ACETAMINOPHEN AND CODEINE phosphate tablet

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

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Active ingredient:
CODEINE PHOSPHATE (UNII: GSL05Y1MN6) (CODEINE ANHYDROUS - UNII:UX6OWY2V7J)
Available from:
Preferred Pharmaceuticals, Inc.
INN (International Name):
CODEINE PHOSPHATE
Composition:
CODEINE PHOSPHATE 60 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

ACETAMINOPHEN AND CODEINE- acetaminophen and codeine phosphate tablet

Preferred Pharmaceuticals, Inc.

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Acetaminophen and Codeine Phosphate Tablets, USP

(300 mg/30 mg and 300 mg/60 mg)

CIII

Rx Only

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

RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID

METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-

THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID

WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING

CYTOCHROME P450 ISOENZYMES; HEPATOTOXICITY; 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].

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 of the reported cases occurred following tonsillectomy and/or

adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of

codeine due to a CYP2D6 polymorphism [see WARNINGS, PRECAUTIONS; Information

for Patients/Caregivers, Nursing Mothers]. Acetaminophen and codeine phosphate tablets

are contraindicated in children younger than 12 years of age and in children younger than

18 years of age following 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.

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, and requires management according to protocols developed by

neonatology experts. If opioid use is required for a prolonged period in a pregnant woman,

advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that

appropriate treatment will be available [see WARNINGS].

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 [see WARNINGS, PRECAUTIONS: DRUG

INTERACTIONS].

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in

liver transplant and death. Most of the cases of liver injury are associated with the use of

acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than

one acetaminophen-containing product [see WARNINGS].

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, Drug Interactions].

DESCRIPTION

Acetaminophen and codeine phosphate tablets are supplied in tablet form 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 Acetaminophen and Codeine Phosphate Tablet USP (300 mg/30 mg) contains:

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

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.

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

Each Acetaminophen and Codeine Phosphate Tablet USP (300 mg/60 mg) contains:

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

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

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]

CONTRAINDICATIONS

WARNINGS

Addiction, Abuse, and Misuse

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

acetaminophen, is a Schedule III controlled substance. As an opioid, acetaminophen and codeine

phosphate tablets expose users to the risks of addiction, abuse, and misuse [see DRUG ABUSE and

DEPENDENCE].

Although the risk of addiction in any individual is unknown, it can occur in 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 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

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 ].

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 ].

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

tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity

and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for

Patients/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.

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 (CO ) 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 24-72 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.

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.

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 younger 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 post-operative management in

pediatric patients younger than 18 years of age following 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 conditions

associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity,

severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that

cause respiratory depression [see WARNINGS].

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

Nursing Mothers

At least one 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 Metabolizers

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 to 4% for Blacks (African

Americans), 1 to 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 acetaminophen and codeine phosphate tablets.

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 [see PRECAUTIONS, Information for Patients/Caregivers, Pregnancy].

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

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].

acetaminophen and codeine phosphate tablets are used in conjunction with inhibitors and inducers of

CYP3A4 [see WARNINGS, Drug Interactions].

If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued,

consider dosage reduction of acetaminophen and codeine phosphate tablets until stable drug effects are

achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If concomitant use of a CYP3A4 inducer is necessary or 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 [see 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 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.

If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced

efficacy or opioid withdrawal and consider increasing the acetaminophen and codeine phosphate tablets

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

phosphate tablets dosage and follow the patient for signs and symptoms of respiratory depression or

sedation [see PRECAUTIONS, Drug Interactions].

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver

transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at

doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing

product. 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.

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 and/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; Drug Interactions, Information for

Patients /Caregivers ].

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.

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 may cause severe hypotension including orthostatic hypotension and

syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood

pressure has already been compromised by a reduced blood volume or concurrent administration of

certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS;

Drug Interactions]. 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 with circulatory shock.

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.

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

Impaired Consciousness

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

of increased intracranial pressure or brain tumors), acetaminophen and codeine phosphate tablets may

reduce respiratory drive, and the resultant CO 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.

