BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE capsule

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

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Active ingredient:
CODEINE PHOSPHATE (UNII: GSL05Y1MN6) (CODEINE ANHYDROUS - UNII:UX6OWY2V7J), BUTALBITAL (UNII: KHS0AZ4JVK) (BUTALBITAL - UNII:KHS0AZ4JVK), CAFFEINE (UNII: 3G6A5W338E) (CAFFEINE - UNII:3G6A5W338E), ACETAMINOPHEN (UNII: 362O9ITL9D) (ACETAMINOPHEN - UNII:362O9ITL9D)
Available from:
Actavis Pharma, Inc.
INN (International Name):
BUTALBITAL
Composition:
BUTALBITAL 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses [see Warnings and Precautions ( 5.1)], reserve Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics]: - Have not been tolerated, or are not expected to be tolerated, - Have not provided adequate analgesia, or are not expected to provide adequate analgesia. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for: - All children younger than 12 years of age [see Warnings and Precautions ( 5.5)] . - Post-operative management in children younger than 18 years of age following tonsillectomy and/or adeno
Product summary:
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted with “3220” in red. Bottles of 100 are supplied with child-resistant closures (NDC 0591-3220-01). Store below 30°C (86°F); and dispense in a tight container. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of properly [see Patient Counseling Information (17)] .
Authorization status:
New Drug Application Authorized Generic
Authorization number:
0591-3220-01

acetaminophen, caffeine, and codeine phosphate capsule

Actavis Pharma, Inc.

----------

Medication Guide

Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules, C

Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules are:

A strong

prescription pain

medicine that

contains an

opioid (narcotic)

that is indicated

for the relief of

the symptom

complex of

tension (or

muscle

contraction)

headache, 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 Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules:

Get emergency

help right away

if you take too

much Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules

(overdose) .

When you first

start taking

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules, 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

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules 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

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules. They

could die from

taking it. Selling

or giving away

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules is

against the law.

Store Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules

securely, out of

sight and reach

of children, and

in a location not

accessible by

others, including

visitors to the

home.

Get emergency

help right away

if you take more

than 4,000 mg of

acetaminophen

in 1 day. Taking

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules with

other products

that contain

acetaminophen

can lead to

serious liver

problems and

death.

Important Information

Guiding Use in

Pediatric Patients:

Do not give

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules to a

child younger

than 12 years of

age.

Do not give

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules to a

child younger

than 18 years of

age after surgery

to remove the

tonsils and/or

adenoids.

Avoid giving

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules 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 Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules if

you have:

severe asthma,

trouble

breathing, or

other lung

problems.

a bowel

blockage or have

narrowing of the

stomach or

intestines.

Before taking

Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules, tell

your healthcare provider

if you have a history of:

head injury,

seizures

problems

urinating

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

liver, kidney,

thyroid problems

pancreas or

gallbladder

problems

Tell your healthcare

provider if you are:

pregnant or

planning to

become

pregnant.

Prolonged use of

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules, during

pregnancy can

cause

withdrawal

symptoms in

your newborn

baby that could

be life-

threatening if not

recognized and

treated.

breastfeeding.

recommended;

may harm your

baby.

taking

prescription or

over-the-counter

medicines,

vitamins, or

herbal

supplements.

Taking

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules with

certain other

medicines can

cause serious

side effects that

could lead to

death.

When taking Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules:

Do not change

your dose. Take

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules exactly

as prescribed by

your healthcare

provider. Use the

lowest dose

possible for the

shortest time

needed.

Take your

prescribed dose

of 1 or 2

capsules every 4

hours. Total

daily dosage

should not

exceed 6

capsules. Do not

take more than

your prescribed

dose. If you miss

a dose, take your

next dose at your

usual time.

Call your

healthcare

provider if the

dose you are

taking does not

control your

pain.

If you have been

taking Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules

regularly, do not

stop taking

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules without

talking to your

healthcare

provider.

After you stop

taking Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules,

dispose the

unused

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules in

accordance with

the local state

guidelines and/or

regulations.

Dispose of

expired,

unwanted, or

unused

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules by

taking your drug

to an authorized

DEA-registered

collector or drug

take-back

program. If one

is not available,

you can dispose

of Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules 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.

While taking Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules DO

NOT:

Drive or operate

heavy

machinery, until

you know how

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules affect

you. Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules 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

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules may

cause you to

overdose and

die.

The possible side effects

of Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules:

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.

are a nursing

mother taking

Butalbital,

Acetaminophen,

Caffeine, and

Codeine

Phosphate

Capsules, and

your

breastfeeding

baby has

increased

sleepiness,

confusion,

difficulty

breathing,

shallow

breathing,

limpness, or

difficulty

breastfeeding.

These are not all the

possible side effects of

Butalbital,

Acetaminophen,

Caffeine, and Codeine

Phosphate Capsules.

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: Actavis

Pharma, Inc.,

Parsippany, NJ 07054

©2019 Teva

Pharmaceuticals USA,

Inc. All rights reserved.

