Procarbazine

221.3

221.30

211-582-2

35S93Y190K

759626

DTXSID4021189

C62072

L - Antineoplastic and immunomodulating agents

2928000090

53.2

2.6

Solid

1.0±0.1 g/cm3

223 °C

384.6±35.0 °C at 760 mmHg

148.9±26.1 °C

1.529

2.28e-01 g/L

Procarbazine hydrochloride capsules should be stored in tight, light-resistant containers at a temperature less than 40 deg C, preferably between 15-30 deg C. /Procarbazine hydrochloride/

8.4X10-7 mm Hg @ 25 deg C /Estimated/

Henry's Law constant = 8.9X10-15 atm-cu m/mole @ 25 °C /Estimated/

pKa = 6.6

MW: 257.77. Crystals from methanol, mp 223-226 °C. /Hydrochloride/|White to pale yellow crystalline powder ... soluble but unstable in water or aqueous solutions, mw = 257.76 /Hydrochloride/|Crystals from methanol and ether, decomposes at 216-217 °C /Hydrobromide/|White to pale yellow, crystalline powder; slight odor and bitter taste; 1 g sol in about 7 mL water, 100 mL alcohol, 10 mL methanol, 1000 mL acetone, ether, 1000 mL benzene, 1000 mL chloroform; solution are acid to litmus; pKa at room temp 6.8 /hydrochloride/|Hydroxyl radical reaction rate constant = 1.5X10-10 cu cm/molecule-sec @ 25 °C /Estimated/

Procarbazine hydrochloride is unstable in aqueous solution. /Procarbazine hydrochloride/

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for PROCARBAZINE (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl procarbazine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Procarbazine Hydrochloride/

REED DJ; PROCARBAZINE; IN: HANDBOOK OF EXPTL PHARMACOLOGY, VOL 38 PART 2, SARTORELLI AC & JOHNS DG (EDS); BERLIN, HEIDELBERG, NY, SPRINGER VERLAG (1974-1975). REVIEW ON PROCARBAZINE.|OLIVER VT; DERIVATIVES OF TRIAZENES AND HYDRAZINES; IN: HOLLAND JF, FREI E, III, (EDS); CANCER MEDICINE. PHILADELPHIA, LED AND PEBIGER 1973. REVIEW ON PROCARBAZINE.|National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Procarbazine Hydrochloride (366-70-1) is listed as reasonably anticipated to be a human carcinogen. /Procarbazine Hydrochloride/[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s151proc.pdf]|DHEW/NCI; Bioassay of Procarbazine for Possible Carcinogenicity (1979) Technical Rpt Series No. 19 DHEW Pub No. (NIH) 79-819

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for PROCARBAZINE (19 total), please visit the HSDB record page.

LD50=785 mg/kg (orally in rats)

Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of procarbazine in these abnormalities is often not clear. Aminotransferase elevations arise in more than half of patients and rise above 5 times ULN in 10 to 20% of patients. However, dose modification for serum enzyme elevations is rarely necessary. Clinically apparent liver disease with fever and marked elevations in serum aminotransferase levels without jaundice has been reported but is very rare. A single case report described self-limited, hepatocellular injury without jaundice during a second course of combination therapy and recurrence upon rechallenge with procarbazine, but not with the other antineoplastic agents being used.

Concurrent use /of alcohol/ with procarbazine may result in a disulfiram like reaction and additive central nervous system depression and postural hypotension; also, possible tyramine content in alcoholic beverages, especially beer, wine, or ale, may induce hypertensive reactions.|Concurrent use /of local anesthetics with epinephrine or levonordefrin, or cocaine/ with procarbazine may cause severe hypertension due to sympathomimetic effects. Cocaine should not be administered during or within 14 days following administration of an MAO inhibitor.|Hypotensive effects may be potentiated when spinal anesthetics are used concurrently with procarbazine; discontinuation of procarbazine at least 10 days before elective surgery if spinal anesthesia is planned may be advisable.|Concurrent use /of anticholinergics or other medications with anticholinergic activity, antidyskinetic agents, or antihistamines/ with procarbazine may intensify anticholinergic effects because of the secondary anticholinergic activities of MAO inhibitors; also MAO inhibitors may block detoxification of anticholinergics, thus potentiating their action; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. Concurrent use with MAO inhibitors may also prolong and intensify CNS depressant and anticholinergic effects of antihistamines; concurrent use is not recommended.|For more Interactions (Complete) data for PROCARBAZINE (22 total), please visit the HSDB record page.

