PROMETHAZINE WITH CODEINE- promethazine hydrochloride and codeine phosphate solution

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

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Active ingredient:
PROMETHAZINE HYDROCHLORIDE (UNII: R61ZEH7I1I) (PROMETHAZINE - UNII:FF28EJQ494), CODEINE PHOSPHATE (UNII: GSL05Y1MN6) (CODEINE ANHYDROUS - UNII:UX6OWY2V7J)
Available from:
ATLANTIC BIOLOGICALS CORP.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Promethazine with Codeine Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. Important Limitations of Use - Not indicated for pediatric patients under 18 years of age [see Use in Specific Populations (8.4) ]. - Contraindicated in pediatric patients under 12 years of age [see Contraindications (4), Use in Specific Populations (8.4) ]. - Contraindicated in pediatric patients 12 to 18 years of age after tonsillectomy or adenoidectomy [see Contraindications (4), Use in Specific Populations (8.4) ]. - Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1) ], reserve Promethazine with Codeine Oral Solution for use in adult  patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. -   Promethazine with Codei
Product summary:
Promethazine with Codeine Oral Solution, 6.25 mg and 10 mg per 5 mL, is a clear, purple solution, supplied as: NDC Number              Size 60432-606-16             16 fl. oz. (473 mL) bottle Keep bottles tightly closed. Store at 20° to 25°C (68° to 77°F).  [See USP Controlled Room Temperature.] Protect from light. Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure. Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.
Authorization status:
Abbreviated New Drug Application
Authorization number:
17856-0605-1

PROMETHAZINE WITH CODEINE- promethazine hydrochloride and codeine

phosphate solution

ATLANTIC BIOLOGICALS CORP.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PROMETHAZINE WITH CODEINE ORAL

SOLUTION safely and effectively. See full prescribing information for PROMETHAZINE WITH CODEINE

ORAL SOLUTION Initial U.S. Approval:1952

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

ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS

FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; PROMETHAZINE AND

RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS

AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR

OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME

See full prescribing information for complete boxed warning.

Promethazine with Codeine Oral Solution exposes users to risks of addiction, abuse, and misuse,

which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for

these behaviors and conditions. (5.1)

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

initiation or when used in patients at higher risk. (5.2)

Accidental ingestion of Promethazine with Codeine Oral Solution, especially by children, can result in

a fatal overdose of codeine. (5.2)

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. (5.3) Promethazine with

Codeine Oral Solution is 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

Promethazine with Codeine Oral Solution 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.

Postmarketing cases of respiratory depression, including fatalities have been reported with use of

promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory

depressant effects when promethazine is combined with other respiratory depressants, including

codeine. (5.4).

Ensure accuracy when prescribing, dispensing, and administering Promethazine with Codeine Oral

Solution. Dosing errors can result in accidental overdose and death. (2.1, 5.7)

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

or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the

parent drug, codeine, and the active metabolite, morphine. Avoid the use of Promethazine with

Codeine Oral Solution in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6

inhibitor. (5.9, 7.1, 7.2, 7.3)

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants,

including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid

the use of Promethazine with Codeine Oral Solution in patients taking benzodiazepines, other CNS

depressants, or alcohol. (5.10, 7.4)

Promethazine with Codeine Oral Solution is not recommended for use in pregnant women. Prolonged

use of Promethazine with Codeine Oral Solution during pregnancy can result in neonatal opioid

withdrawal syndrome, which may be life-threatening if not recognized and treated. If Promethazine

with Codeine Oral Solution is used 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 (5.19, 8.1)

RECENT MAJOR CHANGES

Boxed Warning 05/2018

Indications and Usage (1) 05/2018

Dosage and Administration (2.1, 2.2, 2.3) 05/2018

Contraindications (4) 05/2018

Warnings and Precautions (5.3, 5.4) 05/2018

Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,

5.9, 5.11, 5.16, 5.18, 5.19, 5.20) 05/2018

INDICATIONS AND USAGE

Promethazine with Codeine Oral Solution is a combination of codeine, an opioid agonist; and promethazine, a

phenothiazine, indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the

common cold in patients 18 years of age and older. (1)

Important Limitations of Use (1)

Not indicated for pediatric patients under 18 years of age.

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

with Codeine Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to

outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.

DOSAGE AND ADMINISTRATION

Adults 18 years of age and older : 5 mL every 4 to 6 hours as needed, not to exceed 6 doses (30 mL) in 24 hours. (2.2)

Measure Promethazine with Codeine Oral Solution with an accurate milliliter measuring device. (2.1, 5.7)

Do not increase the dose or dosing frequency. (2.1)

Prescribe for the shortest duration consistent with treatment goals. (2.3)

Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. (2.3)

Reevaluate patient prior to refilling. (2.3)

DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a flavored syrup

base. (3)

CONTRAINDICATIONS

Children younger than 12 years of age. (4)

Significant respiratory depression. (4)

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

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

Concurrent use of monoamine oxidase inhibitor (MAOI) therapy or within the last 14 days. (4)

History of an idiosyncratic reaction to promethazine or to other phenothiazines. (4)

Hypersensitivity to codeine or other opiates, promethazine, or any of the inactive ingredients in Promethazine with

Codeine Oral Solution.

WARNINGS AND PRECAUTIONS

See Boxed WARNINGS (5)

Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or

debilitated patients : Monitor closely, particularly during initiation of therapy. (5.6)

Activities requiring mental alertness : Avoid engaging in hazardous tasks requiring mental alertness such as driving or

operating machinery. (5.8)

Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors :

Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. (5.12)

Neuroleptic Malignant Syndrome : Monitor during therapy. (5.13)

Paradoxical Reactions : Monitor during therapy. (5.14)

Seizures in patients with seizure disorders : Monitor during therapy. (5.15)

Bone marrow depression : Use with caution in patients with bone marrow depression. (5.17)

Severe hypotension : Monitor during initiation of therapy. Avoid use in patients with circulatory shock. (5.18)

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

opioid. (5.20)

ADVERSE REACTIONS

Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical

performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, and

sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA, LLC at 1-800-445-4290 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch. (6)

DRUG INTERACTIONS

Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is

suspected. (7.5)

Muscle relaxants : Avoid concomitant use. (7.7)

Diuretics : Codeine may reduce the efficacy of diuretics. Monitor for reduced effect. (7.8)

Anticholinergic drugs : Concurrent use may cause paralytic ileus. (5.11, 7.9)

USE IN SPECIFIC POPULATIONS

Pregnancy : Avoid use in pregnant women. May cause fetal harm. (8.1)

Lactation : Breastfeeding not recommended. (8.2)

Renal Impairment : Use with caution in patients with severe renal impairment. (8.6)

Hepatic Impairment : Use with caution in patients with severe hepatic impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. (8)

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

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

DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE

AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION

IN CHILDREN; PROMETHAZINE AND RESPIRATORY DEPRESSION IN CHILDREN;

MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME

P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS

DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Recommended Dosage

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

5.2 Life-Threatening Respiratory Depression

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

Depression in Children

5.4 Promethazine and Respiratory Depression

5.5 Risks with Use in Pediatric Populations

5.6 Risks with Use in Other At-Risk Populations

5.7 Risk of Accidental Overdose and Death due to Medication Errors

5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery

5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

5.11 Risks of Use in Patients with Gastrointestinal Conditions

5.12 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial

Pressure, or Brain Tumors

5.13 Risk of Neuroleptic Malignant Syndrome

5.14 Risk of Paradoxical Reactions, including Dystonias

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

5.16 Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

5.17 Bone-Marrow Depression

5.18 Severe Hypotension

5.19 Neonatal Opioid Withdrawal Syndrome

5.20 Adrenal Insufficiency

5.21 Drug/Laboratory Test Interactions

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

7.1 Inhibitors of CYP3A4

7.2 CYP3A4 Inducers

7.3 Inhibitors of CYP2D6

7.4 Benzodiazepines, and Other Depressants

7.5 Serotonergic Drugs

7.6 Monoamine Oxidase Inhibitors (MAOIs)

7.7 Muscle Relaxants

7.8 Diuretics

7.9 Anticholinergic Drugs

8 USE IN SPECIFIC POPULATIONS

8.6 Pregnancy

8.7 Lactation

8.8 Females and Males of Reproductive Potential

8.9 Pediatric Use

8.10 Geriatric Use

8.11 Renal Impairment

8.12 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.4 Controlled Substance

9.5 Abuse

9.6 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.4 Mechanism of Action

12.5 Pharmacodynamics

12.6 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility

16 HOW SUPPLIED/STORAGE AND HANDLING

FULL PRESCRIBING INFORMATION

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

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

RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID

METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-

THREATENING RESPIRATORY DEPRESSION IN CHILDREN; PROMETHAZINE

AND RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS;

INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES;

CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS;

NEONATAL OPIOID WITHDRAWAL SYNDROME

Addiction, Abuse, and Misuse

Promethazine with Codeine Oral Solution exposes patients and other users to the risks of

opioid addiction, abuse, and misuse, which can lead to overdose and death. Reserve

Promethazine with Codeine Oral Solution for use in adult patients for whom the benefits of

cough suppression are expected to outweigh the risks, and in whom an adequate

assessment of the etiology of the cough has been made. Assess each patient's risk prior to

prescribing Promethazine with Codeine Oral Solution, prescribe Promethazine with

Codeine Oral Solution for the shortest duration that is consistent with individual patient

treatment goals, monitor all patients regularly for the development of addition or abuse, and

refill only after reevaluation of the need for continued treatment. [see Warnings and

Precautions (5.1)]

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of

Promethazine with Codeine Oral Solution. Monitor for respiratory depression, especially

during initiation of Promethazine with Codeine Oral Solution therapy or when used in

patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of Promethazine with Codeine Oral Solution,

especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions

(5.2)].

