natulan

Natulan

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Natulan buy in Germany at a discount. Express delivery. Write to us pillsgermany@gmail.com

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Natulan

Commonly used brand name(s): Matulane; Natulan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Lymphomas, Hodgkin’s (treatment) or
[Lymphomas, non-Hodgkin’s (treatment)]1—Procarbazine is indicated, in combination with other agents, for treatment of Hodgkin’s disease (Stage III and IV) {01} {02} and some non-Hodgkin’s lymphomas {03}.

[Tumors, brain, primary (treatment)]1—Procarbazine is indicated for treatment of primary brain tumors {04} {05}.

[Multiple myeloma (treatment)]1—Procarbazine is indicated for treatment of multiple myeloma.

1 Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
257.76

Mechanism of action/Effect:

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.

Other actions/effects:

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.

Absorption:

Rapidly and completely absorbed from the gastrointestinal tract {01}.

Distribution:

Crosses the blood-brain barrier {01}.

Biotransformation:

Hepatic {01}.

Half-life:

Approximately 10 minutes {01}.

Elimination:
Renal—70% (as metabolite) {01}.

Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Procarbazine is a potent carcinogen in animals and, because it is an alkylating agent, is also likely to be carcinogenic in humans.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. Procarbazine affects spermatogenesis in humans.

Pregnancy—
Procarbazine is frequently teratogenic in animals and there have been reports of minor malformations or premature births when it is given later in pregnancy in humans.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

FDA Pregnancy Category D {01}.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while procarbazine is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Appropriate studies with procarbazine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.

Geriatrics

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.

Dental

The bone marrow depressant effects of procarbazine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Procarbazine may also cause stomatitis that is associated with considerable discomfort.

The secondary anticholinergic effects of procarbazine may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Most drug interactions are due to procarbazine’s monoamine oxidase–inhibiting activity.

» Alcohol    (concurrent use with procarbazine may result in a disulfiram-like reaction and additive central nervous system (CNS) depression and postural hypotension; also, possible tyramine content in alcoholic beverages, especially beer, wine, or ale, may induce hypertensive reactions)

» Anesthetics, local, with epinephrine or levonordefrin or
» Cocaine    (concurrent use 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)

» Anesthetics, spinal    (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)

» Anticholinergics or other medications with anticholinergic activity (see Appendix II ) or
Antidyskinetic agents or
» Antihistamines    (concurrent use 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)

Anticoagulants, coumarin- and indandione-derivative    (concurrent use may increase anticoagulant activity; although the mechanism of action and clinical significance are unknown, caution is recommended)

Anticonvulsants    (concurrent use of anticonvulsants with procarbazine may lead to increased CNS depressant effects as well as a change in the pattern of epileptiform seizures; dosage adjustment of anticonvulsant may be necessary)

» Antidepressants, tricyclic    (in addition to increased anticholinergic effects, concurrent use with procarbazine may result in hyperpyretic crises, severe convulsions, and death; however, recent studies have shown that some tricyclic antidepressants can be used concurrently with MAO inhibitors with no adverse effects if both medications are initiated simultaneously at lower than usual doses and the doses raised gradually, or if the MAO inhibitor is gradually added to the tricyclic also at low doses; tricyclics should not be added to an established MAO inhibitor regimen; careful monitoring for side effects of either medication is necessary)

» Antidiabetic agents, sulfonylurea or
» Insulin    (procarbazine may enhance hypoglycemic effects; dosage reduction of hypoglycemic medication may be necessary during and after such combined therapy)

Antihypertensives or
Diuretics or
Hypotension-producing medications, other (see Appendix II )    (concurrent use with procarbazine may result in an enhanced hypotensive effect; dosage adjustment may be necessary)

(antihypertensives with CNS depressant effects, such as clonidine, guanabenz, methyldopa, or metyrosine, may increase CNS depression)

Beta-adrenergic blocking agents, including ophthalmic beta-blockers absorbed systemically    (possible significant hypertension may theoretically occur up to 14 days following discontinuation of procarbazine; however, sufficient clinical reports are lacking)

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of procarbazine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of procarbazine, if necessary, should be based on blood counts)

» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)

Bromocriptine    (concurrent use may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustment of bromocriptine may be necessary)