LD50 Rat IV 600 mg/kg body weight (at day 59)

A bioassay of procarbazine for possible carcinogenicity was conducted by administering the test chemical by ip injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 34 or 35 males and 35 or 36 females of both species were administered procarbazine at one of two doses, either 15 or 30 mg/kg for rats, and either 6 or 12 mg/kg for mice. Injections were made 3 times/wk for 26 wk for rats and 52 wk for the mice. Following the periods of injection, the dosed animals were observed for a maximum period of 60 wk for rats and 33 wk for mice depending upon survival. Vehicle controls, used for statistical evaluation, consisted of 10 rats and 15 mice of each sex administered saline soln on the same schedule as the test soln; the same numbers of rats and mice served as untreated controls. Pooled controls consisted of the vehicle controls from this bioassay together with the vehicle controls from two other bioassays similarly performed at the same laboratory. The pooled control groups consisted of 40 rats of each sex and 45 mice of each sex. Surviving rats were /sacrificed/ at 86 wk and surviving mice were /sacrificed/ at 85 wk. ... In rats, malignant lymphomas, adenocarcinomas of the mammary gland, and the combination of olfactory neuroblastomas, adenocarcinomas, or carcinomas of the brain, olfactory bulb, or cerebrum were induced in statistically significant numbers. In mice, malignant lymphomas or leukemias, olfactory neuroblastomas or undifferentiated carcinomas, alveolar/bronchiolar adenomas, and adenocarcinomas of the uterus were induced in statistically significant numbers. It is concluded under the conditions of this bioassay, procarbazine was carcinogenic in both Sprague-Dawley rats and B6C3F1 mice producing several types of tumors in both of these two species. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive.

...Soluble but unstable in water or aqueous solutions /Hydrochloride/

NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,328 workers (289 of these are female) are potentially exposed to procarbazine in the US(1).

For use with other anticancer drugs for the treatment of stage III and stage IV Hodgkin's disease.

Procarbazine is an orally administered alkylating agent used in combination with other antineoplastic agents in the therapy of Hodgkin’s disease and malignant melanoma. Procarbazine therapy has been associated with serum enzyme elevations during therapy and with rare cases of idiosyncratic, clinically apparent acute liver injury.

Antineoplastic Agents, Alkylating Agents

Antineoplastic Agents; Carcinogens|MEDICATION (VET): Antineoplastic... /it is used/ exptl, against wide variety of transplanted animal tumors. /hydrochloride/|Procarbazine is indicated, in combination with other agents, for treatment of Hodgkin's disease (Stage III and IV) ... . /Included in US product labeling/|/Procarbazine is indicated, in combination with other agents, for treatment of/ some non-Hodgkin's lymphomas. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.

Procarbazine is a highly toxic drug and should be used only under constant supervision by a clinician experienced in cancer chemotherapy. When appropriate, procarbazine therapy should be initiated with the patient hospitalized; the patient's clinical and histologic diagnosis and hematologic, renal, and hepatic status should be carefully considered.|Although appropriate studies with procarbazine have not been performed in the geriatric population, the potential for increased vascular accidents (especially in the event of sudden hypertensive episodes), increased sensitivity to hypotensive effects, and reduced metabolic capacity discourages the first-time use of MAO inhibitors in patients over 60 years of age. When an MAo inhibitor is prescribed for an elderly patient, the patient's history of depression, ability to comply with prescribing instructions, and any potential drug interactions must also be considered. In addition, elderly patients are more likely to have age-related renal function impairment, which may require a lower dosage or, in severe cases, avoidance of use of procarbazine.|Patients should be warned not to drink alcoholic beverages and to avoid food with high tyramine content, such as yogurt, cheese, and bananas, while receiving procarbazine. Patients should also be instructed to avoid use of over-the-counter preparations containing antihistamine or sympathomimetic drugs and to discuss any prescription medications they are taking with the clinician who is supervising procarbazine therapy.|Pregnancy risk category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|For more Drug Warnings (Complete) data for PROCARBAZINE (24 total), please visit the HSDB record page.