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

Revised: 10/2019

Revised: 10/2019

Document Id: bf9b2caa-b9b0-4a5d-90cf-201b6d22fb87

34391-3

Set id: a58819b8-a52c-44a7-9ab0-c74480d98506

Version: 27

Effective Time: 20191017

Actavis Pharma, Inc.

BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE- butalbital,

acetaminophen, caffeine, and codeine phosphate capsule

Actavis Pharma, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules safely and effectively. See full prescribing information for Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for oral use, CIII

Initial U.S. Approval: 1992

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY

(REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM

CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; 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; and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules expose users to the risks of

addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before

prescribing and monitor regularly for these behaviors and conditions. (5.1)

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. (5.2)

Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon

initiation or following a dose increase. (5.3)

Accidental ingestion of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules,

especially by children, can result in fatal overdose. Keep out of reach of children. (5.3)

Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous system

(CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma,

and death. Reserve concomitant prescribing for use in patients for whom alternative treatment

options are inadequate; limit dosages and durations to the minimum required; and follow patients for

signs and symptoms of respiratory depression and sedation. (5.4, 7)

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

most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of

being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. (5.5). Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in children younger

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

adenoidectomy (4). Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules 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.

Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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. (5.6)

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules requires

careful consideration of the effects on codeine, and the active metabolite, morphine. (5.7, 7)

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. (5.8)

RECENT MAJOR CHANGES

Dosage and Administration (2.3) 10/2019

Warnings and Precautions (5.3, 5.16) 10/2019

INDICATIONS AND USAGE

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsule is a combination product of butalbital, a barbiturate;

acetaminophen; caffeine, a methylxanthine; and codeine phosphate, an opioid agonist; and is indicated for the management

of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesic and alternative

treatments are inadequate. (1)

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules for use in patients for whom alternative treatment options

(e.g., non-opioid, non-barbiturate analgesics):

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

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

DOSAGE AND ADMINISTRATION

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1)

Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for

addiction, abuse, and misuse. (2.1)

Initiate treatment with one or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6

capsules. (2.2)

Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a physically

dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms,

uncontrolled pain, and suicide. (2.3)

DOSAGE FORMS AND STRENGTHS

Capsules: 50 mg butalbital, 325 mg acetaminophen, 40 mg caffeine, and 30 mg codeine phosphate.

CONTRAINDICATIONS

Children younger than 12 years of age. (4)

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

Significant respiratory depression. (4)

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. (4)

Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)

Intolerance or hypersensitivity to acetaminophen, caffeine, butalbital or codeine, or components of Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules. (4)

Porphyria. (4)

WARNINGS AND PRECAUTIONS

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

Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.9)

Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the

opioid. (5.11)

Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Butalbital, Acetaminophen, Caffeine,

and Codeine Phosphate Capsules in patients with circulatory shock. (5.12)

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

Monitor for sedation and respiratory depression. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules in patients with impaired consciousness or coma. (5.13)

ADVERSE REACTIONS

Frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea,

vomiting, abdominal pain, and intoxicated feeling. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis Pharma, Inc. at 1-800-272-5525 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules if serotonin syndrome is suspected. (7)

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Butalbital, Acetaminophen, Caffeine,

and Codeine Phosphate Capsules because they may reduce analgesic effect of Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules or precipitate withdrawal symptoms. (7)

USE IN SPECIFIC POPULATIONS

Pregnancy: May cause fetal harm. (8.1)

Lactation: Breastfeeding not recommended. (8.2)

Geriatric: Respiratory depression has occurred after large initial doses were administered. Increase dosage slowly.

(8.5)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 10/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

RECENT MAJOR CHANGES

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

STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION;

ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; 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; and

HEPATOTOXICITY

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Dosing Information

2.3 Safe Reduction or Discontinuation of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

5.3 Life-Threatening Respiratory Depression

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

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

Depression in Children

5.6 Neonatal Opioid Withdrawal Syndrome

5.7 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.8 Hepatotoxicity

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

Elderly, Cachectic, or Debilitated Patients

5.10 Interaction with Monoamine Oxidase Inhibitors

5.11 Adrenal Insufficiency

5.12 Severe Hypotension

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

Impaired Consciousness

5.14 Risks of Use in Patients with Gastrointestinal Conditions

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

5.16 Withdrawal

5.17 Risks of Driving and Operating Machinery

5.18 Serious Skin Reactions

5.19 Hypersensitivity/Anaphylaxis

5.20 Drug/Laboratory Test Interactions

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

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

MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE

WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; 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; and HEPATOTOXICITY

Addiction, Abuse, and Misuse

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules, and monitor all patients regularly for the

development of these behaviors and conditions [see Warnings and Precautions (5.1)].

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 and Precautions (5.2)]. 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Monitor for respiratory

depression, especially during initiation of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules or following a dose increase [see Warnings and Precautions (5.3)].

Accidental Ingestion

Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules, especially by children, can result in a fatal overdose of Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous

system (CNS) depressants, including alcohol, may result in profound sedation, respiratory

depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].

Reserve concomitant prescribing of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules 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.

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 an ultra-rapid metabolizer

of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions (5.5)]. Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 (4)]. Avoid the use of Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

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 and Precautions (5.6)].

