VA Class:AN900
Procarbazine hydrochloride, which is considered a polyfunctional alkylating agent by some experts, is an antineoplastic agent.
Procarbazine hydrochloride is used in the treatment of Hodgkin's disease.100, 101 Various regimens have been used in combination therapy and comparative efficacy is continually being evaluated.102, 103, 104 Procarbazine is used with mechlorethamine, vincristine, and prednisone (known as the MOPP regimen) in an alternating schedule with the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) for the treatment of Hodgkin's disease.101, 102, 103, 104 Procarbazine is used in combination with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (in the increased-dose BEACOPP regimen) for the treatment of advanced Hodgkin's disease.101, 104 The use of procarbazine in other combination regimens for the treatment of advanced Hodgkin's disease is being investigated.104
Procarbazine, an active agent in the treatment of brain tumors†, 106 readily crosses the blood-brain barrier.100 Procarbazine is 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 (See Uses: Brain Tumors in Lomustine 10:00 for further discussion of the treatment of malignant gliomas using the PCV regimen.)
Procarbazine also has been used as a component of combination chemotherapy regimens in the treatment of intermediate-grade non-Hodgkin's lymphomas†.101
Procarbazine hydrochloride is administered orally.100
Dosage of procarbazine hydrochloride is expressed in terms of procarbazine. Procarbazine hydrochloride dosage must be highly individualized based on clinical and hematologic response. Dosage is based on the patient's body weight; if the patient has abnormal fluid retention (e.g., edema, ascites), ideal body weight is used to calculate dosage.100 Clinicians should consult published protocols for the dosage of procarbazine hydrochloride and other chemotherapeutic agents and the method and sequence of administration.
For the first week of therapy, the usual adult dosage of procarbazine recommended by the manufacturer for use as a single agent is 2-4 mg/kg daily given in single or divided doses.100 Thereafter, 4-6 mg/kg may be given daily until maximum response is obtained, unless the leukocyte count falls below 4000/mm3 or the platelet count falls below 100,000/mm3, at which time therapy must be interrupted.100
After a remission is attained, the usual maintenance dosage recommended by the manufacturer is 1-2 mg/kg daily.100 If therapy must be interrupted because of drug toxicity, administration of 1-2 mg/kg daily may be resumed after satisfactory recovery from toxicity.100
When used as a component of the MOPP regimen in the treatment of advanced Hodgkin's disease, the usual dosage of procarbazine is 100 mg/m2 daily on days 1-14 of a 28-day cycle.100, 102, 103
Dosage must be individualized and close clinical monitoring is necessary in children receiving procarbazine.100 Pediatric dosage of procarbazine has not been definitely established, but the manufacturer suggests a dosage of 50 mg/m2 daily for the first week of therapy, followed by a dosage of 100 mg/m2 daily.100 When maximum response is attained, the usual maintenance dosage is 50 mg/m2 daily.100 If therapy must be interrupted because of drug toxicity, administration of 50 mg/m2 daily may be resumed after satisfactory recovery of the bone marrow is achieved.100
IV† therapy has been used but has produced a higher incidence of toxicity than oral therapy.
Dosage Modification for Toxicity and Contraindications to Continued Therapy
Procarbazine therapy should be discontinued promptly in patients experiencing any of the following toxicities.100 Upon satisfactory recovery from toxicity, procarbazine therapy may be resumed at the discretion of the clinician.100
If leukopenia occurs, hospitalization and preventive therapy may be necessary to avoid systemic infection.100
If the leukocyte count falls below 4000/mm3, or if the platelet count falls below 100,000/mm3, procarbazine therapy should be interrupted.100 When clinical evaluation and appropriate laboratory studies indicate satisfactory recovery, procarbazine therapy may be resumed at the discretion of the clinician; dosage reduction may be necessary.100
If hemorrhage or bleeding tendencies develop, procarbazine therapy should be discontinued.100
If diarrhea or stomatitis occurs, procarbazine therapy should be discontinued.100 At the onset of stomatitis, which may manifest as a small ulceration or persistent soreness around the mouth, procarbazine therapy should be discontinued immediately.100
If manifestations of CNS toxicity occur, such as paresthesia, neuropathy, or confusion, procarbazine therapy should be discontinued.100
If a sensitivity reaction occurs, procarbazine therapy should be discontinued.100
The major toxic effects of procarbazine are on the normal, rapidly proliferating tissues (particularly of the bone marrow and lining of the GI tract) and on the CNS. The drug's principal toxic effect is bone marrow depression, resulting in leukopenia, anemia, and thrombocytopenia. In patients with preexisting renal, hepatic, or bone marrow impairment, severe toxicity may occur.100
Leukopenia, anemia, and thrombocytopenia occur frequently in patients receiving procarbazine.100 Myelosuppression often occurs at 2-8 weeks following initiation of procarbazine therapy.100 Procarbazine therapy should be discontinued if the leukocyte count falls below 4000/mm3, or if the platelet count falls below 100,000/mm3.100
Pancytopenia, eosinophilia, and hemolytic anemia have been reported in patients receiving procarbazine.100 In addition, hemolysis, anisocytosis, poikilocytosis, lymphocytosis, and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes may occur with procarbazine therapy. Mild reticulocytosis and decreased haptoglobin concentrations may also occur. The patient's hematologic status must be carefully monitored.100 (See Cautions: Precautions and Contraindications.)