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 (5.3)].

Promethazine with Codeine Oral Solution is 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 Promethazine with Codeine Oral

Solution 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.

Promethazine and Respiratory Depression in Children

Postmarketing cases of respiratory depression, including fatalities have been reported with

use of promethazine in pediatric patients. Children may be particularly sensitive to the

additive respiratory depressant effects when promethazine is combined with other

respiratory depressants, including codeine. [see Warnings and Precautions (5.4)].

Risk of Medication Errors

Ensure accuracy when prescribing, dispensing, and administering Promethazine with

Codeine Oral Solution.Dosing errors can result in accidental overdose and death. Always

use an accurate milliliter measuring device when measuring and administering

Promethazine with Codeine Oral Solution [see Dosage and Administration (2.1), Warnings and

Precautions (5.7)].

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, requiring careful consideration of

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

of Promethazine with Codeine Oral Solution in patients who are taking a CYP3A4 inhibitor,

CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.9), Drug Interactions (7.1,

7.2, 7.3)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death. Avoid the use of Promethazine with Codeine Oral Solution in patients

taking benzodiazepines, other CNS depressants, or alcohol. [see Warnings and Precautions

(5.10), Drug Interactions (7.4)].

Neonatal Opioid Withdrawal Syndrome

Promethazine with Codeine Oral Solution is not recommended for use in pregnant women

[see Use in Specific Populations (8.1)]. Prolonged use of Promethazine with Codeine Oral

Solution 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 Promethazine with Codeine Oral Solution is

used 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 (5.20)].

1 INDICATIONS AND USAGE

Promethazine with Codeine Oral Solution is indicated for the temporary relief of coughs and upper

respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older.

Important Limitations of Use

Not indicated for pediatric patients under 18 years of age [see Use in Specific Populations (8.4) ].

Contraindicated in pediatric patients under 12 years of age [see Contraindications (4), Use in Specific

Populations (8.4) ].

Contraindicated in pediatric patients 12 to 18 years of age after tonsillectomy or adenoidectomy [see

Contraindications (4), Use in Specific Populations (8.4) ].

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see

Warnings and Precautions (5.1) ], reserve Promethazine with Codeine Oral Solution for use in adult

patients for whom the benefits of cough suppression are expected to outweigh the risks, and in

whom an adequate assessment of the etiology of the cough has been made.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Administer Promethazine with Codeine Oral Solution by the oral route only.

Always use an accurate milliliter measuring device when administering Promethazine with Codeine

Oral Solution to ensure that the dose is measured and administered accurately. A household teaspoon is

not an accurate measuring device and could lead to overdosage [see Warnings and Precautions (5.7)].

For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate

measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse

the measuring device with water after each use.

Advise patients not to increase the dose or dosing frequency of Promethazine with Codeine Oral

Solution because serious adverse events such as respiratory depression may occur with overdosage

[see Warnings and Precautions (5.1), Overdosage (10)]. The dosage of Promethazine with Codeine Oral

Solution should not be increased if cough fails to respond; an unresponsive cough should be

reevaluated for possible underlying pathology [see Dosage and Administration (2.3), Warnings and

Precautions (5.6)].

2.2 Recommended Dosage

Adults 18 years of age and older: 5 mL every 4 to 6 hours as needed, not to exceed 6 doses (30 mL) in

24 hours.

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

Prescribe Promethazine with Codeine Oral Solution for the shortest duration that is consistent with

individual patient treatment goals [see Warnings and Precautions (5.1)].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating

therapy [see Warnings and Precautions (5.2)].

Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology,

such as foreign body or lower respiratory tract disease [see Warnings and Precautions (5.5)]. If a patient

requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with

Promethazine with Codeine Oral Solution, the relative incidence of adverse reactions, and the

development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)].

Do not abruptly discontinue Promethazine with Codeine Oral Solution in a physically-dependent patient

[see Drug Abuse and Dependence (9.3)]. When a patient who has been taking Promethazine with Codeine

Oral Solution regularly and may be physically dependent no longer requires therapy with Promethazine

with Codeine Oral Solution, taper the dose gradually, by 25% to 50% every 2 to 4 days, while

monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or

symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval

between decreases, decreasing the amount of change in dose, or both.

3 DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg,

in a flavored syrup base [see Description (11)].

4 CONTRAINDICATIONS

Promethazine with Codeine Oral Solution is contraindicated for:

All children younger than 12 years of age [see Warnings and Precautions (5.2, 5.3, 5.5), Use in

Specific Populations (8.4) ].

Postoperative pain management in children younger than 18 years of age following tonsillectomy

and/or adenoidectomy [see Warnings and Precautions (5.2, 5.3) ].

Promethazine with Codeine Oral Solution is also contraindicated in patients with:

Significant respiratory depression [see Warnings and Precautions (5.2) ].

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

equipment [see Warnings and Precautions (5.6) ].

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

Precautions (5.11) ].

A history of an idiosyncratic reaction to promethazine or to other phenothiazines [see Warnings and

Precautions (5.14) ].

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [see

Warnings and Precautions (5.16), Drug Interactions (7.6) ].

Hypersensitivity to codeine, promethazine, or any of the inactive ingredients in Promethazine with

Codeine Oral Solution [see Adverse Reactions (6) ]. Persons known to be hypersensitive to certain

other opioids may exhibit cross-reactivity to codeine.

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

Promethazine with Codeine Oral Solution contains codeine, a Schedule V controlled substance. As an

opioid, Promethazine with Codeine Oral Solution exposes users to the risks of addiction, abuse, and

misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death [see Overdosage

(10)].Reserve Promethazine with Codeine Oral Solution for use in adult patients for whom the

benefits of cough suppression are expected to outweigh the risks, and in whom an adequate

assessment of the etiology of the cough has been made. Assess each patient's risk prior to

prescribing Promethazine with Codeine Oral Solution, prescribe Promethazine with Codeine

Oral Solution for the shortest duration that is consistent with individual patient treatment goals,

monitor all patients regularly for the development of addiction or abuse, and refill only after

reevaluation of the need for continued treatment.

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

prescribed Promethazine with Codeine Oral Solution. Addiction can occur at recommended dosages

and if the drug is misused or abused. 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).

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

diversion. Consider these risks when prescribing or dispensing Promethazine with Codeine Oral

Solution. 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 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids,

including codeine, one of the active ingredients in Promethazine with Codeine Oral Solution. Codeine

produces dose-related respiratory depression by directly acting on the brain stem respiratory center that

controls respiratory rhythm and may produce irregular and periodic breathing. Codeine is subject to

variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to the

active metabolite morphine [see Warnings and Precautions (5.3)]. Promethazine exerts a depressant

effect on the respiratory center that is independent of and additive to that of other respiratory

depressants, including codeine [see Warnings and Precautions (5.4)]. Respiratory depression, if not

immediately recognized and treated, may lead to respiratory arrest and death. Management of

respiratory depression includes discontinuation of Promethazine with Codeine Oral Solution, close

observation, supportive measures, and use of opioid antagonists (e.g. naloxone), 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

Promethazine with Codeine Oral Solution, the risk is greatest during the initiation of therapy, when

Promethazine with Codeine Oral Solution is used concomitantly with other drugs that may cause

respiratory depression [see Warnings and Precautions (5.10)], in patients with chronic pulmonary disease

or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance

(e.g. elderly, cachectic, or debilitated patients) [see Warnings and Precautions (5.6)].

To reduce the risk of respiratory depression, proper dosing of Promethazine with Codeine Oral

Solution is essential [see Dosage and Administration (2.1), Warnings and Precautions (5.7)]. Monitor

patients closely, especially within the first 24-72 hours of initiating therapy or when used in patients at

higher risk.

Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of

codeine in children younger than 12 years of age has been associated with fatal respiratory depression

when used as recommended [see Warnings and Precautions (5.3)]. Accidental ingestion of even one

dose of Promethazine with Codeine Oral Solution, especially by children, can result in respiratory

depression and death.

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

Depression in Children

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

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

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

reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant

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

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

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

Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy

and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of

the risk of life-threatening respiratory depression and death:

Promethazine with Codeine Oral Solution is contraindicated in all children younger than 12 years of

age [see Contraindications (4) ].

Promethazine with Codeine Oral Solution is 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 Promethazine with Codeine Oral Solution 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. Risk factors include conditions associated with hypoventilation, such as postoperative

status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and

concomitant use of other medications that cause respiratory depression. [see Warnings and

Precautions (5.10), Use in Specific Populations (8.4) ]

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 Warnings

and Precautions (5.1), Overdosage (10) ].

Lactation

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 Promethazine with Codeine Oral Solution [see Use in Specific

Populations (8.2)].

CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

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

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

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

(African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10%

in certain 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 Promethazine with Codeine Oral Solution.

5.4 Promethazine and Respiratory Depression

Children

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of

promethazine in pediatric patients. Concomitant administration with other respiratory depressants may

increase the risk of respiratory depression. Children may be particularly sensitive to the additive

respiratory depressant effects when promethazine is combined with other respiratory depressants,

including codeine [see Warnings and Precautions (5.3, 5.5, 5.10)].

Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric

patients may cause sudden death [see Overdosage (10)].

Concomitant Conditions and Other Risk Factors

Avoid use of promethazine in patients at risk for respiratory depression. Risk factors include

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

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

that cause respiratory depression [see Warnings and Precautions (5.6, 5.10)].

5.5 Risks with Use in Pediatric Populations

Children are particularly sensitive to the respiratory depressant effects of codeine [see Warnings and

Precautions (5.2, 5.3)] and promethazine [see Warnings and Precautions (5.4)]. Because of the risk of

life-threatening respiratory depression and death, Promethazine with Codeine Oral Solution is

contraindicated in children less than 12 years of age, and in pediatric patients younger than 18 years of

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

Use of Promethazine with Codeine Oral Solution in children also exposes them to the risks of

addiction, abuse, and misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death

[see Warnings and Precautions (5.1), Overdosage (10)]. Because the benefits of symptomatic treatment of

cough associated with allergies or the common cold do not outweigh the risks of use of codeine in

pediatric patients, Promethazine with Codeine Oral Solution is not indicated for use in patients younger

than 18 years of age [see Indications (1), Use in Specific Populations (8.4)].

5.6 Risks with Use in Other At-Risk Populations

Unresponsive Cough

The dosage of Promethazine with Codeine Oral Solution should not be increased if cough fails to

respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying

pathology, such as foreign body or lower respiratory tract disease [see Dosage and Administration

(2.3)].

Asthma and Other Pulmonary Disease

The use of Promethazine with Codeine Oral Solution in patients with acute or severe bronchial asthma

in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [see

Contraindications (4)].

Opioid analgesics and antitussives, including codeine, one of the active ingredients in Promethazine

with Codeine Oral Solution, should not be used in patients with acute febrile illness associated with

productive cough or in patients with chronic respiratory disease where interference with ability to

clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's

respiratory function.

Promethazine with Codeine Oral Solution-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 Promethazine with Codeine Oral

Solution [see Warnings and Precautions (5.2)].

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 (5.2)].

Because of the risk of respiratory depression, avoid the use of opioid antitussives, including

Promethazine with Codeine Oral Solution in patients with compromised respiratory function, patients at

risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If Promethazine with

Codeine Oral Solution is prescribed, monitor such patients closely, particularly when initiating

Promethazine with Codeine Oral Solution and when Promethazine with Codeine Oral Solution is given

concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.10)].

5.7 Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and

respiratory depression, ensure that the dose of Promethazine with Codeine Oral Solution is

communicated clearly and dispensed accurately [see Dosage and Administration (2.1)].

Advise patients to always use an accurate milliliter measuring device when measuring and administering

Promethazine with Codeine Oral Solution. Inform patients that a household teaspoon is not an accurate

measuring device and such use could lead to overdosage and serious adverse reactions [see Overdosage

(10)]. For prescriptions where a measuring device is not provided, a pharmacist can provide an

appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery

Codeine and promethazine, two of the active ingredients in Promethazine with Codeine Oral Solution,

may produce marked drowsiness and impair the mental and/or physical abilities required for the

performance of potentially hazardous tasks such as driving a car or operating machinery. Advise

patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after

ingestion of Promethazine with Codeine Oral Solution. Avoid concurrent use of Promethazine with

Codeine Oral Solution with alcohol or other central nervous system depressants because additional

impairment of central nervous system performance may occur [see Warnings and Precautions (5.10)].

5.9 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 Promethazine with Codeine Oral Solution requires careful consideration of the

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

Cytochrome P450 3A4 Interaction

The concomitant use of Promethazine with Codeine Oral Solution 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 Promethazine with Codeine Oral Solution 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.

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking a CYP3A4

inhibitor or CYP3A4 inducer. If concomitant use of Promethazine with Codeine Oral Solution with

inhibitors and inducers of CYP3A4 is necessary, monitor patients for signs and symptoms that may

reflect opioid toxicity and opioid withdrawal [see Drug Interactions (7.1, 7.2)].

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

The concomitant use of Promethazine with Codeine Oral Solution 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.

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking a CYP2D6

inhibitor. If concomitant use of Promethazine with Codeine Oral Solution with inhibitors of CYP2D6 is

necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid

withdrawal [see Drug Interactions (7.3)].

5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

Concomitant use of opioids, including Promethazine with Codeine Oral Solution, with benzodiazepines,

or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking

benzodiazepines, other CNS depressants, or alcohol [see Drug Interactions (7.4)].

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines

increases the risk of drug-related mortality compared to use of opioids alone. Because of similar

pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough

medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if

Promethazine with Codeine Oral Solution is used with benzodiazepines, alcohol, or other CNS

depressants [see Patient Counseling Information (17)].

5.11 Risks of Use in Patients with Gastrointestinal Conditions

Promethazine with Codeine Oral Solution is contraindicated in patients with known or suspected

gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The use of codeine in

Promethazine with Codeine Oral Solution may obscure the diagnosis or clinical course of patients with

acute abdominal conditions.

The concurrent use of anticholinergics with Promethazine with Codeine Oral Solution may produce

paralytic ileus [see Drug Interactions (7.9)].

The codeine in Promethazine with Codeine Oral Solution may result in constipation or obstructive

bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in

patients with underlying intestinal motility disorders.

The codeine in Promethazine with Codeine Oral Solution may cause spasm of the sphincter of Oddi,

resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [see

Warnings and Precautions (5.21)]. Monitor patients with biliary tract disease, including acute

pancreatitis for worsening symptoms.

Administration of promethazine has been associated with reported cholestatic jaundice.

5.12 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial

Pressure, or Brain Tumors

Avoid the use of Promethazine with Codeine Oral Solution in patients with head injury, intracranial

lesions, or a pre-existing increase in intracranial pressure. 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), Promethazine with Codeine Oral Solution may reduce respiratory drive, and the resultant

CO retention can further increase intracranial pressure. Furthermore, opioids produce adverse

reactions that may obscure the clinical course of patients with head injuries.

5.13 Risk of Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)

has been reported in association with promethazine HCl alone or in combination with antipsychotic

drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and

evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and

cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is

important to identify cases where the clinical presentation includes both serious medical illness (e.g.,

pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and

symptoms (EPS). Other important considerations in the differential diagnosis include central

anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine HCl,

antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic

treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for

which specific treatments are available. There is no general agreement about specific pharmacological

treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, avoid use of Promethazine with

Codeine Oral Solution in patients with a history consistent with NMS.

5.14 Risk of Paradoxical Reactions, including Dystonias

Promethazine with Codeine Oral Solution contains promethazine, a phenothiazine. Phenothiazines are

associated with dystonic reactions, particularly in pediatric patients who have an acute illness

associated with dehydration. Paradoxical reactions, including dystonia, torticollis, tongue protrusion,

hyperexcitability, and abnormal movements have been reported in patients following a single

administration of promethazine. Discontinue Promethazine with Codeine Oral Solution if a paradoxical

reaction occurs.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

The codeine and promethazine in Promethazine with Codeine Oral Solution 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 Promethazine with Codeine Oral Solution therapy.

5.16 Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

Concurrent use of Promethazine with Codeine Oral Solution is contraindicated in patients receiving

monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such therapy [see

Contraindications (4)]. MAOIs may potentiate the effects of morphine, codeine's active metabolite,

including respiratory depression, coma, and confusion MAOIs [see Drug Interactions (7.6)].