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 Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules requires careful consideration of the effects on codeine, and

the active metabolite, morphine [see Warnings and Precautions (5.7)].

Hepatotoxicity

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain

acetaminophen. 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 and Precautions

(5.8)].

1 INDICATIONS AND USAGE

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are indicated for the management

of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and

alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended

doses [see Warnings and Precautions (5.1)], reserve Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-

barbiturate analgesics]:

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

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

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

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

goals [see Warnings and Precautions (5)].

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 and Precautions (5.1)].

Evidence supporting the efficacy and safety of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules in the treatment of multiple recurrent headaches is unavailable.

2.2 Dosing Information

One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6

capsules.

2.3 Safe Reduction or Discontinuation of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules

Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, there are a variety

of factors that should be considered, including the dose of Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 and Precautions (5.16), Drug Abuse

and Dependence (9.3)].

3 DOSAGE FORMS AND STRENGTHS

Capsules: Butalbital 50 mg, Acetaminophen 325 mg, Caffeine 40 mg, Codeine Phosphate 30 mg

Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted

with “3220” in red.

4 CONTRAINDICATIONS

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for:

All children younger than 12 years of age [see Warnings and Precautions (5.5)].

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

adenoidectomy [see Warnings and Precautions (5.5)].

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are also contraindicated in

patients with:

Significant respiratory depression [see Warnings and Precautions (5.3)]

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative

equipment [see Warnings and Precautions (5.9)]

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

[see Warnings and Precautions (5.10), Drug Interactions (7)]

Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and

Precautions (5.14)]

Known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the

components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

Porphyria

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in

combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. As

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain butalbital and codeine,

they expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

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

prescribed Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Addiction can occur

at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor all patients receiving

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules, but use in such patients necessitates intensive counseling

about the risks and proper use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids and barbiturates are sought by drug abusers and people with addiction disorders and are subject

to criminal diversion. Consider these risks when prescribing or dispensing Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules. 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 Patient Counseling Information (17)]. 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.

5.2 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 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can

be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.3 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 (10)].

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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

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

Caffeine, and Codeine Phosphate Capsules are essential [see Dosage and Administration (2.2)].

Overestimating the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage when

converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of (or exposure to) Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules, especially by children, can result in respiratory depression and death due to an overdose of

codeine and butalbital.

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 (2.3)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Drug Interactions (7)].

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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Drug Interactions (7), Patient Counseling Information

(17)].

5.5 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 of age 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:

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all

children younger than 12 years of age [see Contraindications (4)].

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-

operative management in pediatric patients younger than 18 years of age following tonsillectomy

and/or adenoidectomy [see Contraindications (4)].

Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 post-operative status, obstructive sleep

apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other

medications that cause respiratory depression.

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 Use in Specific Populations (8), Overdosage (10)].

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules [see Use in Specific Populations (8.2)].

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (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 (10)]. Therefore, individuals who are ultra-rapid metabolizers

should not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

5.6 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Use in Specific Populations (8.1, 8.2), Patient Counseling Information

(17)].

5.7 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules require

careful consideration of the effects on codeine and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and

opioid withdrawal when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are

used in conjunction with inhibitors and inducers of CYP3A4.

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

consider dosage reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal [see Drug

Interactions (7)].

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

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid

withdrawal when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules dosage. After stopping use of a CYP2D6 inhibitor, consider reducing

the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage and follow the

patient for signs and symptoms of respiratory depression or sedation [see Drug Interactions (7)].

5.8 Hepatotoxicity

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain acetaminophen.

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

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

doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing

product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional

as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing

products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals

who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one

product that contains acetaminophen. Instruct patients to seek medical attention immediately upon

ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

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

Elderly, Cachectic, or Debilitated Patients

The use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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: Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules-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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see

Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to

occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or

altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

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

Caffeine, and Codeine Phosphate Capsules and when Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules are given concomitantly with other drugs that depress respiration [see Warnings and

Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.10 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. Butalbital, Acetaminophen, Caffeine,

and Codeine Phosphate Capsules should not be used in patients taking MAOIs or within 14 days of

stopping such treatment.

5.11 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than

one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs

including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal

insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal

insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the

patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until

adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid

without recurrence of adrenal insufficiency. The information available does not identify any particular

opioids as being more likely to be associated with adrenal insufficiency.

5.12 Severe Hypotension

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the

dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In patients with

circulatory shock, Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause

vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock.

5.13 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), Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules.

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

Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with impaired consciousness or

coma.

5.14 Risks of Use in Patients with Gastrointestinal Conditions

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in patients

with known or suspected gastrointestinal obstruction, including paralytic ileus.

The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules therapy.

5.16 Withdrawal

Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine in a patient physically

dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and Codeine in a patient

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

Administration (2.3), Drug Abuse and Dependence (9.3)].

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In these

patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or

precipitate withdrawal symptoms.

When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, in a

physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.3)]. Abrupt

discontinuation of butalbital can cause seizures [see Drug Abuse and Dependence (9.3)].