Procarbazine is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Procarbazine is cell-phase specific for the S phase of cell division.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Procarbazine is rapidly and completely absorbed.|Procarbazine hydrochloride is rapidly and nearly completely absorbed from the GI tract following oral administration. Following oral administration of a single 30 mg dose of radiolabeled procarbazine hydrochloride, peak plasma radioactive concentrations of the drug were attained within 1 hour. Oral administration generally results in plasma concentrations similar to those achieved following IV administration of the drug. /Procarbazine hydrochloride/|Approximately 45% to 70% of a dose is excreted in the urine during the first 24 hr as metabolites.|From 25 to 70% of an oral or parenteral dose given to man is recovered from the urine during the first 24 hours after administration; less than 5% is excreted as the unchanged compound, and the rest is mostly in the form of a metabolite, N-isopropylterephthalanic acid.|Distribution studies in animals and humans using radiolabeled procarbazine hydrochloride administered IV have shown concentrations of radioactivity to be present in the liver, kidneys, intestinal wall and skin. The drug crosses the blood-brain barrier and distributes into CSF. Equilibration of procarbazine between plasma and CSF occurs rapidly following oral administration. It is not known whether procarbazine is distributed into milk.|For more Absorption, Distribution and Excretion (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.

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.|It is rapidly metabolized in man ... . Oxidation of procarbazine produces the corresponding azo compound and hydrogen peroxide. Further metabolism, presumably in the liver, yields azoxy derivatives that circulate in the bloodstream and have potent cytotoxic activity.|Procarbazine yields demethylprocarbazine probably in rats; yields n-isopropyl-alpha-methylazo-p-toluamide and terephthalic isopropylamide in rats. /from table/|Rats biotransformed ip dose of (14)C-monomethylhydrazine to (14)C-methane within 3 min of injection. ... Rats produced 25% (14)C-CH4 and 3% (14)C-CO2 in 90 min. ...(14)C-procarbazine ... was less readily biotransformed to CH4. After 90 min, 4% of dose...excreted as (14)C-CH4. /hydrochloride/|The NADPH-dependent microsomal metabolism of [14C]procarbazine labeled on the terminal N-methyl group resulted in the covalent binding of the drug to exogenously added DNA; this reaction was inhibited by metyrapone. Procarbazine metabolism was also shown to result in covalent binding of the methyl group of the drug to microsomal protein upon metabolism but the extent of protein binding was at least an order of magnitude smaller than that see with its primary oxidative metabolite. N-isopropyl-alpha-(2-methylazo)-p-toluamide. The characteristics of the reactions leading to the covalent binding of the N-methyl group of the azo derivative to microsomal protein and its metabolism to form methane, possessed a number of similarities in the apparent kinetic parameters (Km and Vmax), induction and inhibition patterns indicating a common pathway of metabolism to form a reactive intermediate and the involvement of cytochrome p450. Reduced glutathione stimulated methane formation and inhibited covalent binding to protein.|For more Metabolism/Metabolites (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.

10 minutes|The biological half-life of procarbazine hydrochloride in both plasma and CSF is approximately 1 hour. /Procarbazine hydrochloride/|... Half-life in blood after iv injection is approx 7 min.|The plasma half-life of parent drug is approximately 10 minutes.

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 an alkylating agent. The exact mechanism of antineoplastic action is unknown but is thought to resemble that of the alkylating agents; procarbazine is cell cycle-specific for the S phase of cell division. Procarbazine is thought to inhibit DNA, RNA, and protein synthesis.|O-6-Methylguanine was measured in blood leukocyte DNA of seven patients with Hodgkin's or non-Hodgkin's lymphoma during therapeutic exposure to procarbazine involving three daily p.o. doses (50 mg each) for 10 days (corresponding to 2.1 mg/kg/day for a 70-kg human). Adduct accumulation was observed in all seven cases, reaching levels up to 0.28 fmol/microgram of DNA (0.45 umol/mol of guanine). In one individual, maximal levels of adduct were reached after 7 days of exposure, followed by a steady decline, whereas in all other individuals continuous accumulation was observed throughout the exposure period. In four individuals for which data were available for day 11 (12 to 16 hr after the final intake of procarbazine), decreased amounts of O-6-methylguanine were observed relative to the last previous measurements. The accumulation of O-6-methylguanine was linearly correlated with the cumulative dose of procarbazine, with a slope of 0.011 fmol of O-6-methylguanine/microgram of DNA per mg/kg of body weight or 2.68x10-4 fmol of O-6-methylguanine DNA per mg/sq m. Two hr after the administration of single p.o. doses of l to 10 mg/kg of procarbazine to rats, O-6-methylguanine formation in leukocyte DNA was just under half that in liver DNA and showed a linear relationship with dose with a slope of 0.017 fmol/microgram of DNA per mg/kg of body weight or 5.67x10-4 fmol of O-6-methylguanine/microgram of DNA per mg/sq m. A negative correlation between the rate of accumulation of O-6-methylguanine in different individuals and lymphocyte O-6-alkylguanine-DNA alkyltransferase was observed, demonstrating a probable protective effect of O-6-alkylguanine-DNA alkyltransferase against the accumulation of O-6-methylguanine during exposure to methylating agents. This observation supports the suggestion of a possible role of procarbazine-induced O-6-methylguanine in the pathogenesis of acute nonlymphocytic leukemia appearing after treatment with chemotherapeutic protocols which include procarbazine, based on the finding of low lymphocyte O-6-alkylguanine-DNA alkyltransferase levels in patients with such therapy-related neoplastic disease. Lymphocyte O-6-alkylguanine-DNA alkyltransferase levels were mainly in the range of 5 to 10 fmol/micrograms of DNA and showed no consistent variation during procarbazine exposure.|Procarbazine causes weak inhibition of monoamine oxidase (MAO). MAO inhibitors prevent the inactivation of tyramine by hepatic and gastrointestinal monoamine oxidase. Tyramine in the bloodstream releases norepinephrine from the sympathetic nerve terminals and produces a sudden increase in blood pressure.