5.17 Bone-Marrow Depression

Promethazine with Codeine Oral Solution should be used with caution in patients with bone-marrow

depression. Leukopenia and agranulocytosis have been reported, usually when promethazine has been

used in association with other known marrow-toxic agents.

5.18 Severe Hypotension

Promethazine with Codeine Oral Solution 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 (7.4)]. Monitor these patients for signs of hypotension after initiating Promethazine with

Codeine Oral Solution.

In patients with circulatory shock, Promethazine with Codeine Oral Solution may cause vasodilation that

can further reduce cardiac output and blood pressure. Avoid the use of Promethazine with Codeine

Oral Solution in patients with circulatory shock.

5.19 Neonatal Opioid Withdrawal Syndrome

Promethazine with Codeine Oral Solution is not recommended for use in pregnant women. Prolonged

use of Promethazine with Codeine Oral Solution 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), Patient Counseling Information (17)]

5.20 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.

5.21 Drug/Laboratory Test Interactions

Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase

or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after

administration of a dose of Promethazine with Codeine Oral Solution.

The following laboratory tests may be affected in patients who are receiving promethazine:

Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-

HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving

promethazine.

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), Drug Abuse and Dependence (9.3) ]

Life-threatening respiratory depression [see Warnings and Precautions (5.2, 5.3, 5.4, 5.5, 5.6),

Overdosage (10) ]

Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression

in children [see Warnings and Precautions (5.3) ]

Accidental overdose and death due to medication errors [see Warnings and Precautions (5.7) ]

Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and

Precautions (5.8) ]

Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions (5.10) ]

Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions (5.11) ]

Increased intracranial pressure [see Warnings and Precautions (5.12) ]

Obscured clinical course in patients with head injuries [see Warnings and Precautions (5.12) ]

Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.13) ]

Paradoxical reactions, including dystonias [see Warnings and Precautions (5.14) ]

Seizures [see Warnings and Precautions (5.15) ]

Interactions with MAOI [see Warnings and Precautions (5.16) ]

Bone marrow suppression [see Warnings and Precautions (5.17) ]

Severe hypotension [see Warnings and Precautions (5.18) ]

Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.19) ]

Adrenal insufficiency [see Warnings and Precautions (5.20) ]

The following adverse reactions have been identified during clinical studies, in the literature, or during

post-approval use of codeine and/or promethazine. Because these reactions may be 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.

The most common adverse reactions to Promethazine with Codeine Oral Solution include: Sedation

(somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness,

dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, sweating.

Other reactions include:

Anaphylaxis: Anaphylaxis has been reported with codeine, one of the ingredients in Promethazine with

Codeine Oral Solution.

Body as a whole: Coma, death, fatigue, falling injuries, lethargy.

Cardiovascular: Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia,

chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush.

Central Nervous System: Ataxia, diplopia, facial dyskinesia, insomnia, migraine, increased intracranial

pressure, seizure, tinnitus, tremor, vertigo.

Dermatologic: Flushing, hyperhidrosis, photosensitivity, pruritus, rash, urticaria.

Endocrine/Metabolic: Cases of serotonin syndrome, a potentially life-threatening condition, have been

reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency

have been reported with opioid use, more often following greater than one month of use. Cases of

androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Gastrointestinal: Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty

swallowing, dry mouth, GERD, indigestion, jaundice, pancreatitis, paralytic ileus, biliary tract spasm

(spasm of the sphincter of Oddi).

Genitourinary: Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention.

Hematologic: Bone marrow suppression, agranulocytosis, aplastic anemia, and thrombocytopenia have

been reported.

Laboratory: Increases in serum amylase.

Musculoskeletal: Arthralgia, backache, muscle spasm.

Ophthalmic: Blurred vision, miosis (constricted pupils), visual disturbances.

Paradoxical Reactions: Dystonias, torticollis, tongue protrusion, hyperexcitability, and abnormal

movements have been reported following a single administration of promethazine.

Psychiatric: Agitation, anxiety, confusion, fear, dysphoria, depression, hallucinations.

Reproductive: Hypogonadism, infertility.

Respiratory: Apnea, bronchitis, cough, dry nose, dry throat, dyspnea, nasal congestion, nasopharyngitis,

respiratory depression, sinusitis, thickening of bronchial secretions, tightness of chest and wheezing,

upper respiratory tract infection.

Other: Drug abuse, drug dependence, Neuroleptic Malignant Syndrome, opioid withdrawal syndrome.

7 DRUG INTERACTIONS

No specific drug interaction studies have been conducted with Promethazine with Codeine Oral

Solution.

7.1 Inhibitors of CYP3A4

The concomitant use of Promethazine with Codeine Oral Solution with CYP3A4 inhibitors, such as

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

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

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

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

an inhibitor is added after a stable dose of Promethazine with Codeine Oral Solution is achieved [see

Warnings and Precautions (5.9)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor

decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via

CYP2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)], resulting in decreased

opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to

codeine.

Avoid the use of Promethazine with Codeine Oral Solution while taking a CYP3A4 inhibitor. If

concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent

intervals.

7.2 CYP3A4 Inducers

The concomitant use of Promethazine with Codeine Oral Solution and CYP3A4 inducers, such as

rifampin, carbamazepine, or phenytoin, 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 (5.9)]. After stopping a CYP3A4 inducer, as the

effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater

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

(12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may

cause serious respiratory depression.

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking CYP3A4

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

efficacy.

7.3 Inhibitors of CYP2D6

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

Codeine Oral Solution and CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, or quinidine,

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

metabolite morphine, which could result in reduced efficacy [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)].

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking inhibitors of

CYP2D6.

7.4 Benzodiazepines, and Other Depressants

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

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

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

depression, profound sedation, coma, and death. Avoid the use of Promethazine with Codeine Oral

Solution in patients who are taking benzodiazepines or other CNS depressants. [see Warnings and

Precautions (5.10)].

7.5 Serotonergic Drugs

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

has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient,

particularly during treatment initiation. Discontinue Promethazine with Codeine Oral Solution if

serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs)

Promethazine with Codeine Oral Solution is contraindicated in patients who are taking MAOIs (i.e.,

certain drugs used for depression, psychiatric or emotional conditions, or Parkinson's disease) or have

taken MAOIs within 14 days [see Contraindications (4)].

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory

depression, coma) [see Warnings and Precautions (5.16)].

Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when

some MAOI and phenothiazines are used concomitantly.

7.7 Muscle Relaxants

Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an

increased degree of respiratory depression. Avoid the use of Promethazine with Codeine Oral

Solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs

of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics

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

patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of

the diuretic as needed.

7.9 Anticholinergic Drugs

7.9 Anticholinergic Drugs

The concomitant use of anticholinergic drugs with Promethazine with Codeine Oral Solution may

increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see

Warnings and Precautions (5.11)]. Monitor patients for signs of urinary retention or reduced gastric

motility when Promethazine with Codeine Oral Solution is used concomitantly with anticholinergic

drugs.

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or

constipation) may occur when anticholinergic drugs are administered with promethazine].

8 USE IN SPECIFIC POPULATIONS

8.6 Pregnancy

Risk Summary

Promethazine with Codeine Oral Solution is not recommended for use in pregnant women, including

during or immediately prior to labor.

Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [see

Warnings and Precautions (5.19), Clinical Considerations].

There are no available data with Promethazine with Codeine Oral Solution use in pregnant women to

inform a drug-associated risk for adverse developmental outcomes. Published studies with codeine

have reported inconsistent findings and have important methodological limitations (see Data). There are

reports of respiratory depression when codeine is used during labor and delivery (see Clinical

Considerations).

Reproductive toxicity studies have not been conducted with Promethazine with Codeine Oral Solution;

however, studies are available with individual active ingredients (see Data).

In animal reproduction studies, codeine administered by the oral route to pregnant rats during the period

of organogenesis increased resorptions and decreased fetal weights at a dose approximately 25 times

the maximum recommended human dose (MRHD) in the presence of maternal toxicity (see Data).

For pregnant mice and rats that received promethazine at doses 0.2 and 3-6 times the MRHD, during

various periods of gestation, there were findings of increased fetal resorptions and skeletal fragility,

decreased pup weight, and developmental delays of pups (see Data).

Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated

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 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

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

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

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

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

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

newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings

and Precautions (5.19)].

Labor or Delivery

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

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

respiratory depression in the neonate. Opioids, including Promethazine with Codeine Oral Solution, 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 opioids during labor for signs of

excess sedation and respiratory depression.

Data

Human Data

Codeine

Published data from case-control and observational studies on codeine use during pregnancy are

inconsistent in their findings. Some studies of codeine exposure showed an increased risk of overall

congenital malformations while others did not. An increased risk of specific malformations with

codeine exposure such as respiratory malformations, spina bifida and congenital heart defects were

reported in some studies.

