overdose of hydrocodone [see WARNINGS ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Hydrocodone Bitartrate and Acetaminophen Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see WARNINGS , PRECAUTIONS; Drug Interactions ]. Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see WARNINGS ]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see WARNINGS ]. Cytochrome P450 3A4 Interaction The concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets with all Cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used Cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentrations. Monitor patients receiving Hydrocodone Bitartrate and Acetaminophen Tablets and any Cytochrome P450 3A4 inhibitor or inducer for signs of respiratory depression or sedation [see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS; Drug Interactions ]. Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see WARNINGS , OVERDOSAGE ].

Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Hydrocodone Bitartrate and Acetaminophen Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone Bitartrate and Acetaminophen Tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydrocodone Bitartrate and Acetaminophen Tablets [see WARNINGS; Life-Threatening Respiratory Depression ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS; Life-Threatening Respiratory Depression ]. Regularly evaluate, particularly when initiating and titrating Hydrocodone Bitartrate and Acetaminophen Tablets and when Hydrocodone Bitartrate and Acetaminophen Tablets are given concomitantly with other drugs that depress respiration [see WARNINGS; Life-Threatening Respiratory Depression ] . Alternatively, consider the use of non-opioid analgesics in these patients.

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 particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension Hydrocodone Bitartrate and Acetaminophen 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 PRECAUTIONS; Drug Interactions ] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets. In patients with circulatory shock Hydrocodone Bitartrate and Acetaminophen Tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Acetaminophen Tablets with circulatory shock.

ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of Hydrocodone and Acetaminophen Tablets. 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. The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. Other adverse reactions include: Central Nervous System Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychological dependence, mood changes. Gastrointestinal System Constipation. Genitourinary System Ureteral spasm, spasm of vesical sphincters, and urinary retention. Special Senses Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose. Dermatological Skin rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions. Hematological Thrombocytopenia, agranulocytosis. 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 Hydrocodone Bitartrate and Acetaminophen Tablets. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see CLINICAL PHARMACOLOGY ]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see WARNINGS ]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). To report SUSPECTED ADVERSE REACTIONS, contact Cranbury Pharmaceuticals, LLC at (732) 940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch