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Procarbazine Hydrochloride

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
Brands: Matulane

Warning(s)

  • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.100

  • Use only when adequate treatment facilities for appropriate management of therapy and complications are available.100

Introduction

Antineoplastic agent; a polyfunctional alkylating agent.100 b d

Uses for Procarbazine Hydrochloride

Hodgkin’s Disease

Treatment of stage III and IV Hodgkin’s disease.100 101

Used in various combination therapy regimens; comparative efficacy continually being evaluated.102 103 104

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.101 102 103 104

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Used in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (increased-dose BEACOPP regimen) for treatment of advanced Hodgkin’s disease.101 104

Use in other combination regimens for treatment of advanced Hodgkin’s disease being investigated.104

Brain Tumors

Treatment of brain tumors.106

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).101 107 108 109

Non-Hodgkin’s Lymphoma

Has been used as a component of combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas.101

Procarbazine Hydrochloride Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.100 b

  • Individualize dosage according to clinical and hematologic response.100 b

Administration

Oral Administration

Administer orally in single or divided doses.100 b

IV Administration

Has been administered IV (IV preparation not commercially available in the US); however, produced a higher incidence of toxicity than oral therapy.b

Dosage

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

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.100

Consult published protocols for dosage of procarbazine and other chemotherapeutic agents and method and sequence of administration.100 b

Pediatric Patients

Hodgkin’s Disease
Oral

Not definitely established; manufacturer recommends 50 mg/m2 daily for first week of therapy.100

Subsequently, 100 mg/m2 daily until maximum response obtained, unless hematologic or other toxicity occurs.100 (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.100

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Interruption or discontinuance of the drug may be required in patients experiencing toxicity.100 Upon satisfactory recovery from toxicity, resume therapy at discretion of the clinician.100

Hematologic Toxicity

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

If hemorrhage or bleeding tendencies develop, discontinue therapy.100 (See Hematologic Effects under Cautions.)

GI Toxicity

At onset of stomatitis, discontinue therapy immediately.100

If diarrhea occurs, discontinue therapy.100 (See GI Effects under Cautions.)

Neurotoxicity

If manifestations of CNS toxicity occur (e.g., paresthesia, neuropathy, confusion), discontinue therapy.100 (See Pediatric Use and also see Nervous System Effects under Cautions.)

Hypersensitivity Reactions

If hypersensitivity reaction occurs, discontinue therapy.100 (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.100

Subsequently, 4–6 mg/kg daily until maximum response obtained, unless hematologic or other toxicity occurs.100 (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.100

Component of MOPP regimen: Usually, 100 mg/m2 daily on days 1–14 of a 28-day cycle.100 102 103

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Interruption or discontinuance of the drug may be required in patients experiencing toxicity.100 Upon satisfactory recovery from toxicity, resume therapy at discretion of the clinician.100

Single-agent therapy: After satisfactory recovery from toxicity, may resume dosage at 1–2 mg/kg daily.100

Hematologic Toxicity

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

If hemorrhage or bleeding tendencies develop, discontinue therapy.100 (See Hematologic Effects Under Cautions.)

GI Toxicity

At onset of stomatitis, discontinue therapy immediately.100

If diarrhea occurs, discontinue therapy.100 (See GI Effects under Cautions.)

Neurotoxicity

If manifestations of CNS toxicity occur (e.g., paresthesia, neuropathy, confusion), discontinue therapy.100 (See Nervous System Effects under Cautions.)

Hypersensitivity Reactions

If hypersensitivity reaction occurs, discontinue therapy.100 (See Sensitivity Reactions under Cautions.)

Special Populations

No special population dosage recommendations at this time.100 (See Hepatic Impairment and also see Renal Impairment under Cautions.)

Cautions for Procarbazine Hydrochloride

Contraindications

  • Inadequate marrow reserve as demonstrated by bone marrow aspiration.100

  • Known hypersensitivity to procarbazine.100

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.100 (See Specific Drugs, Foods, and Therapies under Interactions.)

Hematologic Effects

Leukopenia, anemia, and thrombocytopenia occur frequently.100 Discontinue therapy if leukocyte count is <4000/mm3 or platelet count is <100,000/mm3.100 Consider possibility of inadequate marrow reserve in patients with leukopenia, thrombocytopenia, or anemia.100 (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.100 Leukopenia may require hospitalization for appropriate treatment to prevent systemic infection.100

Possible hemolysis and appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.100 Hemorrhagic tendencies (e.g., petechiae, purpura, epistaxis, hemoptysis, hematemesis, hematuria, melena) reported.100 Discontinue therapy if bleeding or bleeding tendencies occur.100

If the patient received previous radiation or chemotherapy with myelosuppressive effects, delay procarbazine administration for ≥1 month.100 Perform successive bone marrow studies to determine when bone marrow recovery is sufficient to allow procarbazine therapy initiation.100

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.100 Avoid pregnancy during therapy.100 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.100

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.100

Increased risk of secondary lung cancer reported in patients receiving procarbazine in combination with tobacco products; discontinue tobacco use.100

Sensitivity Reactions

Generalized allergic reactions reported. 100

If hypersensitivity reaction occurs, discontinue therapy.100

Photosensitivity reported.b

Major Toxicities

GI Effects

Severe nausea and vomiting occur frequently.100

Discontinue therapy if stomatitis (e.g., small ulceration or persistent soreness around the mouth) or diarrhea (frequent bowel movements or watery stools) occurs.100 (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.100

Possible mental depression, hallucinations, dizziness, headache, apprehension, nervousness, insomnia, nightmares, falling, unsteadiness, ataxia, footdrop, nystagmus, decreased reflexes, tremors, coma, confusion, and seizures.100 (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.100 When appropriate, initiate therapy with the patient hospitalized;100 carefully consider patient’s clinical and histologic diagnosis and hematologic, renal, and hepatic status.100 b

Monitor hematologic status carefully.100 Perform blood counts (hemoglobin, hematocrit, leukocyte and differential counts, reticulocyte and platelet determinations) prior to therapy and at least every 3–4 days thereafter.100 (See Hematologic Effects under Cautions.)

Perform urinalysis, serum transaminase, serum alkaline phosphatase, and BUN determinations prior to therapy and at least weekly thereafter.100

Specific Populations

Pregnancy

Category D.100 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether procarbazine is distributed into milk;100 discontinue nursing.100

Pediatric Use

Undue toxicity (i.e., coma, seizures, tremor) has occurred in a few pediatric patients.100 (See Nervous System Effects under Cautions.)

Individualize dosage; careful monitoring required.100

Hepatic Impairment

Possible increased incidence of toxicity.100 Consider initiating therapy with the patient hospitalized.100 (See Adequate Patient Evaluation and Monitoring and also see Major Toxicities under Cautions.)

Renal Impairment

Possible increased incidence of toxicity.100 Consider initiating therapy with the patient hospitalized.100 (See Adequate Patient Evaluation and Monitoring and also see Major Toxicities under Cautions.)

Common Adverse Effects

Leukopenia, anemia, thrombocytopenia, nausea, vomiting.100

Interactions for Procarbazine Hydrochloride

Specific Drugs, Foods, and Therapies

Drug, Food, or Therapy

Interaction

Comments

Alcohol

Possible disulfiram-like reactions100

Alcohol should not be consumed during procarbazine therapy100

Antidepressants, tricyclics (e.g., amitriptyline, imipramine)

Potential serious and life-threatening serotonin syndromec

Avoid concomitant use100 b

CNS depressants (antihistamines, barbiturates, hypotensive agents, opiates, phenothiazines)

Possible additive CNS depression100

Use concomitantly with caution100

Avoid concomitant use with OTC preparations containing antihistamines.

Food, tyramine-containing (e.g., bananas, cheese, caffeine, yogurt)

Potential for hypertensive reactionsc

Avoid food and drinks with high tyramine content 100

Consult specialized references on food constituents or a dietician for specific information on the tyramine content of foods and beveragesc

Myelosuppressive agents

Possible additive myelosuppressive effects100

An interval of ≥1 month without myelosuppressive therapy should elapse before initiating procarbazine;100 during this interval, perform bone marrow studies to determine when to initiate therapy100

Radiation therapy

Possible additive myelosuppressive effects100

An interval of ≥1 month without radiation therapy should elapse before initiating procarbazine;100 during this interval, perform bone marrow studies to determine when to initiate therapy100

Sympathomimetic agents (e.g., ephedrine, phenylpropanolamine [no longer commercially available in the US])

Potential for hypertensive reactionsc

Avoid concomitant usec

Tobacco

Concomitant use may increase risk of secondary lung cancer100

Discontinue tobacco use100

Procarbazine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed;100 peak plasma concentrations attained within 1 hour following oral administration.100

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).b

Distribution

Extent

Readily crosses the blood-brain barrier; rapidly equilibrates between plasma and CSF following oral administration.100

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

Not known whether procarbazine is distributed into milk.100

Elimination

Metabolism

Metabolized principally in liver and kidneys.100

Elimination Route

Excreted in urine as metabolites.100

Half-life

IV: Approximately 10 minutes.100

Stability

Storage

Oral

Capsules

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

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.100 b d

  • Cycle-phase nonspecific.d

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

  • 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.100

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

  • Also has MAO inhibiting properties.100

Advice to Patients

  • Risk of bone marrow suppression, nausea, vomiting, and secondary malignancies.100

  • Importance of close medical supervision during therapy.100

  • Importance of avoiding alcoholic beverages and tobacco during therapy.100

  • Importance of avoiding foods with known high tyramine content such as wine, yogurt, ripe cheese, and bananas.100

  • 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.100

  • 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.100

  • Importance of advising patients of other important precautionary information.100 (See Cautions.)

Preparations

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

Procarbazine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg (of procarbazine)

Matulane

Sigma-Tau

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Sigma-Tau Pharmaceuticals, Inc. Matulane (procarbazine hydrochloride) capsules prescribing information. Gaithersburg, MD; 2004 Feb.

101. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

102. Urba WJ, Longo DL. Hodgkin’s disease. N Engl J Med. 1992; 326:678-687. [IDIS 292239] [PubMed 1736106]

103. DeVita VT Jr, Hubbard SM. Hodgkin’s disease. N Engl J Med. 1993; 328:560-5. [IDIS 309839] [PubMed 8426624]

104. Adult Hodgkin lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 3.

105. Food and Drug Administration. Prescription drug advertising; content and format for labeling of human prescription drugs. Fed Regist. 1979; 44:37434-67.

106. Green SB, Byar DP, Walker MD et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep. 1983; 67:121-32. [IDIS 168449] [PubMed 6337710]

107. Levin VA, Silver P, Hannigan J et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990; 18:321-4. [PubMed 2154418]

108. Cairncross G, Macdonald D, Ludwin S et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994; 12:2013-21. [IDIS 337224] [PubMed 7931469]

109. Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology. 2000; 54:1442-8. [IDIS 446653] [PubMed 10751254]

110. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 [4-1-87 Ed.]). 1987:18-24.

b. AHFS drug information 2009. McEvoy GK, ed. Procarbazine. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2009:1217–20.

c. AHFS drug information 2009. McEvoy GK, ed. MAO inhibitors general statement. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2009:2331–6.

d. AHFS drug information 2009. McEvoy GK, ed. Antineoplastic agents general statement. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2009. From website: .

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