Matulane - Leadiant Biosciences, Inc.

The recommended dosage of MATULANE for adult and pediatric patients is 100 mg/m² orally once a day.

Use the patient's actual bodyweight for the recommended dosage, unless the patient is obese or experiencing weight gain due to edema, ascites, or abnormal fluid retention and then use estimated lean body mass.

Individualize the dose and dosing schedule of MATULANE based on the specific regimen administered, response to treatment, and patient risk factors.

Refer to the Prescribing Information for the agents used in combination for dosing information as appropriate.

Monitor complete blood counts (CBCs) prior to initiation of, and as clinically indicated, during treatment with MATULANE [see Warnings and Precautions (5.1)]. If the following adverse reactions occur, permanently discontinue MATULANE:

• Anaphylaxis or other hypersensitivity reactions [see Contraindications (4)]

If any of the following adverse reactions occur, consider withholding until clinically stable or permanently discontinuing depending on adverse reaction severity:

• Grade 4 neutropenia, febrile neutropenia, or signs or symptoms of infection [see Warnings and Precautions (5.1)]
• Grade 4 thrombocytopenia, hemorrhage, or signs of bleeding [see Warnings and Precautions (5.1)]
• Central nervous system signs or symptoms such as paresthesia, neuropathies, or confusion [see Adverse Reactions (6)]
• Stomatitis (ulcerative or persistent pain) [see Adverse Reactions (6)]
• Diarrhea [see Adverse Reactions (6)]

MATULANE is a hazardous drug. Follow applicable handling and disposal procedures.¹

MATULANE can be administered with or without food.

Advise patients to avoid consumption of alcohol during treatment with MATULANE [see Warnings and Precautions (5.3)].

Matulane can cause myelosuppression, including severe neutropenia, anemia, and thrombocytopenia.

Obtain complete blood counts prior to initiation of MATULANE and monitor patients during treatment for clinical complications due to myelosuppression. During treatment with MATULANE, monitor hemoglobin, hematocrit, white blood count (WBC) including differential, reticulocytes, and platelets weekly or as clinically necessary.

Myelosuppression often occurs 2 to 8 weeks after the start of MATULANE treatment. If severe myelosuppression occurs, withhold MATULANE until clinically stable, or permanently discontinue depending on severity [see Dosage and Administration (2.2)].

If radiation or a chemotherapeutic agent known to have myelosuppressive 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.

Secondary malignancies have been reported in patients treated with MATULANE when used in combination with other chemotherapy, including lung cancer, myelodysplastic syndrome, acute myeloid leukemia, and non-Hodgkin Lymphoma. The risks of secondary lung cancer from treatment appear to be increased by tobacco use.

Monitor patients for the development of secondary malignancies during and after treatment with MATULANE.

Increased adverse reactions may occur if Matulane is used in patients with renal or hepatic impairment.

Evaluate renal and hepatic function prior to beginning therapy. Repeat urinalysis, transaminase, alkaline phosphatase and blood urea nitrogen tests at least weekly and as clinically indicated.

When appropriate, consider hospitalization for the initial course of treatment.

MATULANE can cause a disulfiram-like reaction in patients who consume alcohol during treatment with MATULANE.

Advise patients to avoid consumption of alcohol or products containing propylene glycol before, after, and during treatment with MATULANE.

Male and female reproductive function and fertility may be impaired in patients treated with MATULANE. Patients treated with MATULANE when used in combination with other chemotherapy have reported azoospermia and premature ovarian failure. Advise patients on the potential risks for infertility [see Use in Specific Populations (8.3)].

Based on findings from human case reports and animal studies, MATULANE can cause fetal harm when administered to a pregnant woman. 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. In reproductive studies in rats, procarbazine hydrochloride caused adverse developmental outcomes including embryo-fetal mortality, structural abnormalities, and neurogenic tumors. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with MATULANE. Advise males with female partners of reproductive potential to use effective contraception during treatment with MATULANE [see Use in Specific Populations (8.1, 8.3)].

