Prochlorperazine

Prochlorperazine is a Phenothiazine Derivative belonging to Antiemetic agent.

Prochlorperazine is a phenothiazine derivative used in the treatment of schizophrenia and anxiety and to relieve severe nausea and vomiting.

Following oral administration, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen. Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6 N-desmethyl prochlorperazine was detected in the plasma, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Excreted mainly via faeces.

Prochlorperazine shows side effects like Low white blood cell count, Drowsiness, Tremors, Constipation, Dry mouth, Decreased body movements, Irregular heartbeat, Anxiety, Weakness, Skin rash.

Prochlorperazine is available in the form of Oral capsule, Injectable solution, rectal suppository, Oral syrup.

Prochlorperazine is available in India, US, Canada, China, France, Japan, Italy, Russia, Germany, Spain, and Australia.

Prochlorperazine belongs to the Antiemetic agent acts as a Phenothiazine Derivative.

The mechanism of action of prochlorperazine has not been fully determined but may be primarily related to its anti-dopaminergic effects. Prochlorperazine blocks the D2 dopamine receptors in the brain, which are somatodendritic auto receptors. Inhibition of D2 receptor signaling results in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Nausea and vomiting are proposed to arise from peripheral or central stimulation of serotonin type 3 (5-HT3) and dopamine type 2 receptors, the predominant receptors expressed at the chemoreceptor trigger zone (CTZ). Prochlorperazine exerts antiemetic effects and was shown to inhibit apomorphine-induced vomiting by blocking D2 dopamine receptors in the CTZ.

The Onset action of Prochlorperazine is about 30-40 minutes (oral), 10-20 minutes (IM) and approximately 60 minutes (rectal).

The duration of action of Prochlorperazine is 3-12 hours (rectal) and 3-4 hours (IM and oral).

The Tmax of Prochlorperazine is within 30-60 minute (IV).

Prochlorperazine is available in the form of Oral capsule, Injectable solution, rectal suppository, Oral syrup.

Prochlorperazine is an antipsychotic medicine that is used to relieve nausea and vomiting and that also controls the symptoms of schizophrenia. This medicine should be started at low doses and the dose should be increased gradually.

Prochlorperazine is a Phenothiazine Derivative belonging to Antiemetic agent.

Prochlorperazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic D₁ and D₂ receptors in the brain, including the chemoreceptor trigger zone; exhibits a strong alpha-adrenergic and anticholinergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones; believed to depress the reticular activating system, thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Prochlorperazine is approved for use in the following clinical indications

Adult indication

• Chemotherapy-induced nausea and vomiting
• Migraine, moderate to severe, acute treatment
• Nausea and/or vomiting, acute
• Postoperative nausea and/or vomiting, prevention
• Postoperative nausea and/or vomiting, treatment, or rescue therapy
• Pregnancy-associated nausea and vomiting
• Radiation therapy–associated nausea and vomiting, rescue therapy

Paediatric indication

• Chemotherapy-induced nausea and vomiting; refractory, treatment
• Migraine, intractable
• Nausea and vomiting, severe; treatment

Adult Dose

• Chemotherapy-induced nausea and vomiting

IV chemotherapy agents: Low emetogenic risk (10% to 30% risk of emesis), prevention (alternative agent)

IV, Oral: 5 to 10 mg once prior to chemotherapy.

Oral chemotherapy agents: Low/minimal emetogenic risk (<30%), treatment and/or prevention

Oral: 10 mg every 6 hours as needed.

Breakthrough nausea or vomiting, rescue therapy (adjunctive therapy) (alternative agent)

IV, Oral: 5 to 10 mg every 4 to 6 hours as needed; maximum: 40 mg/day.

• Migraine, moderate to severe, acute treatment

IM, IV: 10 mg once.

Rectal: 25 mg once.

• Nausea and/or vomiting, acute

Oral: 5 to 10 mg every 6 to 8 hours as needed; maximum: 40 mg/day.

IM: 5 to 10 mg every 3 to 4 hours as needed; maximum: 40 mg/day.

IV: 2.5 to 10 mg every 3 to 4 hours as needed; maximum: 40 mg/day.

Rectal:

25 mg suppository: 25 mg every 12 hours as needed.

10 mg suppository: 5 to 10 mg 3 to 4 times/day as needed.

• Postoperative nausea and/or vomiting, prevention

IV, IM: 5 to 10 mg once at the end of procedure.

• Postoperative nausea and/or vomiting, treatment, or rescue therapy

IV, IM: 5 to 10 mg once; may repeat once after 4 hours if needed.

• Pregnancy-associated nausea and vomiting

Oral, IV, IM: 5 to 10 mg every 6 to 8 hours as needed.

Rectal: 25 mg every 12 hours as needed.

• Suppository: 5 to 10 mg 3 to 4 times/day.

• Radiation therapy–associated nausea and vomiting, rescue therapy

Low-emetogenic risk radiation therapy (head and neck, thorax, or pelvis irradiation):

Oral, IV: 5 to 10 mg once if needed after each radiation treatment, then 5 to 10 mg every 6 to 8 hours if needed (maximum: 40 mg/day). Depending on symptom severity and remaining duration of therapy, patients can receive subsequent rescue therapy as needed or begin prophylactic therapy.

