Promethazine

Mechanism of Action

Promethazine is a phenothiazine derivative with antidopaminergic, antihistamine, and anticholinergic properties. Other phenothiazine derivatives include prochlorperazine and chlorpromazine. Promethazine works as a direct antagonist at the mesolimbic dopamine receptors and alpha-adrenergic receptors in the brain. Promethazine exhibits its antihistamine effects as an H1-receptor blocker.[11][12]

Administration

Promethazine has several routes of administration, including oral, rectal, intramuscular, and intravenous. The tablets, solutions, and suppository dose is generally 12.5 mg to 50 mg.

• Promethazine hydrochloride injection solution: 25 mg/mL; 50 mg/mL
• Promethazine hydrochloride oral solution: 6.25 mg/5 mL
• Promethazine hydrochloride suppository: 12.5 mg; 25 mg; 50 mg
• Promethazine hydrochloride oral syrup: 6.25 mg/5 mL
• Promethazine hydrochloride oral tablets: 12.5 mg, 25 mg, 50 mg

Promethazine should be given with food, water, or milk to decrease gastrointestinal discomfort when administered orally. The intramuscular injection must be into deep muscle tissue as the subcutaneous injection may damage tissue. Intravenous use should be performed with caution as severe tissue damage may also occur. Promethazine may be diluted before IV administration in selected patients to prevent promethazine-induced tissue necrosis.[13][14]

In pediatric patients, promethazine utilizes the same routes of administration as adults. However, dosing adjustments are necessary based on the weight of the patient and the indication. Using the lowest dose of efficacy is recommended.

Allergy 

The normal recommended oral dose is 25 mg administered before bed; alternatively, a patient can be given 6.25 to 12.5 mg three times before meals and on retiring, as necessary. After initiation of the treatment, the dose should be adjusted to the minimum dose to relieve the symptoms adequately in children or adults.

Motion Sickness

The average recommended adult dose is 25 mg, taken twice daily. The initial dose needs to be taken one-half to one hour before travel and repeated every eight to twelve hours later if needed. On days following travel, 25 mg can be administered when up and repeated before the evening meal. Promethazine hydrochloride syrup, tablets, or rectal suppositories are administered at 12.5 to 25 mg twice daily for children.[7]

Nausea and Vomiting

Antiemetics are not recommended to treat vomiting of unknown etiology in children and adolescents. The average effective dose of promethazine for the active treatment of nausea and vomiting in children or adults is 25 mg. Patients who do not tolerate oral medication can be administered parenterally or rectally. Promethazine, 12.5 mg to 25 mg, may be repeated at 4 to 6-hour intervals. To treat nausea and vomiting in children, the usual recommended dose is 0.5 mg/pound (body weight). The dose should be based on the patient's age, body weight, and the severity of nausea/vomiting. During surgery and the postoperative period, the recommended dose is 25 mg administered at four to six-hour intervals for prophylaxis of nausea and vomiting.[10]

Sedation 

Promethazine relieves apprehension, inducing a quiet sleep from which the person can be easily aroused. Administer 12.5 mg to 25 mg promethazine orally or rectally at bedtime to provide sedation in children. Adults usually need 25 mg to 50 mg before surgery to relieve apprehension and produce quiet sleep for nighttime, obstetrical, or presurgical sedation. Children need 0.5 mg promethazine/pound (body weight) as a preoperative medication combined with adequately reduced narcotic/barbiturate and the required amount of an atropine-like drug.

The usual recommended adult dosage is 50 mg promethazine with an adequately reduced dose of narcotic/barbiturate and the appropriate dose of a belladonna alkaloid. Postoperative sedation and adjunctive use with analgesic medicines may be achieved by the 12.5 mg to 25 mg promethazine in children and 25 mg to 50 mg promethazine in adults.

Specific Patient Population

Patients With Hepatic Impairment: No dose adjustment is provided in the manufacturer's labeling. Use with caution due to the risk of cholestatic jaundice.[15]

Patients With Renal Impairment: No dose adjustment is required in patients with renal impairment.