Hemorrhagic tendencies including petechiae, purpura, epistaxis, hemoptysis, hematemesis, hematuria, and melena have been reported.100 Procarbazine therapy should be discontinued if bleeding or bleeding tendencies occur.100
Nausea and vomiting are the most common adverse effects of procarbazine.100 Severe nausea and vomiting occur frequently in patients receiving procarbazine in therapeutic dosage following both oral and IV† administration. Other adverse GI effects may include anorexia, abdominal pain, stomatitis, dryness of the mouth, dysphagia, diarrhea, and constipation.100 Procarbazine therapy should be discontinued if stomatitis or diarrhea occurs.100
CNS reactions include paresthesia and neuropathies, mental depression, hallucinations, dizziness, headache, apprehension, nervousness, insomnia, nightmares, falling, unsteadiness, ataxia, footdrop, nystagmus, decreased reflexes, tremors, coma, confusion, and seizures.100 Acute exogenous psychosis, manic reactions, disorientation, and delirium also have been reported. In some instances, severe reactions including tremors, coma, and seizures have occurred when procarbazine hydrochloride has been administered to children.100 Pain, including myalgia and arthralgia, weakness, fatigue, lethargy, drowsiness, slurred speech, and hoarseness have also occurred with procarbazine therapy.100 Procarbazine should be discontinued if paresthesia, neuropathies, or confusion occurs.100
Hepatic dysfunction and jaundice have been reported in patients receiving procarbazine.100 Ascites also has been reported with procarbazine therapy.
Urinary tract infections secondary to leukopenia have occurred and hospitalization may be necessary for treatment to prevent systemic infection. Herpes and intercurrent infections have been reported.100
Hypotension, tachycardia, syncope (fainting), diaphoresis (sweating), and edema have occurred in patients receiving procarbazine.100
Retinal hemorrhage, papilledema, photophobia, diplopia, and inability to focus have occurred in patients receiving procarbazine.100
Pneumonitis, pleural effusion, and cough or other respiratory disorders have occurred in patients receiving procarbazine.100
Hematuria, urinary frequency, and nocturia,100 as well as other genitourinary disorders, have been reported with procarbazine therapy.
Dermatologic and Sensitivity Reactions
Alopecia, dermatitis, pruritus, rash, urticaria, hyperpigmentation, and flushing have been reported with procarbazine.100
Generalized allergic reactions have occurred in patients receiving procarbazine.100 Procarbazine should be discontinued if hypersensitivity reaction occurs.100 Photosensitivity also has been reported.
Myalgia and arthralgia have been reported in patients receiving procarbazine.100
Gynecomastia has occurred in prepubertal and early pubertal boys during procarbazine therapy.100
Other adverse effects reported in patients receiving procarbazine include chills and hearing loss.100 Fever has been reported in some patients receiving procarbazine.100 The drug has been associated with at least one case (in an 8-year-old child) of fulminant hyperpyrexia, which recurred upon rechallenge, and was accompanied by palpitations, dyspnea, cyanosis, rigor, rigid/stiff muscles, tachypnea, tachycardia, tremors, and severe emesis. It is not known if antipyretics, antihistamines, and/or corticosteroids may prevent this drug-induced fever.
Precautions and Contraindications
Procarbazine is a highly toxic drug and should be used only under constant supervision by a clinician experienced in cancer chemotherapy.100 When appropriate, procarbazine therapy should be initiated with the patient hospitalized;100 the patient's clinical and histologic diagnosis and hematologic, renal, and hepatic status should be carefully considered.