5.17 Risks of Driving and Operating Machinery

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and know how they

will react to the medication.

5.18 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.

5.19 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 Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules immediately and seek medical care if they experience these

symptoms. Do not prescribe Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for

patients with acetaminophen allergy.

5.20 Drug/Laboratory Test Interactions

Codeine: Codeine may increase serum amylase levels.

Acetaminophen: Acetaminophen may produce false positive test results for urinary

5 hydroxyindoleacetic acid.

6 ADVERSE REACTIONS

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

sections:

Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]

Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions (5.4)]

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

Depression in Children [see Warnings and Precautions (5.5)]

Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.6)]

Hepatotoxicity [see Warnings and Precautions (5.8)]

Adrenal Insufficiency [see Warnings and Precautions (5.11)]

Severe Hypotension [see Warnings and Precautions (5.12)]

Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)]

Seizures [see Warnings and Precautions (5.15)]

Withdrawal [see Warnings and Precautions (5.16)]

Serious Skin Reactions [see Warnings and Precautions (5.18)]

Anaphylaxis [see Warnings and Precautions (5.19)]

The following adverse reactions associated with the use of butalbital, acetaminophen, caffeine, and

codeine phosphate were identified in clinical studies or post-marketing 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.

Frequently Observed

The most frequently reported adverse reactions were drowsiness, lightheadedness, dizziness, sedation,

shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling.

Infrequently Observed

All adverse events tabulated below are classified as infrequent.

Central Nervous: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high

energy, hot spells, numbness, sluggishness, seizure. Mental confusion, excitement or depression can

also occur due to intolerance, particularly in elderly or debilitated patients, or due to overdosage of

butalbital.

Autonomic Nervous: dry mouth, hyperhidrosis.

Gastrointestinal: difficulty swallowing, heartburn, flatulence, constipation.

Cardiovascular: tachycardia.

Musculoskeletal: leg pain, muscle fatigue.

Genitourinary: diuresis.

Miscellaneous: pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions.

The following adverse reactions have been voluntarily reported as temporally associated with

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, a related product containing aspirin,

butalbital, caffeine, and codeine phosphate.

Central Nervous: abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido

decrease, nervousness, neuropathy, psychosis, sexual activity increase, slurred speech, twitching,

unconsciousness, vertigo.

Autonomic Nervous: epistaxis, flushing, miosis, salivation.

Gastrointestinal: anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal

spasms, hiccup, mouth burning, pyloric ulcer.

Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope.

Skin: erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis.

Urinary: kidney impairment, urinary difficulty.

Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with

erythromycin (stomach upset), edema.

The following adverse reactions have been reported with the components of Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules. Potential effects of high dosage are listed in the

OVERDOSAGE section.

Acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis.

Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.

Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.

Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema

multiforme, have been reported for butalbital, acetaminophen, and caffeine tablets, USP.

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.

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

Clinical Pharmacology (12.2)].

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules.

Table 1: Clinically Significant Drug Interactions with Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules with CYP3A4 inhibitors 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

is achieved [see Warnings and Precautions (5.7)].

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 2D6 with resultant lower morphine levels [see Clinical

Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal

syndrome in patients who had developed physical dependence to codeine.

Intervention:

If concomitant use with CYP3A4 inhibitor is necessary, consider dosage

reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable

drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.

ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice

CYP3A4 Inducers

Clinical Impact:

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules and CYP3A4 inducers can result in lower codeine levels,

greater norcodeine levels, and less metabolism via 2D6 with resultant lower

morphine levels [see Clinical Pharmacology (12.3)], resulting in decreased

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

physical dependence [see Warnings and Precautions (5.7)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the

codeine plasma concentration may increase with subsequently greater

metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see

Clinical Pharmacology (12.3)], which could increase or prolong both the

therapeutic effects and adverse reactions, and may cause serious respiratory

depression.

Intervention:

If concomitant use of a CYP3A4 inducer is necessary, follow the patient for

reduced efficacy and signs of opioid withdrawal and consider increasing the

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage

as needed.

If a CYP3A4 inducer is discontinued, consider Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules dosage reduction, and monitor for

signs of respiratory depression and sedation at frequent intervals.

Examples:

Rifampin, carbamazepine, phenytoin

Inhibitors of CYP2D6

Clinical Impact:

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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and

CYP2D6 inhibitors can increase the plasma concentration of codeine, but can

decrease the plasma concentrations 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see

Clinical Pharmacology (12.3)].

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, which could increase or prolong adverse

reactions and may cause potentially fatal respiratory depression [see Clinical

Pharmacology (12.3)].

Intervention:

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

inhibitor is discontinued after concomitant use, consider dosage adjustment of

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules and monitor the

patient for signs and symptoms of respiratory depression or sedation.

Examples:

paroxetine, fluoxetine, bupropion, quinidine

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines

or other CNS depressants, including alcohol, can increase the risk of

hypotension, respiratory depression, profound sedation, coma, and death.

Intervention:

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 and Precautions (5.4)].

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers,

muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs

Clinical Impact:

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

neurotransmitter system has resulted in serotonin syndrome.

