Hydrocodone Bitartrate and Acetaminophen Tablets, USP CII

BOXED WARNING SECTION

id: 638c2fd5-5dc5-ac05-e053-2a91aa0aa8d8
displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; HEPATIC ENZYME WARNING, DRUG INTERACTION, HEPATOTOXICITY AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse

Hydrocodone bitartrate and acetaminophen tablets expose 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 hydrocodone bitartrate and acetaminophen tablets and monitor all patients regularly for the development of these behaviors or conditions [see WARNINGS].
Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone bitartrate and acetaminophen tablets. Monitor for respiratory depression, especially during initiation of hydrocodone bitartrate and acetaminophen tablets or following a dose increase [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 bitartrate and acetaminophen tablets [see WARNINGS].
Neonatal Opioid Withdrawal Syndrome

Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [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 bitartrate and acetaminophen tablets 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 bitartrate and acetaminophen tablets plasma concentrations. Monitor patients receiving hydrocodone bitartrate and acetaminophen tablets and any CYP3A4 inhibitor or inducer [see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions]. Drug Interactions

CYP3A4

Inhibitor

The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone bitartrate and acetaminophen tablets resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved [see WARNINGS]. Inducer

The concomitant use of hydrocodone bitartrate and acetaminophen tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone bitartrate and acetaminophen tablets [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone bitartrate and acetaminophen tablets [see WARNINGS]. Drug/Drug Interactions with Hydrocodone

Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression [see WARNINGS].

Drug/Drug Interactions with Acetaminophen

Alcohol, ethyl: Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen [see WARNINGS]. 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 4000 milligrams per day, and often involve more than one acetaminophen-containing product. WARNING: 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 [see WARNINGS, PRECAUTIONS; Drug Interactions].

• 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.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

DESCRIPTION

id: 638c2fd5-5dc6-ac05-e053-2a91aa0aa8d8
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Hydrocodone Bitartrate and Acetaminophen Tablets, USP are supplied in tablet form for oral administration.

WARNING: May be habit-forming [see PRECAUTIONS, Information for Patients, and DRUG ABUSE AND DEPENDENCE].

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is: 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula: Acetaminophen, USP, 4′-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula: Each Hydrocodone Bitartrate and Acetaminophen Tablet, USP contains: Hydrocodone Bitartrate, USP ……………………… 5 mg Acetaminophen, USP ……………………………… 325 mg In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch and stearic acid. Meets USP Dissolution Test 1.

CLINICAL PHARMACOLOGY

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displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opiates is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding. The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Pharmacokinetics The behavior of the individual components is described below. Hydrocodone: Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites. See
OVERDOSAGE for toxicity information. Acetaminophen: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. See
OVERDOSAGE for toxicity information.

INDICATIONS AND USAGE

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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

Hydrocodone bitartrate and acetaminophen tablets, USP are indicated for the relief of moderate to moderately severe pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses [see WARNINGS], reserve hydrocodone bitartrate and acetaminophen tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics].

• Have not been tolerated, or are not expected to be tolerated,

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia

CONTRAINDICATIONS

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displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Hydrocodone bitartrate and acetaminophen tablets is contraindicated in patients with:

• Significant respiratory depression [see WARNINGS].

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS].

• Hydrocodone bitartrate and acetaminophen tablets should not be administered to patients with known hypersensitivity to hydrocodone, acetaminophen, or any other component of this product.

• Hydrocodone is contraindicated in any situation where opioids are contraindicated including patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Hydrocodone is contraindicated in the setting of suspected or known paralytic ileus.

WARNINGS

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displayName: WARNINGS SECTION
FDA Article Code: 34071-1

Addiction, Abuse, and Misuse

Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone bitartrate, a Schedule II controlled substance. As an opioid, hydrocodone and acetaminophen tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate and acetaminophen 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 hydrocodone bitartrate and acetaminophen tablets, and monitor all patients receiving hydrocodone bitartrate and acetaminophen tablets for the development of these behaviors or 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 hydrocodone bitartrate and acetaminophen tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen 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 hydrocodone bitartrate and acetaminophen 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 PRECAUTIONS; Information for Patients]. 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. 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, depending on the patient’s clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) 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 hydrocodone bitartrate and acetaminophen tablets, 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 hydrocodone bitartrate and acetaminophen tablets.

To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the hydrocodone bitartrate and acetaminophen tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate.

In case of respiratory depression, a reversal agent such as naloxone hydrochloride may be utilized [see OVERDOSAGE]. Neonatal Opioid Withdrawal Syndrome Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy]. Drug/Drug Interactions with Hydrocodone

Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression.

Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. The concurrent use of anticholinergics with opioids may produce paralytic ileus.

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as hydrocodone. These agonist/antagonist analgesics may reduce the analgesic effect of hydrocodone or may precipitate withdrawal symptoms. Drug/Drug Interactions with Acetaminophen

Alcohol, ethyl: Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen.

