Procarbazine 50mg Capsules

What Procarbazine 50mg Capsules are and what they are used for

What you need to know before you take Procarbazine

• if you are allergic to procarbazine or any of the other ingredients of this medicine (listed in section 6)
• if you have anything wrong with your blood, in particular, too few white cells or platelets (your doctor will be able to advise you).
• if you suffer from any severe kidney or liver disorder
• if you have a non-cancerous tumour
• if you are in the first trimester of pregnancy
• if you are breast-feeding

Make sure your doctor knows if any of the above applies to you.

Talk to your doctor before taking Procarbazine 50mg Capsules:

• if you suffer from any kidney or liver disorder
• if you have any disorder of the heart or circulation
• if you are, or could be, pregnant or may want to become pregnant in the future (for further information refer to the following sections of this leaflet: ‘Do not take Procarbazine 50mg Capsules’ and ‘Pregnancy, breast-feeding and fertility’)
• if you have a tumour on the adrenal gland (near the kidney), causing high blood pressure
• if you suffer from epilepsy
• if you have had a stroke

Some types of vaccinations should not be given to you during or within at least six months of treatment with chemotherapy drugs such as procarbazine. Your doctor will be able to advise you on this. If you need any other medical treatment or surgery whilst taking Procarbazine 50mg Capsules, remember to tell the doctor or dentist treating you that you are taking this medicine.

Try to avoid people with infections whilst taking procarbazine. Check with your doctor immediately if you get a cough, cold, or any other infection.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, check with your doctor or pharmacist if you are taking any of the following:

• strong painkillers (especially Pethidine)
• medicines for anxiety or difficulty in sleeping
• anticholinergic medicines, these include some medicines used for irritable bowel syndrome, asthma or incontinence
• medicines for depression
• medicines for high blood pressure or for your heart
• anaesthetic products
• medicines for epilepsy
• clozapine (an anti-psychotic medication)

It is safe to use plain Paracetamol or Aspirin without speaking to your pharmacist.

Certain foods, drinks and medicines may cause an unpleasant reaction if taken whilst you are being treated with Procarbazine 50mg Capsules or during the two weeks after the course of treatment is completed. The most important foods and drinks that might cause such an effect are:

Mature cheeses (including processed cheeses), yeast or meat extracts, broad bean pods, pickled herring, salami sausage, pepperoni sausage, bologna sausage, overripe fruit, alcoholic drinks (especially heavy red wines such as Chianti), non-alcoholic beers, lagers and wines and other foods which are not fresh, particularly if they have been fermented, pickled, smoked, ‘hung’ or ‘matured’. These reactions are extremely rare and if you want to eat or drink anything on the list you could try a little at a time, until you are sure that it does not upset you. However, it is best to avoid alcohol altogether.

If you are pregnant, think you might be pregnant, are planning to become pregnant or are breast-feeding, you should tell your doctor.

Pregnancy
Procarbazine should not be taken during the first trimester of pregnancy. Its use should also be avoided throughout the remainder of the pregnancy period.

Breast-feeding
Do not take Procarbazine if you are breast-feeding.

Fertility
Procarbazine may cause infertility which might mean that you are not able to have children.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
Procarbazine can cause drowsiness. If affected you should not drive or use machinery.

How to take Procarbazine

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Procarbazine is usually given in combination with other drugs and it is important that you (or your child) take each medicine at the right time. Sometimes treatment starts with a small dose (1 capsule per day) and is increased each day up to a maximum of six capsules per day.

If you swallow too many capsules or someone else accidentally takes your medicine, contact your doctor, pharmacist or nearest hospital straight away. Overdose can cause severe vomiting and feeling sick, dizziness, imagining sensations (hallucinations), depression, fits, low blood pressure and increased pulse rate.

If you miss a dose, take it as soon as you remember unless your next dose is due within a couple of hours. In this case you should skip the missed dose, go back to your regular dosing schedule and check with your doctor. Do not take a double dose to make up for a forgotten capsule. The same applies if you forget to give a dose to your child at the right time.

