DailyMed - PROMETHAZINE HCL, PHENYLEPHRINE HCL, CODEINE PHOSPHATE (2024)

5.1 Addiction, Abuse, and Misuse

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution contains codeine, a Schedule V controlled substance. As an opioid, Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution, prescribe Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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.

5.2Life-Threatening RespiratoryDepression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including codeine, one of the active ingredients in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 (CO2) 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution, especially by children, can result in respiratory depression and death.

5.3 Ultra-Rapid Metabolism of Codeine and Other Risk Factors forLife-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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is contraindicated in all children younger than 12 years of age [see Contraindications (4)].
Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 Riskswith 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is prescribed, monitor such patients closely, particularly when initiating Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution and when Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.10)].

5.7Risks of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with codeine and promethazine solutions of different concentrations, when prescribing, dispensing, and administering Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately [see Dosage and Administration (2.1)].

Instruct patients and caregivers on how to measure and take or administer the correct dose of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solutionand to use extreme caution when measuring the dose. Strongly advise patients to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices. 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.

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

Codeine and promethazine, two of the active ingredients in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution. Avoid concurrent use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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)].

5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

Concomitant use of opioids, including Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants [see Patient Counseling Information (17)].

5.11Risks of Use in Patients with Gastrointestinal Conditions

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The use of codeine in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

The concurrent use of anticholinergics with Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution may produce paralytic ileus [see Drug Interactions (7.9)].

The codeine in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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 (5.22)]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

Administration of promethazine has been associated with reported cholestatic jaundice.

5.12Risks of Use in Patients with Head Injury, Impaired Consciousness, IncreasedIntracranial Pressure, or Brain Tumors

Avoid the use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate 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.

5.13Cardiovascular and Central Nervous System Effects

The phenylephrine contained in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution can produce cardiovascular and central nervous system effects in some patients such as, insomnia, dizziness, weakness, tremor, transient elevations in blood pressure, or arrhythmias. Central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has also been reported. Phenylephrine can cause a decrease in cardiac output. In patients with hypertension or with peripheral vascular insufficiency, phenylephrine may cause ischemia, increasing the risk of gangrene or thrombosis of compromised vascular beds. Therefore, Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is contraindicated in patients with severe hypertension, coronary artery disease, or peripheral vascular insufficiency [see Contraindications (4)], and should be used with caution in patients with other cardiovascular disorders, including patients with arteriosclerosis, elderly individuals, or patients with poor cerebral circulation.

5.14Risk 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in patients with a history consistent with NMS.

5.15 Risk ofParadoxical Reactions, including Dystonias

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution if a paradoxical reaction occurs.

5.16Increased Risk of Seizures in Patients with Seizure Disorders

The codeine and promethazine in Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution therapy.

5.17Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

Concurrent use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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. The cardiac pressor response may be potentiated and acute hypertensive crisis may occur when phenylephrine containing preparations are used with prior administration of MAOIs[see Drug Interactions (7.6)].

5.18Bone-Marrow Depression

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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.

5.19Severe Hypotension

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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 HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution.

In patients with circulatory shock, Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in patients with circulatory shock.

5.20Neonatal Opioid Withdrawal Syndrome

Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women. Prolonged use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate 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)].

5.21Adrenal 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.

5.22Drug/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 HCl, Phenylephrine HCl and Codeine Phosphate 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.