» Buspirone    (concurrent use with MAO inhibitors is not recommended because elevation of blood pressure may occur)

» Caffeine-containing preparations    (concurrent use of excessive amounts of caffeine, consumed in chocolate, coffee, cola, tea, or “stay awake” products, with procarbazine may produce dangerous cardiac arrhythmias or severe hypertension because of sympathomimetic effects of caffeine)

» Carbamazepine or
» Cyclobenzaprine or
» Maprotiline or
» Monoamine oxidase (MAO) inhibitors, other, including furazolidone and pargyline    (concurrent use with procarbazine is not recommended on an outpatient basis, as hyperpyretic crises, severe seizures, and death could result; prior to initiation of procarbazine therapy, 14 days should elapse after discontinuance of any of these medications)

» CNS depression–producing medications, other (see Appendix II )    (CNS depression and postural hypotension may be enhanced; concurrent use with antihistamines is not recommended)

» Dextromethorphan    (concurrent use with procarbazine may cause excitation, hypertension, and hyperpyrexia)

» Doxapram    (concurrent use may increase the pressor effects of either doxapram or procarbazine)

» Fluoxetine    (concurrent use may result in confusion, agitation, restlessness, and gastrointestinal symptoms, or possibly hyperpyretic episodes, severe convulsions, and hypertensive crises. Based on experience with tricyclic antidepressants, at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of fluoxetine. However, because of the long half-lives of fluoxetine and its active metabolite, at least 5 weeks [approximately 5 half-lives of norfluoxetine] should elapse between discontinuation of fluoxetine and initiation of therapy with an MAO inhibitor. Administration of an MAO inhibitor within 5 weeks of discontinuation of fluoxetine may increase the risk of serious events. While a causal relationship to fluoxetine has not been established, death has been reported following the initiation of an MAO inhibitor shortly after fluoxetine administration was stopped)

» Guanadrel or
» Guanethidine or
» Rauwolfia alkaloids    (administration to patients receiving procarbazine may result in sudden release of accumulated catecholamines and a hypertensive reaction; parenteral administration is not recommended during and for 1 week following procarbazine therapy)

(when an MAO inhibitor is added to existing therapy with a rauwolfia alkaloid, serious potentiation of CNS depressant effects may result; however, if a rauwolfia alkaloid is added to an MAO inhibitor regimen, CNS excitation and hypertension may result from release of excessive amounts of accumulated norepinephrine and serotonin)

Haloperidol or
Loxapine or
Molindone or
Phenothiazines or
Pimozide or
Thioxanthenes    (concurrent use may prolong and intensify the sedative, hypotensive, and anticholinergic effects of either these medications or procarbazine)

» Levodopa    (concurrent use with MAO inhibitors is not recommended, as the combination may result in sudden moderate to severe hypertensive crisis; a period of 2 to 4 weeks is recommended after withdrawal of MAO inhibitors before levodopa is administered)

» Meperidine and possibly other opioid (narcotic) analgesics    (concurrent use with procarbazine may produce immediate excitation, sweating, rigidity, and severe hypertension; in some patients, hypotension, severe respiratory depression, coma, convulsions, hyperpyrexia, vascular collapse, and death may occur; reactions may be due to accumulation of serotonin resulting from MAO inhibition; avoidance of meperidine use within 2 to 3 weeks following procarbazine is recommended; other opioid analgesics, such as morphine, are not likely to cause such severe reactions and may be used cautiously in reduced dosage in patients receiving MAO inhibitors; however, it is recommended that a small test dose [one quarter of the usual dose] or several small incremental test doses over a period of several hours should first be administered to permit observation of any adverse effects)

(caution is also recommended in the use of alfentanil, fentanyl, or sufentanil as an adjunct to anesthesia if the patient has received procarbazine within 14 days; although the risk of a significant interaction has been questioned, the use of a small test dose is advised to detect any possible interaction)

» Methyldopa    (concurrent use with procarbazine may cause hyperexcitability; also headache, severe hypertension, and hallucinations have been reported)

» Methylphenidate    (concurrent use with procarbazine may potentiate the CNS stimulant effects of methylphenidate, possibly resulting in a hypertensive crisis; should not be administered during or within 14 days following the administration of procarbazine)