Hypers ens itivity/Anaphylaxis

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

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

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

requiring emergency medical attention. Instruct patients to discontinue 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 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

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).

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 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 caregivers that acetaminophen and codeine phosphate tablets are contraindicated in all children

younger than 12 years of age and in children younger than 18 years of age following tonsillectomy

and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving acetaminophen

and codeine phosphate tablets to monitor for signs of respiratory depression [see WARNINGS].

Interactions with Benzodiazepines and Other CNS Depressants

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

codeine phosphate tablets used with benzodiazepines or other CNS depressants, including alcohol, and

not to use these drugs concomitantly unless supervised by a healthcare provider [see WARNINGS,

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].

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.

Hypotens ion

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 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

tablets and seek medical attention. [see CONTRAINDICATIONS, ADVERSE REACTIONS].

Advise patients not to adjust the dose of acetaminophen and codeine phosphate tablets without

consulting a physician or other healthcare professional.

If patients have been receiving treatment with acetaminophen and codeine phosphate tablets for

more than a few weeks and cessation of therapy is indicated, counsel them on the importance of

safely tapering the dose and that abruptly discontinuing the medication could precipitate

withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the

medication [see WARNINGS].

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, 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 [see PRECAUTIONS; Nursing Mothers].

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.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to

seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].

Disposal of Unused Acetaminophen and Codeine Phosphate Tablets

Advise patients to properly dispose of acetaminophen and codeine phosphate tablets. Advise patients to

throw the drug in the household trash following these steps:

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 can decrease the plasma concentration of active

metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid

withdrawal, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine

phosphate tablets are achieved [see CLINICAL PHARMACOLOGY].

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

concentration will decrease but the active metabolite morphine plasma concentration will increase,

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).

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 dispose of unused tablets in accordance with local state

guidelines and/or regulations.

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, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants,

general anesthetics, antipsychotics and other opioids, can increase the risk of hypotension, 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

has resulted in serotonin syndrome. Examples of these drugs include, 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), and monoamine oxidase (MAO) inhibitors (used to treat

psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see

PRECAUTIONS; Information for Patients].

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

dose adjustment. Discontinue acetaminophen and codeine phosphate tablets immediately 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 tablets and/or

precipitate withdrawal symptoms.

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants

Acetaminophen and codeine 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 tablets

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 tablets are 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, and 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.

Nursing Mothers

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 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 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].

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effect on nursing

infants is not known. Because of the potential for serious adverse reactions in nursing infants from

acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug,

taking into account the importance of the drug to the mother.

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 breastfeeding

is stopped.

Pediatric Use

The safety and effectiveness 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

WARNINGS]. 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 2D6 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:

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

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 post-operative management

in pediatric patients younger than 18 years of age following 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 conditions

associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity,

severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that

cause respiratory depression [see WARNINGS].

The following serious adverse reactions are described, or described in greater detail, in other

sections:

The following adverse reactions associated with the use of codeine were identified in postmarketing

reports. Because some of these reactions were 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.

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.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

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

acetaminophen, is a Schedule III controlled substance.

Abus e

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

Addiction, Abuse, and Misuse [see WARNINGS]

Life-Threatening Respiratory Depression [see WARNINGS]

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

Depression in Children [see WARNINGS]

Neonatal Opioid Withdrawal Syndrome [see WARNINGS]

Interactions with CNS Depressants [see WARNINGS]

Severe Hypotension [see WARNINGS]

Gastrointestinal Adverse Reactions [see WARNINGS]

Seizures [see WARNINGS]

Withdrawal [see WARNINGS]

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].

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 results 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.

Acetaminophen and codeine phosphate tablets should not be abruptly discontinued [see DOSAGE AND

ADMINISTRATION]. If acetaminophen and codeine phosphate tablets are abruptly discontinued in a

physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can

characterize this syndrome: 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.

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 acetaminophen

overdose. 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

Important Dosage and Administration Instructions

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

goals [see WARNINGS].

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 24-72 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 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 1,000 mg

4,000 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.