Anticholinergics: The onset of acetaminophen effect may be delayed or decreased slightly, but the ultimate pharmacological effect is not significantly affected by anticholinergics.

Oral Contraceptives: Increase in glucuronidation resulting in increased plasma clearance and a decreased half-life of acetaminophen.

Charcoal (activated): Reduces acetaminophen absorption when administered as soon as possible after overdose.

Beta Blockers (Propanolol): Propranolol appears to inhibit the enzyme systems responsible for the glucuronidation and oxidation of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be increased.

Loop diuretics: The effects of the loop diuretic may be decreased because acetaminophen may decrease renal prostaglandin excretion and decrease plasma renin activity.

Lamotrigine: Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects.

Probenecid: Probenecid may increase the therapeutic effectiveness of acetaminophen slightly.

Zidovudine: The pharmacologic effects of zidovudine may be decreased because of enhanced nonhepatic or renal clearance of zidovudine. Drug/Laboratory Test Interactions

Depending on the sensitivity/specificity and the test methodology, the individual components of hydrocodone bitartrate and acetaminophen tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

Acetaminophen may interfere with home blood glucose measurement systems; decreases of > 20% in mean glucose values may be noted. This effect appears to be drug, concentration and system dependent. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and acetaminophen tablets and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS], particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and acetaminophen tablets treated patients may increase hydrocodone bitartrate and acetaminophen tablets plasma concentrations and prolong opioid adverse reactions. When using hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets treated patients, monitor patients closely at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved (Note to applicant: If there is a specific dosage adjustment, include the dosage adjustment in the D&A section and include the cross-reference in this section) [see PRECAUTIONS; Drug Interactions, DOSAGE AND ADMINISTRATION].

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone bitartrate and acetaminophen tablets plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone and acetaminophen tablets. When using hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal [see PRECAUTIONS; Drug Interactions, DOSAGE AND ADMINISTRATION].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and acetaminophen tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS; Drug Interactions and PRECAUTIONS; Information for Patients]. 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 tablets 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]. Elderly, Cachetic, 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].

Monitor such patients closely, particularly when initiating and titrating hydrocodone bitartrate and acetaminophen tablets is given concomitantly with other drugs that depress respiration [see WARNINGS]. 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 1 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. Pregnancy

Teratogenic Effects

Pregnancy Category C:

Animal reproductive studies have not been conducted with hydrocodone and acetaminophen. It is also not known whether hydrocodone and acetaminophen can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Hydrocodone bitartrate and acetaminophen tablets should not be given to a pregnant woman unless in the judgment of the physician, the potential benefits outweigh the possible hazards.

Nonteratogenic Effects: Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Labor and Delivery

Hydrocodone and acetaminophen tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Nursing Mothers

Ordinarily, nursing should not be undertaken while a patient is receiving hydrocodone bitartrate and acetaminophen tablets because of the possibility of sedation and/or respiratory depression in the infant. Hydrocodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking a hydrocodone/acetaminophen product. Acetaminophen is also excreted in breast milk in low concentrations. Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Geriatric Use

Special precaution should be given when determining the dosing amount and frequency of hydrocodone bitartrate and acetaminophen tablets for geriatric patients, since clearance of hydrocodone may be slightly reduced in this patient population when compared to younger patients. Hepatic Impairment

In a pharmacokinetic study of hydrocodone in patients with end-stage liver disease, hydrocodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when hydrocodone is used in patients with hepatic impairment. Renal Impairment

In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Hydrocodone should be used with caution in patients with renal impairment. 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 4000 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 4000 milligrams of acetaminophen per day, even if they feel well. Serious skin reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Hypersensitivity/ anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs include swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritis, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hydrocodone Bitartrate and Acetaminophen Tablets, USP immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Tablets, USP for patients with acetaminophen allergy.

ADVERSE REACTIONS

id: 638c2fd5-5dda-ac05-e053-2a91aa0aa8d8
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include: Central Nervous System: Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychic dependence, mood changes. Gastrointestinal System: Prolonged administration of hydrocodone bitartrate and acetaminophen tablets may produce constipation. Genitourinary System: Ureteral spasm, spasm of vesical sphincters and urinary retention have been reported with opiates. Respiratory Depression: Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on the brain stem respiratory centers (see
OVERDOSAGE ). Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose. Dermatological: Skin rash, pruritus. The following adverse drug events may be borne in mind as potential effects of acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis. Potential effects of high dosage are listed in the
OVERDOSAGE section.

Postmarketing Experience

• serotonin syndrome

• adrenal insufficiency

Androgen deficiency

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as symptoms of hypogonadism, such as impotence, erectile dysfunction, or amenorrhea. The causal role of opioids in the 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993;
 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

OVERDOSAGE

id: 638c2fd5-5ddd-ac05-e053-2a91aa0aa8d8
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.