The majority of studies examining the use of promethazine in pregnancy did not find an association with

an increased risk of congenital anomalies. In the few studies reporting an association, no consistent

pattern of malformations was noted.

Most of the studies, both positive and negative, were limited by small sample size, recall bias and lack

of information regarding dose and timing of exposure.

Animal Data

Reproductive toxicity studies have not been conducted with Promethazine with Codeine Oral Solution;

however, studies are available with individual active ingredients.

Codeine

In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis,

codeine increased resorptions and decreased fetal weights at a dose approximately 25 times the MRHD

(on a mg/m2 basis with a maternal oral dose of 120 mg/kg/day); however, these effects occurred in the

presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed

throughout the period of organogenesis, codeine produced no adverse developmental effects at doses

approximately 15 and 65 times, respectively, the MRHD (on a mg/m2 basis with maternal oral doses of

30 mg/kg/day in rabbits and 600 mg/kg/day in mice).

Promethazine

In pregnant mice dosed during the period of implantation from gestation days 1 to 5, promethazine

increased resorption at doses approximately 0.2 times the MRHD (on a mg/m2 basis with maternal

intraperitoneal and subcutaneous doses up to 1 mg/kg/day).

In pregnant rats dosed during the period of organogenesis from gestation days 5 to 16, promethazine

hydrochloride induced complete resorption at doses approximately 6 times the MRHD (on a mg/m2

basis with maternal oral doses up to 20 mg/kg/day).

In pregnant rats dosed during the period of organogenesis from gestation days 7 to 13, promethazine

resulted in skeletal fragility of pups at doses approximately 3 times the MRHD (on a mg/m2 basis with

maternal oral doses up to 10 mg/kg/day).

In pregnant rats dosed during the period of organogenesis from gestation days 10 to 12, promethazine

resulted in decreased weight and delays in initial occurrence of behavioral/reflex of pups at doses

approximately 3 times the MRHD (on a mg/m2 basis with maternal oral doses up to 10 mg/kg/day). The

relevance of these findings to humans is unclear.

8.7 Lactation

Risk Summary

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 Promethazine with Codeine Oral Solution [see Warnings and Precautions (5.3)].

There are no data on the presence of Promethazine with Codeine Oral Solution in human milk, the

effects of Promethazine with Codeine Oral Solution on the breastfed infant, or the effects of

Promethazine with Codeine Oral Solution on milk production; however, data are available with codeine

and promethazine.

Codeine

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 one infant) 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.

Promethazine

There are no data on the presence of promethazine in human milk. However, direct oral administration

of promethazine has been associated with respiratory depression, including fatalities, in pediatric

patients [see Warnings and Precautions (5.4)]. Promethazine has been shown to decrease basal prolactin

levels in non-nursing women, and therefore may affect milk production.

Clinical Considerations

Infants exposed to Promethazine with Codeine Oral Solution through breast milk should be monitored

for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants

when maternal administration of an opioid is stopped, or when breastfeeding is stopped.

8.8 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids, such as codeine, a component of Promethazine with Codeine Oral Solution,

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)].

8.9 Pediatric Use

Promethazine with Codeine Oral Solution is not indicated for use in patients younger than 18 years of

age because the benefits of symptomatic treatment of cough associated with allergies or the common

cold do not outweigh the risks for use of codeine in these patients [see Indications (1), Warnings and

Precautions (5.5)].

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

Warnings and Precautions (5.2)]. 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.

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

promethazine [see Warnings and Precautions (5.4)].

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

Promethazine with Codeine Oral Solution is contraindicated for all children younger than 12 years

of age [see Contraindications (4) ].

Promethazine with Codeine Oral Solution is 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 Promethazine with Codeine Oral Solution in adolescents 12 to 18 years of age

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

of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with

hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary

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

depression [see Warnings and Precautions (5.3, 5.6) ].

8.10 Geriatric Use

Clinical studies have not been conducted with Promethazine with Codeine Oral Solution in geriatric

populations.

Use caution when considering the use of Promethazine with Codeine Oral Solution in patients 65 years

of age or older. Elderly patients may have increased sensitivity to codeine; greater frequency of

decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see

Warnings and Precautions (5.6)].

Respiratory depression is the chief risk for elderly patients treated with opioids, including

Promethazine with Codeine Oral Solution. Respiratory depression has occurred after large initial

doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-

administered with other agents that depress respiration [see Warnings and Precautions (5.6, 5.10)].

Codeine is 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, monitor these patients closely for respiratory depression, sedation, and

hypotension.

8.11 Renal Impairment

The pharmacokinetics of Promethazine with Codeine Oral Solution has not been characterized in

patients with 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. Promethazine with

Codeine Oral Solution should be used with caution in patients with severe impairment of renal function,

and patients should be monitored closely for respiratory depression, sedation, and hypotension.

8.12 Hepatic Impairment

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

Promethazine with Codeine Oral Solution in this patient population are unknown. Promethazine with

Codeine Oral Solution should be used with caution in patients with impairment of hepatic function, and

patients should be monitored closely for respiratory depression, sedation, and hypotension.

9 DRUG ABUSE AND DEPENDENCE

9.4 Controlled Substance

Promethazine with Codeine Oral Solution contains codeine, a Schedule V controlled substance.

9.5 Abuse

Codeine

Promethazine with Codeine Oral Solution contains codeine, a substance with a high potential for abuse

similar to other opioids including morphine and codeine. Promethazine with Codeine Oral Solution 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 and antitussive 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 health care

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. Health care

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.

Promethazine with Codeine Oral Solution, 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 Promethazine with Codeine Oral Solution

Promethazine with Codeine Oral Solution is for oral use only. Abuse of Promethazine with Codeine

Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of

Promethazine with Codeine Oral Solution with alcohol and other central nervous system depressants

[see Warnings and Precautions (5.10)].

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

and HIV.

9.6 Dependence

Psychological dependence, physical dependence, and tolerance may develop upon repeated

administration of opioids; therefore, Promethazine with Codeine Oral Solution should be prescribed

and administered for the shortest duration that is consistent with individual patient treatment goals and

patients should be reevaluated prior to refills [see Dosage and Administration (2.3), Warnings and

Precautions (5.1)].

Physical dependence, the condition in which continued administration of the drug is required to prevent

the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several

weeks of continued oral opioid use, although some mild degree of physical dependence may develop

after a few days of opioid therapy.

If Promethazine with Codeine Oral Solution is abruptly discontinued in a physically-dependent patient, a

withdrawal syndrome may occur. 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). Some or all of the

following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration,

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

anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,

diarrhea, or increased blood pressure, respiratory rate, or heart rate.

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

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

10 OVERDOSAGE

Clinical Presentation

Codeine

Acute overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate

and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor

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

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

circulatory collapse, cardiac arrest, and death.

Codeine may cause 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 origin may produce similar

findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see

Clinical Pharmacology (12.2)].

Promethazine

Signs and symptoms of overdosage with promethazine range from mild depression of the central

nervous system and cardiovascular system to profound hypotension, respiratory depression,

unconsciousness and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia,

athetosis and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur.

A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally,

characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms (dry mouth, fixed dilated pupils, flushing, tachycardia, hallucinations,

gastrointestinal symptoms, convulsions, urinary retention, cardiac arrhythmias and coma) may be

observed.

Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects

may predispose to hyperthermia.

Treatment of Overdose

Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation

of Promethazine with Codeine Oral Solution together with institution of appropriate therapy. Give

primary attention to the reestablishment of adequate respiratory exchange through provision of a patent

and protected airway and the institution of assisted or controlled ventilation. 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.

Gastric emptying may be useful in removing unabsorbed drug.

The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression

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

secondary to codeine overdose, administer an opioid antagonist. An antagonist should not be

administered in the absence of clinically significant respiratory depression. Because the duration of

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

Codeine Oral Solution, carefully monitor the patient until spontaneous respiration is reliably

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

additional antagonist as directed by the product's prescribing information. The respiratory depressant

effects of promethazine are not reversed by opioid antagonists, such as naloxone.

Because of the potential for promethazine to reverse epinephrine's vasopressor effect, epinephrine

should NOT be used to treat hypotension associated with promethazine overdose.

Hemodialysis is not routinely used to enhance the elimination of codeine or promethazine from the

body.

11 DESCRIPTION

Promethazine with Codeine Oral Solution contains codeine, an opioid agonist, and promethazine, a

phenothiazine.

Each 5 mL of Promethazine with Codeine Oral Solution contains 10 mg of codeine phosphate and 6.25

mg of promethazine hydrochloride for oral administration.

Promethazine with Codeine Oral Solution has a pH between 4.8 and 5.4 and contains alcohol 7%.

