PROCARBAZINE HCL
WARNING
IT IS RECOMMENDED THAT PROCARBAZINE 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.
Procarbazine (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 corn starch, 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-alpha-(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.
ACTIONS/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:
Procarbazine is indicated for use in combination with other anticancer drugs for the
treatment of Stage III and IV Hodgkin's disease. Procarbazine is used as part of the
MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
CONTRAINDICATIONS:
Procarbazine 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:
IT IS RECOMMENDED THAT PROCARBAZINE 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.
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 Procarbazine exhibits some monoamine oxidase
inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg,
amitriptyline HCl, imipramine HCl) 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.
Pregnancy: 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. Procarbazine 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, Mutagenesis And Impairment Of Fertility:
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 acute myelocytic leukemia, have been
reported in patients with Hodgkin's disease treated with procarbazine in
combination with other chemotherapy and/or radiation. 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 l
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:
General: Undue toxicity may occur if Procarbazine 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 Procarbazine. 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.
Information For Patients: Patients should be warned not to drink alcoholic
beverages while on Procarbazine 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 Procarbazine should also be warned against the use
of prescription drugs without the knowledge and consent of their physician.
Laboratory Tests: 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.
Drug Interactions: See WARNINGS section.
No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids
has been demonstrated.
Carcinogenesis, Mutagenesis And Impairment Of Fertility: See WARNINGS section.
Pregnancy: Pregnancy Category D. See WARNINGS section.
Nursing Mothers: It is not known whether Procarbazine 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.
Pediatric Use: 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.
DRUG INTERACTIONS:
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 Procarbazine exhibits some monoamine oxidase
inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg,
amitriptyline HCl, imipramine HCl) 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.
No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids
has been demonstrated.
(See Also WARNINGS and PRECAUTIONS)
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 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.
OVERDOSAGE:
The major manifestations of overdosage with Procarbazine 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 Procarbazine dose should be
appropriately reduced, eg, in the MOPP regimen, the Procarbazine dose is 100
mg/M(squared) 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 Procarbazine 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.
Children--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. (REF. 1-6)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
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
253:1590-1592, Mar 15, 1985.
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 1:426-428, Apr 30, 1983.
5. Jones RB, Frank R, Mass T: Safe handling of chemotherapeutic agents: a report
from the Mount Sinai Medical Center. CA 33:258-263, Sept-Oct 1983.
6. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals.
Am J Hosp Pharm 42:131-137, Jan 1985.
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