DOSAGE AND ADMINISTRATION

id: 638c2fd5-5ddf-ac05-e053-2a91aa0aa8d8
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related. The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dose should not exceed 8 tablets.

Important Dosage and Administration Instructions

Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS].

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate and acetaminophen tablets and adjust the dosage accordingly [see WARNINGS].

Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician.

Patients should be advised that hydrocodone bitartrate and acetaminophen tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).

HOW SUPPLIED

id: 638c2fd5-5de1-ac05-e053-2a91aa0aa8d8
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Hydrocodone bitartrate and acetaminophen tablets, USP
5 mg/325 mg are supplied as white to off-white, scored, oblong biconvex tablets, debossed “IP 109” on obverse and bisected on the reverse. Each tablet contains 5 mg hydrocodone bitartrate and 325 mg acetaminophen. They are available as follows: Bottles of 100:             NDC 42291-332-01 Storage:  Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. A Schedule CII Narcotic.

Manufactured for:

AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 09-2016-04 AV Rev. 10/16

SPL MEDGUIDE SECTION

id: 638c2fd5-5de2-ac05-e053-2a91aa0aa8d8
displayName: SPL MEDGUIDE SECTION
FDA Article Code: 42231-1

Medication Guide

Hydrocodone Bitartrate and Acetaminophen

(hye-droe-KOE-dohne bye-TAR-trate/a-SEET-a-MIN-oh-fen) Tablets, USP C II

Hydrocodone bitartrate and acetaminophen tablets are:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage moderate to moderately severe pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.

• An opioid pain medicine 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 hydrocodone bitartrate and acetaminophen tablets:

• Get emergency help right away if you take too much hydrocodone bitartrate and acetaminophen tablets (overdose). When you first start taking hydrocodone bitartrate and acetaminophen tablets, 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 hydrocodone bitartrate and acetaminophen tablets 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 hydrocodone bitartrate and acetaminophen tablets. They could die from taking it. Store hydrocodone bitartrate and acetaminophen tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away hydrocodone bitartrate and acetaminophen tablets is against the law.

  Do not take hydrocodone bitartrate and acetaminophen tablets if you have:

• severe asthma, trouble breathing, or other lung problems.

• a bowel blockage or have narrowing of the stomach or intestines. Before taking hydrocodone bitartrate and acetaminophen tablets, tell your healthcare provider if you have a history of:

• head injury, seizures

• problems urinating

• liver, kidney, thyroid problems

• 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 hydrocodone bitartrate and acetaminophen tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

•
breastfeeding. Hydrocodone and acetaminophen passes into breast milk and may harm your baby.

• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking hydrocodone bitartrate and acetaminophen tablets with certain other medicines can cause serious side effects that could lead to death. When taking hydrocodone bitartrate and acetaminophen tablets:

• Do not change your dose. Take hydrocodone bitartrate and acetaminophen tablets exactly as prescribed by your healthcare provider.

• Take your prescribed dose every 6 hours at the same time every day. 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 hydrocodone bitartrate and acetaminophen tablets regularly, do not stop taking hydrocodone bitartrate and acetaminophen tablets without talking to your healthcare provider.

• After you stop taking hydrocodone bitartrate and acetaminophen tablets dispose of unused drug. The possible side effects of hydrocodone bitartrate and acetaminophen tablets:

• 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 hydrocodone bitartrate and acetaminophen tablets. 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

This Medication Guide has been approved by U.S. Food and Drug Administration.

Manufactured for:

AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 09-2016-01     AV Rev. 10/16

Manufactured for:

id: 638c2fd5-5de3-ac05-e053-2a91aa0aa8d8
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5

AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 09-2016-04          AV 10/16

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

id: 638c2fd5-5de4-ac05-e053-2a91aa0aa8d8
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

AvKARE

NDC 42291-
332-01

CII

Hydrocodone Bitartrate and Acetaminophen Tablets, USP

5 mg / 325 mg

Dispense the accompanying Medication Guide to each patient.

MULTIPLE STRENGTHS: DO NOT DISPENSE UNLESS STRENGTH IS STATED.

100 Tablets        
Rx only

Each tablet contains:

Hydrocodone Bitartrate, USP………5 mg

WARNING: May be habit forming.

Acetaminophen, USP………325 mg

USUAL DOSAGE: See package insert for complete dosage recommendations.

WARNING: Keep this and all drugs out of the reach of children.

PHARMACIST: Dispense in a tight, light-resistant container with a child-resistant closure.

Protect from light.

STORAGE: Store at 20
^o to 25
^oC (68
^o to 77
^oF); excursions permitted to 15
^o to 30
^oC (59
^o to 86
^oF) [see USP Controlled Room Temperature].

DEA ORDER FORM REQUIRED.

Manufactured for:
AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 04-2016-02        AV 10/16

N3   42291 33201   0