Promethazine with Codeine Oral Solution also contains the following inactive ingredients: artificial and

natural flavors, citric acid, D&C Red 33, FD&C Blue 1, FD&C Yellow 6, glycerin, saccharin sodium,

sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients.

Codeine Phosphate

The chemical name for codeine phosphate is 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-

methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Codeine is one of the naturally occurring

phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a

narcotic analgesic. The phosphate salt of codeine occurs as white, needle-shaped crystals or white

crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. The

molecular weight is 406.37. Its molecular formula is C

H NO H PO ½ H O, and it has the

following chemical structure.

Promethazine Hydrochloride

The chemical name for promethazine hydrochloride, a phenothiazine derivative, is (±)-10-[2-

(Dimethylamino)propyl] phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a

white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on

prolonged exposure to air. It is soluble in water and freely soluble in alcohol. The molecular weight is

320.88. Its molecular formula is C17H20N2SHCl, and it has the following chemical structure

12 CLINICAL PHARMACOLOGY

12.4 Mechanism of Action

Codeine

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

affinity than morphine. The analgesic and antitussive properties of codeine have been speculated to

come from its conversion to morphine. The precise mechanism of action of codeine and other opiates

is not known; however, codeine is believed to act centrally on the cough center. In excessive doses,

codeine will depress respiration.

Promethazine

Promethazine is a phenothiazine derivative, which differs structurally from the antipsychotic

phenothiazines by the presence of a branched side chain and no ring substitution. Promethazine

possesses antihistamine (H1 receptor antagonist), antiemetic, sedative, and anticholinergic effects. It

prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.

12.5 Pharmacodynamics

Codeine

Effects on the Central Nervous System

Codeine produces respiratory depression by direct action on brain stem respiratory centers. The

respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers

to both increases in carbon dioxide tension and 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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

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

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

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

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

serum amylase.

Effects on the Cardiovascular System

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

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

eyes 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–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.

Promethazine

Promethazine competitively antagonize H receptors located in most of the smooth muscle including the

gastrointestinal tract, uterus, large blood vessels and bronchial muscle. Actions of histamine on H

receptors increases capillary permeability and edema formation, flare and pruritus.

12.6 Pharmacokinetics

Absorption

Codeine is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60

minutes post administration. The presence of a high-fat, high-calorie meal did not significantly impact

the PK of codeine.

Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20

minutes after oral administration and generally last four to six hours, although they may persist as long

as 12 hours.

Distribution

Codeine has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg,

indicating extensive distribution of the drug into tissues. Codeine has low plasma protein binding with

about 7 to 25% of codeine bound to plasma proteins. Codeine passes the blood brain barrier and the

placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast

milk.

Promethazine is widely distributed in body tissues. Promethazine has high protein binding with about 80

to 93% of promethazine bound to plasma proteins. Promethazine passes the blood brain barrier and the

placental barrier.

Elimination

Metabolism

Codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (about 70 to

80%), by O-demethylation to morphine (about 5 to 10%), and by N-demethylation to norcodeine (about

10%). 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 its M6 glucuronide conjugate are pharmacologically active.

Whether C6G has pharmacological activity is unknown. Norcodeine and M3 glucuronide conjugate of

morphine are generally not considered to be pharmacologically active.

Promethazine is metabolized by the liver to a variety of inactive metabolites such as sulfoxides of

promethazine, N-demethylpromethazine and other glucuronides.

Excretion

Approximately 90% of the total dose of codeine is excreted through the kidneys, of which

approximately 10% is unchanged codeine. Plasma half-lives of codeine and its metabolites have been

reported to be approximately 3 hours.

Promethazine has an elimination half-life of 10-14 hours, with excretion of metabolites appearing in the

urine and feces. The sulfoxides of promethazine and N-demethylpromethazine are the predominant

metabolites appearing in the urine.

13 NONCLINICAL TOXICOLOGY

13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Promethazine with

Codeine Oral Solution; however, published information is available for the individual active

ingredients.

Codeine

Carcinogenicity studies were conducted with codeine. Two-year studies in F344/N rats and B6C3F1

mice were conducted to assess the carcinogenic potential of codeine. No evidence of tumorigenicity

was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately

equivalent to 15 and 20 times, the MRHD on a mg/m2 basis, respectively). No evidence of

tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day

(approximately equivalent to 45 times the MRHD on a mg/m2 basis).

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

Chinese hamster ovary (CHO) cell chromosomal aberration assay.

Fertility studies with codeine have not been conducted.

Promethazine

Carcinogenicity studies were conducted with promethazine hydrochloride. Two-year studies in

F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of promethazine

hydrochloride. No evidence of tumorigenicity was observed in male and female rats at promethazine

hydrochloride oral doses up to 33 mg/kg/day for 5 days/week (approximately equivalent to 10 times the

MRHD on a mg/m2 basis). No evidence of tumorigenicity was observed in male and female mice at

promethazine hydrochloride oral doses up to 45 and 15 mg/kg/day for 5 days/week (approximately

equivalent to 7 and 2 times the MRHD on a mg/m2 basis, respectively).

Promethazine hydrochloride was not mutagenic in the in vitro bacterial reverse mutation assay or

clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.

Fertility studies with promethazine have not been conducted

16 HOW SUPPLIED/STORAGE AND HANDLING

Promethazine with Codeine Oral Solution, 6.25 mg and 10 mg per 5 mL, is a clear, purple solution,

supplied as:

NDC Number Size

60432-606-16 16 fl. oz. (473 mL) bottle

Keep bottles tightly closed.

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

Protect from light.

Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure.

Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters.

Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension

as prescribed.

PATIENT COUNSELING INFORMATION

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

Addiction, Abuse, and Misuse

Inform patients that the use of Promethazine with Codeine Oral Solution, even when taken as

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

Warnings and Precautions (5.1)]. Instruct patients not to share Promethazine with Codeine Oral Solution

with others and to take steps to protect Promethazine with Codeine Oral Solution from theft or misuse.

Important Dosing and Administration Instructions

Instruct patients how to measure and take the correct dose of Promethazine with Codeine Oral Solution.

Advise patients to measure Promethazine with Codeine Oral Solution with an accurate milliliter

measuring device. Patients should be informed that a household teaspoon is not an accurate measuring

device and could lead to overdosage. Advise patients to ask their pharmacist to recommend an

appropriate measuring device and for instructions for measuring the correct dose [see Dosage and

Administration (2.1), Warnings and Precautions (5.7)]. Advise patients not to increase the dose or dosing

frequency of Promethazine with Codeine Oral Solution because serious adverse events such as

respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage

(10)].

Life-Threatening Respiratory Depression

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

is greatest when starting Promethazine with Codeine Oral Solution and that it can occur even at

recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize

respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

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

death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store Promethazine with

Codeine Oral Solution securely and to properly dispose of unused Promethazine with Codeine Oral

Solution in accordance with the local state guidelines and/or regulations.

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

Depression in Children

Advise caregivers that Promethazine with Codeine Oral Solution is not indicated for pediatric patients

under 18 years of age, and is contraindicated in all children younger than 12 years of age and in children

younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Activities Requiring Mental Alertness

Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor

coordination such as operating machinery or driving a motor vehicle as Promethazine with Codeine

Oral Solution may produce marked drowsiness [see Warnings and Precautions (5.8)].

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

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

Codeine Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol.

Advise patients to avoid concomitant use of Promethazine with Codeine Oral Solution with

benzodiazepines or other CNS depressants and to not use alcohol while taking Promethazine with

Codeine Oral Solution [see Warnings and Precautions (5.10), Drug Interactions (7.4)].

Constipation

Advise patients of the potential for severe constipation [see Warnings and Precautions (5.11), Adverse

Reactions (6)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Promethazine with

Codeine Oral Solution. Advise patients how to recognize such a reaction and when to seek medical

attention [see Contraindications (4), Adverse Reactions (6)].

MAOI Interaction

Inform patients not to take Promethazine with Codeine Oral Solution while using or within 14 days of

stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking

Promethazine with Codeine Oral Solution [see Warnings and Precautions (5.16), Drug Interactions (7.6)].

Hypotension

Inform patients that Promethazine with Codeine Oral Solution may cause orthostatic hypotension and

syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the

risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a

sitting or lying position) [see Warnings and Precautions (5.18)].

Pregnancy

Advise patients that use of Promethazine with Codeine Oral Solution is not recommended during

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

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of Promethazine with Codeine Oral Solution

during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if

not recognized and treated [see Warnings and Precautions (5.19), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Promethazine with Codeine Oral Solution can

cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in

Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with Promethazine with Codeine

Oral Solution [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids, such as codeine, a component of Promethazine with Codeine

Oral Solution, may cause reduced fertility. It is not known whether these effects on fertility are

reversible [see Use in Specific Populations (8.3)].

