Procarbazine (Monograph)

Brand name: Matulane
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: N-Isopropyl-α-(2-methylhydrazino)-p-toluamide monohydrochloride
Molecular formula: C₁₆H₂₂N₂O₃•HCl
CAS number: 366-70-1

Medically reviewed by Drugs.com on Jul 24, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a polyfunctional alkylating agent.

Uses for Procarbazine

Hodgkin’s Disease

Treatment of stage III and IV Hodgkin’s disease.

Used in various combination therapy regimens; comparative efficacy continually being evaluated.

Used in combination with mechlorethamine, vincristine, and prednisone (known as the MOPP regimen) in an alternating schedule with the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) for treatment of Hodgkin’s disease.

Used in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (increased-dose BEACOPP regimen) for treatment of advanced Hodgkin’s disease.

Use in other combination regimens for treatment of advanced Hodgkin’s disease being investigated.

Brain Tumors

Treatment of brain tumors^{† [off-label]}.

Used in combination with lomustine and vincristine (PCV) as adjuvant therapy following surgery and radiation therapy for malignant gliomas (e.g., anaplastic astrocytoma, glioblastoma multiforme, anaplastic oligodendroglioma)^{† [off-label]}.

Non-Hodgkin’s Lymphoma

Has been used as a component of combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas^{† [off-label]}.

Related/similar drugs

Keytruda, pembrolizumab, Avastin, cyclophosphamide, doxorubicin, bevacizumab, nivolumab

Procarbazine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

• Individualize dosage according to clinical and hematologic response.

Administration

Oral Administration

Administer orally in single or divided doses.

IV Administration

Has been administered IV^{† [off-label]} (IV preparation not commercially available in the US); however, produced a higher incidence of toxicity than oral therapy.

Dosage

Available as procarbazine hydrochloride; dosage expressed in terms of procarbazine.

Dosage based on patient’s actual body weight; if patient is obese or has abnormal fluid retention (e.g., edema, ascites), use ideal body weight to calculate dosage.

Consult published protocols for dosage of procarbazine and other chemotherapeutic agents and method and sequence of administration.

Pediatric Patients

Hodgkin’s Disease

Oral

Not definitely established; manufacturer recommends 50 mg/m² daily for first week of therapy.

Subsequently, 100 mg/m² daily until maximum response obtained, unless hematologic or other toxicity occurs. (See Pediatric Patients: Dosage Modification for Toxicity and Contraindications for Continued Therapy, under Dosage and Administration.)

After maximum response attained, usual maintenance dosage is 50 mg/m² daily.

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Interruption or discontinuance of the drug may be required in patients experiencing toxicity. Upon satisfactory recovery from toxicity, resume therapy at discretion of the clinician.

Hematologic Toxicity

If leukocyte count is <4000/mm³ or if platelet count is <100,000/mm³, interrupt therapy.

If hemorrhage or bleeding tendencies develop, discontinue therapy. (See Hematologic Effects under Cautions.)

GI Toxicity

At onset of stomatitis, discontinue therapy immediately.

If diarrhea occurs, discontinue therapy. (See GI Effects under Cautions.)

Neurotoxicity

If manifestations of CNS toxicity occur (e.g., paresthesia, neuropathy, confusion), discontinue therapy. (See Pediatric Use and also see Nervous System Effects under Cautions.)

Hypersensitivity Reactions

If hypersensitivity reaction occurs, discontinue therapy. (See Sensitivity Reactions under Cautions.)

Adults

Hodgkin’s Disease

Oral

Single-agent therapy: Initially, 2–4 mg/kg daily, in single or divided doses, for first week.

Subsequently, 4–6 mg/kg daily until maximum response obtained, unless hematologic or other toxicity occurs. (See Adults: Dosage Modification for Toxicity and Contraindications for Continued Therapy, under Dosage and Administration.)

After maximum response attained, usual maintenance dosage is 1–2 mg/kg daily.

Component of MOPP regimen: Usually, 100 mg/m² daily on days 1–14 of a 28-day cycle.

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Interruption or discontinuance of the drug may be required in patients experiencing toxicity. Upon satisfactory recovery from toxicity, resume therapy at discretion of the clinician.

Single-agent therapy: After satisfactory recovery from toxicity, may resume dosage at 1–2 mg/kg daily.

Hematologic Toxicity

If leukocyte count is <4000/mm³ or if platelet count is <100,000/mm³, interrupt therapy.

If hemorrhage or bleeding tendencies develop, discontinue therapy. (See Hematologic Effects Under Cautions.)

GI Toxicity

At onset of stomatitis, discontinue therapy immediately.

If diarrhea occurs, discontinue therapy. (See GI Effects under Cautions.)

Neurotoxicity

If manifestations of CNS toxicity occur (e.g., paresthesia, neuropathy, confusion), discontinue therapy. (See Nervous System Effects under Cautions.)

Hypersensitivity Reactions

If hypersensitivity reaction occurs, discontinue therapy. (See Sensitivity Reactions under Cautions.)

Special Populations

No special population dosage recommendations at this time. (See Hepatic Impairment and also see Renal Impairment under Cautions.)

Cautions for Procarbazine

Contraindications

• Inadequate marrow reserve as demonstrated by bone marrow aspiration.

• Known hypersensitivity to procarbazine.

Warnings/Precautions

Warnings

Risks Associated with MAO Inhibition

Procarbazine possesses some MAO inhibitory activity; avoid concomitant use with certain food or prescription and OTC drugs. (See Specific Drugs, Foods, and Therapies under Interactions.)