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.

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.

Discontinuation of Acetaminophen and Codeine Phosphate Tablets

When a patient who has been taking acetaminophen and codeine phosphate tablets regularly and may be

physically dependent no longer requires therapy with acetaminophen and codeine phosphate tablets,

taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and

symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous

level and taper more slowly, either by increasing the interval between decreases, decreasing the amount

of change in dose, or both. Do not abruptly discontinue acetaminophen and codeine phosphate tablets in

a physically-dependent patient [see WARNINGS, DRUG ABUSE AND DEPENDENCE].

HOW SUPPLIED

Acetaminophen and Codeine Phosphate Tablets, USP 300 mg/60 mg are white, round, flat-faced,

beveled edge, scored (bisect bar) tablets, debossed "2065" and "V" on one side and debossed "4" on

the reverse side. They are available as follows:

Bottle of 15 - 68788-9259-1

Bottle of 20 - 68788-9259-2

Bottle of 30 - 68788-9259-3

Bottle of 60 - 68788-9259-6

Store Acetaminophen and Codeine Phosphate Tablets at 20° to 25°C (68° to 77°F). (See USP

Controlled Room Temperature.)

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

Distributed by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

8182436

Revised: 07/17

Repackaged By: Preferred Pharmaceuticals Inc.

Medication Guide

Acetaminophen and Codeine Phosphate Tablets (a seet' a min' oh fen and koe' deen fos' fate),

CIII

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.

Important information about Acetaminophen and Codeine Phosphate Tablets:

Important Information Guiding Use in Pediatric Patients:

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

Before taking Acetaminophen and Codeine Phosphate Tablets, tell your healthcare provider if

you have a history of:

Tell your healthcare provider if you are:

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.

Get emergency help right away if you take too much 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 street 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. Store acetaminophen and codeine tablets away from children and in a safe place to

prevent stealing or abuse. Selling or giving away acetaminophen and codeine phosphate tablets are

against the law.

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.

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.

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.

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.

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

When taking Acetaminophen and Codeine Phosphate Tablets:

While taking Acetaminophen and Codeine Phosphate Tablets DO NOT:

The possible side effects of Acetaminophen and Codeine Tablets :

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 report side effects to FDA at 1-800-FDA-1088.

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

Distributed by: Par Pharmaceutical, Chestnut Ridge, NY 10977 1-800-828-9393

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

Issued: July

2017

8183823

Repackaged By: Preferred Pharmaceuticals Inc.

PRINCIPAL DISPLAY PANEL - 300 mg/60 mg

effects that could lead to death.

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 dispose of any unused tablets

in accordance with local state guidelines and/or regulations.

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

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.

ACETAMINOPHEN AND CODEINE

acetaminophen and codeine phosphate tablet

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 78 8 -

9 259 (NDC:0 6 0 3-2339 )

Route of Administration

ORAL

DEA Sche dule

CIII

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

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

CODEINE PHOSPHATE 6 0 mg

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

ACETAMINOPHEN

30 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

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

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM METABISULFITE (UNII: 4VON5FNS3C)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

Product Characteristics

Color

WHITE

S core

2 pieces

S hap e

ROUND

S iz e

12mm

Flavor

Imprint Code

20 6 5;V;4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

Preferred Pharmaceuticals, Inc.

1

NDC:6 8 78 8 -9 259 -

15 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

11/13/20 14

2

NDC:6 8 78 8 -9 259 -

20 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

11/13/20 14

3

NDC:6 8 78 8 -9 259 -

30 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

11/13/20 14

4

NDC:6 8 78 8 -9 259 -

6 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

11/13/20 14

5

NDC:6 8 78 8 -9 259 -

9 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

11/13/20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 9 8 28

11/13/20 14

Labeler -

Preferred Pharmaceuticals, Inc. (791119022)

Registrant -

Preferred Pharmaceuticals, Inc. (791119022)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Preferred Pharmaceuticals, Inc.

79 1119 0 22

REPACK(6 8 78 8 -9 259 )

Revised: 1/2018

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