Adrenal Insufficiency

Inform patients that Promethazine with Codeine Oral Solution could cause adrenal insufficiency, a

potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms

and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

Advise patients to seek medical attention if they experience a constellation of these symptoms [see

Warnings and Precautions (5.20)].

Serotonin Syndrome

Inform patients that Promethazine with Codeine Oral Solution could cause a rare but potentially life-

threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of

the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.

Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

[see Adverse Reactions (6), Drug Interactions (7.5)].

Disposal of Unused Promethazine with Codeine Oral Solution

Advise patients to properly dispose of unused Promethazine with Codeine Oral Solution. Advise

patients to throw the drug in the household trash following these steps. 1) Remove them from their

original containers and mix them with an undesirable substance, such as used coffee grounds or kitty

litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may

intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or

other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in

accordance with local state guidelines and/or regulations.

Distributed by:

Altantic Biologicals Corp.

20101 N.E 16th Place

Miami, FL 33179

MEDICATION GUIDE

Promethazine Hydrochloride and Codeine Phosphate Oral Solution

C-V

What is the most important information I should know about Promethazine with Codeine Oral

Solution?

Promethazine with Codeine Oral Solutionis not for children under 18 years of age.

Promethazine with Codeine Oral Solutioncan cause serious side effects, including:

Addiction, abuse and misuse. Taking Promethazine with Codeine Oral Solutionor other

medicines that contain an opioid can cause addiction, abuse, and misuse, which can lead to overdose

and death. This can happen even if you take Promethazine with Codeine Oral Solutionexactly as

prescribed by your healthcare provider. Your risk of addiction, abuse, and misuse is increased if

you or a family member has a history of drug or alcohol abuse or addiction, or mental health

problems.

Do not share your Promethazine with Codeine Oral Solution with other people.

Keep Promethazine with Codeine Oral Solution in a safe place away from children.

Life-threatening breathing problems (respiratory depression) . Promethazine with Codeine

Oral Solution can cause breathing problems (respiratory depression) that can happen at any time

during treatment and can lead to death. Your risk of breathing problems is greatest when you first

start taking Promethazine with Codeine Oral Solution, are taking other medicines that can cause

breathing problems, have certain lung problems, are elderly or have certain other health problems.

Children are at higher risk for respiratory depression. Breathing problems can happen even if

you take Promethazine with Codeine Oral Solution exactly as prescribed by your healthcare

provider.

Call your healthcare provider or get emergency medical help right away if anyone taking

Promethazine Hydrochloride and Codeine Phosphate Oral Solution, or your breastfeeding baby, has

any of the symptoms below:

increased sleepiness

confusion

difficulty breathing

shallow breathing

limpness

Keep Promethazine with Codeine Oral Solutionin a safe place away from children. Accidental use

of even 1 dose of Promethazine with Codeine Oral Solution, especially by a child, is a medical

emergency and can cause breathing problems (respiratory depression) which can lead to death. If a child

accidentally takes Promethazine with Codeine Oral Solution, get emergency help right away.

Overdose and death due to medicine dosing errors. Overdose and death can happen if you

measure the wrong dose of Promethazine with Codeine Oral Solution. Always use an accurate

milliliter (mL) measuring device to measure the correct amount of Promethazine with Codeine Oral

Solution. Do not use a household teaspoon to measure your medicine. You may accidentally take

too much. You can ask your pharmacist for the measuring device you should use and how to

measure the correct dose.

Breathing problems (respiratory depression) that can lead to death and opioid withdrawal can

happen if you start taking or stop taking other medicines while taking Promethazine with Codeine

Oral Solution, including:

certain antibiotics

certain medicines to treat a fungal infection

certain medicines to treat Human Immunodeficiency Virus (HIV)-1 infection, Acquired Immune

Deficiency Syndrome (AIDS), or Hepatitis C

rifampin

carbamazepine

phenytoin

Severe drowsiness, breathing problems (respiratory depression), coma, and death can happen

in adults and children who take Promethazine with Codeine Oral Solution with benzodiazepines, or

other central nervous system depressants, including alcohol.

Do not take any benzodiazepines or medicines that can cause drowsiness or sleepiness during

treatment with Promethazine with Codeine Oral Solution. Ask your healthcare provider for a list of

these medicines if you are not sure.

Do not drink alcohol during treatment with Promethazine with Codeine Oral Solution.

Opioid withdrawal in a newborn. Use of Promethazine with Codeine Oral Solution during

pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not

recognized and treated. You should not take Promethazine with Codeine Oral Solution if you are

pregnant. Tell your healthcare provider right away if you are pregnant or think you may be pregnant.

What is Promethazine with Codeine Oral Solution?

Promethazine with Codeine Oral Solution is a prescription medicine used in adults to temporarily

treat cough and upper respiratory symptoms that you can have with allergies or a common cold.

Promethazine with Codeine Oral Solution contains 2 medicines, promethazine and codeine.

Promethazine is an antihistamine. Codeine is an opioid (narcotic) cough suppressant.

Promethazine with Codeine Oral Solution is a federal controlled substance (C-V) because it

contains codeine that can be abused or lead to dependence. Keep Promethazine with Codeine Oral

Solution in a safe place to prevent misuse and abuse. Selling or giving away Promethazine with

Codeine Oral Solution may harm others, and is against the law. Tell your healthcare provider if you

have ever abused or been dependent on alcohol, prescription medicines or street drugs.

Who should not take Promethazine with Codeine Oral Solution?

Promethazine with Codeine Oral Solutionis not for children under 18 years of age. See "What is

the most important information I should know about Promethazine with Codeine Oral Solution?"

Do not take Promethazine with Codeine Oral Solution if you:

have severe breathing problems (respiratory depression). See "What is the most important

information I should know about Promethazine with Codeine Oral Solution?"

have a blockage (obstruction) in your bowel such as a paralytic ileus.

take a medicine called a monoamine oxidase inhibitor (MAOI).

Do not take an MAOI within 14 days after you stop taking Promethazine and Codeine Oral Solution.

Do not start taking Promethazine with Codeine Oral Solution if you stopped taking an MAOI in the last

14 days.

have a type of glaucoma called "narrow angle glaucoma".

have problems with your urinary tract or difficulty urinating (urinary retention).

are allergic to promethazine, codeine, or any of the ingredients in Promethazine with Codeine

Oral Solution. See the end of this Medication Guide for a complete list of ingredients in Promethazine

with Codeine Oral Solution. You may have an increased risk of an allergic reaction to Promethazine

with Codeine Oral Solutionif you are allergic to certain other opioid medicines

Ask your healthcare provider if you have any questions about this information.

Before you take Promethazine Hydrochloride and Codeine Phosphate Oral Solution, tell your

healthcare provider about all of your medical conditions, including if you:

have a drug addiction

have lung or breathing problems

have a fever and are coughing up mucus

have had a recent head injury

have had brain tumor or other brain problems

have or have had seizures

have pain in your stomach-area (abdomen)

have constipation or other bowel problems

have bile duct or pancreas problems

have prostate problems

have problems with your urinary tract or difficulty urinating

have uncontrolled spasms of your face, neck or muscles of your body, arms and legs (dystonia)

have a history of neuroleptic malignant syndrome (NMS)

have blood disorders including low white blood cells

have low blood pressure (hypotension)

have adrenal gland problems

have kidney or liver problems

plan to have surgery

are pregnant or plan to become pregnant. Promethazine with Codeine Oral Solution can harm your

unborn baby. See "What is the most important information I should know about Promethazine with

Codeine Oral Solution?"

are breastfeeding or plan to breastfeed. Codeine passes into your breast milk and can cause

serious side effects in your baby including increased sleepiness, breathing problems (respiratory

depression), and death. It is not known if promethazine can pass into your breast milk. You and your

healthcare provider should decide if you will take Promethazine with Codeine Oral Solution or

breastfeed. You should not do both. See "What should I avoid while taking Promethazine with Codeine

Oral Solution?"

plan to have children. Promethazine with Codeine Oral Solution may affect the ability to have a

child in females and males (fertility problems). It is not known if these fertility problems will be

reversible, even after you stop taking Promethazine with Codeine Oral Solution.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements.

Taking Promethazine with Codeine Oral Solution with certain other medicines can cause side effects or

affect how well Promethazine with Codeine Oral Solution or the other medicines work. Do not start or

stop taking other medicines without talking to your healthcare provider.