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly

during treatment initiation and dose adjustment. Discontinue Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules if serotonin

syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine

reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3

receptor antagonists, drugs that affect the serotonin neurotransmitter system

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

cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those

intended to treat psychiatric disorders and also others, such as linezolid and

intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid

toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions

(5.10)].

Intervention:

Do not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules in patients taking 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, hydromorphone, or buprenorphine) to treat pain while closely

monitoring blood pressure and signs and symptoms of CNS and respiratory

depression.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules and/or precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact:

Codeine may enhance the neuromuscular blocking action of skeletal muscle

relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

otherwise expected and decrease the dosage of Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules and/or the muscle relaxant as

necessary.

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of

antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood

pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary

retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility

when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

are used concomitantly with anticholinergic drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome

[see Warnings and Precautions (5.6)]. Available data with Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules in pregnant women are insufficient to inform a drug-associated risk for

major birth defects and miscarriage. Animal reproduction studies have not been conducted with the

combination of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or with butalbital

alone. In animal reproduction studies, codeine administration during organogenesis has been shown to

produce delayed ossification in the offspring of mice at 2.8 times maximum recommended human dose

(MRHD) of 180 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at

approximately 4 to 6 times the MRHD, and cranial malformations/cranioschisis in the offspring of

hamsters between 2 and 8 times the MRHD. Reproductive and developmental studies in rats and mice

from the published literature identified adverse events at clinically relevant doses with acetaminophen.

Treatment of pregnant rats with doses of acetaminophen approximately 2 times the maximum human daily

dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In

another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses

approximately 2 times the MHDD. In mice treated with acetaminophen at doses within the clinical

dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A

reduction in number of litters of the parental mating pair was observed as well as retarded growth and

abnormal sperm in their offspring and reduced birth weight in the next generation [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All

pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general

population, the estimated background risk of major birth defects and miscarriage in clinically

recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or non-medical 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 and

Precautions (5.6)].

Labor or Delivery

Use of codeine during labor may lead to respiratory depression in the neonate.

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. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules are not recommended for use in pregnant women during or immediately prior to labor, when

other analgesic techniques are more appropriate. Opioid analgesics, including Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules, 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.

Data

Human Data

Published data from a large population-based prospective cohort study and a population-based, case-

control study do not clearly report an association with oral acetaminophen and major birth defects,

miscarriage, or adverse maternal or fetal outcomes when acetaminophen is used during pregnancy.

However, these studies cannot definitely establish the absence of any risk because of methodological

limitations including recall bias.

Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital

containing drug during the last 2 months of pregnancy. Butalbital was found in the infant's serum. The

infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal

symptoms.

Animal Data

Animal reproduction studies have not been conducted with Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules or with butalbital alone.

The following data are based on findings from studies performed with either codeine or acetaminophen

alone.

Codeine

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral;

approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m

basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were

reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of

50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an

earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral;

approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m

basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended

daily dose of 180 mg/day for adults on a mg/m basis) during organogenesis, in the toxic range for the

adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended

daily dose of 180 mg/day for adults on a mg/mg basis) administered between Gestation Day 7 and 12

reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the

maximum recommended daily dose of 180 mg/day for adults on a mg/m basis) of codeine during

organogenesis.

Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after

delivery increased neonatal mortality at birth. This dose is 1.6 times the maximum recommended human

dose of 180 mg/day on a body surface area comparison.

Acetaminophen

Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.7 the

maximum human daily dose (MHDD) of 1950 mg/day based on a body surface area comparison showed

evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations

(reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or

skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses

of 2.4 times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both

the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received

oral acetaminophen at doses 0.6 times the MHDD, based on a body surface area comparison. In a

continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357,

715, or 1430 mg/kg/day). These doses are approximately 0.86, 1.7, and 3.4 times the MHDD,

respectively, based on a body surface area comparison. A dose-related reduction in body weights of

fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at

all doses. Animals in the high dose group had a reduced number of litters per mating pair, male

offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next

generation pups.

Caffeine

In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as

sustained release pellets at 50 mg/kg (less than the maximum recommended daily dose on a mg/m basis),

during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the

fetuses.

8.2 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 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Warnings and Precautions (5.5)].

Acetaminophen is present in human milk in small quantities after oral administration. Based on data from

more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to

2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that

resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen

use.

Barbiturates and caffeine are also excreted in breast milk in small amounts. Because of potential for

serious adverse reactions in nursing infants from Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules, a decision should be made whether to discontinue nursing or to discontinue the

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

Clinical Considerations

If infants are exposed to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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.

8.3 Females and Males of Reproductive Potential

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 (6), Clinical

Pharmacology (12.2), Nonclinical Pharmacology (13.1)].

Published literature indicates that acetaminophen affects sperm development in mice with consequent

reduction in litter size in a multigeneration study [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

in pediatric patients have not been established.

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

[see Warnings and Precautions (5.5)]. 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:

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all

children younger than 12 years of age [see Contraindications (4)].

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-

operative management in pediatric patients younger than 18 years of age following tonsillectomy

and/or adenoidectomy [see Contraindications (4)].

Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 post-operative status, obstructive sleep

apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other

medications that cause respiratory depression [see Warnings and Precautions (5.5)].

8.5 Geriatric Use

Clinical studies of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules did not

include sufficient numbers of subjects aged 65 and over to determine whether they respond differently

from younger subjects. Other reported clinical experience has not identified differences in responses

between the elderly and younger patients. In general, dose selection for an elderly patient should be

cautious, 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.

Butalbital is known to be substantially excreted by the kidney, and the risk of toxic 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.

Elderly patients (aged 65 years or older) may have increased sensitivity to Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules. 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 Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules slowly in geriatric patients and monitor

closely for signs of respiratory depression [see Warnings and Precautions (5.9)].

Components of this product 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.

8.6 Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of

butalbital, codeine, and acetaminophen in this patient population are unknown. Start these patients

cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while

carefully monitoring for side effects.

8.7 Renal Impairment

Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and

the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared

to patients with normal renal function. Start these patients cautiously with lower doses of codeine

sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In

patients with renal disease, monitor effects of therapy with serial renal function tests.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in

combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance.

9.2 Abuse

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contains codeine, a substance

with a high potential for abuse similar to other opioids including fentanyl, hydrocodone,

hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules can be abused and is subject to misuse,

addiction, and criminal diversion [see Warnings and Precautions (5.1)].

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

provider(s). “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.

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are for oral use only. Abuse of

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules poses a risk of overdose and

death. The risk is increased with concurrent use of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules with alcohol and other central nervous system depressants.

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

and HIV.

Butalbital

Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may

occur especially following prolonged use of high doses of barbiturates. The average daily dose for

the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount

needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does

not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal

dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major

withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after

abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of

approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual

withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different

withdrawal regimens. One method involves initiating treatment at the patient's regular dosage level and

gradually decreasing the daily dosage as tolerated by the patient.

9.3 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a

patient physically dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, gradually

taper the dosage using a patient-specific plan that considers the following: the dose of Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 (2.3), Warnings and Precautions

(5.16)].

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

exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

10 OVERDOSAGE

Clinical Presentation

Acute overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 [see Clinical Pharmacology (12.2)].

Signs and Symptoms

Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma;

respiratory depression; hypotension; and hypovolemic shock.

Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of

respiration, and loss of consciousness. Convulsions may occur.

In acetaminophen overdosage: dose dependent, potentially fatal hepatic necrosis is the most serious

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

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

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

apparent until 48 to 72 hours post-ingestion. Acute caffeine poisoning may cause insomnia,

restlessness, tremor, and delirium, tachycardia, and extrasystoles.

Treatment of Overdose

In case of overdose, priorities are the re-establishment 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 arrhythmias will require advanced life-support techniques.

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 codeine phosphate 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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, carefully monitor the patient

until spontaneous respiration is reliably re-established. 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.

A single or multiple drug overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules is a potentially lethal polydrug overdose, and consultation with a regional poison control

center is recommended. Immediate treatment includes support of cardiorespiratory function and

measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive

measures should be employed as indicated. Assisted or controlled ventilation should also be

considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral

naloxone is a specific and effective antagonist.

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.

11 DESCRIPTION

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are supplied in capsule form for

oral administration. Each capsule contains:

Butalbital, USP…………..........50 mg

Acetaminophen, USP………...325 mg

Caffeine, USP……………........40 mg

Codeine phosphate, USP….......30 mg

Butalbital (5-allyl-5-isobutylbarbituric acid), is a short-to intermediate-acting barbiturate. It has the

following structural formula:

Acetaminophen (4'hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has

the following structural formula:

Caffeine (1,3,7trimethylxanthine), a methylxanthine, is a central nervous system stimulant. 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) is an opioid agonist. It has the following structural formula:

Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch. Gelatin

capsules contain D&C Red No. 33, FD&C Blue No. 1, gelatin, and titanium dioxide. The capsules are

printed with edible inks containing D&C Red No. 7 Calcium Lake, FD&C Blue No. 1 Aluminum Lake,

and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Butalbital, a barbiturate, is a GABA receptor agonist and may inhibit excitatory AMPA receptors.

The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to

involve central actions.

Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is

not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors.

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.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Butalbital, a barbiturate, is a central nervous system (CNS) depressant that can produce sedation,

respiratory depression, and euphoria. The potential impact of butalbital on painful stimuli is not clear

and in some individuals barbiturates may increase reaction to painful stimuli.

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 to 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.

Acetaminophen has been shown to have analgesic activity in animal and human studies.

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

Butalbital may decrease blood pressure and heart rate when administered at sedative and hypnotic doses.

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 and 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 (6)]. 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 (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro

and animal models. 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 (2.1, 2.2)].

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 (2.1, 2.2, 2.3)].

12.3 Pharmacokinetics

The behavior of the individual components is described below.

Butalbital

Absorption

Butalbital is well absorbed from the gastrointestinal tract.

Distribution

Butalbital is expected to distribute to most tissues in the body. Barbiturates in general may appear in

breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a

varying degree and binding increases directly as a function of lipid solubility.

