ACETAMINOPHEN AND CODEINE PHOSPHATE- acetaminophen and codeine phosphate tablet

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

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Active ingredient:
ACETAMINOPHEN (UNII: 362O9ITL9D) (ACETAMINOPHEN - UNII:362O9ITL9D), CODEINE PHOSPHATE (UNII: GSL05Y1MN6) (CODEINE ANHYDROUS - UNII:UX6OWY2V7J)
Available from:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate pain,where treatment with an opioid is appropriate 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 acetaminophen and codeine phosphate tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics] •Have not provided adequate analgesia, or are not expected to provide adequate analgesia •Have not been tolerated, or are not expected to be tolerated Acetaminophen and codeine phosphate tablets are contraindicated for: - All children younger than 12 years of age (see WARNINGS ). - Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see WARNINGS ).  Acetaminophen and codeine phosphate tablets are contraindicated in patients with:  - Significant respiratory depression [see WARNINGS ].
Product summary:
300 mg/30 mg White to off-white, round, flat-faced, beveled-edged tablets, debossed with U36 on one side and plain on the other side. NDC 68071-5025-6 BOTTLES OF 6 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Store acetaminophen and codeine phosphate tablets securely and dispose of properly [see PRECAUTIONS/ Information for Patients ]. Keep this and all medication out of the reach of children. Protect from moisture. Dispense in a tight, light-resistant container as described in the USP. PROTECT FROM LIGHT Dispense with Medication Guide available at www.aurobindousa.com/product-medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Revised:04/2019
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-5025-6

ACETAMINOPHEN AND CODEINE PHOSPHATE- acetaminophen and codeine phosphate tablet

NuCare Pharmaceuticals,Inc.

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Medication Guide

Acetaminophen and Codeine Phosphate Tablets, USP CIII

ass-cet-ah-MEE-noe-fen with KOE-deen FOSS-fate

Acetaminophen and Codeine Phosphate Tablets are:

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

moderate 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 Acetaminophen and Codeine Phosphate tablets:

Get emergency help right away if you take too many acetaminophen and codeine phosphate tablets

(overdose). When you first start taking acetaminophen and codeine 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 acetaminophen and Codeine Tablets with other opioid medicines, benzodiazepines, alcohol, or

other central nervous system depressants (including strret drugs) can cause severe drowsiness,

decreased awareness, breathing problems, coma and death.

Never give anyone else your acetaminophen and codeine phosphate tablets. They could die from

taking it. Selling or giving away acetaminophen and codeine phosphate tablets are against the law.

Store acetaminophen and codeine phosphate tablets securely, out of sight and reach of children, and in

a location not accessible by others, including visitors to the home.

Important Information Guiding Use in Pediatric Patients:

Do not give acetaminophen and codeine phosphate tablets to a child younger than 12 years of age.

Do not give acetaminophen and codeine phosphate tablets to a child younger than 18 years of age

after surgery to remove the tonsils and/or adenoids.

Avoid giving acetaminophen and codeine phosphate tablets to children between 12 to 18 years of age

who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying

lung problems.

Do not take Acetaminophen and Codeine Phosphate Tablets if you have:

severe asthma, trouble breathing, or other lung problems.

a bowel blockage or narrowing of the stomach or intestines.

previously had an allergic reaction to codeine or acetaminophen.

Before taking acetaminophen and codeine phosphate 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.

Have been told by your healthcare provider that you are a "rapid metabolizer" of certain medicines.

Tell your healthcare provider if you are:

pregnant or planning to become pregnant. Prolonged use of acetaminophen and codeine phosphate

tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-

threatening if not recognized and treated.

breastfeeding. Not recommended; may harm your baby. taking prescription or over-the-counter

medicines, vitamins, or herbal supplements. Taking acetaminophen and codeine phosphate tablets

with certain other medicines can cause serious side effects that could lead to death.

Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking

acetaminophen and codeine phosphate tablets with certain other medicines can cause serious side

effects that could lead to death.

When taking Acetaminophen and Codeine Phosphate Tablets:

Do not change your dose. Take Acetaminophen and Codeine Phosphate Tablets exactly as prescribed

by your healthcare provider. Use the lowest dose possible for the shortest time needed.

Take your prescribed dose every 4 hours as needed. Do not take more than your prescribed dose. If

you miss a dose, take your next dose when needed.

Call your healthcare provider if the dose you are taking does not control your pain.

If you have been taking Acetaminophen and Codeine Phosphate Tablets regularly, do not stop taking

acetaminophen and codeine phosphate Tablets without talking to your healthcare provider.

After you stop taking acetaminophen and codeine phosphate Tablets to dispose of any unused tablets

in accordance with local state guidelines and/or regulations.

While taking Acetaminophen and Codeine Phosphate tablets DO NOT:

Dispose of expired, unwanted, or unused acetaminophen and codeine phosphate tablets by taking your

drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you

can dispose of acetaminophen and codeine phosphate tablets by mixing the product with dirt, cat

litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the bag in your

trash.

Drive or operate heavy machinery, until you know how acetaminophen and codeine phosphate tablets

affect you. Acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate tablets may cause

you to overdose and die.

The possible side effects of Acetaminophen and Codeine Phosphate 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 acetaminophen and codeine phosphate tablets. Call your doctor

for medical advice about side effects. You may also request medical information or to report suspected

adverse reactions, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088. For

more information go to dailymed.nlm.nih.gov.

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

Dispense with Medication Guide available at www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Revised:04/2019

Revised: 8/2019

Document Id: 9015d6da-a305-2586-e053-2995a90a6f0a

34391-3

Set id: 9015f096-b0c8-ccac-e053-2a95a90af86a

Version: 1

Effective Time: 20190814

NuCare Pharmaceuticals,Inc.

