Promethazine

Promethazine is a first-generation antihistamine used for the treatment of allergic conditions, nausea and vomiting, and motion sickness

Promethazine is indicated for the treatment of including allergic reactions, pain, sedation, nausea, and vomiting

Promethazine is well absorbed from the gastrointestinal tract after IM inj. Bioavailability: approx 25% (oral); 21.7-23.4% (rectal). Time to peak plasma concentration: 2.8 ± 1.4 hours (oral syr); 8.2 ± 3.4 hours (rectal).Widely distributed in the body. Crosses the blood-brain barrier and placenta; enters breast milk (small amounts). Volume of distribution: 13.4 ± 3.6 L/kg. Plasma protein binding: 76-93%.Extensively metabolised in the liver via hydroxylation by CYP2D6 and N-demethylation by CYP2B6 to promethazine sulfoxide and N-desmethylpromethazine; undergoes significant first-pass effect.

Promethazine shows common side effects like Insomnia, nervousness, irritability, anxiety.Respiratory, thoracic and mediastinal disorders: Elevated respiration.

Promethazine is available in the form of Tablets, suppository, syrup, Capsules and Injections.

Promethazine is available in India, Germany, Canada, Italy.

Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting.

Promethazine tablets and suppositories are indicated to treat rhinitis, allergic conjunctivitis, allergic reactions to blood or plasma, dermographism, anaphylactic reactions, sedation, nausea, vomiting, pain, motion sickness, and allergic skin reactions

Promethazine tablets and suppositories are indicated to treat rhinitis, allergic conjunctivitis, allergic reactions to blood or plasma, dermographism, anaphylactic reactions, sedation, nausea, vomiting, pain, motion sickness, and allergic skin reactions.

Promethazine cough syrup with phenylephrine and codeine is indicated to relieve cough and upper respiratory symptoms, and nasal congestion associated with allergy or the common cold.

• Nausea and/or vomiting, acute:

Note: May use short-term (eg, up to 48 to 72 hours) for self-limiting nausea/vomiting (eg, postoperative rescue therapy, acute vertigo) (Ref).

Oral, rectal: 12.5 to 25 mg every 4 to 6 hours as needed. To avoid intolerable adverse effects, some experts recommend a maximum dose of 50 mg/day.

IM or IV (alternative routes): Note: IV and IM administration is generally avoided due to risk of severe tissue injury. When parenteral therapy is indicated, other parenteral antiemetics with less risk of tissue injury are preferred.

12.5 to 25 mg IM or IV every 4 to 6 hours as needed ; for postoperative rescue, may administer 6.25 mg IV as a single dose . To avoid intolerable adverse effects, some experts recommend a maximum dose of 50 mg/day.

• Peripartum management, adjunct to opioids:

Note: Other parenteral antiemetics with less risk of tissue injury are preferred. May be used to potentiate opioid analgesia and decrease side effects (eg, nausea and vomiting) .

IM (preferred route), IV (alternative route): 25 mg once; may repeat every 4 hours for up to 2 additional doses.

• Pregnancy-associated nausea and vomiting (off-label use):

Note: Safety: IV and IM administration is generally avoided due to risk of severe tissue injury. When parenteral therapy is indicated, other parenteral antiemetics with less risk of tissue injury are preferred . Use: May use as add-on therapy when symptoms persist following initial pharmacologic treatment

Patients without hypovolemia : Oral, rectal, IM (alternative route): 12.5 to 25 mg every 4 to 6 hours as needed (Ref).

Patients with hypovolemia (alternative agent, alternative route):

Note: Consider for persistent nausea and vomiting in addition to treatment of hypovolemia (eg, IV fluids).

IV: 12.5 to 25 mg every 4 to 6 hours

Promethazine is available in various strengths as

• Tablets (12.5,25 and 50mg)
• Capsules (50mg)
• Injection (1mg/ml )
• Suppositories (25mg)
• Syrup (6.25 mg/5 mL)

Promethazine is available in the form of Tablets, suppository, syrup, Capsules and Injections.

Dosage Adjustment in Kidney Patient

● Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (only 0.6% of an administered dose excreted in the urine unchanged)

● Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large Vd): No supplemental dose or dosage adjustment necessary.

● Peritoneal dialysis: Unlikely to be dialyzed (large Vd): No dosage adjustment necessary.

● CRRT: No dosage adjustment necessary.

● PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary

Dosage Adjustment in Hepatic impairment Patient

• Mild impairment: No dosage adjustment necessary.
• Moderate to severe impairment: There are no dosage adjustments provided in manufacturer’s labeling

Dosage Adjustment for Pediatric Patients

Nausea and vomiting:

Note: Promethazine has been used as an antiemetic for various presenting conditions (eg, postoperative nausea/vomiting, chemotherapy-induced nausea/vomiting, cyclic vomiting syndrome, migraine). In most clinical situations, routine use has been replaced by alternate agents from other therapeutic classes; however, promethazine may be necessary in refractory situations or as rescue therapy; may consider concomitant diphenhydramine to decrease risk of dystonic adverse effects.

