Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
procarbazine
Procarbazine was discovered in the late 1950's during a search for monoamine oxidase (MAO) inhibitors with less serious side effects. As early as 1962, clinical trials were reported describing procarbazine's effectiveness in Hodgkin's disease. Procarbazine is an unique antineoplastic agent with multiple sites of action. It inhibits incorporation of small DNA precursors, as well as RNA and protein synthesis. Procarbazine can also directly damage DNA through an alkylation reaction. Procarbazine is not cross-resistant with other alkylating agents. Cell cycle phase-specific (S-phase).
Highest levels in liver, kidney, intestinal wall and skin.
| Cross blood brain barrier? | Yes, rapid equilibration |
| PPB | no information found |
By kidneys and liver (CYP450)
| Active metabolites | yes |
| Inactive metabolites | yes |
Predominantly in urine as N-isopropyl-terephthalamic acid
| Half-life | 1 hour |
| Urine | 70% within 24 hours (as metabolites) |
-
Hodgkin’s lymphoma (Stage III and IV)
Other Uses:
-
Non-Hodgkin’s lymphoma
-
Gliomas
Emetogenic Potential:
Extravasation Potential: Not applicable
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Flushing | E | |||
| Hypertension (rare) | E | ||||
| Hypotension (rare) | E | ||||
| Pericarditis | E | ||||
| Tachycardia (rare) | I | ||||
| Thromboembolism | E | ||||
| Dermatological | Alopecia (rare) | E | |||
| Photosensitivity (rare) | E | ||||
| Pruritus | E | ||||
| Radiation recall reaction | I | ||||
| Rash (may be severe) | E | ||||
| Skin hyperpigmentation (rare) | E D | ||||
| Urticaria (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain | E | |||
| Anorexia | E | ||||
| Ascites (rare) | E | ||||
| Constipation | E | ||||
| Diarrhea | E | ||||
| Dysphagia | E | ||||
| GI hemorrhage (or melena) | E | ||||
| Mucositis (mild) | E | ||||
| Nausea (<50%) | I | ||||
| Vomiting (<50%) | I | ||||
| General | Edema | E | |||
| Fatigue | E | ||||
| Flu-like symptoms (myalgia, arthralgia, chills, fever) | I | ||||
| Pain | E | ||||
| Hematological | Eosinophilia | E | |||
| Hemolysis | E | ||||
| Hemorrhage | E | ||||
| Myelosuppression (common) | E | ||||
| Hepatobiliary | Jaundice (rare) | E | |||
| ↑ LFTs | E | ||||
| Pancreatitis | E | ||||
| Hypersensitivity | Anaphylaxis (rare) | I | |||
| Serum sickness (rare) | I | ||||
| Infection | Infection | E | |||
| Neoplastic | Leukemia (secondary) (2-15%) | L | |||
| MDS (2-15%) | L | ||||
| Secondary malignancy (NSCLC) | L | ||||
| Nervous System | Ataxia | E | |||
| Depressed level of consciousness | E D | ||||
| Dizziness | E D | ||||
| Hallucinations (10-30%) | E | ||||
| Headache | E | ||||
| Insomnia (10-30%) | E | ||||
| Nystagmus | E | ||||
| Other (nightmares - 10-30%) | E | ||||
| Peripheral neuropathy (10-20%) | E | ||||
| Seizure (rare) | E | ||||
| Somnolence | E D | ||||
| Syncope (rare) | E | ||||
| Ophthalmic | Eye disorders (diplopia - rare) | E | |||
| Papilledema | E | ||||
| Photophobia | E | ||||
| Renal | Nephritis | E | |||
| Reproductive and breast disorders | Azoospermia (>10%) | E D | |||
| Gynecomastia | D L | ||||
| Infertility | D L | ||||
| Irregular menstruation (amenorrhea: >10%) | E D | ||||
| Respiratory | Cough | E | |||
| Dysphonia | E | ||||
| Epistaxis | E | ||||
| Hemoptysis | E | ||||
| Lung infiltrate (<1%) | D | ||||
| Pleural effusion | E | ||||
| Pulmonary fibrosis (<1%) | D | ||||
| Urinary | Hematuria | E | |||
| Urinary frequency | E | ||||
| Vascular | Peripheral ischemia (Raynaud-like syndrome) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common adverse effects of procarbazine are nausea, vomiting and myelosuppression.
Hypersensitivity pneumonitis can occur within hours of ingesting procarbazine and is characterized by fever, non-productive cough and dyspnea. On chest radiographs, bilateral interstitial infiltrates and pleural effusion can be observed. Patients usually recover following discontinuation of procarbazine. May also consider corticosteroid treatment.
Procarbazine is a weak monoamine oxidase inhibitor that crosses the blood-brain barrier rapidly. Neurotoxic effects may take the form of altered levels of consciousness, peripheral neuropathy, ataxia or effects of MAO inhibition. Particularly distressing to the patient are frequent nightmares, depression, insomnia, nervousness and hallucinations which occur in 10-30% of patients. Peripheral neuropathy has been reported in 10-20% of patients and consists of paresthesias in hands and feet, decreased deep tendon reflexes and myalgia.
Bleeding tendencies (petechiae, nosebleeds, vomiting of blood) occur frequently.