Pregnancy Considerations: Research has also identified phenothiazines as a potential cause of congenital malformations in one study, but other studies attest to their safety.[16] Promethazine is classified as a former FDA pregnancy category C by the FDA. Alternative therapies may be indicated before promethazine, considering the risks to the fetus and adverse effects on the mother.[17]

Breastfeeding Considerations: Short-term use of promethazine poses little risk to the breastfed infant due to the minimal excretion of phenothiazine derivatives. However, observe infants for excess sedation with repeated doses. Promethazine can reduce prolactin secretion but may interfere with lactation if given during labor before lactation is established. Consider risk-benefit evaluation before prescribing promethazine.[18]

Pediatric Patients: Promethazine is included in the KIDs List (Key Potentially Inappropriate Drugs in Pediatrics).[19] Promethazine has also been associated with sudden infant death syndrome.[20]

Older Patients: Promethazine is included in American Geriatric Society Beers Criteria as a potentially inappropriate medication for older adults due to anticholinergic adverse effects.[21]

Adverse Effects

Promethazine has several potential adverse effects related to its mechanism of action. The most common side effects include sedation, confusion, and disorientation, which may impair physical and mental abilities. However, promethazine may paradoxically cause excitability, restlessness, or, rarely, seizures.

Promethazine’s anticholinergic properties may cause adverse effects, including blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention.[20]

Promethazine’s antidopaminergic properties may result in extrapyramidal symptoms, including pseuodoparkinsonism, acute dystonia, akathisia, and tardive dyskinesia. Promethazine, therefore, may worsen symptoms in patients with Parkinson disease.[21]

Less common adverse effects that prescribers should be aware of include:

• The neuroleptic malignant syndrome may also have associations with promethazine usage, which manifests as increased body temperature, confusion or altered mental status, sweating, autonomic instability, and “lead pipe” rigidity.
• Cardiovascular side effects include arrhythmias and hypotension.
• Reports also exist of liver damage and cholestatic jaundice with its use.
• Bone marrow suppression potentially results in agranulocytosis, thrombocytopenia, and leukopenia.
• Depression of the thermoregulatory mechanism results in hypothermia/hyperthermia.

Boxed Warnings

• In children less than two years old, reports exist of respiratory depression resulting in fatalities.[22] For this reason, there is a US-boxed warning on the use of promethazine in children less than two years of age.[19]
• Promethazine may cause serious tissue injury on injection, including gangrene, regardless of the route of administration. This effect may occur due to extravasation, unintentional intra-arterial administration, and intraneuronal or perineuronal infiltration, manifesting as burning, pain, erythema, edema, severe spasms, phlebitis, thrombophlebitis, venous thrombosis, sensory loss, paralysis, and palsies.[13][14]

Contraindications

Promethazine contraindications include patients with hypersensitivity to the drug, any drug components, or other phenothiazines. The drug is contraindicated in children under two years of age due to the risk of potentially fatal respiratory depression. Promethazine is contraindicated for subcutaneous or intra-arterial administration due to the risk of tissue damage. Contraindications also include comatose patients and patients with lower respiratory tract symptoms.[13][19]

Precautions/Warnings

Seizures: Promethazine should be used cautiously in patients with seizure disorders or in persons taking concomitant medications, which may also lower seizure threshold (ie, 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 (diaphoresis, irregular heartbeats or blood pressure, tachycardia, and cardiac dysrhythmias). The diagnostic evaluation of patients with NMS is complicated. Clinicians must identify patients when the clinical presentation includes untreated or inadequately treated EPS and serious medical conditions (eg, pneumonia, systemic infection, etc).[23]

Drug Interactions

Central-Nervous-System Depressants: Promethazine may intensify, increase, or prolong the sedative action of other CNS depressants, such as tricyclic antidepressants, sedatives/hypnotics, narcotics, narcotic analgesics, alcohol, general anesthetics, and tranquilizers; therefore, those medicines should be avoided or administered in a lower dosage to patients taking promethazine concomitantly.

