Promethazine + Codeine

Pharmacogenomics:

Codeine

Codeine, an opioid analgesic prodrug, is metabolised in the liver via O-demethylation by CYP2D6 into the active metabolite, morphine. Polymorphisms in the CYP2D6 gene may result in higher morphine levels which may lead to toxic systemic concentrations of morphine even in low doses or a decrease in morphine levels that eventually cause an attenuated analgesic effect. Genetic testing should be considered for children and adults before initiation of codeine therapy to identify those with a predisposition to adverse effects from codeine use.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of December 2020:

Phenotype	Implications	Recommendations
CYP2D6 ultrarapid metaboliser (activity score range of >2.25)	Increased morphine formation, thereby increasing the risk of toxicity.	Avoid codeine administration. Consider the administration of non-tramadol opioids if opioid use is desired.
CYP2D6 intermediate metaboliser (activity score 0 < x ≤ 2.25)	Decreased morphine formation.	No dose adjustment needed. If there is no response and opioid use is desired, consider the administration of non-tramadol opioids.
CYP2D6 poor metaboliser (activity score range 0)	Greatly decreased morphine formation, resulting in decreased analgesia.	Avoid codeine administration. Consider the administration of non-tramadol opioids if opioid use is desired.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:

Phenotype	Implications	Recommendations
CYP2D6 ultrarapid metaboliser	Increased conversion to morphine, thereby increasing the risk of adverse effects.	For pain: Morphine may be used as an alternative; oxycodone is metabolised by CYP2D6 to a certain extent (this does not cause any differences in side effects in patients); avoid the use of tramadol. For cough: Alternative agents not metabolised by CYP2D6 should be used. Refer to international guidelines for dosage adjustments and specific recommendations on use for adults, children, and patients with certain risk factors.
CYP2D6 intermediate metaboliser	Decreased conversion to morphine, resulting in decreased analgesic effect.	For pain: Due to the limited data available, recommendations for dosage adjustment are not possible (refer to international guidelines). Monitor for reduced efficacy. For cases of reduced efficacy, doses may be increased. If desired effect is not achieved, morphine may be used as an alternative, oxycodone is metabolised by CYP2D6 to a certain extent (this does not cause any differences in side effects in patients), avoid the use of tramadol. Report for inadequate analgesia if no alternative agent is selected. For cough: No dose adjustment needed.
CYP2D6 poor metaboliser	Decreased conversion to morphine, resulting in decreased analgesic effect.	For pain: Due to the limited data available, recommendations for dosage adjustment are not possible (refer to international guidelines). Morphine may be used as an alternative, oxycodone is metabolised by CYP2D6 to a certain extent (this does not cause any differences in side effects in patients), avoid the use of tramadol. Report for inadequate analgesia if no alternative agent is selected. For cough: No dose adjustment needed.

Significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or lack of resuscitative equipment; suspected or known gastrointestinal obstruction (e.g. paralytic ileus). CYP2D6 ultrarapid and poor metabolisers. Children <12 years; 12-18 years who have undergone adenoidectomy or tonsillectomy. Concomitant use or within 14 days after MAOI therapy.

Patient with significant COPD or cor pulmonale, decreased respiratory reserve, hypoxia, hypercarbia, pre-existing respiratory depression; CV disease (e.g. MI), hypovolaemia, circulatory shock; bone marrow suppression, delirium tremens, toxic psychosis, mental disorders (e.g. major depression), current or history of substance abuse; predisposing conditions to seizures (e.g. history of seizures, brain damage, head trauma, alcoholism); intracranial lesions, increased intracranial pressure, head injury;  myasthenia gravis, sleep-related disorders (e.g. sleep apnoea); adrenal insufficiency (including Addison's disease), narrow-angle glaucoma, acute abdominal conditions, intestinal motility disorders, biliary tract dysfunction, acute pancreatitis, prostatic hyperplasia and/or urinary stricture. Patients subjected to strenuous exercise, heat, and dehydration. Avoid use in those aged 12-18 years who have risk factors for respiratory depression. Not recommended for long-term use. Avoid abrupt withdrawal. Concomitant use with CYP3A4 inhibitors, CYP3A4 inducers, and CYP2D6 inhibitors. CYP2D6 intermediate metabolisers. Morbidly obese, cachectic, or debilitated patients. Hepatic and severe renal impairment. Children 12-18 years or elderly. Pregnancy and lactation.