Procarbazine has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of procarbazine. Recurrent injury to a previously radiated site may occur weeks to months following radiation.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Use estimated lean weight if obese or ascites present. Patients must have recovered from effects of prior therapy, including radiation; a minimum of 1 month lapse between the end of previous chemotherapy and/or radiation and the initiation of procarbazine is recommended
Round dose to the nearest 50 mg. Total daily dose may be taken orally at a single time or in divided fractions throughout the day.
Single-agent (Hodgkin’s):
- 2-4 mg/kg daily for the first week, then 4-6 mg/kg daily until maximum response or myelosuppression occurs (See Dosage in Myelosuppression)
- Maintenance: 1-2 mg/kg daily
In combination:
Refer to individual chemotherapy regimen for specific details.
q3w: 100 mg/m2/day p.o x 2 days
q4w: 100 mg/m2/day p.o x 14 days (MOPP regimen)
q6w: 60 mg/m2/day p.o x 14 days (PCV regimen)
Dosage in myelosuppression:
- Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities."
- Procarbazine should be held if myelosuppression develops (i.e. platelets < 100 x 109/L or leukocytes < 4 x 109/L); restart after recovery with a reduced dose.
Dosage with toxicity (GI/CNS):
- Hold with neurotoxicity, stomatitis, diarrhea, or bleeding; may restart at a reduced dose after recovery. Discontinue if hypersensitivity or pneumonitis.
Toxicity increased. Exercise caution and monitor patient closely; decrease dose by 25% for elevated liver function tests (> 1.5 – 5 x ULN). Hold treatment if serum bilirubin > 1.5 X ULN or liver transaminases > 5 X ULN, until recovery occurs.
Toxicity increased; monitor patient closely. If creatinine > 1.5 X ULN or BUN > 14.3 mmol/L, the dose should be decreased; no details found.
Safety and effectiveness have not been established. Tremors, coma, and convulsions have occurred in a few cases.
- Oral self-administration; drug available by outpatient prescription.
- DO NOT drink alcoholic beverages while taking procarbazine, or for 10-14 days after taking the last capsule(s).
- Follow diet restrictions to avoid food or drinks containing tyramine, caffeine and alcohol while taking procarbazine. Consult a dietician.
Procarbazine is contraindicated in patients with known hypersensitivity to the drug or inadequate marrow reserve. Ethyl alcohol should not be used since there may be a disulfiram-like reaction. Procarbazine exhibits some MAO inhibitory activity; therefore, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCI, imipramine HCI), dietary supplements (e.g. ginseng), and other drugs and food with known high tyramine content, such as aged cheese and ripe bananas, should be avoided. Agents which are CNS depressants should also be avoided. There is an increased risk of second malignancies including NSCLC; patients should be advised to discontinue smoking.
Procarbazine may be responsible for the infertility seen in males treated with MOPP (mechlorethamine, Oncovin®, procarbazine, prednisone) for Hodgkin's disease. Procarbazine can cause azoospermia, which is often irreversible; and amenorrhea in females. Procarbazine is teratogenic, carcinogenic, mutagenic and fetotoxic and should not be used in pregnancy. Breast feeding is not recommended due to the potential secretion into breast milk.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Sympathomimetic agents, tricyclic antidepressants, tyramine-rich foods, ginseng, levodopa, MOA and COMT inhibitors | Headache, flushed face, palpitations, rise in blood pressure | Procarbazine is a weak MAO inhibitor | Avoid these drugs and foods during procarbazine therapy (See "Procarbazine Diet" patient information sheet) |
| Alcohol | Disulfiram-like reaction | Unknown | Avoid alcohol |
| CNS depressants | Potentiation of CNS depression | Additive | Caution |
| Digoxin | ↓ digoxin effect | Procarbazine interferes with the absorption of digoxin | Monitor blood levels and adjust dose |
| Antidiabetic agents | ↑ hypoglycemia | ↓ response to hypoglycemia | Caution |
| Methotrexate | ↑ renal toxicity | Unknown | Use >/= 72 hours apart |
| Anticonvulsants (i.e. carbamazepine, phenytoin, phenobarbital) | ↑ risk of hypersensitivity reactions to procarbazine | May induce procarbazine oxidation to a reactive metabolite that can cause hypersensitivity | Avoid concomitant use; use non-enzyme inducing anticonvulsants |
| Drugs which should not be used with MAOI | ↑ toxicity of these agents | Avoid concomitant use |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and regular |
Clinical toxicity assessment (including pulmonary, infection, bleeding, stomatitis, diarrhea, CNS, skin, neurotoxicity) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Renal function tests |
Baseline and regular |
Liver function tests |
Baseline and regular |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)
Dart RC, Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams and Wilkins, 2004.
Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of chemotherapy. Semin Oncol. 2006;33(1):50-67.
Lehmann DF, Hurteau TE, Newman N, et al. Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors. Clin.Pharmacol Ther 1997;62(2):225-229.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1217-20.
Product Monograph: Matulane® (procarbazine). Sigma-Tau Pharmaceuticals, April 15, 2008.
Summary of Product Characteristics: Procarbazine. Cambridge Laboratories (UK), Dec 2006.
Procarbazine: Clin-eguide Cancer Chemotherapy Manual.
Mahmood T, Mudad R. Pulmonary Toxicity Secondary to Procarbazine. Am J Clin Oncol 2002; 25(2): 187–8.
Peedell C. Concise clinical oncology. Philadelphia: Elsevier, 2005.
Pratt WB, Ruddon RW, Ensminger WD, et al. The Anticancer Drugs. 2nd ed. New York: Oxford University Press; 1987.
June 2019 Updated emetic risk category.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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