When promethazine is concomitantly administered, the dose of barbiturates should be reduced by at least 50% and narcotics by 25% to 50%. Dosage must be individualized according to the patient's clinical presentation. High amounts of promethazine relative to narcotics may lead to motor hyperactivity and restlessness in the patient with pain, and these symptoms normally disappear with adequate pain management.

Anticholinergics: Concomitant use of other medicines with anticholinergic properties requires caution.

Monoamine Oxidase Inhibitors (MAOI): Concomitant use can result in drug interactions, including an increased incidence of EPS.

Drug/Laboratory Test Interactions: Some laboratory tests may be altered in patients receiving promethazine therapy. Diagnostic pregnancy test results based on HCG and anti-HCG immunological reactions could result in false-positive or false-negative interpretations. Also, a glucose tolerance test may report falsely elevated blood glucose levels in patients receiving promethazine. False-positive urine amphetamine results can occur due to promethazine.[24][25]

Monitoring

Due to promethazine’s side effect profile, any medical personnel who administers the drug should be aware of potential side effects. Healthcare providers must monitor patients for burning or pain at the injection site, phlebitis, blistering, or swelling, which may indicate tissue damage.[14]

Extrapyramidal and anticholinergic side effects also require monitoring, and providers should be notified immediately if they appear. Promethazine is also a CNS depressant, so safety measures such as side rail up and call light within reach should be in place.

Toxicity

The main feature of promethazine toxicity is CNS depression, tachycardia, respiratory depression, and delirium. Supportive care and monitoring are the treatment for most overdoses, as no known antidote exists. Significant overdoses with profoundly depressed mental status or coma may require airway support, hemodynamic monitoring, and a higher level of care. Some studies have shown that early administration of charcoal within two hours may be beneficial. However, the evidence is still lacking, and further studies are necessary.[11] Because promethazine can reverse epinephrine’s vasopressor effect, epinephrine should not be used for hypotension associated with promethazine overdose.

Management of NMS

Immediate discontinuation of promethazine, antipsychotic drugs, and other drugs is essential to concurrent treatment. Intensive symptomatic treatment and medical monitoring are required. Provide therapy for concomitant serious medical problems where specific treatments are available. There are no general recommendations or specific pharmacological treatment protocols for uncomplicated NMS.

However, as reoccurrences of NMS have been reported with phenothiazines class medicines, the reintroduction of promethazine should be carefully done. Facilitate heat dissipation and administer IV fluids for dehydration. Administer IV benzodiazepines for seizures and agitation. Consider bromocriptine and dantrolene(off-label) in consultation with a neurologist and critical care specialist.[26][27]

Enhancing Healthcare Team Outcomes

Promethazine is a relatively safe medication that is very useful in treating several conditions, such as nausea/vomiting, allergic disorders, prevention of motion sickness, and pre/post-operative or obstetric sedation. However, drug prescribers should be aware of the potential side effects and contraindications. In addition, providers must be mindful of the two boxed warnings associated, which include the potential to cause severe tissue damage with IM/IV injection and potentially fatal respiratory depression in children under two years of age.

Therefore, close interprofessional coordination between physicians, advanced practice practitioners, specialists, nursing staff, pharmacists, and other healthcare workers is necessary to improve patient outcomes and decrease promethazine's adverse effects. Pharmacists can reconcile the patient's medication profile and report to the nurse or prescribing clinician if any interactions exist. Nurses will often be the first to see the patient and monitor for apparent adverse effects, either reporting to the prescriber or checking with the pharmacist regarding the adverse event profile of promethazine. Nursing is also in charge of IV administration to have first-line exposure to issues such as extravasation and can inform the clinician. The interprofessional healthcare team must collaborate, each discipline bringing expertise to support shared decision-making, leading to positive patient outcomes.