Minimal-emetogenic risk radiation therapy (extremities, breast irradiation):

Oral, IV: 5 to 10 mg once if needed after each radiation treatment.

Paediatric Dose

• Chemotherapy-induced nausea and vomiting; refractory, treatment

Children ≥2 years weighing ≥9 kg and Adolescents:

Oral: 0.1 mg/kg/dose every 6 hours; maximum dose: 10 mg/dose.

IV: 0.1 to 0.15 mg/kg/dose every 3 to 4 hours; maximum dose: 10 mg/dose; maximum daily dose: 40 mg/day.

• Migraine, intractable

Migraine, intractable: Children ≥7 years and Adolescents: IV (as edisylate): 0.15 mg/kg as a single dose; maximum dose: 10 mg/dose; dosing based on multicenter, prospective, double-blind, randomized ketorolac comparative trial (prochlorperazine group, n=33) and several retrospective trials.

• Nausea and vomiting, severe; treatment

Oral:

Fixed dosing:

Children ≥2 years weighing ≥9 kg and Adolescents:

9 to 13 kg: Oral: 2.5 mg every 12 to 24 hours as needed; maximum daily dose: 7.5 mg/day.

>13 to 18 kg: Oral: 2.5 mg every 8 to 12 hours as needed; maximum daily dose: 10 mg/day.

>18 to 39 kg: Oral: 2.5 mg every 8 hours or 5 mg every 12 hours as needed; maximum daily dose: 15 mg/day.

>39 kg: Oral: 5 to 10 mg every 6 to 8 hours; usual maximum daily dose: 40 mg/day.

Weight-directed dosing: Children ≥2 years weighing >10 kg and Adolescents: Oral: 0.4 mg/kg/day divided every 6 to 8 hours; maximum dose: 10 mg/dose.

Parenteral: Prochlorperazine edisylate: Limited data available for IV route of administration:

Children ≥2 years weighing ≥9 kg and Adolescents: IM (preferred), IV: 0.1 to 0.2 mg/kg/dose; maximum single dose: 10 mg/dose; frequency of administration typically every 8 to 12 hours based upon patient response.

Prochlorperazine is available in various strengths as 5 mg/mL; 10 mg; 15 mg; 2.5 mg; 5 mg; 25 mg; 5 mg/5 mL.

Prochlorperazine is available in the form of Oral capsule, Injectable solution, rectal suppository, Oral syrup.

• Dosage Adjustment in Kidney Patient

Altered kidney function: Mild to severe impairment: No dosage adjustment necessary.

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

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

CRRT: No dosage adjustment necessary.

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

Prochlorperazine is contraindicated in patients with

• Do not use in patients with known hypersensitivity to phenothiazines.
• Do not use in comatose states or in the presence of large amounts of central nervous system depressants (alcohol, barbiturates, narcotics, etc.).
• Do not use in pediatric surgery.
• Do not use in pediatric patients under 2 years of age or under 20 lbs. Do not use in children for conditions for which dosage has not been established.

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Prochlorperazine Suppositories USP is not approved for the treatment of patients with dementia-related psychosis. The extrapyramidal symptoms which can occur secondary to prochlorperazine may be confused with the central nervous system signs of an undiagnosed primary disease responsible for the vomiting, e.g., Reye’s Syndrome or other encephalopathy. The us e of prochlorperazine and other potential hepatotoxins should be avoided in children and adolescents whose signs and symptoms suggest Reye’s Syndrome.

• Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex some- times referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association 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).If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

• General

Patients with bone marrow depression or who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) with a phenothiazine should not receive any phenothiazine, including prochlorperazine, unless in the judgment of the physician the potential benefits of treatment outweigh the possible hazards. Prochlorperazine may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, caution patients about activities requiring alertness (e.g., operating vehicles or machinery). Phenothiazines may intensify or prolong the action of central nervous system depressants (e.g., alcohol, anesthetics, narcotics).

Consumption of alcohol is not recommended with this medicine due to an increase in the risk of dizziness, seizures, and irregular heartbeats.

There is evidence that phenothiazines are excreted in the breast milk of nursing mothers. Caution should be exercised when prochlorperazine is administered to a nursing woman.

Safety for the use of prochlorperazine during pregnancy has not been established. Therefore, prochlorperazine is not recommended for use in pregnant patients except in cases of severe nausea and vomiting that are so serious and intractable that, in the judgment of the physician, drug intervention is required, and potential benefits outweigh possible hazards. There have been reported instances of prolonged jaundice, extrapyramidal signs, hyperreflexia or hyporeflexia in newborn infants whose mothers received phenothiazines.