Metrizamide    (concurrent use with procarbazine may lower the seizure threshold; procarbazine should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours after procedure)

Phenylephrine, nasal or ophthalmic    (if significant systemic absorption of nasal or ophthalmic phenylephrine occurs, concurrent use with procarbazine may potentiate pressor effects; these medications should not be administered during or within 14 days following the administration of procarbazine)

» Sympathomimetics    (concurrent use with procarbazine may prolong and intensify cardiac stimulant and vasopressor effects [including headache, cardiac arrhythmias, vomiting, sudden and severe hypertensive and hyperpyretic crises] of these medications because of release of catecholamines that accumulate in intraneuronal storage sites during MAO inhibitor therapy; these medications should not be administered during or within 14 days following the administration of procarbazine)

» Tryptophan    (concurrent use with MAO inhibitors may cause hyperreflexia, shivering, hyperventilation, hyperthermia, mania or hypomania, and disorientation or confusion; when tryptophan is added to an MAOI regimen, it should be started in low dosages and the dose titrated upwards gradually with close monitoring of mental status and blood pressure)

» Tyramine- or other high pressor amine–containing foods and beverages, such as aged cheese; beer; reduced-alcohol and alcohol-free beer and wine; red and white wines; sherry; liqueurs; yeast/protein extracts; fava or broad bean pods; smoked or pickled meats, poultry, or fish; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; and any overripe fruit    (concurrent use with procarbazine may cause sudden and severe hypertensive reactions; reactions are usually limited to a few hours and easily treated with phentolamine; severity depends on amount of tyramine ingested, rate of gastric emptying, and length of interval between dose of procarbazine and ingestion of tyramine; when procarbazine is discontinued, dietary restrictions must continue for at least 2 weeks; other tyramine- or high pressor amine–containing foods, such as yogurt, sour cream, cream cheese, cottage cheese, chocolate, and soy sauce, if eaten when fresh and in moderation, are considered unlikely to cause serious problems)

Vaccines, killed virus    (because normal defense mechanisms may be suppressed by procarbazine therapy, the patient’s antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient’s ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)

» Vaccines, live virus    (because normal defense mechanisms may be suppressed by procarbazine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient’s antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient’s hematologic status and only with the knowledge and consent of the physician managing the procarbazine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient’s ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Alcoholism, active
» Congestive heart failure
» Hepatic function impairment, severe    (procarbazine may precipitate hepatic precoma in patients with cirrhosis, who are extremely sensitive to its effects)

» Pheochromocytoma    (pressor substances secreted by such tumors may alter blood pressure during therapy with MAO inhibitors)

» Renal function impairment, severe    (cumulative effects of procarbazine may occur because of reduced renal excretion)

Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Cardiac arrhythmias
» Cardiovascular disease or coronary insufficiency    (ischemia may be aggravated as a result of reduced blood pressure)

Cerebrovascular disease    (cerebral ischemia may be aggravated as a result of reduced blood pressure)

» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)

Diabetes mellitus    (procarbazine may alter insulin or oral hypoglycemic requirements)

Epilepsy    (pattern of epileptiform seizures may be changed)

» Headaches, severe or frequent    (headache as a first sign of hypertensive reaction during therapy may be masked)

» Hepatic function impairment    (procarbazine may precipitate hepatic precoma in patients with cirrhosis, who are extremely sensitive to its effects; lower dosage is recommended; use not recommended in severe function impairment)

Hyperthyroidism    (sensitivity to pressor amines may be increased)

» Infection
» Paranoid schizophrenia or other hyperexcitable personality states    (MAO inhibitors may cause excessive stimulation in schizophrenic patients; in manic-depressive states, may effect a swing from depressive to manic phase)

Parkinsonism    (may be aggravated)

» Renal function impairment    (cumulative effects may occur; lower dosage is recommended; use not recommended in severe function impairment)

Sensitivity to procarbazine
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.
» In addition, caution should be used in patients who have undergone sympathectomy, who may be more sensitive to the hypotensive effects of MAO inhibitors.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) values, serum and
» Aspartate aminotransferase (AST [SGOT]) values, serum and
» Bilirubin concentrations, serum and
» Lactate dehydrogenase (LDH) values, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

