Procarbazine

Procarbazine is a cytostatic derived from methylhydrazine, with weak inhibitory activity on monoamine oxidase. It is classed among the alkylating agents and acts on cells in the S phase of the cell cycle. After oral dosing it is rapidly and completely absorbed and then rapidly metabolised.

Mechanism of Action

• Cytotoxic action: the precise mode of action has not been clearly defined. The evidence suggests inhibition of protein, RNA and DNA synthesis; the drug may block the transfer of methyl groups from methionine into transfer RNA, which would halt protein synthesis and so DNA and RNA synthesis, and it may also damage DNA directly.
• Auto-oxidation: hydrogen peroxide formed when the drug auto-oxidises may attack protein sulfhydryl groups in the protein tightly bound to DNA.
• Weak MAO inhibition: procarbazine is a weak inhibitor of monoamine oxidase, which is why the SmPC advises avoiding tyramine-rich food and takes care with other central nervous system depressants and sympathomimetics (see Drug Interactions).
• Paediatric experience: in uncontrolled studies in children with brain tumours, procarbazine combined with other antitumour agents produced partial and complete responses; data from controlled randomised paediatric studies are limited.

Pharmacokinetics

• Absorption: oral procarbazine is completely absorbed from the gastrointestinal tract.
• Distribution: widespread, including the cerebrospinal fluid, where the concentration is in equilibrium with plasma.
• Metabolism: rapid, by erythrocyte and liver enzymes, in four steps (oxidation, isomerisation, hydrolysis, then oxidation) to an inactive end product, N-isopropylterephthalamic acid.
• Elimination: plasma half-life is about 7 minutes. Elimination is mainly urinary, as inactive metabolite: 55 % of the dose by 6 hours and 70 % by 24 hours, with only 5 % unchanged. A further 10–20 % is eliminated through the lungs.

Natulan is used mainly in combination with other antineoplastic medicines.

• Hodgkin lymphoma.
• Non-Hodgkin lymphomas, nodal and visceral forms.
• Brain tumours.
• Small-cell lung cancer.
• Children: Hodgkin lymphoma in children aged 2 to 18 years, when combined with other antineoplastic medicines in an appropriate protocol.

• Hypersensitivity to procarbazine or to any of the excipients, including a history of hypersensitivity to procarbazine.
• Severe renal impairment.
• Severe hepatic impairment.
• Pregnancy.
• Breastfeeding.
• Severe leukopenia or thrombocytopenia.
• Combination with yellow fever vaccine (see Drug Interactions).

The most common serious side effects are alopecia, gastrointestinal disorders such as anorexia, nausea and vomiting, and bone marrow depression. Like many antineoplastic medicines, procarbazine suppresses normal immunity profoundly, and patients may be at considerably higher risk of serious, disseminated infection. The SmPC frequencies are below; most reactions have no frequency category.

Common (≥1/100 to <1/10): infection; leukopenia, thrombocytopenia, anaemia; anorexia; haemorrhage; nausea, vomiting; alopecia.

Very rare (<1/10,000): bone marrow depression, pancytopenia, eosinophilia, haemolytic anaemia.

Not known: herpes zoster; secondary cancers, including lung cancer, acute myeloid leukaemia and myelodysplastic syndrome; hypersensitivity reactions including anaphylactic shock, anaphylactoid shock, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome; hallucination, depression, confusion, psychosis; convulsion, peripheral neuropathy, paraesthesia, headache; visual disturbances (including blurred vision and visual impairment); interstitial lung disease, dyspnoea, cough; stomatitis, constipation, diarrhoea, abdominal pain; hepatotoxicity, hepatitis, jaundice; toxic skin eruption, generalised eruption, rash, urticaria, pruritus; osteonecrosis, myalgia, back pain, arthralgia, jaw pain, bone pain; renal failure, acute kidney injury; permanent azoospermia.

Urticarial or maculopapular rash with itching, sometimes with joint pain, has appeared soon after starting or restarting treatment; this requires stopping treatment.

Procarbazine is a weak monoamine oxidase inhibitor, and its interactions follow from that and from its action as a cytostatic.

• Alcohol (not recommended): antabuse effect (warmth, flushing, vomiting, tachycardia). Alcoholic drinks and medicines containing alcohol should be avoided.
• Food (not recommended): eating cheese during treatment with monoamine oxidase inhibitors can, in rare cases, raise blood pressure. This has never been reported with Natulan, but for safety patients should be advised not to eat foods high in tyramine, such as cheese, yoghurt or bananas, during treatment.
• Yellow fever vaccine (contraindicated): risk of fatal generalised vaccine disease.
• Other live attenuated vaccines (not recommended): risk of generalised, possibly fatal vaccine disease, higher in patients already immunodepressed by their disease. An inactivated vaccine should be used where one exists (poliomyelitis).
• Phenytoin and, by extrapolation, fosphenytoin (not recommended): risk of seizures because the cytotoxic reduces phenytoin absorption, or of greater toxicity or loss of efficacy of the cytotoxic because phenytoin or fosphenytoin increases its hepatic metabolism.
• Other central nervous system depressants (precautions for use): because procarbazine is a weak monoamine oxidase inhibitor, most H1 antihistamines, barbiturates, benzodiazepines, clonidine and related substances, hypnotics, morphine derivatives (opioids), neuroleptics and anxiolytics other than benzodiazepines can add to central depression, with important consequences especially when driving or using machines.
• Adrenaline and noradrenaline (to be taken into account): risk of a stronger pressor effect, by extrapolation from non-selective monoamine oxidase inhibitors.
• Enzyme-inducing anticonvulsants (to be taken into account): carbamazepine, phenytoin, phenobarbital and primidone raise the risk of hypersensitivity reactions (hypereosinophilia, rash), possibly through a reactive intermediate produced by induction of the CYP3A enzymes. In patients with brain tumours treated with procarbazine, anticonvulsants that do not induce enzymes may be more suitable.
• Immunosuppressants (to be taken into account): excessive immunosuppression with a risk of lymphoproliferation.
• Oral anticoagulants: tumour disease raises the risk of thrombosis, so anticoagulants are often used, and coagulability varies greatly in these patients. Chemotherapy may also interact with them, so INR checks should be more frequent.