Monitor signs and symptoms of neurotoxicity with concomitant use of MATULANE and other central nervous system (CNS) depressing agents. Concomitant use of MATULANE with other CNS depressing agents may result in potentiation of CNS depression with MATULANE.

Avoid monoamine oxidase (MAO) inhibitors and other drugs with MAO inhibition activity within two weeks before, and during treatment with MATULANE. MATULANE exhibits MAO inhibitory activity. Concomitant use of MATULANE with other MAO inhibitors may increase the risk of a hypertensive crisis.

Avoid consumption of alcohol or products containing propylene glycol before, after, and during therapy with MATULANE [see Warnings and Precautions (5.3)]. Use of MATULANE is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing.

Avoid tyramine-containing foods during therapy with MATULANE. Concurrent ingestion of foods rich in tyramine may cause sudden and severe high blood pressure in patients receiving MATULANE.

Risk Summary

Based on findings from human case reports and animal studies, MATULANE can cause fetal harm when administered to a pregnant woman (see Data ). In reproductive studies in rats, procarbazine hydrochloride caused adverse developmental outcomes including embryo-fetal mortality, structural abnormalities, and neurogenic tumors.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with MATULANE.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.

Data

Human

There are case reports of malformations in the offspring of women exposed to procarbazine hydrochloride in combination with other antineoplastic agents during pregnancy.

Animal

Procarbazine hydrochloride caused embryo-fetal mortality and structural abnormalities in rats when administered intraperitoneally at doses approximately 1.5 to 4.5 times the maximum recommended human therapeutic dose of 100 mg/m² based on body surface area. Procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumors developed in the offspring of rats that were intravenously administered procarbazine hydrochloride on day 22 of gestation at a dose approximately 7.5 times the maximum recommended human therapeutic dose of 100 mg/m² based on body surface area.

Risk Summary

There are no data on the presence of MATULANE or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including tumorigenicity in the breastfed child, advise women not to breastfeed during treatment with MATULANE.

MATULANE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating MATULANE.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with MATULANE.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with MATULANE.

Infertility

Females

MATULANE administered in combination with other chemotherapeutic agents can cause premature ovarian failure and infertility based on human clinical studies.

Males

MATULANE administered in combination with other chemotherapeutic agents can cause azoospermia and infertility based on human clinical studies. Based on findings in animals, procarbazine hydrochloride may impair male fertility [see Nonclinical Toxicology (13.1)].

Tremors, coma, and convulsions have occurred in pediatric patients treated with MATULANE. Pediatric patients should be closely monitored. Individualize the dosage based on the incidence and severity of adverse reactions [see Dosage and Administration (2.2)].

Clinical studies of MATULANE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

The precise mode of cytotoxic action of procarbazine has not been clearly defined. After metabolic activation, procarbazine may inhibit the transmethylation of methyl groups of methionine into transfer RNA (t-RNA). The unavailability of t-RNA prevents protein synthesis, and consequently prevents DNA and RNA synthesis. Procarbazine may also undergo auto-oxidation, resulting in the formation of cytotoxic free radicals which directly damage DNA through an alkylation reaction.

Procarbazine exposure-response relationships and the time course of pharmacodynamic responses have not been fully characterized.

Absorption

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.

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

Elimination

After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes.

Metabolism

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.

Excretion

Approximately 70% of the drug is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of ¹⁴C-labeled procarbazine.

Procarbazine hydrochloride was carcinogenic in mice, rats, and monkeys.

Procarbazine hydrochloride was mutagenic and clastogenic in a variety of in vitro and in vivo test systems.

Compounds which inhibit DNA, RNA and/or protein synthesis might be expected to have adverse effects on gametogenesis. In animal studies, procarbazine hydrochloride caused unscheduled DNA synthesis in the testis of rabbits and decreased fertility in male mice.

Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].

Dispense in light-resistant container as defined in USP/NF.

MATULANE is a hazardous drug. Follow applicable special handling and disposal procedures.¹