The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20

mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other

barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood

concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into

either plasma or blood cells.

Elimination

Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or

metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug

(about 3.6% of the dose), 5-isobutyl-5-(2,3dihydroxypropyl) barbituric acid (about 24% of the dose), 5-

allyl-5-(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the

barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified

materials. Of the material excreted in the urine, 32% is conjugated.

[See Overdosage (10) for toxicity information].

Acetaminophen

Absorption

Acetaminophen is rapidly absorbed from the gastrointestinal tract.

Metabolism

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.

Distribution

Distribution

Acetaminophen is distributed throughout most body tissues. A small fraction (10-25%) of

acetaminophen is bound to plasma proteins.

Elimination

Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal

excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of

administration, most as the glucuronide conjugate, with small amounts of other conjugates and

unchanged drug. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and

following overdosage. [See Overdosage (10) for toxicity information].

Caffeine

Absorption

Like most xanthines, caffeine is rapidly absorbed.

Distribution

Caffeine is distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.

Elimination

Caffeine is cleared through metabolism and excretion in the urine.

Metabolism

Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and

CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in

about equal amounts of 1methylxanthine and 1-methyluric acid.

Excretion

Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug. The plasma half-life

is about 3 hours.

[See Overdosage (10) for toxicity information].

Codeine

Absorption

Codeine is readily absorbed from the gastrointestinal tract. At therapeutic doses, the analgesic effect

reaches a peak within 2 hours and persists between 4 and 6 hours.

Distribution

Codeine 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; however, codeine is not bound to plasma proteins

and does not accumulate in body tissues.

Elimination

Metabolism

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

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

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.

Excretion

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 (about 4%), and

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

[See Overdosage (10) for toxicity information].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of the combination of butalbital,

acetaminophen, caffeine, and codeine or butalbital alone have not been conducted.

Two-year carcinogenicity studies with codeine sulfate 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 4 times the maximum

recommended daily dose of 180 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 10 times the maximum recommended daily dose of 180 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 1.6 times the maximum human daily dose (MHDD) of 1950 mg/day, based on a body surface

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

up to 1.4 times or mice at up to 2.4 to 2.8 times the MHDD, based on a body surface area comparison.

In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was

not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg

(approximately 4 and 7 times, respectively, the maximum human daily dose on a mg/m basis). In an 18-

month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg

(equivalent to the MHDD on a mg/m basis).

Mutagenesis

There are no genetic toxicology data for butalbital.

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 (7.2-times the MHDD, based on a body surface area comparison). In

contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (3.6-times the MHDD, based on a body

surface area comparison), suggesting a threshold effect.

Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase

(exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the

genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient

mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary

cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine

guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In

addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine was negative in

the in vitro bacterial reverse mutation assay (Ames test).

Impairment of Fertility

No adequate studies have been conducted in animals to characterize the impact of the combinations of

butalbital, acetaminophen, caffeine, and codeine on fertility. There are also no data on butalbital alone or

codeine alone.

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 3.4 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 3.6

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

2.4 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.

Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (2 times the

MHDD on a mg/m basis) for 4 days prior to mating with untreated females, caused decreased male

reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high

oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell

degeneration.

16 HOW SUPPLIED/STORAGE AND HANDLING

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted

with “3220” in red. Bottles of 100 are supplied with child-resistant closures (NDC 0591-3220-01).

Store below 30°C (86°F); and dispense in a tight container.

Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of

properly [see Patient Counseling Information (17)].

17 PATIENT COUNSELING INFORMATION

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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely, out of sight and reach

of children, and in a location not accessible by others, including visitors to the home [see Warnings and

Precautions (5.1, 5.3), Drug Abuse and Dependence (9.2)]. Inform patients that leaving Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules by following these four steps:

Mix Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules,

even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose

and death [see Warnings and Precautions (5.1)]. Instruct patients not to share Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules with others and to take steps to protect Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or when

the dosage is increased, and that it can occur even at recommended dosages [see Warnings and

Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical

attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or

death [see Warnings and Precautions (5.3)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (Including Alcohol)

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

Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used with benzodiazepines or other

CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a

healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

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

Depression in Children

Advise caregivers that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 12-18 years of age

receiving codeine to monitor for signs of respiratory depression [see Warnings and Precautions (5.5)].

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 of serotonin syndrome

and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians

if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

MAOI Interaction

Inform patients not to take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules while

using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Drug Interactions (7)].

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 and Precautions (5.11)].

Important Administration Instructions

Instruct patients how to properly take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules, including the following:

To take the drug only for as long as it is prescribed, in the amounts prescribed, and no more

frequently than prescribed [see Dosage and Administration (2.1, 2.2)].

Do not take more than 4000 milligrams of acetaminophen per day and to call their healthcare

provider if they took more than the recommended dose.

Important Discontinuation Instructions

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

Acetaminophen, Caffeine, and Codeine Phosphate Capsules without first discussing a tapering plan with

the prescriber [see Dosage and Administration (2.3)].