Natulan is an anticancer medicine, and the recommendations for handling and using antineoplastic medicines must be followed. Doses are calculated per m² of body surface area.

Recommended Dose

• Used alone: the dose rises gradually, from 50 mg on the first day, increasing by 50 mg a day, to a daily dose of 150 to 200 mg/m².
• In combination (usual use): 100 to 150 mg/m² a day for 5 to 14 days.
• Children: the dose per m² in most published studies was broadly similar to the adult dose (100 mg/m² for up to 14 days). It should be adjusted for the chemotherapy protocol used, the functional state of the bone marrow, previous cycles of chemo-radiotherapy and the myelosuppressive effect of the other cytostatics. Treatment and maintenance doses must be set only by a physician experienced in the use of major antineoplastic medicines in children.

Dose Adjustments

• The recommended daily dose of 100 mg/m² should be reduced by one third or one half according to the severity of bone marrow depression with leukopenia and/or thrombocytopenia. Similar reductions apply for nausea and vomiting. If Natulan is reduced, the other drugs in the combination may also need adjusting, because most of them have similar effects on bone marrow and the gastrointestinal tract.
• Treatment must be interrupted if the leucocyte count falls below 1,000/mm³ or platelets below 50,000/mm³, and restarted at cautious doses only after the cytopenias improve.
• Stopping should be considered for leukopenia or thrombocytopenia; central nervous system symptoms such as paraesthesia, neuropathy or confusion; hypersensitivity reactions; severe diarrhoea; stomatitis; or severe vomiting. Treatment should be stopped if neurological disorders occur.

Special Populations

• Renal or hepatic impairment: treatment should be started in hospital, and renal and hepatic function checked at least once a week. Severe impairment is a contraindication.
• Children: toxicity is greater in children, including tremor, coma and convulsions. The dose must be set individually and close clinical monitoring is essential.

Blood Counts and Organ Function

Before any dose, check the blood count and look for renal and/or hepatic impairment. Haematological monitoring is needed twice a week, and checks every 2 to 3 days may be necessary to prevent severe leukopenia or thrombocytopenia and the infection and bleeding that follow.

Fertility and Sperm Preservation

Before treatment, patients must be warned of the risk of sterility from azoospermia, sometimes permanent, which relates to the number of combination chemotherapy cycles. A fertility assessment, sperm collection and cryopreservation are desirable before treatment. Permanent azoospermia and sterility have been reported.

Secondary Cancers

Animal studies showed mutagenic and carcinogenic effects. Secondary non-lymphoid leukaemias have been reported with procarbazine in combination chemotherapy, and secondary malignancies such as acute myeloid leukaemia and lung cancer have occurred in patients with Hodgkin disease given procarbazine with other chemotherapy and/or radiotherapy.

Immunosuppression and Vaccines

The immunosuppressive effect can raise the risk of infection by pathogenic or opportunistic organisms and reduce the response to vaccines, and generalised infection with live vaccines is possible. Live vaccines should generally be avoided.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: Natulan is formally contraindicated. Procarbazine crosses the placenta at concentrations sufficient to cause foetal toxicity, with a risk of malformation especially in the first trimester, and it was teratogenic in animals. Women of childbearing age must be warned of the risk of malformations and avoid pregnancy.
• Contraception: men and women must use contraception during treatment and for up to 3 months (men) and 6 months (women) after it ends.
• Breastfeeding: contraindicated, as there are no data on passage into milk.
• Fertility: Natulan can impair fertility (see above).

Effect on Driving

Procarbazine has a minor influence on the ability to drive and use machines. Patients should be warned that dizziness and drowsiness are possible.

In the brown glass bottle, store at a temperature not above 25 °C. Capsules in aluminium/aluminium blister packs need no special storage precautions. Natulan is supplied as 50 capsules in a brown glass (type III) bottle with a stopper containing desiccant, or as 50 capsules in blisters; not all presentations may be marketed.

3 years.

Prescription only (Rx), as an anticancer medicine. In children the doses must be set by a physician experienced in the use of major antineoplastic medicines in children, and in renal or hepatic impairment treatment is started in hospital. Natulan capsules are taken by the patient, so they are supplied to the patient or to the treating clinic on prescription.