Hematologic Precautions and Contraindications
Procarbazine therapy is contraindicated in patients with inadequate marrow reserve as demonstrated by bone marrow aspiration.100 The possibility of inadequate marrow reserve should be considered in patients with leukopenia, thrombocytopenia, or anemia.100
For patients who have received radiation therapy or previous chemotherapy with myelosuppressive effects, an interval of 1 month or longer without such therapy should elapse before beginning procarbazine administration.100 During this interval, bone marrow studies should be carried out periodically to determine when bone marrow recovery is sufficient to allow initiation of procarbazine therapy.100
Bone marrow studies should be performed prior to therapy and again at the time of maximum hematologic response, usually within 2-8 weeks after treatment is initiated.100 It is essential that hemoglobin, hematocrit, leukocyte and differential counts, and reticulocyte and platelet determinations be made prior to therapy and at least every 3-4 days thereafter.100
Other Precautions and Contraindications
Hepatic and renal evaluation, including urinalysis, serum transaminase, serum alkaline phosphatase, and BUN determinations, should be made prior to therapy and at least weekly thereafter.100
Procarbazine therapy is contraindicated in patients with known hypersensitivity to the drug.100
Interruption or discontinuance of procarbazine therapy may be required in patients experiencing toxicity.100 See Dosage Modification for Toxicity and Contraindications to Continued Therapy under Dosage: Dosage and Administration.
Patients should be warned not to drink alcoholic beverages and to avoid food with high tyramine content, such as yogurt, cheese, and bananas, while receiving procarbazine.100 (For additional information on foods and beverages with high tyramine contents, see Drug Interactions: Foods and Drugs Associated with Hypertensive Crisis in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.) Patients should also be instructed to avoid use of over-the-counter preparations containing antihistamine or sympathomimetic drugs and to discuss any prescription medications they are taking with the clinician who is supervising procarbazine therapy.100
Because tobacco use may increase their risk of secondary lung cancer, patients receiving procarbazine therapy should be advised to quit smoking or discontinue any other tobacco use.100
Undue toxicity, including coma, seizures, and tremor, has occurred in children receiving procarbazine.100 Dosage must be individualized and close clinical monitoring is required in children receiving the drug.100
Mutagenicity and Carcinogenicity
Procarbazine has been shown to be mutagenic in bacterial and mammalian test systems.100 Procarbazine has produced tumors in animal studies, including lung adenomas in mice and adenocarcinomas of the breast in rats; the carcinogenicity of procarbazine also has been reported in monkeys. Secondary malignancies, including lung cancer and acute myeloid leukemia, have occurred in patients with Hodgkin's disease receiving procarbazine in combination with other chemotherapy and/or radiation therapy.100 The risk of secondary lung cancer associated with procarbazine therapy seems to be multiplied in patients who use tobacco products.100 The International Agency for Research on Cancer considers there to be sufficient evidence for the carcinogenicity of procarbazine in humans when it is administered in intensive regimens that include other antineoplastic agents, but there is insufficient evidence of its carcinogenic effect when administered alone.100
Pregnancy, Fertility, and Lactation
Procarbazine can cause fetal toxicity when administered to a pregnant woman,100 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.105, 110 Although there are no adequate and well-controlled studies using procarbazine in pregnant women, malformations have been reported in infants born to women receiving procarbazine in combination with other antineoplastic agents during pregnancy.100 Procarbazine hydrochloride has been reported to cause fetal toxicity and teratogenicity in rats. Procarbazine is teratogenic in rats when given at dosages approximately 4-13 times the maximum recommended human dosage of 6 mg/kg daily.100 Although procarbazine has not been adequately studied in animals for its effects on perinatal or postnatal development, neurogenic tumors were observed in the offspring of rats given procarbazine 125 mg/kg IV on day 22 of gestation; compounds such as procarbazine that inhibit synthesis of DNA, RNA, and protein may be expected to have adverse effects on fetal and child development.100
Procarbazine should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.100, 105 When procarbazine is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.100 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with procarbazine.100
Azoospermia and antifertility effects have been reported in humans in clinical studies of patients receiving procarbazine in combination with other antineoplastic agents for the treatment of Hodgkin's disease; the relative contribution of procarbazine to these effects has not been established.100 Because procarbazine interferes with the synthesis of DNA, RNA, and protein, the drug may be expected to have adverse effects on gametogenesis.100 Unscheduled DNA synthesis in the testes of rabbits and decreased fertility in male mice treated with procarbazine have been reported.100
It is not known whether procarbazine is distributed into milk.100 Because of the potential for tumorigenicity demonstrated in animal studies and the potential for serious adverse reactions to procarbazine in nursing infants, nursing should not be undertaken by women receiving the drug.100
Concomitant administration of CNS depressants such as barbiturates, antihistamines, opiates, hypotensive agents, or phenothiazines should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by procarbazine hydrochloride.100
Patients receiving procarbazine hydrochloride should not drink alcohol since a disulfiram-like reaction may result.100 Since procarbazine hydrochloride possesses some monoamine oxidase inhibitory activity, sympathomimetic drugs (including those in nose drops and cough preparations), local anesthetics, tricyclic antidepressants (e.g., amitriptyline hydrochloride, imipramine hydrochloride), and other drugs and foods with known high tyramine content such as cheese, bananas, yogurt, tea, coffee, wine and cola drinks, and cigarettes should be avoided. (For additional information on foods and beverages with high tyramine contents, see Drug Interactions: Foods and Drugs Associated with Hypertensive Crisis in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.)