Common Adverse effects

• Cholinergic effects (e.g., constipation, xerostomia, blurred vision, urinary retention), aspiration of vomit, extrapyramidal symptoms, somnolence, orthostatic hypotension, motor instability, hyperprolactinemia, pigmentary retinopathy, lenticular or corneal deposits, impaired body temperature regulation, Amenorrhoea, Nausea, Constipation, intestinal obstruction, vomiting, Jaundice, Angioedema, urticaria, Hyponatraemia, hyperglycaemia, Acute dystonia, dyskinesia, parkinsonism, tardive dyskinesia, agitation, convulsion, Akathisia, insomnia, Urinary retention, Impotence, ejaculatory disorder, Respiratory depression, Contact dermatitis, rash.

Rare Adverse effects

• Arrhythmias, torsade de pointes, blood dyscrasias (e.g. leucopenia, neutropenia, agranulocytosis), hypotension, neuroleptic malignant syndrome (e.g. hyperpyrexia, muscle rigidity, altered mental status).

• Acetylcholinesterase Inhibitors

May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors

• Acetylcholinesterase Inhibitors (Central)

May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients.

• Aclidinium

May enhance the anticholinergic effect of Anticholinergic Agents.

Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased.

• Alcohol (Ethyl)

CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).

• Alizapride

May enhance the CNS depressant effect of CNS Depressants.

• Amifampridine

Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.

• Aminolaevulinic Acid (Systemic)

Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).

• Aminolevulinic Acid (Topical)

Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).

• Amisulpride (Oral)

May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased.

• Amphetamines

Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines.

• Antacids

May decrease the absorption of Antipsychotic Agents (Phenothiazines).

• Anticholinergic Agents

May enhance the adverse/toxic effect of other Anticholinergic Agents.

• Anti-Parkinson Agents (Dopamine Agonist)

May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin).

• Antipsychotic Agents

Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased.

• Azelastine (Nasal)

May enhance the CNS depressant effect of CNS Depressants.

• Beta-Blockers

The common side effect of Prochlorperazine include the following

Common

• Dizziness, feeling unsteady, or having trouble keeping your balance, blurred vision, dry mouth, stuffed nose, headache, nausea, constipation, difficulty urinating, widening or narrowing of the pupils (black circles in the center of the eyes), increased appetite, weight gain, agitation, jitteriness, difficulty falling asleep or staying asleep, drooling, uncontrollable shaking of a part of the body, shuffling walk, breast enlargement, breast milk production, missed menstrual periods, decreased sexual ability in men.

Rare

• Fever, muscle stiffness, falling, confusion, fast or irregular heartbeat, sweating, yellowing of the skin or eyes, flu-like symptoms, sore throat, chills, and other signs of infection, neck cramps, tongue that sticks out of the mouth, tightness in the throat, difficulty breathing or swallowing, fine, worm-like tongue movements, uncontrollable, rhythmic face, mouth, or jaw movements, seizures, rash, hives, itching, swelling of the eyes, face, mouth, lips, tongue, throat, arms, hands, feet, ankles, or lower legs, vision loss, especially at night, coma (loss of consciousness for a period of time), Priapism.

• Pregnancy

Safety for the use of prochlorperazine during pregnancy has not been established. Therefore, prochlorperazine is not recommended for use in pregnant patients except in cases of severe nausea and vomiting that are so serious and intractable that, in the judgment of the physician, drug intervention is required, and potential benefits outweigh possible hazards. There have been reported instances of prolonged jaundice, extrapyramidal signs, hyperreflexia or hyporeflexia in newborn infants whose mothers received phenothiazines.

• Nursing Mothers

There is evidence that phenothiazines are excreted in the breast milk of nursing mothers. Caution should be exercised when prochlorperazine is administered to a nursing woman.

• Pediatric Use

use should be avoided in infants and used with caution in children and adolescents due to risk of acute dystonia (dyskinesia), and with intravenous administration an increased risk of respiratory depression, extravasation, and death.

• Geriatric Use

Clinical studies of prochlorperazine did not include enough subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Geriatric patients are more sensitive to the side effects of antipsychotics, including prochlorperazine. These adverse events include hypotension, anticholinergic effects (such as urinary retention, constipation, and confusion), and neuromuscular reactions (such as parkinsonism and tardive dyskinesia). Also, post marketing safety experience suggests that the incidence of agranulocytosis may be higher in geriatric patients compared to younger individuals who received prochlorperazine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Symptoms: Drowsiness, loss of consciousness, hypotension, tachycardia, EC changes, ventricular arrhythmias, hypothermia, severe extrapyramidal dyskinesias.

Management: Symptomatic and supportive treatment. Empty stomach by gastric lavage immediately up to 6 hours after ingestion of toxic dose. May give dopamine to correct circulatory collapse; procyclidine or orphenadrine via IM/IV for severe dystonic reactions; diazepam IV for convulsions. Restore normal body temperature and correct circulatory or metabolic disturbances.

Pharmacodynamic

Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx.

Pharmacokinetics

• Absorption

Following oral administration, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours.

• Distribution

In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volume of distribution following intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen.

• Metabolism and Excretion

Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6 N-desmethyl prochlorperazine was detected in the plasma1, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Excreted mainly via faeces.

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