» Bone marrow aspiration studies    (recommended prior to initiation of procarbazine therapy and at time of maximum hematologic response to ensure adequate bone marrow reserve)

» Hematocrit or hemoglobin and
» Platelet count and
» Total and, if appropriate, differential leukocyte count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication’s pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Except for hematologic, pulmonary, and gastrointestinal toxicity, adverse effects of procarbazine resemble those of the MAO inhibitors used in treating psychiatric disorders.
Toxicity is increased in patients with renal or hepatic function impairment or bone marrow depression.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Anemia

CNS stimulation, excessive (confusion; convulsions; hallucinations)

immunosuppression, infection, or leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic

thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

hemolytic anemia (continuing tiredness or weakness)

missing menstrual periods

pneumonitis (cough; shortness of breath; thickening of bronchial secretions)

Note: With leukopenia and thrombocytopenia, the nadir of the platelet count occurs after about 4 weeks, followed by the leukocyte count, with recovery complete in about 6 weeks.
Missing menstrual periods occur with high doses.

Incidence less frequent

Gastrointestinal toxicity (diarrhea)

hepatotoxicity (yellow eyes or skin)

peripheral neuropathy (tingling or numbness of fingers or toes; unsteadiness or awkwardness)

stomatitis (sores in mouth and on lips)

Incidence rare

Allergic reaction (skin rash, hives or itching; wheezing)

hypertensive crisis (severe chest pain; enlarged pupils; fast or slow heartbeat; severe headache; increased sensitivity of eyes to light; increased sweating, possibly with fever or cold, clammy skin; stiff or sore neck)

orthostatic hypotension (fainting)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

CNS stimulation, excessive (drowsiness; muscle or joint pain; muscle twitching; nervousness; nightmares; trouble in sleeping)

nausea and vomiting

unusual tiredness or weakness

Incidence less frequent

Constipation

darkening of skin

difficulty in swallowing

dry mouth

feeling of warmth and redness in face

headache

loss of appetite

mental depression

orthostatic hypotension (dizziness or lightheadedness when getting up from a lying or sitting position)

Those not indicating need for medical attention
Incidence less frequent

Loss of hair

Overdose
For more information on the management of overdose or unintentional intestion, contact a Poison Control Center (see Poison Control Center listing ).

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:

• Induction of vomiting or gastric lavage with protected airway followed by 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 a 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 per kg of body weight (mg/kg) 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.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Procarbazine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
Conditions affecting use, especially:
Sensitivity to procarbazine

Pregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspected

Breast-feeding—Not recommended because of risk of serious side effects

Use in the elderly—Potential for increased vascular accidents, increased sensitivity to hypotensive effects; first-time use discouraged in patients over 60 years of age
Other medications, especially alcohol, anticholinergics or other medications with anticholinergic activity, antihistamines, buspirone, caffeine-containing preparations, carbamazepine, CNS-depressants, cocaine, cyclobenzaprine, dextromethorphan, doxapram, fluoxetine, furazolidone, guanadrel, guanethidine, insulin, levodopa, local anesthetics with epinephrine or levonordefrin, maprotiline, meperidine and possibily other opioid analgesics, methyldopa, methylphenidate, other bone marrow depressants, other monoamine oxidase inhibitors, pargyline, previous cytotoxic drug or radiation therapy, rauwolfia alkaloids, spinal anesthetics, sulfyonylurea antidiabetic agents, sympathomimetics, tricyclic antidepressants, or tryptophan
Other medical problems, especially active alcoholism, bone marrow depression, cardiac arrhythmias, chickenpox or recent exposure, congestive heart failure, coronary insufficiency, severe or frequent headaches, hepatic function impairment, herpes zoster, other infection, paranoid schizophrenia or other hyperexcitable personality states, pheochromocytoma, sympathectomy, or renal function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Caution in taking combination chemotherapy; taking each medication at the right time

» Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Missed dose: Taking as soon as remembered if within a few hours; not taking if several hours have passed or if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Checking with hospital emergency room or physician if symptoms of hypertensive crisis develop

» Avoiding use of tyramine-containing foods, alcoholic beverages and large quantities of caffeine-containing beverages, over-the-counter cold and cough medicines, and other medication unless prescribed; having list of such for reference

» