Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Procarbazine is a cell cycle phase-nonspecific2 pro-drug and derivative of hydrazine whose mechanism of action has not yet been clearly defined. Procarbazine may act by inhibiting protein, RNA, and DNA synthesis,3-5 and by causing free-radical damage to DNA and inhibition of mitosis.4,6 Procarbazine also has monoamine oxidase (MAO) inhibiting properties3,4 and is an immunosuppressive agent.3 Cross resistance with other chemotherapy agents has not been demonstrated.3

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindications:

history of hypersensitivity reaction to procarbazine or other components of the product3 inadequate marrow reserve as demonstrated by bone marrow aspiration; consideration of this should be given to each patient who has leukopenia, thrombocytopenia, or anemia3

Caution:

to minimize CNS depression barbiturates, antihistamines, opiod analgesicss, hypotensive agents, phenothiazines, MAO inhibitors, or catechol-O-methyltransferase inhibitors should be used with caution14 alcohol should not be consumed with procarbazine as a disulfiram-like reaction may occur3 (5-30% incidence)2,15 as procarbazine exhibits some MAO inhibitory activity, sympathomimetic drugs (including those in nose drops and cold preparations like pseudoephedrine4), local anesthetics4, tricyclic antidepressants (e.g. amitriptyline, imipramine), and other drugs, dietary supplements (e.g., ginseng) and foods known to react with MAO inhibitors due to high-tyramine content or other physiologic properties should be avoided14; see handout For the Patient: Procarbazine for further details in patients with prexisiting renal, hepatic, and bone marrow impairment, severe toxicity may occur4; assess hepatic and renal function prior to therapy3 Discontinue treatment if any of the following occur3: central nervous system signs or symptoms such as paresthesias, neuropathies, or confusion leukopenia (white blood count <4 x 109/L) thrombocytopenia (platelets count <100 X 109/L) hypersensitivity reaction stomatitis; including the first small ulceration or persistent spot soreness around the oral cavity diarrhea hemorrhage or bleeding tendencies Treatment may be resumed when side effects have resolved; dosage adjustment is recommended.3

If radiation or chemotherapy 3

known to have marrow-depressant activity have been used, an interval of one month or longer is recommended by the manufacturer before starting treatment with procarbazine; the length of this interval may also be determined by evidence of bone marrow recovery based on successive bone marrow studies.

Carcinogenicity: Procarbazine is carcinogenic.3 Instances of new nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, have been reported with procarbazine in combination with other chemotherapy and/or radiation. The risk of secondary lung cancer from procarbazine appears to be multiplied by tobacco use.

Mutagenicity: 3,4

Fertility: Procarbazine may cause acute ovarian failure, acute amenorrhea, and menopause.3 Azoospermia and sterility have occurred in combination with other chemotherapeutic agents; the extent of procarbazine involvement in male germ-cell damage is unknown.3 Pregnancy: FDA Pregnancy Category D.5 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding 3

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.16

ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
allergy/immunology	allergic reactions; including rash
auditory/hearing	hearing loss
blood/bone marrow/ febrile neutropenia	anemia; hemolytic anemia; hemolysis; anisocytosis 4 ; poikilocytosis 4 ; Heinz-Ehrlich inclusion bodies in erythrocytes
	bone marrow suppression ; typically occurs 2-8 weeks after the start of treatment; nadir 3-4 weeks with recovery by 4-6 weeks 6,10,11 ; pancytopenia
	leukopenia; eosinophilia; lymphocytosis
	thrombocytopenia
cardiovascular (arrhythmia)	tachycardia
cardiovascular (general)	angina
	cardiotoxicity
	hypertension ; secondary to MAO inhibition 10
	hypotension
	pericarditis
constitutional symptoms	chills
	diaphoresis
	fatigue
	fever
	insomnia
dermatology/skin	alopecia
	dermatitis
	flushing
	hyperpigmentation
	photosensitivity
	pruritus
	rash (>10%) 16 ; delayed hypersensitivity, 16 typically occurs with the second cycle 16
	toxic epidermal necrolysis
	urticaria
gastrointestinal	emetogenic potential: high-moderate 17 ; dose-dependent 16,18 ; at doses of 100 mg/m 2 emetogenic potential: low to moderate 16,18
gastrointestinal	anorexia
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
	ascites
	constipation
	diarrhea
	dysphagia
	nausea and vomiting ( < 90%) 5,16,18,19 ; may be severe 4 ; may be minimized by increasing the dose over several days 5 ; tolerance may commonly occur within a few days 2,10,11,16
	stomatitis
	xerostomia
hemorrhage	bleeding tendancies: epistaxis, hematemesis, hematuria, hemoptysis, melena, petechiae, purpura, retinal hemorrhage
hepatobiliary/pancreas	hepatic dysfunction
hepatobiliary/pancreas	pancreatitis
infection	immunosuppression; infection including pneumonia, herpes , infection
lymphatics	edema
musculoskeletal	weakness
musculoskeletal	osteonecrosis
neurology	neurological toxicity; related to MAO inhibition; including: ataxia, coma, convulsions, neuropathy, paresthesia, nystagmus, diminished reflexes, syncope, tremors, dizziness, drowsiness, unsteadiness, fainting, hallucinations, depression, nervousness, apprehension, disorientation, 4 confusion, nightmares, slurred speech; nightmares, nervousness, and hallucinations ( < 30%) 10
ocular/visual	diplopia
	inability to focus
	papilledema
	photophobia
pain	abdominal pain
	headache
	myalgia and arthralgia
pulmonary	cough
	hoarseness
	pulmonary toxicity (<1%) 5 ; including pleural effusion and pneumonitis
renal/genitourinary	nephritis
renal/genitourinary	urinary frequency; nocturia
secondary malignancy	secondary malignancies (<1-15%) 5,16 ; including lung cancer, acute myelocytic leukemia, and malignant myelosclerosis; the risk of secondary lung cancer appears to be increased by tobacco use; reported in combination with other chemotherapy and/or radiation
sexual/reproductive	acute ovarian failure; acute amenorrhea; menopause
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
function	azoospermia and sterility ; reported in combination with other chemotherapeutic agents
function	gynecomastia; reported in prepubertal and early pubertal boys
syndromes	Raynaud-like syndrome
vascular	thrombosis including pulmonary, deep vein, and mesenteric