Significant: CNS depression, anticholinergic effects (e.g. blurred vision, constipation, urinary retention, xerostomia), extrapyramidal symptoms (e.g. acute dystonic reactions, akathisia, tardive dyskinesia, pseudoparkinsonism); may alter cardiac conduction; constipation; obstructive bowel disease (chronic use); severe hypotension, syncope, orthostatic hypotension, impaired core body temperature regulation, leucopenia, agranulocytosis, photosensitivity; exacerbation of narrow-angle glaucoma, myasthenia gravis; adrenal insufficiency, secondary hypogonadism which may lead to mood disorders and osteoporosis (long-term use); sphincter of Oddi constriction resulting in increased biliary tract pressure, cholestatic jaundice, exaggerated ICP elevation, increased frequency of seizures; paradoxical reactions (e.g. tongue protrusion, torticollis, hyperexcitability, abnormal movements).
Cardiac disorders: Chest pain, palpitations, tachycardia.
Ear and labyrinth disorders: Vertigo.
Eye disorders: Visual disturbances.
Gastrointestinal disorders: Nausea, vomiting, abdominal pain.
General disorders and administration site conditions: Lethargy, fatigue, peripheral oedema.
Injury, poisoning and procedural complications: Falling injuries.
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, muscle spasm.
Nervous system disorders: Somnolence, lightheadedness, dizziness, mental clouding, tremor, ataxia, diplopia, migraine.
Psychiatric disorders: Insomnia, fear, anxiety, confusion, depression, hallucinations.
Respiratory, thoracic and mediastinal disorders: Shortness of breath, apnoea, bronchitis.
Skin and subcutaneous tissue disorders: Sweating, pruritus, rash, urticaria.
Vascular disorders: Flushing.
Potentially Fatal: Respiratory depression; opioid addiction, abuse, and misuse; neuroleptic malignant syndrome; neonatal opioid withdrawal syndrome (prolonged use during pregnancy).

PO: C

This drug may cause drowsiness, if affected, do not drive or operate machinery.

Monitor symptom relief, bowel function, blood pressure, heart rate. Closely monitor for respiratory depression (particularly 24-72 hours after treatment initiation). Assess for the development of substance abuse, misuse, or addiction; signs and symptoms of mental status changes, muscle stiffness, fever, and/or autonomic instability; hypogonadism or hypoadrenalism (long-term use).

Symptoms: Promethazine: Mild depression of CNS and CV system to profound hypotension, respiratory depression, seizures, deep sleep, unconsciousness; hyperreflexia, hypertonia, ataxia, athetosis and extensor-plantar reflexes; fixed dilated pupils, dry mouth, flushing, tachycardia, urinary retention, gastrointestinal symptoms, convulsion, hallucinations and cardiac arrhythmias. Paradoxical reactions characterised by hyperexcitability, abnormal movements, and nightmares may occur in children. Codeine: Constricted or pinpoint pupils, marked mydriasis with hypoxia, confusion, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, pulmonary oedema, bradycardia, hypotension, hypoglycaemia, atypical snoring, partial or complete airway obstruction, cardiac arrest, circulatory collapse and respiratory depression. Management: Symptomatic and supportive treatment. Re-establish adequate respiratory exchange. Employ the use of vasopressor agents and oxygen as needed. Empty the stomach to remove any unabsorbed drug. Perform advanced life-support techniques for arrhythmias and cardiac arrest. Administer naloxone if clinically significant respiratory or circulatory depression is present.

