Procarbazine

Procarbazine is an antineoplastic agent belonging to the pharmacological class of methylhydrazine.

Procarbazine is approved by the FDA (Food and Drug Administration) for the treatment of stage III and IV Hodgkin's lymphoma.

Procarbazine swiftly absorbs after oral intake, crosses the blood-brain barrier, undergoes liver oxidation, is mainly excreted via urine, and holds a short half-life of about an hour.

The most common side effects of Procarbazine include nausea, vomiting, and loss of appetite.

Procarbazine is available in oral capsules.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Procarbazine is an antineoplastic agent belonging to the pharmacological class of methylhydrazine.

The exact mechanism by which Procarbazine exerts its cytotoxic effects is yet unknown. Based on available data, the medication might function by preventing the synthesis of proteins, RNA, and DNA. According to research, Methionine's methyl groups may not be transmethylated into t-RNA by Procarbazine. DNA and RNA synthesis may stop when there is no functioning t-RNA. This could lead to the synthesis of protein blocking. Procarbazine may harm DNA directly. When residual protein is tightly bound to DNA, its sulfhydryl groups may be attacked by hydrogen peroxide created during the drug's auto-oxidation process.

Procarbazine is available in the form of oral capsules.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily; it can be taken with or without food as directed.

Procarbazine is indicated for use in combination with other anticancer agents for the treatment of Stage III and IV Hodgkin's disease.

Orally: Take Procarbazine capsules orally with water, usually once daily. The prescription advises ingestion on an empty stomach, an hour before or two hours after meals. Swallow the capsules whole, avoiding chewing or opening them. Consistency in dosing times proves critical. Adhere to regular intake for maximum benefit. Ensure standard daily intake times as directed, basing the dosage on your medical condition, weight, and response to therapy.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Follow dietary guidelines while taking Procarbazine for enhanced safety. Reduce intake of high-tyramine foods like overripe fruit, processed cheese, and smoked meats. Consume healthy proteins, fats, fruits, vegetables, and whole grains for energy.

Refrain from combining Procarbazine with alcohol due to potential interactions. Ensure adequate hydration to counter dehydration often linked to cancer. Avoid tobacco to minimize the risk of lung cancer when using Procarbazine. Inform your doctor about any marijuana use.

The dietary restriction should be individualized as per patient requirements.

Stop immediately if one experiences symptoms related to the central nervous system, hypersensitivity reactions, diarrhoea, stomatitis, bleeding, or hemolysis.

If the platelet or white blood cell counts drop below 100,000/mm³ or below 4000/mm³, discontinue the treatment.

Patients with compromised renal or liver function should be treated with caution.

Avoid alcoholic beverages and tyramine-containing foods.

Avoid pregnancy because of the risks. Recognize that Procarbazine might result in infertility.

It should be emphasized that it exhibits MAO inhibitor activity, which raises the possibility of interactions with specific foods and drugs.

The adverse reactions related to Procarbazine can be categorized as:

Common Adverse Effects: Leukopenia, anemia and thrombopenia

Less Common Adverse Effects: Confusion, anemia, and fever.

Rare Adverse Effects: Pancreatitis, liver function abnormalities and lung fibrosis.

The clinically relevant drug interactions of Procarbazine are briefly summarized here.

Drug Interactions: Could decrease the beneficial effects of live vaccinations. It may exacerbate the effects of barbiturates, narcotic analgesics (especially pethidine), anticholinergic agents (like phenothiazine derivatives and TCAs), anaesthetic agents, other CNS depressants, and antihypertensive medications. This may make taking clozapine more likely to cause agranulocytosis. It may reduce the rate at which cardiac glycosides and phenytoin are absorbed. It may make using antiepileptic medications that induce enzyme hypersensitivity reactions more likely.

Food Interaction: There is a higher chance of an alcohol-induced disulfiram-like reaction. Rarely, eating foods high in tyramine (such as aged cheese, cured or pickled meats, fava beans, soy sauce, and wines) can result in an abrupt and severe increase in blood pressure, known as hypertensive crisis or mood disorders.

The common side effects of Procarbazine include:

Nausea

Vomiting

Decreased appetite

Having trouble falling asleep

Stomach cramps

Skin rashes and bruises

Hair loss

Joint pains

Difficulty sleeping

Pregnancy Category D (FDA): Use in situations where there is no safer medication available, and life is in danger. Evidence that human fetal risk exists.