ACETAMINOPHEN AND CODEINE PHOSPHATE- acetaminophen and codeine

phosphate tablet

NuCare Pharmaceuticals,Inc.

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Acetaminophen and Codeine Phosphate Tablets, USP CIII

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE:RISK EVALUATION AND

MITIGATION STRATEGY (REMS), LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL

SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE

TO MORPHINE;HEPATOTOXICITY; CYTOCHROME P450 2D6 INTERACTION; and

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS

DEPRESSANTS

Addiction, Abuse and Misuse

Acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate tablets, and

monitor all patients regularly for the development of these behaviors and conditions [see

WARNINGS].

Opioid Analgesic 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,

counsel patients and/or their caregivers, 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

acetaminophen and codeine phosphate tablets. Monitor for respiratory depression,

especially during initiation of acetaminophen and codeine phosphate tablets or following a

dose increase [see WARNINGS].

Accidental Ingestion

Accidental ingestion of acetaminophen and codeine phosphate tablets, especially by

children, can result in a fatal overdose of acetaminophen and codeine phosphate tablets [see

WARNINGS].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening

Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received

codeine; most cases following tonsillectomy and/or adenoidectomy, and many of the

children had evidence of being an ultra-rapid metabolizers of codeine due to a CYP2D6

polymorphism. Codeine is contraindicated in children younger than twelve years of age and

in children of any age who are undergoing tonsillectomy and/or adenoidectomy. Avoid the

use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age

who have other risk factors that may increase their sensitivity to the respiratory depressant

effects of codeine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of acetaminophen and codeine phosphate tablets during pregnancy can

result in neonatal opioid withdrawal syndrome, which may be life-threatening if not

recognized and treated, If prolonged opioid use is required 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].

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].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4

inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4

inducers, 3A4 inhibitors, or 2D6 inhibitors with Acetaminophen and Codeine Phosphate

Tablets requires careful consideration of the effects on the parent drug, codeine, and the

active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all

cytochrome P450 3A4 inhibitors or discontinuation of a cytochrome P450 3A4 inducer may

result in an increase in codeine plasma concentrations with subsequently greater

metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could

increase or prolong adverse reactions and may cause potentially fatal respiratory

depres s ion.

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all

cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may

result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with

resultant lower morphine levels. This may be associated with a decrease in efficacy, and in

some patients, may result in signs and symptoms of opioid withdrawal.

Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP3A4

inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid

withdrawal when Acetaminophen and Codeine Phosphate Tablets are used in conjunction

with inhibitors and inducers of CYP3A4 [see Warnings, Precautions, Drug Interactions].

Cytochrome P450 2D6 Interaction

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all

cytochrome P450 2D6 inhibitors may result in an increase in codeine plasma

concentrations and a decrease in the plasma concentration of the active metabolite,

morphine, which could result in an analgesic efficacy reduction or symptoms of opioid

withdrawal.

The discontinuation of a cytochrome P450 2D6 inhibitor may result in a decrease in codeine

plasma concentrations and an increase in the plasma concentration of the active metabolite,

morphine, which could which could increase or prolong adverse reactions and may cause

potentially fatal respiratory depression.

Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP2D6

inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal

when Acetaminophen and Codeine Phosphate Tablets are used in conjunction with

inhibitors of CYP2D6 [see WARNINGS, PRECAUTIONS, DRUG INTERACTIONS].

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 acetaminophen and codeine phosphate 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

Acetaminophen and codeine phosphate tablets, USP are for oral administration.

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:

Codeine phosphate, 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1)

(salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the

following structural formula:

Each tablet contains:

Acetaminophen............................300 mg

Codeine Phosphate........................15 mg

(Warning: May be habit forming)

Acetaminophen............................300 mg

Codeine Phosphate........................30 mg

(Warning: May be habit forming)

Acetaminophen............................300 mg

Codeine Phosphate........................60 mg

(Warning: May be habit forming)

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide,

croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone,

pregelatinized starch, sodium lauryl sulfate, and stearic acid.

CLINICAL PHARMACOLOGY

Mechanism of Action

Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker

affinity than morphine. The analgesic properties of codeine have been speculated to come from its

conversion to morphine, although the exact mechanism of analgesic action remains unknown.

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

Codeine 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.

Codeine 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Codeine 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

Codeine 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 low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical 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 codeine 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 codeine 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.

Codeine

Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the

intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs

such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier and is found in fetal tissue

and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain.

Codeine is about 7-25% bound to plasma proteins and does not accumulate in body tissues.

About 70 to 80% of the administered dose of codeine is metabolized by conjugation with glucuronic

acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5 to 10%) and N-

demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and

2B4 are the major enzymes mediating glucuronidation of codeine to C6G. Cytochrome P450 2D6 is the

major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme

mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by

conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-

glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have

analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G

are generally not considered to possess analgesic properties.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and

about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion

products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated

norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and

hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6

hours.

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

Acetaminophen and codeine phosphate tablets are indicated for the management of mild to moderate

pain,where treatment with an opioid is appropriate 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 acetaminophen and codeine phosphate tablets for use in patients for whom

alternative treatment options [e.g., non-opioid analgesics]

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

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

CONTRAINDICATIONS

Acetaminophen and codeine phosphate tablets are contraindicated for:

All children younger than 12 years of age (see WARNINGS).

Post-operative management in children younger than 18 years of age following tonsillectomy and/or

adenoidectomy (see WARNINGS).

Acetaminophen and codeine phosphate 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].

concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14

days [see WARNINGS].

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

Hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis)

[see WARNINGS].

WARNINGS

Addiction, Abuse, and Misuse:

Acetaminophen and Codeine Phosphate Tablets contains codeine, a Schedule II controlled substance.

