Matulane Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Matulane (procarbazine hydrochloride) is indicated for use in combination with other anticancer agents for the treatment of Stage III and IV Hodgkin's disease. Matulane is used as part of the MOPP (mechlorethamine, vincristine, procarbazine, prednizone) regimen.

Matulane has also been used successfully alone or in combination with other chemotherapeutic agents to produce regression in a variety of tumour types such as lymphomas and gliomas but data are not yet sufficient to justify specific recommendations.

CONTRAINDICATIONS

• hypersensitivity to procarbazine or any other component of the product.
• 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.

WARNINGS AND PRECAUTIONS

General

It is recommended that Matulane (procarbazine hydrochloride) be given only by or under the supervision of a physician experienced in the use of potent antineoplastic drugs. Adequate clinical and laboratory facilities should be available for a proper monitoring of a treatment.

To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution.

Ethyl alcohol should not be used since there may be a disulfiram-like reaction.

Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g. amitriptyline hydrochloride, imipramine hydrochloride), and other drugs, dietary supplements (e.g. ginseng) and foods known to react with momoamine oxidase inhibitors due to high tyramine content or other physiologic properties should be avoided. High tyramine content is most common in foods that are aged or fermented to increase flavor such as cheeses, yeast or meat extracts, fava or broad bean pods, smoked or pickled meat, poultry, or fish, fermented sausage (bologna, pepperoni, salami, and summer sausage) or other unfresh meat, or dried or overripe fruit.

Matulane (procarbazine hydrochloride) should be prescribed by a qualified health care professional who is experienced with cancer chemotherapy drugs. Clinically significant treatment- related toxicities include:

• Long-term risk of developing acute leukemia, myelodysplasia, second cancers
• Infertility
• Neuropathy
• MAO (monoamine oxidase) inhibition

The MOPP regimen is not recommended in treating favourable prognosis CS I-II patients.

A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.

If radiation or a chemotherapeutic agent known to have marrow-depressant activity has been used, an interval of one month or longer without such therapy is recommended before starting treatment with Matulane. The length of this interval may also be determined by evidence of bone marrow recovery based on successive bone marrow studies.

Prompt cessation of therapy is recommended if any one of the following occurs:

• Central nervous system signs or symptoms such as paresthesias, neuropathies or confusion.
• Leukopenia (white blood count under 4,000).
• Thrombocytopenia (platelets under 100,000).
• Hypersensitivity reaction.
• Stomatitis - The first small ulceration or persistent spot soreness around the oral cavity is a signal for cessation of therapy.
• Diarrhea - Frequent bowel movements or watery stools.
• Hemorrhage or bleeding tendencies.

Therapy may be resumed, at the discretion of the physician, after toxic side effects have cleared on clinical evaluation and appropriate laboratory studies.

Carcinogenesis and Mutagenesis

Instances of new nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, 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. The International Agency for Research on Cancer (IARC) considers that there is “sufficient evidence” for the human carcinogenicity of procarbazine hydrochloride when it is given in intensive regimens which include other antineoplastic agents but that there is inadequate evidence of carcinogenicity in humans given procarbazine hydrochloride alone.

The international population-based study Hodgkin Lymphoma patients has demonstrated statistically significant risk of acute myeloid leukemia following Hodgkin lymphoma treatments over a 30-year period [Schonfeld, 2006]. One-year Hodgkin lymphoma survivors (N = 35,511) were identified within 14 population-based cancer registries in Nordic countries and North America from January 1, 1970, through December 31, 2001. A total of 217 Hodgkin lymphoma survivors were diagnosed with AML. The excess absolute risk of AML declined statistically significantly after 1984 (7.0 to 4.2 and 16.4 to 9.9 in the < 35 and ≥ 35 age groups, respectively, which may be associated with modifications in chemotherapy. Analytical studies with detailed treatment data are required to correlate these decreases with changes in therapy and to better understand the long term risk of AML after Hodgkin’s Lymphoma.

The carcinogenicity of procarbazine hydrochloride in animals and mutagenicity in test systems has been reported in a number of studies (see TOXICOLOGY).

Hematologic

Leukopenia and thrombocytopenia have been reported in patients on Matulane therapy. Platelets and white blood cell counts should be performed prior to each subsequent cycle.