Hematologic Effects

Leukopenia, anemia, and thrombocytopenia occur frequently. Discontinue therapy if leukocyte count is <4000/mm³ or platelet count is <100,000/mm³. Consider possibility of inadequate marrow reserve in patients with leukopenia, thrombocytopenia, or anemia. (See Dosage Modification for Toxicity and Contraindications for Continued Therapy in Pediatric Patients and also in Adults under Dosage and Administration.)

Myelosuppression often occurs 2–8 weeks after beginning treatment. Leukopenia may require hospitalization for appropriate treatment to prevent systemic infection.

Possible hemolysis and appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. Hemorrhagic tendencies (e.g., petechiae, purpura, epistaxis, hemoptysis, hematemesis, hematuria, melena) reported. Discontinue therapy if bleeding or bleeding tendencies occur.

If the patient received previous radiation or chemotherapy with myelosuppressive effects, delay procarbazine administration for ≥1 month. Perform successive bone marrow studies to determine when bone marrow recovery is sufficient to allow procarbazine therapy initiation.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Carcinogenic Effects

Secondary malignancies (e.g., acute myeloid leukemia, lung cancer, malignant myelosclerosis) reported in patients receiving procarbazine in combination with other chemotherapy and/or radiation therapy.

Increased risk of secondary lung cancer reported in patients receiving procarbazine in combination with tobacco products; discontinue tobacco use.

Sensitivity Reactions

Generalized allergic reactions reported.

If hypersensitivity reaction occurs, discontinue therapy.

Photosensitivity reported.

Major Toxicities

GI Effects

Severe nausea and vomiting occur frequently.

Discontinue therapy if stomatitis (e.g., small ulceration or persistent soreness around the mouth) or diarrhea (frequent bowel movements or watery stools) occurs. (See Dosage Modification for Toxicity and Contraindications for Continued Therapy in Pediatric Patients and also in Adults under Dosage and Administration.)

Nervous System Effects

Discontinue therapy if paresthesia, neuropathy, or confusion occurs.

Possible mental depression, hallucinations, dizziness, headache, apprehension, nervousness, insomnia, nightmares, falling, unsteadiness, ataxia, footdrop, nystagmus, decreased reflexes, tremors, coma, confusion, and seizures. (See Pediatric Use under Cautions.)

General Precautions

Adequate Patient Evaluation and Monitoring

Highly toxic drug; administer only under constant supervision of a qualified clinician experienced in cancer chemotherapy. When appropriate, initiate therapy with the patient hospitalized; carefully consider patient’s clinical and histologic diagnosis and hematologic, renal, and hepatic status.

Monitor hematologic status carefully. Perform blood counts (hemoglobin, hematocrit, leukocyte and differential counts, reticulocyte and platelet determinations) prior to therapy and at least every 3–4 days thereafter. (See Hematologic Effects under Cautions.)

Perform urinalysis, serum transaminase, serum alkaline phosphatase, and BUN determinations prior to therapy and at least weekly thereafter.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether procarbazine is distributed into milk; discontinue nursing.

Pediatric Use

Undue toxicity (i.e., coma, seizures, tremor) has occurred in a few pediatric patients. (See Nervous System Effects under Cautions.)

Individualize dosage; careful monitoring required.

Hepatic Impairment

Possible increased incidence of toxicity. Consider initiating therapy with the patient hospitalized. (See Adequate Patient Evaluation and Monitoring and also see Major Toxicities under Cautions.)

Renal Impairment

Possible increased incidence of toxicity. Consider initiating therapy with the patient hospitalized. (See Adequate Patient Evaluation and Monitoring and also see Major Toxicities under Cautions.)

Common Adverse Effects

Leukopenia, anemia, thrombocytopenia, nausea, vomiting.

Drug Interactions

Specific Drugs, Foods, and Therapies

Procarbazine Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed; peak plasma concentrations attained within 1 hour following oral administration.

Oral administration may result in plasma concentrations similar to those achieved following IV administration of the drug (IV preparation not commercially available in the US).

Distribution

Extent

Readily crosses the blood-brain barrier; rapidly equilibrates between plasma and CSF following oral administration.

Distributed into liver, kidneys, intestinal wall, and skin following IV administration.

Not known whether procarbazine is distributed into milk.

Elimination

Metabolism

Metabolized principally in liver and kidneys.

Elimination Route

Excreted in urine as metabolites.

Half-life

IV: Approximately 10 minutes.

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 15–30°C (may be exposed to ≤40°C).

Actions

• Precise mechanism(s) of cytotoxic action unknown; may inhibit protein, RNA, and DNA synthesis by inhibiting transmethylation of methyl groups of methionine into t-RNA.

• Cycle-phase nonspecific.

• Inhibits mitosis by prolonging the interphase of cell division and causing chromatid breaks in ascites carcinoma cells.

• May directly damage DNA; hydrogen peroxide formed during auto-oxidation of the drug may attack protein sulfhydryl groups contained in residual protein tightly bound to DNA.

• Cytotoxic effects limited to tissues with high rates of cellular proliferation; effects only evident in cells actively synthesizing DNA.

• Also has MAO inhibiting properties.

Advice to Patients

• Risk of bone marrow suppression, nausea, vomiting, and secondary malignancies.

• Importance of close medical supervision during therapy.

• Importance of avoiding alcoholic beverages and tobacco during therapy.

• Importance of avoiding foods with known high tyramine content such as wine, yogurt, ripe cheese, and bananas.

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus.

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs (e.g., antihistamines) and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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