As an opioid, Acetaminophen and Codeine Phosphate 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 Acetaminophen and Codeine Phosphate 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 Acetaminophen

and Codeine Phosphate Tablets, and monitor all patients receiving Acetaminophen and Codeine

Phosphate Tablets with Codeine 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 Acetaminophen and Codeine Phosphate Tablets, but use in such patients

necessitates intensive counseling about the risks and proper use of Acetaminophen and Codeine

Phosphate 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 Acetaminophen and Codeine Phosphate

Tablet. 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/Caregivers]. 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.

Opioid Analgesic 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 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/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

Acetaminophen and Codeine Phosphate 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 24to 72 hours of initiating therapy with and following dosage increases of Acetaminophen and

Codeine Phosphate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Acetaminophen and Codeine

Phosphate Tablets are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the

Acetaminophen and Codeine Phosphate Tablets dosage when converting patients from another opioid

product can result in a fatal overdose with the first dose.

Accidental ingestion of Acetaminophen and Codeine Phosphate Tablets, especially by children, can

result in respiratory depression and death due to an overdose of codeine.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-

related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who

present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see

Dosage and Administration].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory

Depression in Children to Morphine

Life-threatening respiratory depression and death have occurred in children who received codeine.

Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which

can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports,

children less than 12 years old appear to be more susceptible to the respiratory depressant effects of

codeine, particularly if there are risk factors for respiratory depression. For example, many reported

cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy,

and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore,

children with obstructive sleep apnea who are treated with codeine for post tonsillectomy and/or

adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the

risk of life-threatening respiratory depression and death:

Acetaminophen and codeine phosphate tablets are contraindicated for all children younger than 12

years of age [see CONTRAINDICATIONS].

Acetaminophen and codeine phosphate tablets are contraindicated for postoperative pain management

in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see

CONTRAINDICATIONS].

Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age

who have other risk factors that may increase their sensitivity to the respiratory depressant effects of

codeine unless the benefits outweigh the risks. Risk factors include postoperative status, obstructive

sleep apnea, obesity and other conditions

As with adults, when prescribing codeine for adolescents, healthcare providers should choose the

lowest effective dose for the shortest period of time and inform patients and caregivers about these -

risks and the signs of morphine overdose [see OVERDOSAGE].

Nursing Mothers

A death was reported in a nursing infant who was exposed to high levels of morphine in breast milk

because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended

during treatment with acetaminophen and codeine phosphate tablets.

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene

duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely

and has been estimated at 1 to 10% for Whites (European, North American), 3-4% for Blacks (African

Americans), 1-2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain

racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto

Rican).These individuals convert codeine into its active metabolite, morphine, more rapidly and

completely than other people. This rapid conversion results in higher than expected serum morphine

levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-

threatening or fatal respiratory depression or experience signs of overdose (such as extreme

sleepiness, confusion, or shallow breathing) [see OVERDOSAGE]. Therefore, individuals who are

ultra-rapid metabolizers should not use codeine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Acetaminophen and Codeine Phosphate 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 prolonged use of acetaminophen and codeine phosphate 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/Caregivers,

Pregnancy].

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors,

or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or

2D6 inhibitors with Acetaminophen and Codeine Phosphate Tablets requires careful consideration of

the effects on the parent drug, codeine, and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4

inhibitors , such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,

ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4

inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma

concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater

morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal

respiratory depression.

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4

inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels,

greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may

be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of

opioid withdrawal.

Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP3A4 inhibitor or

inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when

Acetaminophen and Codeine Phosphate Tablets are used in conjunction with inhibitors and inducers of

CYP3A4 [see WARNINGS, PRECAUTIONS, Drug Interactions].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 2D6

inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a

decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy

reduction or symptoms of opioid withdrawal.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in

codeine plasma concentration and an increase in active metabolite morphine plasma concentration which

could which could increase or prolong adverse reactions and may cause potentially fatal respiratory

depression.

Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP2D6 inhibitor for

signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Acetaminophen and

Codeine Phosphate Tablets are used in conjunction with inhibitors of CYP2D6 [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

Acetaminophen and Codeine Phosphate 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

Acetaminophen and Codeine Phosphate 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, Information for

Patients/Caregivers, Drug Interactions].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or

Elderly, Cachectic, or Debilitated Patients

The use of Acetaminophen and Codeine Phosphate 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: Acetaminophen and Codeine Phosphate 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 Acetaminophen and Codeine Phosphate 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,

including clearance, compared to younger, healthier patients [see WARNINGS; Respiratory

Depression ].

Monitor such patients closely, particularly when initiating and titrating Acetaminophen and Codeine

Phosphate Tablets and when Acetaminophen and Codeine Phosphate Tablets are given concomitantly

with other drugs that depress respiration [see WARNINGS; Life Threatening-Respiratory

Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-

related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who

present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see

Dosage and Administration].

Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active

metabolite including respiratory depression, coma, and confusion. Acetaminophen and Codeine

Phosphate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such

treatment.

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.

Severe Hypotension

Acetaminophen and Codeine Phosphate Tablets may cause severe hypotension including 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]. Monitor these patients for signs of hypotension after initiating or titrating the

dosage of Acetaminophen and Codeine Phosphate Tablets. In patients with circulatory shock

Acetaminophen and Codeine Phosphate Tablets may cause vasodilatation that can further reduce cardiac

output and blood pressure. Avoid the use of Acetaminophen and Codeine Phosphate 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.

Hypersensitivity/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 acetaminophen and codeine

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

prescribe acetaminophen and codeine phosphate 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 CO2 retention (e.g., those with evidence

of increased intracranial pressure or brain tumors), Acetaminophen and Codeine Phosphate Tablets may

reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

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

therapy with Acetaminophen and Codeine Phosphate Tablets.

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

Acetaminophen and Codeine Phosphate Tablets in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Acetaminophen and Codeine Phosphate Tablets are contraindicated in patients with gastrointestinal

obstruction, including paralytic ileus.