The estimated mean lethal dose of procarbazine ranges from approximately 150 mg/kg in rabbits to 1300 mg/kg in mice.100
The major manifestations of acute overdosage with procarbazine would be expected to include nausea, vomiting, enteritis, diarrhea, hypotension, tremors, seizures, and coma.100
Management of procarbazine overdosage consists of either gastric lavage or the administration of an emetic agent.100 General supportive measures, such as the administration of IV fluids, are advised.100 Because of procarbazine-induced hematologic and hepatic toxicity, complete blood counts and liver function tests should be performed frequently during the recovery period and for a minimum of 2 weeks afterwards; appropriate supportive measures should be undertaken as clinically indicated.100
The precise mechanism(s) of action of procarbazine has not been determined, but it appears the drug has multiple sites of action. In ascites cells of mice bearing lymphoma cell implants, procarbazine was found to inhibit the incorporation of thymidine, deoxycytidine, formate, adenine, and 4-amino-5-imidazolecarboxamide into DNA and to prevent the utilization of orotic acid in the synthesis of RNA and leucine in the synthesis of protein. In addition, procarbazine may directly damage DNA.100 Hydrogen peroxide formed during auto-oxidation of the drug may attack protein sulfhydryl groups contained in residual protein tightly bound to DNA.100 The terminal N -methyl group of procarbazine has been reported to be incorporated into adenine, guanine, and thymine in mice leukemia cells. Procarbazine has also been reported to inhibit mitosis by prolonging the interphase of cell division and causing chromatid breaks in ascites carcinoma cells. Animal studies indicate that the cytotoxic effects of procarbazine are limited to those tissues with high rates of cellular proliferation and the effects are only evident in those cells which are actively synthesizing DNA. Procarbazine also has monoamine oxidase inhibiting properties.
Procarbazine hydrochloride is rapidly and nearly completely absorbed from the GI tract following oral administration.100 Following oral administration of a single 30-mg dose of radiolabeled procarbazine hydrochloride, peak plasma radioactive concentrations of the drug were attained within 1 hour.100 Oral administration generally results in plasma concentrations similar to those achieved following IV†administration of the drug.
Distribution studies in animals and humans using radiolabeled procarbazine hydrochloride administered IV have shown concentrations of radioactivity to be present in the liver, kidneys, intestinal wall, and skin. The drug crosses the blood-brain barrier and distributes into CSF.100 Equilibration of procarbazine between plasma and CSF occurs rapidly following oral administration.100 It is not known whether procarbazine is distributed into milk.100
Following IV injection, the plasma half-life of procarbazine is approximately 10 minutes.100
Procarbazine is metabolized primarily in the liver and kidneys.100 The drug appears to be auto-oxidized to an azo-compound with the release of hydrogen peroxide.100 The azo-compound isomerizes to the hydrazone, which undergoes hydrolysis to form a benzylaldehyde derivative and methylhydrazine.100 The aldehyde is oxidized to N -isopropylterephthalamic acid and the methylhydrazine is further metabolized to carbon dioxide, methane, and possibly hydrazine.100 Following oral or IV administration of procarbazine, about 70% of the dose is excreted in urine as N -isopropylterephthalamic acid within 24 hours.100
Procarbazine hydrochloride is a 1-methyl-2-benzyl derivative of hydrazine. Procarbazine hydrochloride occurs as a white to pale yellow, crystalline powder with a slight odor and is freely soluble in water and sparingly soluble in alcohol. Procarbazine has a pKa of 6.8.
Procarbazine hydrochloride is unstable in aqueous solution.100 Procarbazine hydrochloride capsules should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C. Under normal storage conditions, the commercially available capsules have an expiration date of 4 years after the date of manufacture.
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Only references cited for selected revisions after 1984 are available electronically.
100. Sigma-Tau. 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.
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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. [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. [PubMed 7931469]
109. Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology . 2000; 54:1442-8. [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.