Severe Hypotension

Inform patients that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause

orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood

pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie

down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Butalbital,

Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Advise patients how to recognize such a

reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules during pregnancy can result in neonatal opioid withdrawal

syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions

(5.6), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules can cause fetal harm and to inform their healthcare provider of a known or

suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules [see Use in Specific Populations (8.2)].

Infertility

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

effects on fertility are reversible [see Adverse Reactions (6)].

Risks of Driving and Operating Heavy Machinery

Inform patients that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may impair

the ability to perform potentially hazardous activities such as driving a car or operating heavy

machinery. Advise patients not to perform such tasks until they know how they will react to the

medication [see Warnings and Precautions (5.17)].

Constipation

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

seek medical attention [see Adverse Reactions (6)].

Distributed By: Actavis Pharma, Inc.

Parsippany, NJ 07054

©2019 Teva Pharmaceuticals USA, Inc. All rights reserved.

Rev. 10/2019

Medication Guide

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, C III

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are:

A strong prescription pain medicine that contains an opioid (narcotic) that is indicated for the relief

of the symptom complex of tension (or muscle contraction) headache, 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Caps ules :

Get emergency help right away if you take too much Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules (overdose). When you first start taking Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules, 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules. They could die from taking it. Selling or giving away Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules is against the law.

Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely, out of sight

and reach of children, and in a location not accessible by others, including visitors to the home.

Get emergency help right away if you take more than 4,000 mg of acetaminophen in 1 day. Taking

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with other products that

contain acetaminophen can lead to serious liver problems and death.

Important Information Guiding Use in Pediatric Patients:

Do not give Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a child

younger than 12 years of age.

Do not give Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a child

younger than 18 years of age after surgery to remove the tonsils and/or adenoids.

Avoid giving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if you have:

severe asthma, trouble breathing, or other lung problems.

a bowel blockage or have narrowing of the stomach or intestines.

Before taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, tell your

healthcare provider if you have a history of:

head injury, seizures

problems urinating

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

liver, kidney, thyroid problems

pancreas or gallbladder problems

Tell your healthcare provider if you are:

pregnant or planning to become pregnant. Prolonged use of Butalbital, Acetaminophen,

Caffeine, and Codeine Phosphate Capsules, 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

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with certain other medicines

can cause serious side effects that could lead to death.

When taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

Do not change your dose. Take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the

shortest time needed.

Take your prescribed dose of 1 or 2 capsules every 4 hours. Total daily dosage should not exceed

6 capsules. Do not take more than your prescribed dose. If you miss a dose, take your next dose at

your usual time.

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

If you have been taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

regularly, do not stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

without talking to your healthcare provider.

After you stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules,

dispose the unused Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in

accordance with the local state guidelines and/or regulations.

Dispose of expired, unwanted, or unused Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules by taking your drug to an authorized DEA-registered collector or drug take-

back program. If one is not available, you can dispose of Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules 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.

While taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules DO NOT:

Drive or operate heavy machinery, until you know how Butalbital, Acetaminophen, Caffeine, and

Codeine Phosphate Capsules affect you. Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules 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 Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules may cause you to overdose and die.

The possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Caps ules :

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.

are a nursing mother taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules,

and your breastfeeding baby has increased sleepiness, confusion, difficulty breathing, shallow

breathing, limpness, or difficulty breastfeeding.

These are not all the possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine

Phosphate Capsules. 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: Actavis Pharma, Inc., Parsippany, NJ 07054

©2019 Teva Pharmaceuticals USA, Inc. All rights reserved.

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

Revised: 10/2019

Package/Label Display Panel

NDC 0591-3220-01

CIII

50mg, 325mg, 40mg, 30mg

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

Medication Guide Required: Dispense the accompanying Medication Guide to each patient.

Actavis

100 Capsules

Rx Only

BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE

butalbital, acetaminophen, caffeine, and codeine phosphate capsule

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 59 1-3220

Route of Administration

ORAL

DEA Sche dule

CIII

Actavis Pharma, Inc.

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 30 mg

BUTALBITAL (UNII: KHS0 AZ4JVK) (BUTALBITAL - UNII:KHS0 AZ4JVK)

BUTALBITAL

50 mg

CAFFEINE (UNII: 3G6 A5W338 E) (CAFFEINE - UNII:3G6 A5W338 E)

CAFFEINE

40 mg

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

ACETAMINOPHEN

325 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

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

STARCH, CO RN (UNII: O8 232NY3SJ)

D&C RED NO . 3 3 (UNII: 9 DBA0 SBB0 L)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

GELATIN (UNII: 2G8 6 QN327L)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

D&C RED NO . 7 (UNII: ECW0 LZ41X8 )

Product Characteristics

Color

BLUE (DARK BLUE) , WHITE (OPAQUE WHITE)

S core

no sco re

S hap e

CAPSULE

S iz e

22mm

Flavor

Imprint Code

WATSON;3220

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 59 1-3220 -0 1

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /18 /20 0 3

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA AUTHORIZED GENERIC

NDA0 20 232

0 9 /18 /20 0 3

Labeler -

Actavis Pharma, Inc. (119723554)

Revised: 10/2019

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