Promethazine with Codeine (Page 4 of 11)

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 CO2 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 CO2 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.

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