If given to a pregnant patient, proparbazine hydrochloride may harm the developing foetus. Procarbazine hydrochloride has not been thoroughly studied in pregnant women. Still, there have been case reports of congenital disabilities in the progeny of women who took it in conjunction with other antineoplastic drugs while pregnant. Only if the possible benefits outweigh the possible risks to the developing foetus should Procarbazine be used during pregnancy. The potential risk to the fetus should be explained to the patient if this medication is taken during pregnancy or if the patient gets pregnant while taking this medication. It is advisable to advise women capable of bearing children not to become pregnant.

It is unknown if human milk contains procarbazine excretion. Procarbazine hydrochloride has been demonstrated in animal studies to have carcinogenic potential; therefore, mothers taking this medication shouldn't breastfeed.

No suitable prospective controlled studies have been done on children. Tremors, coma, and convulsions are signs of undue toxicity that have happened in a few cases. As such, the dosage needs to be adjusted. A vigilant assessment is required.

Dose adjustment

Hodgkin's disease

For seven days, take 50 mg/m² PO qDay; then, increase to 100 mg/m²/day until the most significant response is attained or leukopenia or thrombocytopenia is noted.

CBC should be monitored.

Procarbazine safety and efficacy in the geriatric population requires cautious monitoring due to age-related variations in organ function. Elderly individuals may experience increased susceptibility to adverse effects and decreased medication tolerance. Careful assessment of renal and hepatic functions and vigilant monitoring for potential side effects are crucial for ensuring the safe and effective use of Procarbazine in this demographic.

Hodgkin's disease

If required, make adjustments for renal impairment.

A regimen component of BEACOPP, MOPP, and COPP

2-4 mg/kg/day in single or divided doses for 7 days; after the maximum effect is reached, reduce dosage to 1-2 mg/kg/day. Increase dosage by 4-6 mg/kg/day until maximum response or WBC<4,000 cells/mm³ or platelets<100,000 cells/mm³.

Alternatively, 100 mg/m² PO qDay in combination with other antineoplastics for 7–14 days during each 28-day cycle

CBC should be monitored.

Renal impairment: Use caution, as BUN levels above 40 mg/dL may lead to increased toxicity.

Hepatic Impairment: Be cautious; if AST or ALT are more significant than 1.6 ULN, there may be an increase in toxicity.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of Procarbazineoverdosage.

Overconsumption of Procarbazine may lead to Severe nausea, vomiting, dizziness, hallucinations, depression, convulsion, hypotension or tachycardia.

There is no known specific antidote for procarbazine overdoses. Use supportive interventions such as ingesting activated charcoal within one hour after consumption. Treat symptoms as soon as they appear, prioritising managing fluids appropriately and improving electrolyte imbalances to prevent infections or haematological problems. For a minimum of three weeks, periodically check blood counts; the frequency should be adjusted following clinical assessment and symptoms. Ideally, this should be done once a week. To treat symptoms and provide the best possible care for patients, it is crucial to assess Procarbazine overdose cases and modify treatment plans regularly.

Timely medical intervention plays a crucial role in managing Procarbazine overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

When conditions are present in cells, Procarbazine, an alkylating agent, can add an alkyl group to many electronegative groups. By directly attacking DNA, they stop the growth of tumours by creating cross-links between the guanine bases in DNA double helices. The strands can't uncoil and separate as a result of this. The cells can no longer divide since this is required for DNA replication. Furthermore, these medications add methyl or other alkyl groups to molecules that shouldn't be there. This prevents the bases from correctly pairing and disrupts DNA coding. Propracarbazine is only active during the S phase of cell division.

Absorption: Upon oral administration, Procarbazine exhibits rapid and complete absorption within the gastrointestinal tract, reaching peak plasma concentrations in approximately 0.5-1 hour.

Distribution: It penetrates the blood-brain barrier and reaches the cerebrospinal fluid.

Metabolism: The liver rapidly metabolizes it through oxidation, forming active metabolites like methylazoxy-procarbazine and benzylazoxy-procarbazine. Subsequent metabolism in the kidneys produces inactive metabolites.

Elimination: Elimination of Procarbazine primarily occurs through urine, with approximately 70% excreted as N-isopropylterepththalamic acid, a primary inactive metabolite found in urine. A small portion, around 5%, exits the body unchanged.