Treatment of overdose: NOTE: Symptoms resulting from overdose may be absent or minimal for nearly 12 hours following ingestion, and develop slowly thereafter, reaching a maximum in 24 to 48 hours. Immediate hospitalization and close monitoring of patient are essential during this period. Treatment may include the following: ... instillation of charcoal slurry in early overdose. Treatment of signs and symptoms of CNS stimulation with diazepam, administered intravenously and slowly. Treatment of hypotension and vascular collapse with intravenous fluids and a dilute pressor agent. Support of respiration by management of the airway, and mechanical ventilation with the use of supplemental oxygen, as required. Close monitoring of body temperature and vigorous treatment of hyperpyrexia with antipyretics and as cooling blanket. Maintenance of fluid and electrolyte balance is essential. Reduction of symptoms of hypermetabolic state (coma, respiratory failure, hyperpyrexia, tachycardia, muscular rigidity, tremor, and hyperreflexia) with intravenous dantrolene sodium at 2.5 mg/kg of body weight a day in divided doses, with careful monitoring for signs of hepatotoxicity and pleural or pericardial effusions. Hemodialysis may be beneficial but is of unproven value. Pathophysiologic effects of massive overdose may persist for several days; recovery from mild overdose may take 3 to 4 days.|Emergency and supportive measures; 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur. 3. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. 4. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. 5. Extravasation. Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment. a. Dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin-C, mitoxantrone, and plicamycin. Apply ice compresses to the extravasation site for 15 minutes 4 times daily for 4 days. Topical application of dimethyl sulfoxide (DMSO) may be beneficial (commercially available 50% solution is less concentrated than those used in experimental studies, but may be tried). There is no justification for injection of hydrocortisone or sodium bicarbonate. b. Mechlorethamine (and concentrated dacarbazine and cisplatin). Infiltrate the site of extravasation with 10 mL of sterile 2.5% sodium thiosulfate (dilute 1 mL of 25% thiosulfate with sterile water to a volume of 10 mL); apply ice compresses for 6-12 hours. c. Etoposide, paclitaxel, vincristine, or vinblastine. Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase (150-900 units) may be beneficial. Do not use ice pack /Antineoplastic Agents/.|Decontamination; 1. Prehospital. Administer activated charcoal, if available. IF a delay of more than 60 minutes is expected before charcoal can be given, consider u sing ipecac to induce vomiting, if it can be administered within a few minutes of exposure and there are no contraindications. 2. Hospital. Administer activated charcoal. Gastric emptying is not necessary after a small ingestion if activated charcoal can be given promptly /Antineoplastic Agents/.|Enhanced elimination; Because of the rapid intracellular incorporation of most agents, dialysis and other extracorporeal removal procedures are generally not effective /Antineoplastic Agents/.|For more Antidote and Emergency Treatment (Complete) data for PROCARBAZINE (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ the major manifestations of acute overdosage with procarbazine would be expected to include nausea, vomiting, enteritis, diarrhea, hypotension, tremors, seizures, and coma.|/EPIDEMIOLOGY STUDIES/ Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up /were matched/. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95% CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95% CI: 2-125) after chemotherapy alone (1 STS) and 19 (95% CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.

Hydrochloride, Procarbazine

Oral: Capsules: 50 mg (of procarbazine), Matulane (with parabens), Sigma-Tau

PATENTS: US PATENT 3,520,926. /HYDROCHLORIDE/

Stability indicating assay for degradation products of hydrogen chloride salt developed using high pressure liquid chromatography. Concentrations as low as 0.04 mg/mL, 0.02% quant using internal standard of cinnamyl alc. Typical range for products in capsules is 0.1-0.5% after as long as 4.5 yrs.

Pharmaceuticals