HYDROCODONE BITARTRATE AND ACETAMINOPHEN tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
HYDROCODONE BITARTRATE (UNII: NO70W886KK) (HYDROCODONE - UNII:6YKS4Y3WQ7), ACETAMINOPHEN (UNII: 362O9ITL9D) (ACETAMINOPHEN - UNII:362O9ITL9D)
Available from:
Quality Care Products, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Hydrocodone bitartrate and acetaminophen tablets, USP are indicated for the management of 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, USP 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 Hydrocodone bitartrate and acetaminophen tablets are 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 ] - Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] - Hypersensitivity to hydrocodone or ace
Product summary:
Hydrocodone Bitartrate and Acetaminophen Tablets, USP are supplied as 2.5 mg/325 mg containing 2.5 mg hydrocodone bitartrate and 325 mg acetaminophen. Off white/white capsule shaped tablet debossed 'T 256' on one side and plain on other side. 5 mg/325 mg containing 5 mg hydrocodone bitartrate and 325 mg acetaminophen. Off white with orange specks, capsule shaped tablet debossed 'T 257' on one side and plain on other side with bisect line. 7.5 mg/325 mg containing 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen. Off white/white capsule shaped tablet debossed 'T 258 ' on one side and plain on other side with bisect line. 10 mg/325 mg containing 10 mg hydrocodone bitartrate and 325 mg acetaminophen. Light yellow to yellow color shaped tablet debossed 'T 259' on one side and plain on other side with bisect line. 55700-781-30 55700-781-40 55700-781-60 55700-781-90 55700-781-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure. Manufactured by: Ascent Pharmaceuticals Inc Central Islip, NY 11722 Manufactured for: Camber Pharmaceuticals Inc Piscataway, NJ 08854 Revised: 11/2018 Barcode: 943-11-2018
Authorization status:
Abbreviated New Drug Application
Authorization number:
55700-781-01, 55700-781-10, 55700-781-30, 55700-781-40, 55700-781-60, 55700-781-90

acetaminophen tablet

Quality Care Products, LLC

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MEDICATION GUIDE

Hydrocodone Bitartrate (hye" droe koe' done bye tar’ trate) and Acetaminophen (a seet"a min' oh fen)

Tablets USP, CII

Hydrocodone Bitartrate and Acetaminophen Tablets are:

A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain

severe enough to require an opioid pain medicine, 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.

known hypersensitivity to hydrocodone or acetaminophen, or any ingredient in Hydrocodone

Bitartrate and Acetaminophen Tablets

Before taking Hydrocodone Bitartrate and Acetaminophen Tablets, tell your healthcare provider if you have

a history of:

head injury, seizures

liver, kidney, thyroid problems

problems urinating

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 bitartrate 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. Use the lowest dose possible for the shortest time needed.

Take your prescribed dose every four to six hours as needed for pain.

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, the unused tablets should

be disposed of by flushing down the toilet.

While taking Hydrocodone Bitartrate and Acetaminophen Tablets DO NOT:

Drive or operate heavy machinery, until you know how Hydrocodone Bitartrate and Acetaminophen

Tablets affect you. Hydrocodone Bitartrate and Acetaminophen Tablets can make you sleepy, dizzy,

or lightheaded.

Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products

containing alcohol during treatment with Hydrocodone Bitartrate and Acetaminophen Tablets may

cause you to overdose and die.

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 Camber Pharmaceuticals Inc., at

1-866-495-8330 or to FDA at

1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Manufactured by:

Ascent Pharmaceuticals Inc.

Central Islip, NY 11722

Manufactured for:

Camber Pharmaceuticals, Inc.

Piscataway, NJ 08854

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

Revised: 11/2018

Revised: 4/2020

Document Id: 52b375b2-a37c-4570-a721-2ea207563315

34391-3

Set id: d68de0b1-9437-447c-b2bb-a028b1109781

Version: 4

Effective Time: 20200428

Quality Care Products, LLC

HYDROCODONE BITARTRATE AND ACETAMINOPHEN- hydrocodone bitartrate and

acetaminophen tablet

Quality Care Products, LLC

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WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING

RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID

WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION;

HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

ADDICTION, ABUSE, AND MISUSE: RISK EVALUATION AND MITIGATION

STRATEGY (REMS)

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 and conditions

[see WARNINGS].

OpioidAnalgesic Risk Evaluation and Mitigation Strategy (REMS):

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and

misuse, the Food and Drug Administration (FDA) has required a REMS for these products

[see Warnings]. Under the requirements of the REMS, drug companies with approved

opioid analgesic products must make REMS-compliant education programs available to

healthcare providers. Healthcare providers are strongly encouraged to

complete a REMS-compliant education program,

counselpatientsand/ortheircaregivers, with every prescription, on safe use, serious

risks, storage, and disposal of these products,

emphasize to patients and their caregivers the importance of reading the Medication

Guide every time it is provided by their pharmacist, and

consider other tools to improve patient, household, and community safety.

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 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 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].

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

Hydrocodone bitartrate and acetaminophen, USP is available in tablet form for oral administration.

Hydrocodone bitartrate is an opioid analgesic 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, 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 Bitartate and Acetaminophen Tablet, USP contains:

Strength

Hydrocodone Bitartrate Acetaminophen

2.5 mg/325 mg 2.5 mg

325 mg

5 mg/325 mg

5 mg

325 mg

7.5 mg/325 mg 7.5 mg

325 mg

10 mg/325 mg 10 mg

325 mg

In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, corn

starch, colloidal silicon dioxide, crospovidone, pregelatinized starch, povidone, FD&C Yellow No 6

(for strength 5mg/325 mg), D&C Yellow No 10 (for strength 10 mg/325 mg) and stearic acid.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP complies to USP Dissolution Test 1.