Hepatic/Renal

Undue toxicity may occur if Matulane is used in patients with impairment of renal and/or hepatic function. When appropriate, hospitalization for the initial course of treatment should be considered.

The metabolism of procarbazine is dependent on hepatic transformation and renal elimination. Therefore, dosing modifications may be required in patients with compromised renal or hepatic function.

Sexual Function/Reproduction

Exposure to procarbazine has been reported to be an independent risk factor for acute ovarian failure and acute amenorrhea in females. Azoospermia which can be prolonged resulting in male infertility has been reported to be associated with procarbazine when used in combination with other chemotherapeutic agents.

The standard battery of fertility/reproduction studies in laboratory animals have not been carried out with procarbazine hydrochloride (see TOXICOLOGY).

Special Populations

Pregnancy: Procarbazine hydrochloride can cause fetal harm when administered to a pregnant woman. While there are no adequate and well-controlled studies with procarbazine hydrochloride in pregnant women, there are case reports of malformations in the offspring of women who were exposed to procarbazine hydrochloride in combination with other antineoplastic agents during pregnancy. Procarbazine is teratogenic, mutagenic, and carcinogenic. Matulane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Procarbazine hydrochloride was found to be teratogenic in animal studies (see TOXICOLOGY). Procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumours were noted in the offspring in animal studies (See TOXICOLOGY).

Nursing Mothers: It is not known whether Matulane is excreted in human milk. Because of the potential for tumorigenicity shown for procarbazine hydrochloride in animal studies, mothers should not nurse while receiving this drug.

Pediatric use: Appropriate prospective controlled studies in the pediatric population have not been performed. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. Very close monitoring is mandatory.

Monitoring and Laboratory Tests

Baseline laboratory data should be obtained prior to initiation of therapy. The hematologic status as indicated by hemoglobin, hematocrit, white blood count (WBC), differential, reticulocytes and platelets should be monitored closely - at least every 3 or 4 days. Bone marrow depression often occurs 2 to 8 weeks after the start of treatment. If leukopenia occurs, hospitalization of the patient may be needed for appropriate treatment to prevent systemic infection.

Hepatic and renal evaluation are indicated prior to beginning therapy. Urinalysis, transaminase, alkaline phosphatase and blood urea nitrogen should be repeated at least weekly.

As part of routine monitoring clinical pulmonary exam, including auscultation, pulmonary toxicity ratings (Cough, SOB) should be performed periodically.

Information for Patients: 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 and tricyclic antidepressants (e.g. amitriptyline HCl, imipramine HCl) should not be used. 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.

ADVERSE REACTIONS

In dealing with cancer chemotherapeutic agents, adverse effects are not only common but are to be expected, and actually serve as a guideline to dosage and duration of administration; Matulane (procarbazine hydrochloride) is no exception as to toxicity.

The following adverse reactions include both adverse experiences from clinical trials as well as post-marketing surveillance.

The most serious adverse effects are associated with leukopenia, thrombopenia and a variety of neurological effects (MAO inhibition).

The most commonly reported adverse effects are nausea and vomiting. Leukopenia, anemia and thrombopenia occur frequently.

Other adverse reactions grouped by Body System:

Hematologic: Immunosuppression, pancytopenia, eosinophilia, hemolytic anemia, bleeding tendencies such as petechiae, purpura, epistaxis and hemoptysis; thrombosis including pulmonary, deep vein, and mesenteric.

Gastrointestinal: Hepatic dysfunction, jaundice, stomatitis, ascites, hematemesis, melena, diarrhea, dysphagia, anorexia, abdominal pain, constipation, dry mouth, pancreatitis.

Neurologic: Coma, convulsions, neuropathy, ataxia, paresthesia, nystagmus, diminished reflexes, falling, foot drop, headache, dizziness, unsteadiness, fainting.

Cardiovascular: Hypotension, tachycardia, syncope, hypertension, angina, pericarditis, cardiotoxicity, Raynaud-like syndrome.

Ophthalmic: Retinal hemorrhage, papilledema, photophobia, diplopia, inability to focus.

Respiratory: Pneumonitis, pleural effusion, cough, pneumonia, pulmonary toxicity.

Dermatologic: Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria, flushing, photosensitivity, Lyell syndrome, toxic epidermal necrolysis.

Allergic: Generalized allergic reactions.

Genitourinary: Hematuria, urinary frequency, nocturia, nephritis.

Musculoskeletal: Pain, including myalgia and arthralgia; tremors, osteonecrosis.

Psychiatric: Hallucinations, depression, apprehension, nervousness, confusion, nightmares, insomnia.

Endocrine: Acute ovarian failure, acute amenhorrhea, gynecomastia in prepubertal and early pubertal boys.

Miscellaneous: Intercurrent infections, hearing loss, pyrexia, sweating, diaphoresis, lethargy, weakness, fatigue, edema, chills, slurred speech, hoarseness, drowsiness.

Second 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

Matulane (procarbazine hydrochloride) is used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/hematologic and gastrointestinal effects (see WARNINGS AND PRECAUTIONS).

Drug-Drug Interactions

CNS depression and possible potentiation may occur with barbiturates, antihistamines, narcotics, hypotensive agents, phenothiazines, momoamine oxidase (MAO) inhibitors, or catechol-O- mthyltransferase (COMT) inhibitors. Matulane can interfere with the absorption of digoxin. The effects of antidiabetics and levodopa may be enhanced by Matulane use. Sensitivity to Matulane can be increased when used with carbamazepine. Concomitant use of these drugs with Matulane should be avoided. Matulane also exhibits monoamine oxidase inhibitory activity.

Sympathomimetic drugs and tricyclic antidepressant drugs may interact with Matulane to cause hypertensive reactions (see WARNINGS AND PRECAUTIONS).

Drug-Food Interactions

Dietary supplements or foods known to react with monoamine oxidase inhibitors due to high tyramine content or other physiologic properties should be avoided (see WARNINGS AND PRECATIONS). Typical reactions include headache, flushed face, palpitations, nausea and vomiting or hypertension.

DOSAGE AND ADMINISTRATION

Matulane (procarbazine hydrochloride) should only be used by physicians experienced with cancer chemotherapeutic drugs.

As part of the MOPP (mechlorethamine, vincristine, and prednisone) and c-MOPP (cyclophosphamide, mechlorethamine, vincristine, and prednisone) regimens Matulane is given orally in a dose of 100mg/m²/day for 14 days and repeated every 4 weeks.

Upon evidence of hematologic or other toxicity (see WARNINGS 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.

OVERDOSAGE

The major manifestations of overdosage with Matulane (procarbazine hydrochloride) 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.

ACTION AND CLINICAL PHARMACOLOGY

Matulane (procarbazine hydrochloride) is one of the methylhydrazine derivatives that has demonstrated an antineoplastic effect against Hodgkin's Disease. The mode of cytotoxic action of Matulane has not yet been clearly defined; however, there is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. No cross resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.

Pharmacokinetics:

Procarbazine hydrochloride 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 hydrochloride is rapidly and completely absorbed. Following oral administration of 30 mg of ¹⁴C-labeled procarbazine hydrochloride, maximum peak plasma radioactive concentrations were reached within 60 minutes.

After intravenous injection, the plasma half-life of procarbazine hydrochloride 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 hydrochloride.

Procarbazine hydrochloride crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.

STORAGE AND STABILITY

Matulane (procarbazine hydrochloride) should be stored at 15 - 30^"C in a tightly closed, light resistant container.

SPECIAL HANDLING INSTRUCTIONS

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. Patients and patient caregivers should not open or crush capsules. Do not take Matulane if the capsule is broken. Keep out of reach of children.

DOSAGE FORM, COMPOSITION AND PACKAGING

Matulane (procarbazine hydrochloride) Capsules: 100 size No. 2 ivory gelatin capsules containing 50 mg procarbazine incorporated as procarbazine hydrochloride in a plastic bottle. Inactive ingredients (alphabetical order): cornstarch, gelatin, mannitol, methylparaben, potassium sorbate, propylparaben, quinoline yellow WS, sunset yellow FCF, talc, and titanium dioxide.

PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION

Structural Formula:

O

(CH₃)₂CHNHC CH₂NHNHCH₃

.HCl

Molecular Formula: C₁₂H₁₉N₃O•HCl Molecular Weight: 257.76

Chemical Name: N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide monohydrochloride. Appearance: It is a white to pale yellow crystalline substance.

Solubility: Soluble but unstable in water or aqueous solutions.

CLINICAL TRIALS

Original sponsor generated clinical trial data are not available; however, for information regarding efficacy in Hodgkin’s disease refer to the published literature, for example:

Bonadonna G, Viviani S, Bonfante V, Gianni AM, Valagussa Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute. Eur J Cancer. 2005 May;41(7):998-1006. Epub 2005 Feb 24.

Longo DL, Young RC, Wesley M, Hubbard SM, Duffey PL, Jaffe ES, DeVita VT Jr. Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol. 1986 Sep; 4(9):1295-306.

DETAILED PHARMACOLOGY

Procarbazine is a unique antineoplastic agent with multiple sites of action. It belongs to N-methyl anti-tumor agents which are inactive prodrugs, require conversion to tumorstatic active metabolites. Oral absorption of procarbazine is rapid and complete. Mean maximum plasma concentration in humans is 12.5 min.

The elimination rate of procarbazine from plasma is high. The mean apparent oral systemic clearance and the plasma elimination half-life are 38.8 L/min and 9.2 min, respectively.

Considerable amounts of azo-procarbazine are found in human plasma. The mean Cmax and AUC ratios of azo-procarbazine /procarbazine are 5.5 and 45.2. Procarbazine is oxidized by both mitochondrial monoamine oxidase and hepatic microsomal cytochrome P450 iso-enzymes. Azo- procarbazine is formed very rapidly from procarbazine, but eliminated much more slowly from plasma than procarbazine. Considerable interindividual differences in the conversion rate of azo- procarbazine should have consequences for the individual tumor therapeutic efficiency of procarbazine.

Distribution of the drug in body fluids, studies in dog and man, showed rapid equilibration between plasma and cerebrospinal fluid after oral administration. Pharmacological studies indicated excellent gastrointestinal absorption. The major portion of the drug was excreted in the urine as N-isopropyl-terephthalamic acid with approximately 25 to 42 percent appearing during the first 24 hours after administration.

In laboratory studies, procarbazine hydrochloride produced a variety of biologic effects. Among these have been immuno-suppression, teratogenesis, carcinogenesis, cytotoxicity with mitotic suppression and chromatin derangement and an antineoplastic effect against a spectrum of transplanted tumours in mice and rats.

The major drug toxicities in acute and chronic animal studies were hematologic with granulocyte depression, thrombocyte depression, anemia and hemolysis.

Reticuloendiothelial system lymphocytic depletion, marrow cell depression, testicular atrophy and mucous membrane ulceration were further evidence of in vivo cytotoxicity.

TOXICOLOGY

The oral LD₅₀ of procarbazine hydrochloride in rabbits and mice was determined to be 150 to 1300 mg/kg respectively. The carcinogenicity of procarbazine hydrochloride in mice, rats and monkeys has been reported in a considerable number of studies. Mammary adenocarcinomas in rats have been observed subsequent to procarbazine hydrochloride administration in high doses. Carcinogenicity studies performed with procarbazine hydrochloride in the 1960’s revealed that multiple pulmonary tumors and leukemia were induced in mice by single and repeated intraperitoneal or oral administration. Instances of new nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, have been reported in patients with Hodgkin’s disease treated with procarbazine in combination with other chemotherapy and/or radiation. Recent clinical findings suggest that the risks of secondary lung cancer from treatment appears to be multiplied by tobacco use.

Procarbazine hydrochloride has been shown to be mutagenic in a variety of bacterial and mammalian test systems.

Procarbazine hydrochloride is teratogenic in the rat when given at doses approximately 4 to 13 times the maximum recommended human therapeutic dose of 6 mg/kg/day. Procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumours were noted in the offspring of rats given intravenous injections of 125 mg/kg of procarbazine hydrochloride on day 22 of gestation.

The usual Segment I fertility/reproduction studies in laboratory animals have not been carried out with procarbazine hydrochloride. However, compounds which inhibit DNA, RNA and/or protein synthesis might be expected to have adverse effects on gametogenesis. Unscheduled DNA synthesis in the testis of rabbits and decreased fertility in male mice treated with procarbazine hydrochloride have been reported.

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