The administration of Acetaminophen and Codeine Phosphate Tablets or other opioids may obscure the

diagnosis or clinical course in patients with acute abdominal conditions.

Acetaminophen and Codeine Phosphate Tablets 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.

Sulfite Sensitivity

Acetaminophen and Codeine Phosphate Tablets contain sodium metabisulfite, a sulfite that may cause

allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic

episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general

population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in

nonasthmatic people.

Increased Risk of Seizures in Patients with Seizure Disorders

The codeine in Acetaminophen and Codeine Phosphate 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. Monitor patients with a history of seizure disorders for worsened

seizure control during Acetaminophen and Codeine Phosphate Tablets therapy.

Withdrawal

Do not abruptly discontinue acetaminophen and codeine phosphate tablets in a patient physically

dependent on opioids. Rapid tapering of acetaminophen and codeine phosphate tablets in a patient

physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE

AND ADMINISTRATION, DRUG ABUSE AND DEPENDENCE].

Additionally 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 Acetaminophen and Codeine Phosphate Tablets. In these patients, mixed

agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal

symptoms.

When discontinuing Acetaminophen and Codeine Phosphate Tablets, gradually taper the dosage [see

DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue Acetaminophen and Codeine

Phosphate Tablets [see DRUG ABUSE AND DEPENDENCE].

PRECAUTIONS

Risks of Driving and Operating Machinery

Acetaminophen and Codeine Phosphate Tablets may impair the mental or physical abilities needed to

perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not

to drive or operate dangerous machinery unless they are tolerant to the effects of Acetaminophen and

Codeine Phosphate Tablets and know how they will react to the medication [see PRECAUTIONS;

Information for Patients/Caregivers] .

Information for Patients/Caregivers

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

Storage and Disposal:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store

acetaminophen and codeine phosphate tablets securely, out of sight and reach of children, and in a

location not accessible by others, including visitors to the home [see WARNINGS, DRUG ABUSE

AND DEPENDENCE]. Inform patients that leaving acetaminophen and codeine phosphate tablets

unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of

promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of

most types of unneeded medicines. If no take back programs or DEA-registered collectors are

available, instruct patients to dispose of acetaminophen and codeine phosphate tablets by following

these four steps:

Mix acetaminophen and codeine phosphate tablets (do not crush) with an unpalatable substance such as

dirt, cat litter, or used coffee grounds;

Place the mixture in a container such as a sealed plastic bag;

Throw the container in the household trash;

Delete all personal information on the prescription label of the empty bottle

Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of

unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of acetaminophen and codeine phosphate tablets, even when taken as

recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see

WARNINGS]. Instruct patients not to share acetaminophen and codeine phosphate tablets with others

and to take steps to protect acetaminophen and codeine phosphate tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk

is greatest when starting acetaminophen and codeine phosphate tablets or when the dosage is increased,

and that it can occur even at recommended dosages [see WARNINGS]. 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]. Instruct patients to take steps to store acetaminophen and codeine phosphate

tablets securely. Advise patients to properly dispose of the Acetaminophen and Codeine Phosphate

Tablets in accordance with local state guidelines and/or regulations.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory

Depression in Children:

Advise patients that acetaminophen and codeine phosphate tablets should not be used in children

younger than 12 years of age or in a child of any age for pain treatment after tonsillectomy and/or

adenoidectomy. Advice caregivers of children ages 12-18 receiving codeine to monitor for signs of

respiratory depression [see WARNINGSand PRECAUTIONS].

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Acetaminophen and

Codeine Phosphate Tablets are used with benzodiazepines or other CNS depressants, including

alcohol, and not to use these drugs concomitantly unless supervised by a health care provider [see

WARNINGSand PRECAUTIONS; Drug Interactions].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from

concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin

syndrome, and to seek medical attention right away if symptoms develop.

Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic

medications [see PRECAUTIONS; Drug Interactions].

MAOI Interaction

Inform patients not to take Acetaminophen and Codeine Phosphate Tablets while using any drugs that

inhibit monoamine oxidase. Patients should not start MAOIs while taking

acetaminophen and codeine phosphate tablets [see WARNINGS, Drug Interactions].

Adrenal Insufficiency

Inform patients that opioids 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].

Important Administration Instructions

Instruct patients how to properly take Acetaminophen and Codeine Phosphate Tablets [see DOSAGE

and ADMINISTRATION].

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue acetaminophen

and codeine phosphate tablets, USP without first discussing a tapering plan with the prescriber [see

DOSAGE AND ADMINISTRATION]

Maximum Daily Dose of Acetaminophen

Inform patients not to take more than 4,000 milligrams of acetaminophen per day. Advise patients to call

their healthcare provider if they have taken more than the recommended dose.

Hypotension

Inform patients that Acetaminophen and Codeine Phosphate Tablets 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; Hypotension ].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Acetaminophen and

Codeine Phosphate Oral tablets. Advise patients how to recognize such a reaction, and if they develop

signs of allergy such as a rash or difficulty breathing to stop taking Acetaminophen and Codeine

Phosphate Oral tablets and seek medical attention. [see Contraindications, Adverse Reactions].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Acetaminophen and Codeine

Phosphate Tablets during

pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not

recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that acetaminophen and codeine phosphate tablets

can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see

PRECAUTIONS;Pregnancy].

Lactation

Advise women that breastfeeding is not recommended during treatment with acetaminophen and codeine

phosphate tablets.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these

effects on fertility are reversible.

Driving or Operating Heavy Machinery

Inform patients that Acetaminophen and Codeine Phosphate Tablets may impair the mental and/or

physical abilities required for the performance of potentially hazardous tasks such as driving a car or

operating machinery and to avoid such tasks while taking this product, until they know how they will

react to the medication.