Adapted from standard reference3 unless specified otherwise. Common side effects include dose-limiting severe leukopenia and thrombocytopenia.2 Nausea and vomiting3,11 and neurological effects such as headache, nervousness, and insomnia may also commonly occur.7,8,11

INTERACTIONS:

Since procarbazine exhibits some MAO inhibitory activity, it may theoretically interact with drugs that are normally affected by MAOI, including insulin and sulphonylureas (increased hypoglycemic response),14,23,24 carbamazepine (hypertensive urgency, hyperpyrexia, seizures)15 and levodopa (hypertension).25 Careful monitoring may be needed if concurrent use cannot be avoided.

SUPPLY AND STORAGE:

Tablets: 3

sigma-tau Pharmaceuticals Inc. supplies procarbazine as a 50 mg capsule. Store at room temperature and protect from light.

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

mg/m2 (range 60-100 mg/m2) PO once daily for 14 consecutive days (range 7-14 days) starting on day 1 or 2 2 2

round dose to the nearest 50 mg dose may be given as a single daily dose or in 2-3 divided doses5 n/a5: initial: 2-4 mg/kg PO once daily for 7 consecutive days then increase dose to 4-6 mg/kg PO once daily until response is obtained or leukocyte count <4 x 109/L or the platelet count <100 x 109/L maintenance: 1-2 mg/kg/day PO

modify according to protocol by which patient is being treated; if no guidelines

available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: use with caution; dose modification may be required3; the following modification has been used5: decrease dose if serum creatinine >177 umol/L Dosage in hepatic failure: use with caution; dose modification may be required3; the following modifications have been used:

Cycle Length: Oral: undue toxicity e.g., tremors, coma, and seizures have occurred3,4; dosage should be individualized with careful monitoring3,6 4 weeks6: 50-100 mg/m2 PO once daily for 10-14 consecutive days starting on day 1 (total dose per cycle 500-1400 mg/m2) 2-4 weeks6: 75 mg/m2 PO for one dose on day 1 (total dose per cycle 75 mg/m2)

Oral Absorption	rapid and complete; peak plasma concentration in 1 h
Distribution	rapid distribution including into liver, kidneys, intestinal wall, and skin 4
	cross blood brain barrier?	yes
	volume of distribution	no information found
	plasma protein binding	no information found
Metabolism	complex spontaneous chemical decomposition and biotransformation to active metabolites, 4,7 primarily in the liver 4 via cytochrome P450 oxidoreductase and mitochondrial monoamine oxidase 8
	active metabolite(s) 4,6,7,9	yes; including azo-and methylazoxy-metabolites and hydrogen peroxide
	inactive metabolite(s) 3,10	yes; including N-isopropyl-terephthalmamic acid
Excretion	primarily hepatic with some renal 3,4 and pulmonary 11 elimination
	urine 3-5	25-70% in 24 h primarily as N-isopropyl- terephthalmamic acid; <5-20% unchanged
	feces 8	minimal
	terminal half life 4,5	~1 h; longer for azo-metabolite 9
	clearance 9	35.8 L/min

Primary uses:	Other uses:
Brain tumour 4,5,12,13	Lymphoma, non-Hodgkin's 4,5
* Lymphoma, Hodgkin's	Lung cancer 5
Melanoma 5
Multiple myeloma 5,10

AGENT	EFFECT	MECHANISM	MANAGEMENT
alcohol 14,15	rapid, minor, suspected, disulfiram-like reaction; facial flushing, headache; (5-30% incidence 2,15 )	unknown	avoid alcohol for the duration of treatment 15,20 and for 1 week after stopping treatment 20
sympathomimetic drugs, local anesthetics, tricyclic antidepressants, and other drugs, dietary supplements (e.g., ginseng) and foods known to react with MAO inhibitors due to high- tyramine content or other physiologic properties 3,4,14,15	headache, flushing, palpitations, nausea and vomiting, or hypertension 14 ; flushing has been reported but clinically significant increases in blood pressure have not occurred with the consumption of high- tyramine-containing foods 15	procarbazine is a weak MAO inhibitor; theoretical inhibition of tyramine metabolism	avoid concurrent use for the duration of treatment and for 1 week after stopping treatment 20 ; routine monitoring of blood pressure; limited evidence regarding the clinical significance of consuming tyramine-containing foods; however, it is generally advised to avoid consumption of these foods 3,15
anticonvulsants that induce CYP 3A (e.g., carbamazepine, phenytoin, phenobarbital) 21	induction of CYP 3A may result in the production of a reactive metabolite responsible for hypersensitivity reactions 21	increased risk of procarbazine hypersensitivity	monitoring for hypersensitivity reactions may be needed
digoxin 14,22	decreased effect of digoxin	chemotherapy-induced changes to intestinal mucosa 22 may cause a decrease in digoxin absorption 14	monitor for decreased effect of digoxin; consider monitoring digoxin levels, adjust digoxin dose as needed 22
methotrexate 15	delayed, major, possible, increased methotrexate nephrotoxicity	unknown	allow > 72 h between the final dose of procarbazine and initiation of methotrexate

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COMMON TRADE NAME(S):

CLASSIFICATION: