Indications and Usage
Matulane is indicated for use in combination with other anticancer drugs for the treatment of Stage III and IV Hodgkin's disease. Matulane is used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
Dosage and Administration
The following doses are for administration of the drug as a single agent. When used in combination with other anticancer drugs, the Matulane dose should be appropriately reduced, eg, in the MOPP regimen, the Matulane dose is 100 mg/m2 daily for 14 days. All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.
Adults:To minimize the nausea and vomiting experienced by a high percentage of patients beginning Matulane therapy, single or divided doses of 2 to 4 mg/kg/day for the first week are recommended. Daily dosage should then be maintained at 4 to 6 mg/kg/day until maximum response is obtained or until the white blood count falls below 4000/cmm or the platelets fall below 100,000/ cmm. When maximum response is obtained, the dose may be maintained at 1 to 2 mg/kg/day. Upon evidence of hematologic or other toxicity (see PRECAUTIONS section), the drug should be discontinued until there has been satisfactory recovery. After toxic side effects have subsided, therapy may then be resumed at the discretion of the physician, based on clinical evaluation and appropriate laboratory studies, at a dosage of 1 to 2 mg/kg/day.
Pediatric Patients:Very close clinical monitoring is mandatory. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. The following dosage schedule is provided as a guideline only.
Fifty (50) mg per square meter of body surface per day is recommended for the first week. Dosage should then be maintained at 100 mg per square meter of body surface per day until maximum response is obtained or until leukopenia or thrombocytopenia occurs. When maximum response is attained, the dose may be maintained at 50 mg per square meter of body surface per day. Upon evidence of hematologic or other toxicity (see PRECAUTIONS section), the drug should be discontinued until there has been satisfactory recovery, based on clinical evaluation and appropriate laboratory tests. After toxic side effects have subsided, therapy may then be resumed.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-6There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Contraindications
Matulane is contraindicated in patients with known hypersensitivity to the drug or inadequate marrow reserve as demonstrated by bone marrow aspiration. Due consideration of this possible state should be given to each patient who has leukopenia, thrombocytopenia or anemia.
Adverse Reactions
Leukopenia, anemia and thrombopenia occur frequently. Nausea and vomiting are the most commonly reported side effects.
Other adverse reactions are:
Hematologic
Pancytopenia; eosinophilia; hemolytic anemia; bleeding tendencies such as petechiae, purpura, epistaxis and hemoptysis.
Gastrointestinal
Hepatic dysfunction, jaundice, stomatitis, hematemesis, melena, diarrhea, dysphagia, anorexia, abdominal pain, constipation, dry mouth.
Neurologic
Coma, convulsions, neuropathy, ataxia, paresthesia, nystagmus, diminished reflexes, falling, foot drop, headache, dizziness, unsteadiness.
Cardiovascular
Hypotension, tachycardia, syncope.
Ophthalmic
Retinal hemorrhage, papilledema, photophobia, diplopia, inability to focus.
Respiratory
Pneumonitis, pleural effusion, cough.
Dermatologic
Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria, flushing.
Allergic
Generalized allergic reactions.
Genitourinary
Hematuria, urinary frequency, nocturia.
Musculoskeletal
Pain, including myalgia and arthralgia; tremors.
Psychiatric
Hallucinations, depression, apprehension, nervousness, confusion, nightmares.
Endocrine
Gynecomastia in prepubertal and early pubertal boys.
Miscellaneous
Intercurrent infections, hearing loss, pyrexia, diaphoresis, lethargy, weakness, fatigue, edema, chills, insomnia, slurred speech, hoarseness, drowsiness.
Second nonlymphoid malignancies (including lung cancer, acute myelocytic leukemia and malignant myelosclerosis) and azoospermia have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use.
Drug Interactions
See WARNINGS section.
No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.
Overdosage
The major manifestations of overdosage with Matulane would be anticipated to be nausea, vomiting, enteritis, diarrhea, hypotension, tremors, convulsions and coma. Treatment should consist of either the administration of an emetic or gastric lavage. General supportive measures such as intravenous fluids are advised. Since the major toxicity of procarbazine hydrochloride is hematologic and hepatic, patients should have frequent complete blood counts and liver function tests throughout their period of recovery and for a minimum of two weeks thereafter. Should abnormalities appear in any of these determinations, appropriate measures for correction and stabilization should be immediately undertaken.
The estimated mean lethal dose of procarbazine hydrochloride in laboratory animals varied from approximately 150 mg/kg in rabbits to 1300 mg/kg in mice.
Description
Matulane (procarbazine hydrochloride), a hydrazine derivative antineoplastic agent, is available as capsules containing the equivalent of 50 mg procarbazine as the hydrochloride. Each capsule also contains cornstarch, mannitol and talc. Gelatin capsule shells contain titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.
Chemically, procarbazine hydrochloride is N‑isopropyl-∝-(2‑methylhydrazino)‑p‑toluamide monohydrochloride. It is a white to pale yellow crystalline powder which is soluble but unstable in water or aqueous solutions. The molecular weight of procarbazine hydrochloride is 257.76 and the structural formula is:
Clinical Pharmacology
The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t‑RNA. The absence of functional t‑RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto‑oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.
Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.
Procarbazine is rapidly and completely absorbed. Following oral administration of 30 mg of 14C-labeled procarbazine, maximum peak plasma radioactive concentrations were reached within 60 minutes.
After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes. Approximately 70% of the radioactivity is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of 14C-labeled procarbazine.
Procarbazine crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.
How Supplied / Storage and Handling
Capsules, ivory, containing the equivalent of 50 mg procarbazine as the hydrochloride; in bottles of 100 (NDC 54482-054-01). Imprint on capsules: MATULANE LB213.
Patient Counseling Information
Patients should be warned not to drink alcoholic beverages while on Matulane therapy since there may be an Antabuse (disulfiram)‑like reaction. They should also be cautioned to avoid foods with known high tyramine content such as wine, yogurt, ripe cheese and bananas. Over-the-counter drug preparations which contain antihistamines or sympathomimetic drugs should also be avoided. Patients taking Matulane should also be warned against the use of prescription drugs without the knowledge and consent of their physician. Patients should be advised to discontinue tobacco use.