Patients and carers should use gloves when handling urine or vomit produced for up to 48 hours after a dose of procarbazine has been taken.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions although serious allergic reactions are very rare. Any sudden wheeziness, difficulty in breathing, swelling in any part of the body, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.

Procarbazine may cause the following side effects:

• Infertility, which might mean that you are not able to have children
• Skin rash or any unusual bleeding or bruising. If you (or your child) develop these side effects, check with your doctor as soon as possible
• Nausea and vomiting. Do not stop taking procarbazine if it makes you (or your child) sick in the first few days, as this side effect should disappear. However if it is very bad, or if vomiting occurs shortly after taking a dose, check with the hospital or your own doctor who will tell you what to do. It may be possible to reduce this unpleasant effect
• Liver disorder. If you (or your child) develop signs of liver disorder which include persistent vomiting, feeling sick, feeling tired and yellowing of the skin or the whites of the eyes (jaundice) you should stop treatment and contact your doctor immediately
• Loss of appetite, especially at the start of treatment. This usually improves after a few days
• Lowering of your white blood cell count. Common symptoms include infections, lack of energy, headache, fever and irritability
• Drowsiness and a lack of enthusiasm
• Inflammation of lung tissue. Symptoms include shortness of breath, cough, and a burning sensation in the chest.

Procarbazine in combination with other chemotherapy drugs has been associated with an increased occurrence of a rare cancer of the blood cells.

It is very important that you keep all hospital appointments whilst taking procarbazine so that your progress can be checked.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

How to store Procarbazine

Keep this medicine out of the sight and reach of children – preferably in a locked cupboard or medicine cabinet.

Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of that month.

In order that Procarbazine 50mg Capsules are always clearly identified they should not be removed from their blister packaging until you are ready to take them. Do not mix loose Procarbazine 50mg Capsules with other loose capsules or tablets. Store in the original container in order to protect from moisture. Do not store above 25°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Procarbazine 50mg Capsules

WARNING

It is recommended that MATULANE 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 to patients for proper monitoring of treatment.

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 parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.

Chemically, procarbazine hydrochloride is N-isopropyl-α-(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.

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.

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.

WARNINGS

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 an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.

Teratogenic Effects
Pregnancy Category D. 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. 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 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.

Nonteratogenic Effects
Procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumors were noted in the offspring of rats given intravenous injections of 125 mg/kg of procarbazine hydrochloride on day 22 of gestation. Compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development.

Carcinogenesis
The carcinogenicity of procarbazine hydrochloride in mice, rats and monkeys has been reported in a considerable number of studies. Instances of a second 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.

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

Impairment of Fertility
Azoospermia and antifertility effects associated with procarbazine hydrochloride administration in combination with other chemotherapeutic agents for treating Hodgkin's disease have been reported in human clinical studies. Since these patients received multicombination therapy, it is difficult to determine to what extent procarbazine hydrochloride alone was involved in the male germ-cell damage. 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.

PRECAUTIONS

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.

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 4000).

 

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.

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.

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.

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.

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

See WARNINGS section.

No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.

See WARNINGS section.

Pregnancy Category D. See WARNINGS section.

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.

Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized (see DOSAGE AND ADMINISTRATION). Very close clinical monitoring is mandatory.

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.

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.

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.1-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

Capsules, ivory, containing the equivalent of 50 mg procarbazine as the hydrochloride; in bottles of 100. Imprint on capsules: MATULANE σ sigma-tau.

REFERENCES

1. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: U.S. Government Printing Office NIH Publication No. 83-2621.
2. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA. Mar 15, 1985; 253:1590-1592.
3. National Study Commission on Cytotoxic Exposure: Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.
4. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. Apr 30,1983; 1:426-428.
5. Jones RB, Frank R, Mass T: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA. Sept-Oct 1983; 33:258-263.
6. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals. Am J Hosp Pharm. Jan 1985; 42:131-137.