Promethazine with Codeine (Page 9 of 11)

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 H1 receptors located in most of the smooth muscle including the gastrointestinal tract, uterus, large blood vessels and bronchial muscle. Actions of histamine on H1 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.

Product No.: 6606

Manufactured For:

Wockhardt USA, LLC

Parsippany, NJ 07054

Manufactured By:

Morton Grove Pharmaceuticals, Inc.

Morton Grove, IL 60053

26606P

Rev. 05-18

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