CLINICAL PHARMACOLOGY

Mechanism of Action

Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid (μ) receptor, although

it can interact with other opioid receptors at higher doses. The principal therapeutic action of

hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with

hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse

reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors

for endogenous compounds with opioid-like activity have been identified throughout the brain and

spinal cord and are thought to play a role in the analgesic effects of this drug. The precise mechanism

of the analgesic properties of acetaminophen is not established but is thought to involve central actions.

Pharmacodynamics

Effects on the Central Nervous System

The principal therapeutic action of hydrocodone is analgesia. Hydrocodone produces respiratory

depression by direct action on brain stem respiratory centers. The respiratory depression involves a

reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide

tension and electrical stimulation.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but

are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar

findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory

systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the

antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive

contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be

increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a

reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in

serum amylase.

Effects on the Cardiovascular System

Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red

eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing

hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth

hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen

deficiency that may manifest as symptoms as low libido, impotence, erectile dysfunction, amenorrhea, or

infertility. 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 [see ADVERSE REACTIONS].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system. The clinical

significance of these findings is unknown. Overall, the effects of opioids appear to be modestly

immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among

patients who have been previously treated with potent agonist opioids. The minimum effective analgesic

concentration of hydrocodone for any individual patient may increase over time due to an increase in

pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see

DOSAGE AND ADMINISTRATION].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency

of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory

depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to

opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].

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.

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 PRECAUTIONS; Drug Interactions]. N-demethylation of

hydrocodone to form norhydrocodone via 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. Hydrocodone and its metabolites are eliminated primarily in the kidneys.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most

body tissues. A small fraction (10-25%) of acetaminophen is bound to plasma proteins. 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. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves

three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation

via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive

intermediate metabolite, which conjugates with glutathione and is then further metabolized to form

cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears

to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. 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

Hydrocodone bitartrate and acetaminophen tablets, USP are indicated for the management of 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, USP 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

Hydrocodone bitartrate and acetaminophen tablets are 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]

Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS]

Hypersensitivity to hydrocodone or acetaminophen (e.g., anaphylaxis) [see WARNINGS,

ADVERSE REACTIONS]

WARNINGS

Addiction, Abuse, and Misuse

Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled

substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose 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 patient’s 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 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 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.

OpioidAnalgesicRisk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the

Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS)

for these products. Under the requirements of the REMS, drug companies with approved opioid

analgesic products must make REMS-compliant education programs available to healthcare providers.

Healthcare providers are strongly encouraged to do all of the following:

Complete a REMS-compliant education program offered by an accredited provider of continuing

education (CE) or another education program that includes all the elements of the FDA Education

Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with

patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling

Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

Emphasize to patients and their caregivers the importance of reading the Medication Guide that they

will receive from their pharmacist every time an opioid analgesic is dispensed to them.

Consider using other tools to improve patient, household, and community safety, such as patient-

prescriber agreements that reinforce patient- prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS

CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be

found at www.fda.gov/OpioidAnalgesicREMSBluepri nt.

FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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 24-72 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.

Accidental ingestion of hydrocodone bitartrate and acetaminophen tablets, especially by children, can

result in respiratory depression and death due to an overdose of hydrocodone bitartrate and

acetaminophen tablets.

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. Observe newborns for signs of neonatal opioid

withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged

period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be

available [see PRECAUTIONS; Information for Patients, Pregnancy].

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, and 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 plasma concentrations and prolong opoid adverse

reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone

bitartrate and acetaminophen tablets-treated patients, follow patients at frequent intervals and consider

dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are

achieved [see PRECAUTIONS; Drug Interactions].

Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or

discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease

opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical

dependence to hydrocodone. When using hydrocodone bitartrate and acetaminophen tablets with

CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and

consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of

opioid withdrawal occur [see PRECAUTIONS; Drug Interactions].

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,

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 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].

Follow such patients closely, particularly when initiating and titrating hydrocodone bitartrate and

acetaminophen tablets and when hydrocodone bitartrate and acetaminophen tablets is 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 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]. Follow 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.

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.

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.

Hypers ens itivity/Anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of

acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress,

urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis

requiring emergency medical attention. Instruct patients to discontinue hydrocodone bitartrate and

acetaminophen tablets immediately and seek medical care if they experience these symptoms. Do not

prescribe hydrocodone bitartrate and acetaminophen tablets for patients with acetaminophen allergy [see

PRECAUTIONS; Information for Patients/Caregivers.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or

Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence

of increased intracranial pressure or brain tumors), hydrocodone bitartrate and acetaminophen tablets

may reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure.

Follow such patients for signs of sedation and respiratory depression, particularly when initiating

therapy with hydrocodone bitartrate and acetaminophen tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of

hydrocodone bitartrate and acetaminophen tablets in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with gastrointestinal

obstruction, including paralytic ileus.

The administration of hydrocodone bitartrate and acetaminophen tablets or other opioids may obscure

the diagnosis or clinical course in patients with acute abdominal conditions.

Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum

amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening

symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in hydrocodone bitartrate and acetaminophen tablets may increase the frequency of

seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other

clinical settings associated with seizures. Follow patients with a history of seizure disorders for

worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial

agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic,

including hydrocodone bitartrate and acetaminophen tablets. In these patients, mixed agonist/antagonist

and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing hydrocodone bitartrate and acetaminophen tablets, gradually taper the dosage [see

DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue hydrocodone bitartrate and

acetaminophen tablets [see DRUG ABUSE AND DEPENDENCE] in patients who have been using

hydrocodone bitartrate and acetaminophen tablets around the clock for more than 5 days.

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