Children ≥2 years and Adolescents: Oral, IM, IV, rectal: Usual range: 0.25 to 0.5 mg/kg/dose every 4 to 6 hours as needed; doses up to 1.1 mg/kg/dose may be necessary in some patients; do not exceed usual adult dose of 6.25 to 25 mg/dose

Seizures: Promethazine should be used with caution in patients with seizure disorders or in persons taking concomitant medications, which may also lower seizure threshold (i.e., narcotics, local anesthetics, etc.)

Bone-Marrow Depression: Promethazine should be used cautiously in patients with bone marrow depression (Leukopenia and agranulocytosis). The risk is higher when it is coadministered with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome: A potentially fatal NMS is reported in patients using promethazine alone or combined with other antipsychotic drugs. Clinical symptoms of NMS are hyperpyrexia, altered mental status, muscle rigidity, and autonomic instability (i.e., diaphoresis, irregular heartbeats or blood pressure, tachycardia, and cardiac dysrhythmias). The diagnostic evaluation of patients with NMS is complicated. It is important to identify patients when the clinical presentation includes untreated or inadequately treated EPS and serious medical conditions (e.g., pneumonia, systemic infection, etc.).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies to assess potential carcinogenic effects of Promethazine have not been conducted.

Promethazine was negative for genotoxicity in the following assays: bacterial reverse mutation assay (Ames test), gene mutation assay in Chinese hamster V79 cells, chromosomal aberration assay in Chinese hamster ovary cells, unscheduled DNA synthesis in HELA S3 cells, and in vivo mouse micronucleus assay.

Promethazine is only indicated for use in premature neonates.

Promethazine is only indicated for use in premature neonates.

Promethazine is only indicated for use in premature neonates.

High-fat meal may decrease the rate but not the extent of absorption. Management: May administer with meals.

Significant

Increased left ventricular output, and stroke volume, tachycardia, hyper- or hypoglycaemia, diuresis, electrolyte loss, withdrawal symptoms (e.g. tiredness, decreased alertness), increased metabolism.

Cardiac disorders: Arrhythmia.

Gastrointestinal disorders: Gastrointestinal disturbances.

Nervous system disorders: Convulsion, tremor, headache.

The common side effects of Promethazine include the following Psychiatric disorders: Insomnia, nervousness, irritability, anxiety.

Respiratory, thoracic and mediastinal disorders: Elevated respiration.

Potentially Fatal: Necrotising enterocolitis.

Pediatric Use

Promethazine is indicated for the rescue treatment, including the reduction of mortality and pneumothoraces, of Respiratory Distress Syndrome (RDS) and allergic conditions in children.

Symptoms: Children: Excitation, incoordination, ataxia, athetosis, hallucinations. Adult: Drowsiness, profound hypotension, coma. Convulsions which may be preceded by coma or excitement, may occur in both adults and children. Management: Symptomatic and supportive treatment. Induce vomiting with ipecacuanha or perform gastric lavage. Maintain adequate respiratory and circulatory status. Convulsions may be treated with diazepam or other suitable anticonvulsants. Administer IV fluids and repositioning for hypotension; may consider use of norepinephrine or phenylephrine for severe hypotension unresponsive to IV fluids and repositioning.

Pharmacodynamic

Promethazine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance.Promethazine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, Promethazine acts as a mild diuretic.

Pharmacokinetics

• Absorption

Promethazine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration.After oral administration, onset of action takes place within 45 to 1 hour.15 Food may delay Promethazine absorption.

• Distribution

Well absorbed from the gastrointestinal tract and after IM inj. Bioavailability: Approx 25% (oral); 21.7-23.4% (rectal). Time to peak plasma concentration: 2.8 ± 1.4 hours (oral syr); 8.2 ± 3.4 hours (rectal).

Widely distributed in the body. Crosses the blood-brain barrier and placenta; enters breast milk (small amounts). Volume of distribution: 13.4 ± 3.6 L/kg. Plasma protein binding: 76-93%

• Metabolism

Extensively metabolised in the liver via hydroxylation by CYP2D6 and N-demethylation by CYP2B6 to promethazine sulfoxide and N-desmethylpromethazine; undergoes significant first-pass effect.

• Excretion

Via urine and faeces (as inactive metabolites). Elimination half-life: Oral syr, supp: 16-19 (range: 4-34) hours; IV: 9-16 hours; IM: approx 10 hours

• https://go.drugbank.com/drugs/DB01069
• https://www.uptodate.com/contents/postoperative-nausea-and-vomiting/print?search=PHENERGAN VC/CODEINESearch&source=search_result&selectedTitle=4~95&usage_type=default&display_rank=4
• https://www.mims.com/india/drug/info/promethazine?type=full&mtype=generic