Disposal of Unused Acetaminophen and Codeine Phosphate Tablets

1. Advise patients to properly dispose of the Acetaminophen and Codeine Phosphate Tablets Advise

patients to throw the drug in the household trash following these steps. 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.

Drug Interactions

CYP2D6 Inhibitors

Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Acetaminophen and

Codeine Phosphate Tablets and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine)

can increase the plasma concentration of codeine, but decreased the plasma concentration of active

metabolite morphine, particularly when an inhibitor is added after a stable dose of Acetaminophen and

Codeine Phosphate Tablet is achieved [ see CLINICAL PHARMACOLOGY].

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma

concentration will decrease but the morphine plasma concentration will increase, which could increase

or prolong adverse reactions and may cause potentially fatal respiratory depression [see CLINICAL

PHARMACOLOGY].

If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is

discontinued after concomitant use, consider dosage adjustment of acetaminophen and

codeine phosphate tablets and monitor patients closely at frequent intervals.

If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced

efficacy or signs and symptoms of opioid withdrawal and consider increasing the

acetaminophen and codeine phosphate tablets as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the acetaminophen and

codeine phosphate tablets and monitor the patient for signs and symptoms of respiratory

depression or sedation.

CYP3A4 Inhibitors

The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inhibitors, such as

macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease

inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations , with subsequently

greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase

or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when

an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved

[see WARNINGS].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower

codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower

morphine levels [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a

withdrawal syndrome in patients who had developed physical dependence to codeine.

If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of acetaminophen and

codeine tablets until stable drug effects are achieved. Monitor patients for respiratory depression and

sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the acetaminophen and codeine phosphate

tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers

The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inducers (e.g.,

rifampin, carbamazepine, phenytoin) can result in lower codeine levels, greater norcodeine levels, and

less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology], resulting

in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical

dependence [see WARNINGS].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations

may increase, with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater

morphine levels [see CLINICAL PHARMACOLOGY], which could increase or prolong both the

therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs

of opioid withdrawal and consider increasing the acetaminophen and codeine phosphate tablets dosage

as needed.

If a CYP3A4 inducer is discontinued, consider acetaminophen and codeine phosphate tablets dosage

reduction and monitor for signs of respiratory depression and sedation at frequent intervals.

Benzodiazepines and other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other

CNS depressants such as alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, anti psychotics, and other opioids, can increases the risk of respiratory

depression, profound sedation, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative

treatment options are inadequate. Limit dosages and durations to the minimum required. Follow

patients closely for signs of respiratory depression and sedation [see WARNINGS].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system,

such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors

(SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the

serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol),certain muscle relaxants (i.e.,

cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat

psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in

serotonin syndrome [see PRECAUTIONS; Information for Patients/Caregivers].

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and

dose adjustment. Discontinue acetaminophen and codeine phosphate tablets if serotonin syndrome is

suspected.

Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, linezolid, may

manifest as serotonin syndrome or opioid toxicity.

Advise patients taking Acetaminophen and Codeine Phosphate Tablets not to use MAOIs or within 14

days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent

titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone,

hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and

symptoms of CNS and respiratory depression.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine,

pentazocine, may reduce the analgesic effect of Acetaminophen and Codeine Phosphate Tablet and/or

precipitate withdrawal symptoms.

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants Acetaminophen and codeine phosphate tablets may enhance the neuromuscular

blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater

than otherwise expected and decrease the dosage of acetaminophen and codeine phosphate tablet and/or

the muscle relaxant as necessary.

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on

blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe

constipation, which may lead to paralytic ileus.

If concomitant use is warranted, monitor patients for signs of urinary retention or reduced gastric

motility when Acetaminophen and Codeine Phosphate Tablet is used concomitantly with anticholinergic

drugs.

Drug/Laboratory Test Interactions

Codeine may increase serum amylase levels.

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of the combination of codeine and

acetaminophen have not been conducted.

Two-year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no

evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80

mg/kg/day of codeine sulfate (approximately 2 times the maximum recommended daily dose of 360

mg/day for adults on a mg/m

basis) for two years. Similarly there was no evidence of carcinogenicity

activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately

5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m

basis) for two

years.

Long-term studies in mice and rats have been completed by the National Toxicology Program to

evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and

B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated

equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell

leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface

area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received

up to 0.7 times or mice at up to 1.2-1.4 times the MHDD, based on a body surface area comparison.

Mutagenesis

Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the

in vitro Chinese hamster ovary cell chromosome aberration assay.

In the published literature, acetaminophen has been reported to be clastogenic when administered at

1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In

contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body

surface area comparison), suggesting a threshold effect.

Impairment of Fertility

No nonclinical fertility studies have been conducted with codeine or the combination of codeine and

acetaminophen.

In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen

have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on

fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body

surface area comparison. Although there was no effect on sperm motility or sperm density in the

epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming

1.78 times the MHDD (based on a body surface comparison) and there was a reduction in the number of

mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with

chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are

1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular

weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the

same doses. These effects appear to increase with the duration of treatment. The clinical significance

of these findings is not known.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is

not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Pregnancy

Teratogenic Effects: Pregnancy Category C

Codeine

A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of

organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the

toxic range for the adult animal, were associated with an increase in embryo resorption at the time of

implantation. In another study a single 100 mg/kg subcutaneous dose of codeine administered to pregnant

mice reportedly resulted in delayed ossification in the offspring.

There are no adequate and well-controlled studies in pregnant women. Acetaminophen and codeine

phosphate tablets should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

Nonteratogenic Effects

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in

physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern,

high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity

of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing

and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns

for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in

neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced

respiratory depression in the neonate. Acetaminophen and codeine phosphate tablets are not

recommended for use in pregnant women during or immediately prior to labor, when other analgesic

techniques are more appropriate. Opioid analgesics, including acetaminophen and codeine phosphate

tablets, can prolong labor through actions which temporarily reduce the strength, duration, and

frequency of uterine contractions. However, this effect is not consistent and may be offset by an

increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid

analgesics during labor for signs of excess sedation and respiratory depression.

Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If

the mother has received narcotic analgesics during labor, newborn infants should be observed closely

for signs of respiratory depression. Resuscitation may be required [see OVERDOSAGE]. The effect

of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Lactation

Risk Summary

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and

cases that have reported excessive sedation, respiratory depression, and death (one case) in infants

exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher

than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk

that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal

CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is

no information on the effects of the codeine on milk production. Because of the potential for serious

adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant,

advise patients that breastfeeding is not recommended during treatment with acetaminophen and codeine

phosphate tablets (see WARNINGS and PRECAUTIONS).

Clinical Considerations

If infants are exposed to acetaminophen and codeine phosphate tablets through breast milk, they should

be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in

breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding

is stopped.

Pediatric Use

The safety and effectiveness and the pharmacokinetics of acetaminophen and codeine phosphate tablets

in pediatric patients below the age of 18 have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine [see

WARNINGSand PRECAUTIONS]. In most of the reported cases, these events followed

tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid

metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 206 or high

morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory

depressant effects of codeine.

Because of the risk of life-threatening respiratory depression and death:

Acetaminophen and codeine phosphate tablets are contraindicated for all children younger than 12

years of age [see CONTRAINDICATIONS].

Acetaminophen and codeine phosphate tablets are contraindicated for postoperative pain management

in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see

CONTRAINDICATIONS].

Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age who

have other risk factors that may increase their sensitivity to the respiratory depressant effects of

codeine unless the benefits outweigh the risks. Risk factors include postoperative status, obstructive

sleep apnea, obesity and other conditions associated with hypoventilation syndromes (e.g.

neuromuscular disease), concomitant use of other medications that cause respiratory depression, and

severe pulmonary disease [see WARNINGSand PRECAUTIONS].

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to acetaminophen and codeine

phosphate tablets. In general, use caution when selecting a dosage for an elderly patient, usually starting

at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or

cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after

large initial doses were administered to patients who were not opioid-tolerant or when opioids were

co-administered with other agents that depress respiration. Titrate the dosage of acetaminophen and

codeine phosphate tablets slowly in geriatric patients and monitor closely for signs of central nervous

system depression (see WARNINGS).

These drugs are known to be substantially excreted by the kidney, and the risk of adverse reactions to

this drug may be greater in patients with impaired renal function. Because elderly patients are more

likely to have decreased renal function, care should be taken in dose selection, and it may be useful to

monitor renal function.

ADVERSE REACTIONS

The following adverse reactions have been identified during post approval use of Acetaminophen and

Codeine Phosphate Tablets. Because these reactions are reported voluntarily from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure.

Addiction, Abuse, and Misuse [see WARNINGS]

Life-Threatening Respiratory Depression [see WARNINGS]

Neonatal Opioid Withdrawal Syndrome [see WARNINGS]

Ultra-rapid Metabolizers of Codeine [see WARNINGS]

Interactions with CNS Depressants [see WARNINGS]

Severe Hypotension [see WARNINGS]

Gastrointestinal Adverse Reactions [see WARNINGS]

Seizures [see WARNINGS]

Withdrawal [see WARNINGS]

Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree,

circulatory depression, respiratory arrest, shock, and cardiac arrest.

The most frequently observed adverse reactions with codeine administration include drowsiness,

lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.

Other adverse reactions include allergic reactions, euphoria, dysphoria, , abdominal pain, pruritus, rash,

thrombocytopenia, and agranulocytosis.

Other less frequently observed adverse reactions expected from opioid analgesics, including

acetaminophen and codeine phosphate tablets:

Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope

Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress,

pancreatitis

Nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence,

vertigo, visual disturbances, weakness

Skin and Appendages: rash, sweating, urticarial

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been

reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often

following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Acetaminophen and Codeine

Phosphate Tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see

Clinical Pharmacology].

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Acetaminophen and codeine phosphate tablets contain codeine. Codeine in combination with

acetaminophen, is a Schedule III controlled substance.

Abuse

Acetaminophen and codeine phosphate tablets contain codeine, a substance with a high potential for

abuse similar to other opioids, including fentanyl, hydrocodone, hydromorphone, methadone, morphine,

oxycodone, oxymorphone, and tapentadol. Acetaminophen and codeine phosphate tablets can be abused

and is subject to misuse, addiction, and criminal diversion [see WARNINGS].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because

use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its

rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after

repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use,

persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to

drug use than to other activities and obligations, increased tolerance, and sometimes a physical

withdrawal.

'Drug-seeking' behavior is very common in persons with substance use disorders. Drug-seeking tactics

include emergency calls or visits near the end of office hours, refusal to undergo appropriate

examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and

reluctance to provide prior medical records or contact information for other treating health care

providers. 'Doctor shopping' (visiting multiple prescribers to obtain additional prescriptions) is

common among drug abusers and people suffering from untreated addiction. Preoccupation with

achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare

providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms

of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true

addiction.

Acetaminophen and codeine phosphate tablets, like other opioids, can be diverted for non-medical use

into illicit channels of distribution. Careful record-keeping of prescribing information, including

quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and

proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Acetaminophen and Codeine Phosphate Tablets

Acetaminophen and Codeine Phosphate Tablets are for oral use only. Abuse of Acetaminophen and

Codeine Phosphate Tablets poses a risk of overdose and death. The risk is increased with concurrent

use of Acetaminophen and Codeine Phosphate Tablets with alcohol and other central nervous system

depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis

and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the

need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of

disease progression or other external factors). Tolerance may occur to both the desired and undesired

effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of

regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage

reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with

opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g.,

pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence

may not occur to a clinically significant degree until after several days to weeks of continued opioid

usage.

