Hydromet (Page 8 of 10)

12.3 Pharmacokinetics

Absorption

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. Food has no significant effect on the extent of absorption of hydrocodone.

Distribution

Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.

Elimination

Metabolism

Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7.2)]. Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys. The mean plasma half-life of hydrocodone is approximately 4 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies have not been conducted with hydrocodone bitartrate and homatropine methylbromide oral solution; however, published information is available for the individual active ingredients or related active ingredients.

Hydrocodone

Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine. No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 40 and 45 times the MRHD of hydrocodone on a mg/m2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 110 times the MRHD of hydrocodone on a mg/m2 basis).

Mutagenicity studies with hydrocodone have not been conducted.

Fertility studies with hydrocodone have not been conducted.

Homatropine

Carcinogenicity, mutagenicity, and fertility studies with homatropine have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING

Hydrocodone bitartrate and homatropine methylbromide oral solution is a red colored, cherry flavored oral solution containing 5 mg hydrocodone bitartrate, USP and 1. 5 mg homatropine methylbromide, USP per 5 mL, and is available in one pint (473 mL) bottles (NDC 0472-1030-16).

Store at controlled room temperature 15° to 30°C (59° to 86°F).

Dispense in a tight, light-resistant container as defined in the USP.

Oral prescription where permitted by State Law.

Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of hydrocodone bitartrate and homatropine methylbromide oral solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share hydrocodone bitartrate and homatropine methylbromide oral solution with others and to take steps to protect hydrocodone bitartrate and homatropine methylbromide oral solution from theft or misuse.

Important Dosing and Administration Instructions

Instruct patients how to measure and take the correct dose of hydrocodone bitartrate and homatropine methylbromide oral solution. Advise patients to measure hydrocodone bitartrate and homatropine methylbromide oral solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage. Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. Advise patients not to increase the dose or dosing frequency of hydrocodone bitartrate and homatropine methylbromide oral solution because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and homatropine methylbromide oral solution and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. 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 (5.2)]. Instruct patients to take steps to store hydrocodone bitartrate and homatropine methylbromide oral solution securely and to properly dispose of unused hydrocodone bitartrate and homatropine methylbromide oral solution in accordance with the local state guidelines and/or regulations.

Activities Requiring Mental Alertness

Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as hydrocodone bitartrate and homatropine methylbromide oral solution may produce marked drowsiness [see Warnings and Precautions (5.6)].

Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol

Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and homatropine methylbromide oral solution is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution with benzodiazepines or other CNS depressants and instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with hydrocodone bitartrate and homatropine methylbromide oral solution [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.4)].

Constipation

Advise patients of the potential for severe constipation [see Warnings and Precautions (5.9), Adverse Reactions (6)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and homatropine methylbromide oral solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

MAOI Interaction

Inform patients not to take hydrocodone bitartrate and homatropine methylbromide oral solution while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and homatropine methylbromide oral solution [see Drug Interactions (7.6)].

Hypotension

Inform patients that hydrocodone bitartrate and homatropine methylbromide oral solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)].

Pregnancy

Advise patients that use of hydrocodone bitartrate and homatropine methylbromide oral solution is not recommended during pregnancy [see Use in Specific Populations (8.1)].

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of hydrocodone bitartrate and homatropine methylbromide oral solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.13), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that hydrocodone bitartrate and homatropine methylbromide oral solution can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with hydrocodone bitartrate and homatropine methylbromide oral solution [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids, such as hydrocodone, a component of hydrocodone bitartrate and homatropine methylbromide oral solution, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Adrenal Insufficiency

Inform patients that hydrocodone bitartrate and homatropine methylbromide oral solution could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.14)].

Serotonin Syndrome

Inform patients that hydrocodone bitartrate and homatropine methylbromide oral solution 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 physicians if they are taking, or plan to take serotonergic medications [see Adverse Reactions (6), Drug Interactions (7.5)].

Disposal of Unused Hydrocodone Bitartrate and Homatropine Methylbromide Oral Solution

Advise patients to properly dispose of unused hydrocodone bitartrate and homatropine methylbromide oral solution. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.

Distributed by:
Actavis Pharma, Inc.Parsippany, NJ 07054 USA

Rev. B 8/2020

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