Especially tell your healthcare provider if you:

See "What is the most important information I should know about Promethazine and

Codeine Oral Solution?"

take pain medicines such as opioids (narcotics).

take cold or allergy medicines that contain antihistamines or cough suppressants.

drink alcohol.

take muscles relaxants.

take certain medicines used to treat mood, anxiety, psychotic or thought disorders, or depression,

including monoamine oxidase inhibitors (MAOIs), tricyclics, selective serotonin reuptake inhibitors

(SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), or antipsychotics.

take water pills (diuretics).

take medicines called "anticholinergics" used to treat asthma, chronic bronchitis (COPD), or

stomach problems.

Ask your healthcare provider if you are not sure if you take one of these medicines

How should I take Promethazine and Codeine Oral Solution?

See "What is the most important information I should know about Promethazine and

Codeine Oral Solution?"

Take Promethazine and Codeine Oral Solution exactly as your healthcare provider tells you to

take it. Do not change your dose without talking to your healthcare provider.

Take Promethazine and Codeine Oral Solution by mouth only.

Do not take more than 30 mL of Promethazine and Codeine Oral Solution in 24 hours.

Take Promethazine and Codeine Oral Solution using an accurate milliliter (mL) measuring device.

If you do not have one, ask your pharmacist to give you a measuring device to measure the correct

amount of Promethazine and Codeine Oral Solution. Do not use a household teaspoon to measure

your medicine. You may accidently take too much.

Do not overfill the measuring device.

Rinse your measuring device with water after each use.

If you take too much Promethazine and Codeine Oral Solution, call your healthcare provider or

go to the nearest hospital emergency room right away

Tell your healthcare provider if your cough does not get better within 5 days of treatment with

Promethazine and Codeine Oral Solution.

What should I avoid while taking Promethazine and Codeine Oral Solution?

Avoid driving a car or operating machinery during treatment with Promethazine Hydrochloride

and Codeine Phosphate Oral Solution. Promethazine Hydrochloride and Codeine Phosphate Oral

Solution can cause you to be drowsy, slow your thinking and motor skills, and affect your vision.

Do not drink alcohol during treatment with Promethazine and Codeine Oral Solution. Drinking alcohol

with Promethazine and Codeine Oral Solution can increase your chances of having serious side effects,

accidental overdose, and cause death.

Avoid the use of Promethazine and Codeine Oral Solution if you:

are pregnant. Use of Promethazine and Codeine Oral Solution during pregnancy can cause

withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

Tell your healthcare provider right away if you are pregnant or think you may be pregnant.

are breastfeeding. Use of Promethazine and Codeine Oral Solution while breastfeeding can cause

severe breathing problems (respiratory depression) in your breastfed infant that could be life-

threatening.

What are the possible side effects of Promethazine and Codeine Oral Solution?

Promethazine and Codeine Oral Solution may cause serious side effects, including:

See "What is the most important information I should know about Promethazine and

Codeine Oral Solution?"

Bowel problems including severe constipation or stomach pain. See "Who should not take

Promethazine and Codeine Oral Solution?"

Increased pressure in your head (increased intracranial pressure). Avoid the use of Promethazine

and Codeine Oral Solution if you have a head injury or have been told that you have changes in the

tissue of your brain (brain lesions) or increased pressure in your head.

Neuroleptic malignant syndrome (NMS) which can lead to death. Tell you healthcare provider

right away if you have any of the following symptoms of NMS:

o high fever

o stiff muscles

o confusion

o sweating

o changes in pulse, heart rate, or blood pressure

Uncontrolled spasms of your face and neck muscles, or muscles of your body, arms, and legs

(dystonia). These muscle spasms can cause abnormal movements and body positions, and speech

problems. These spasms may happen after one dose of Promethazine and Codeine Oral Solution. Tell

your healthcare provider if you have any of these symptoms.

Increased risk of seizures in people with seizure disorders. If you have a seizure disorder,

Promethazine and Codeine Oral Solution may increase how often you have seizures.

Low blood pressure. A sudden drop in blood pressure can happen in some people during treatment

with Promethazine and Codeine Oral Solution and this may cause you to feel dizzy, faint, lightheaded, or

weak, especially when you stand up (orthostatic hypotension). Your risk of having this problem may be

increased if you take Promethazine and Codeine Oral Solution with certain other medicines that lower

blood pressure. If you have any of these symptoms while taking Promethazine and Codeine Oral

Solution, sit or lie down. Do not change your body position too fast. Get up slowly from sitting or

lying down.

Adrenal gland problems. Promethazine and Codeine Oral Solution can cause serious and life-

threatening adrenal gland problems. Your healthcare provider may do blood tests to check for adrenal

gland problems. Call your healthcare provider right away if you have any of these symptoms:

o nausea

o vomiting

o not wanting to eat (anorexia)

o fatigue

o weakness

o dizziness

o low blood pressure

Changes in laboratory blood levels, including high blood sugar and false pregnancy test reading

The most common side effects of Promethazine and Codeine Oral Solution include:

sleepiness

confusion

coordination problems

decrease in mental and physical performance

lack of energy

lightheadedness

dizziness

headache

irritability

anxiety

restlessness

nervousness

tremor

dry mouth

difficulty urinating

sweating

shortness of breath

nausea

vomiting

constipation

These are not all the possible side effects of Promethazine with Codeine Oral Solution.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store Promethazine with Codeine Oral Solution?

Store Promethazine and Codeine Oral Solution at room temperature between 68°F to 77°F (20°C

to 25°C).

Store Promethazine and Codeine Oral Solution in a tightly closed container, in a dry, cool place

away from heat or direct sunlight.

Keep Promethazine with Codeine Oral Solution and all medicines out of the reach of children.

How should I dispose of Promethazine with Codeine Oral Solution?

Remove unused Promethazine with Codeine Oral Solution from the container and mix it with an

undesirable, non-toxic substance such as cat litter or used coffee grounds to make it less appealing to

children and pets. Place the mixture in a container such as a sealed plastic bag and throw it away in the

household trash. You can also follow your state or local guidelines on how to safely throw away

Promethazine with Codeine Oral Solution.

General information about the safe and effective use of Promethazine with Codeine Oral Solution.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do

not use Promethazine with Codeine Oral Solution for a condition for which it was not prescribed. Do

not give Promethazine with Codeine Oral Solution to other people, even if they have the same symptoms

that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about Promethazine with Codeine

Oral Solution that is written for health professionals.

What are the ingredients in Promethazine with Codeine Oral Solution?

Active ingredients: promethazine hydrochloride and codeine phosphate

Inactive ingredients: artificial and natural flavors, citric acid, D&C Red 33, FD&C Blue 1, FD&C

Yellow 6, glycerin, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and

other ingredients.

Manufactured For: Wockhardt USA, LLC, Parsippany, NJ 07054

Manufactured By: Morton Grove Pharmaceuticals, Inc., Morton Grove, IL 60053

26606AP

Rev. 05-18

For more information, go to www.wockhardtusa.com or call Wockhardt USA, LLC at 1-800-346-6854.

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

May 2018

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Promethazine with Codeine Label

PROMETHAZINE WITH CODEINE

promethazine hydrochloride and codeine phosphate solution

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:178 56 -

0 6 0 5(NDC:6 0 432-6 0 6 )

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PRO METHAZINE HYDRO CHLO RIDE (UNII: R6 1ZEH7I1I) (PROMETHAZINE -

UNII:FF28 EJQ 49 4)

PROMETHAZINE

HYDROCHLORIDE

6 .25 mg

in 5 mL

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

UNII:UX6 OWY2V7J)

CODEINE PHOSPHATE

10 mg in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

WATER (UNII: 0 59 QF0 KO0 R)

TRISO DIUM CITRATE DIHYDRATE (UNII: B22547B9 5K)

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

SO DIUM BENZO ATE (UNII: OJ245FE5EU)

SACCHARIN SO DIUM (UNII: SB8 ZUX40 TY)

SO DIUM PRO PIO NATE ANHYDRO US (UNII: 39 1O0 PO49 R)

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

ANHYDRO US CITRIC ACID (UNII: XF417D3PSL)

GLYCERIN (UNII: PDC6 A3C0 OX)

ALCO HO L (UNII: 3K9 9 58 V9 0 M)

METHYLPARABEN (UNII: A2I8 C7HI9 T)

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

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

SUCRO SE (UNII: C151H8 M554)

Product Characteristics

Color

PURPLE

S core

S hap e

S iz e

Flavor

RASPBERRY

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:178 56 -0 6 0 5-

72 in 1 BOX, UNIT-DOSE

0 9 /10 /20 19

1

5 mL in 1 CUP, UNIT-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ATLANTIC BIOLOGICALS CORP.

ANDA

ANDA0 8 8 8 75

0 9 /10 /20 19

Labeler -

AT LANT IC BIOLOGICALS CORP. (047437707)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

ATLANTIC BIOLOGICALS CORP.

0 4743770 7

relabel(178 56 -0 6 0 5) , repack(178 56 -0 6 0 5)

Revised: 9/2019

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