Do not abruptly discontinue acetaminophen and codeine phosphate tablets in a patient physically

dependent on opioids. Rapid tapering of acetaminophen and codeine phosphate tablets in a patient

physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and

suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid

analgesics, which may be confused with drug-seeking for abuse.

When discontinuing acetaminophen and codeine phosphate tablets, gradually taper the dosage using a

patient specific plan that considers the following: the dose of acetaminophen and codeine phosphate

tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes

of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is

important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a

long duration at high doses, ensure that a multimodal approach to pain management, including mental

health support (if needed), is in place prior to initiating an opioid analgesic taper [see DOSAGE AND

ADMINISTRATION, WARNINGS].

Infants born to mothers physically dependent on opioids will also be physically dependent and may

exhibit respiratory difficulties and withdrawal signs [see PRECAUTIONS; Pregnancy].

OVERDOSAGE

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

Clinical Presentation

Codeine

Acute overdosage with codeine can be manifested by respiratory depression, somnolence progressing

to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some

cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical

snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose

situations.

Acetaminophen

Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetminophen.

Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur.

Early symptoms following a potentially hepatotoxic overdose may include; anorexia, nausea, vomiting,

diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be

apparent until 48 to 72 hours post-ingestion.

Treatment of Overdose

Codeine

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of

assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and

vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest

or serious arrhythmias will require advanced life-support measures.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression

resulting from opioid overdose. For clinically significant respiratory or circulatory depression

secondary to acetaminophen and codeine overdose, administer an opioid antagonist. Opioid antagonists

should not be administered in the absence of clinically significant respiratory or circulatory depression

secondary to codeine overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of codeine in

acetaminophen and codeine phosphate tablets, carefully monitor the patient until spontaneous respiration

is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature,

administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the

antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms

experienced will depend on the degree of physical dependence and the dose of the antagonist

administered. If a decision is made to treat serious respiratory depression in the physically dependent

patient, administration of the antagonist should be begun with care and by titration with smaller than usual

doses of the antagonist.

Acetaminophen

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine

(NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have

occurred within a few hours of presentation.

Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more

after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours

post-ingestion may be misleading. To obtain the best possible outcome, (NAC) should be administered

as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be

administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing

absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs

early in the course of intoxication.

DOSAGE AND ADMINISTRATION

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment

goals [see WARNINGS].

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 acetaminophen and codeine phosphate tablets and

adjust the dosage accordingly [see WARNINGS].

Initial Dosage

Initiating Treatment with Acetaminophen and Codeine Phosphate Tablets

Dosage should be adjusted according to severity of pain and response of the patient. However, it

should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of

untoward effects is dose related. Adult doses of codeine higher than 60 mg are associated with an

increased incidence of adverse reactions and are not associated with greater efficacy.

The usual adult dosage is:

Acetaminophen and Codeine Phosphate Tablets (codeine 15 mg and acetaminophen 300 mg):

Take 1 to 2 tablets every 4 hours as needed for pain.

Acetaminophen and Codeine Phosphate Tablets (codeine 30 mg and acetaminophen 300 mg):

Take 1 to 2 tablets every 4 hours as needed for pain.

Acetaminophen and Codeine Phosphate Tablets (codeine 60 mg and acetaminophen 300 mg):

Take one tablet every 4 hours as needed for pain.

Single Doses

(Range)

Maximum

24-Hour Dose

Codeine Phosphate

30 mg to 60 mg

360 mg

Acetaminophen

300 mg to 1000 mg

4000 mg

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per

24 hours, based upon the above dosage guidance. This information should be conveyed in the

prescription.

The usual dose of codeine phosphate in children is 0.5 mg/kg. Doses may be repeated up to every 4

hours.

Conversion from Other Opioids to Acetaminophen and Codeine Phosphate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a

conservative approach is advised when determining the total daily dosage of Acetaminophen and

Codeine Phosphate Tablets. It is safer to underestimate a patient’s 24-hour Acetaminophen and Codeine

Phosphate Tablets dosage than to overestimate the 24-hour Acetaminophen and Codeine Phosphate

Tablets dosage and manage an adverse reaction due to overdose.

Initiating Treatment with Acetaminophen and Codeine Phosphate Tablets

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per

24 hours based upon the above dosage guidance. This information should be conveyed in the

prescription.

It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the

incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give

commensurate relief of pain but merely prolong analgesia and are associated with an appreciably

increased incidence of undesirable side effects. Equivalently high doses in children would have similar

effects.

Titration and Maintenance of Therapy

Individually titrate acetaminophen and codeine phosphate tablets to a dose that provides adequate

analgesia and minimizes adverse reactions. Continually reevaluate patients receiving acetaminophen and

codeine phosphate tablets to assess the maintenance of pain control and the relative incidence of

adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see

WARNINGS]. Frequent communication is important among the prescriber, other members of the

healthcare team, the patient, and the caregiver/family during periods of changing analgesic

requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain

before increasing the acetaminophen and codeine phosphate tablets dosage. If unacceptable opioid-

related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an

appropriate balance between management of pain and opioid-related adverse reactions.

Safe Reduction or Discontinuation of acetaminophen and codeine phosphate tablets

Do not abruptly discontinue acetaminophen and codeine phosphate tablets in patients who may be

physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are

physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and

suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid

analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their

pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent

patient taking acetaminophen and codeine phosphate tablets there are a variety of factors that should be

considered, including the dose of acetaminophen and codeine phosphate tablets the patient has been

taking, the duration of treatment, the type of pain being treated, and the physical and psychological

attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an

appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are

clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use

disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use

disorder. Treatment should include evidence-based approaches, such as medication assisted treatment

of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit

from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice

dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on acetaminophen

and codeine phosphate tablets who are physically opioid-dependent, initiate the taper by a small enough

increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and

proceed with dose lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids

for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper.

Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common

withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills,

myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety,

backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or

increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be

necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the

previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in

mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long

duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management,

including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A

multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist

with the successful tapering of the opioid analgesic [see WARNINGS/ Withdrawal, DRUG ABUSE

AND DEPENDENCE].

HOW SUPPLIED

300 mg/30 mg

White to off-white, round, flat-faced, beveled-edged tablets, debossed with U36 on one side and plain

on the other side.

NDC 68071-5025-6 BOTTLES OF 6

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Store acetaminophen and codeine phosphate tablets securely and dispose of properly [see

PRECAUTIONS/ Information for Patients].

Keep this and all medication out of the reach of children. Protect from moisture. Dispense in a tight,

light-resistant container as described in the USP.

PROTECT FROM LIGHT

Dispense with Medication Guide available at www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Revised:04/2019

Medication Guide

Acetaminophen and Codeine Phosphate Tablets, USP CIII

ass-cet-ah-MEE-noe-fen with KOE-deen FOSS-fate

Acetaminophen and Codeine Phosphate Tablets are:

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

moderate 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 Acetaminophen and Codeine Phosphate tablets:

Get emergency help right away if you take too many acetaminophen and codeine phosphate

tablets (overdose). When you first start taking acetaminophen and codeine 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 acetaminophen and Codeine Tablets with other opioid medicines, benzodiazepines, alcohol,

or other central nervous system depressants (including strret drugs) can cause severe drowsiness,

decreased awareness, breathing problems, coma and death.

Never give anyone else your acetaminophen and codeine phosphate tablets. They could die from

taking it. Selling or giving away acetaminophen and codeine phosphate tablets are against the law.

Store acetaminophen and codeine phosphate tablets securely, out of sight and reach of children, and

in a location not accessible by others, including visitors to the home.

Important Information Guiding Use in Pediatric Patients:

Do not give acetaminophen and codeine phosphate tablets to a child younger than 12 years of age.

Do not give acetaminophen and codeine phosphate tablets to a child younger than 18 years of age

after surgery to remove the tonsils and/or adenoids.

Avoid giving acetaminophen and codeine phosphate tablets to children between 12 to 18 years of

age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or

underlying lung problems.

Do not take Acetaminophen and Codeine Phosphate Tablets if you have:

severe asthma, trouble breathing, or other lung problems.

a bowel blockage or narrowing of the stomach or intestines.

previously had an allergic reaction to codeine or acetaminophen.

Before taking acetaminophen and codeine phosphate 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.

Have been told by your healthcare provider that you are a "rapid metabolizer" of certain medicines.

Tell your healthcare provider if you are:

pregnant or planning to become pregnant. Prolonged use of acetaminophen and codeine

phosphate tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could

be life-threatening if not recognized and treated.

breastfeeding. Not recommended; may harm your baby. taking prescription or over-the-counter

medicines, vitamins, or herbal supplements. Taking acetaminophen and codeine phosphate tablets

with certain other medicines can cause serious side effects that could lead to death.

Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking

acetaminophen and codeine phosphate tablets with certain other medicines can cause serious side

effects that could lead to death.

When taking Acetaminophen and Codeine Phosphate Tablets:

Do not change your dose. Take Acetaminophen and Codeine Phosphate Tablets exactly as

prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.

Take your prescribed dose every 4 hours as needed. Do not take more than your prescribed dose. If

you miss a dose, take your next dose when needed.

Call your healthcare provider if the dose you are taking does not control your pain.

If you have been taking Acetaminophen and Codeine Phosphate Tablets regularly, do not stop taking

acetaminophen and codeine phosphate Tablets without talking to your healthcare provider.

After you stop taking acetaminophen and codeine phosphate Tablets to dispose of any unused tablets

in accordance with local state guidelines and/or regulations.

While taking Acetaminophen and Codeine Phosphate tablets DO NOT:

Dispose of expired, unwanted, or unused acetaminophen and codeine phosphate tablets by taking

your drug to an authorized DEA-registered collector or drug take-back program. If one is not

available, you can dispose of acetaminophen and codeine phosphate tablets by mixing the product

with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the

bag in your trash.

Drive or operate heavy machinery, until you know how acetaminophen and codeine phosphate tablets

affect you. Acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate tablets may

cause you to overdose and die.

The possible side effects of Acetaminophen and Codeine Phosphate 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 acetaminophen and codeine phosphate tablets. Call your

doctor for medical advice about side effects. You may also request medical information or to report

suspected adverse reactions, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-

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

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

Dispense with Medication Guide available at www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Revised:04/2019

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL –

ACETAMINOPHEN AND CODEINE PHOSPHATE

acetaminophen and codeine phosphate tablet

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-

50 25(NDC:1310 7-0 59 )

Route of Administration

ORAL

DEA Sche dule

CIII

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ACETAMINO PHEN (UNII: 36 2O9 ITL9 D) (ACETAMINOPHEN - UNII:36 2O9 ITL9 D)

ACETAMINOPHEN

30 0 mg

CO DEINE PHO SPHATE (UNII: GSL0 5Y1MN6 ) (CODEINE ANHYDROUS - UNII:UX6 OWY2V7J)

CODEINE PHOSPHATE 30 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

white (White to Off White)

S core

no sco re

S hap e

ROUND (Flat-faced, Beveled Edge)

S iz e

11mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-50 25-6

6 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /14/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 28 0 0

0 4/15/20 13

Labeler -

NuCare Pharmaceuticals,Inc. (010632300)

NuCare Pharmaceuticals,Inc.

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals,Inc.

0 10 6 3230 0

re pa c k(6 8 0 71-50 25)

Revised: 8/2019

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