May increase the risk of severe constipation or urinary retention with anticholinergics.
Codeine: Concomitant use with CYP2D6 inhibitors (e.g. amiodarone, quinidine) may lead to elevated serum concentrations of morphine (active metabolite) which may prolong or enhance adverse effects. Concomitant use with CYP3A4 inducers, CYP2D6 inhibitors (e.g. amiodarone, quinidine), or discontinuation of CYP3A4 inhibitors may result in reduced serum concentrations of morphine which may cause decreased therapeutic effect or opioid withdrawal symptoms. May cause serotonin syndrome with serotonergic drugs. May enhance the neuromuscular blocking effect of skeletal muscle relaxants. Reduced efficacy of diuretics.
Potentially Fatal: Increased risk of profound sedation, hypotension, respiratory depression, and coma with benzodiazepines or other CNS depressants (e.g. other sedatives or hypnotics, antipsychotics, anxiolytics, general anaesthetics, muscle relaxants, tranquillisers, and other opioids).
Promethazine: Increased risk of extrapyramidal effects with MAOIs.
Codeine: May increase the risk of respiratory depression with CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, ritonavir) or discontinuation of a CYP3A4 inducer (e.g. rifampicin, carbamazepine, phenytoin). Concomitant use with MAOIs may enhance adverse effects, including respiratory depression, confusion and coma.

Increased risk of profound sedation, hypotension, respiratory depression, and coma with alcohol.

Promethazine: May lead to false-negative or false-positive results in pregnancy tests (hCG-based). May cause false-positive results in urine detection of amphetamines or methamphetamines. May increase serum glucose levels in glucose tolerance tests. May alter the flare response in intradermal allergen tests, thereby causing false-negative results.
Codeine: May increase biliary tract pressure, leading to elevated plasma amylase or lipase levels; thus, measuring these enzyme levels may be unreliable for 24 hours following administration.

Description:
Mechanism of Action: Promethazine, a phenothiazine derivative, is a sedating antihistamine with antimuscarinic and some serotonin-antagonist properties. It competes with histamine for H₁ receptor binding, exhibits a potent α-adrenergic blocking effect, and blocks postsynaptic mesolimbic dopaminergic receptors in the brain. Additionally, it decreases stimuli to the brainstem reticular system and suppresses the secretion of hypothalamic and hypophyseal hormones.
Codeine, a phenanthrene derivative, is an opioid agonist antitussive agent with mild analgesic and sedative properties. It acts directly on the medulla in the brain and exerts a drying effect on the respiratory tract mucosa, thereby causing cough suppression and increasing the viscosity of bronchial secretions.
Onset: Promethazine: Approx 20 minutes.
Codeine: 0.5-1 hour.
Duration: Promethazine: 4-6 hours (up to 12 hours).
Codeine: 4-6 hours.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract.
Promethazine: Bioavailability: Approx 25%. Time to peak plasma concentration: 2-3 hours.
Codeine: Bioavailability: 53%. Time to peak plasma concentration: 1 hour.
Distribution: Crosses the placenta.
Promethazine: Crosses the blood-brain barrier; enters breast milk (small amounts). Volume of distribution: 13.4 ± 3.6 L/kg. Plasma protein binding: 76-93%.
Codeine: Enters breast milk. Volume of distribution: Approx 3-6 L/kg. Plasma protein binding: Approx 7-25%.
Metabolism: Promethazine: Extensively metabolised in the liver via hydroxylation by CYP2D6 and N-demethylation by CYP2B6 to promethazine sulfoxide and N-desmethylpromethazine; undergoes first-pass metabolism.
Codeine: Metabolised in the liver via glucuronidation by UGT2B7 and UGT2B4 into codeine-6-glucuronide, via O-demethylation by CYP2D6 into morphine, and via N-demethylation by CYP3A4 into norcodeine. Morphine (active metabolite) is further metabolised via glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide (active metabolite).
Excretion: Promethazine: Via urine and faeces (as inactive metabolites). Elimination half-life: 5-14 hours.
Codeine: Via urine (approx 90%; approx 10% as unchanged drug); faeces. Elimination half-life: Approx 3 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 4927, Promethazine. https://pubchem.ncbi.nlm.nih.gov/compound/Promethazine. Accessed Sept. 23, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5284371, Codeine. https://pubchem.ncbi.nlm.nih.gov/compound/Codeine. Accessed Mar. 25, 2024.

Store between 20-25°C. Protect from light.

Other Drugs Acting on the Respiratory System

R06AD52 - promethazine, combinations ; Belongs to the class of phenothiazine derivatives used as systemic antihistamines.

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