Promethazine with Codeine (Page 5 of 11)

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:

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.

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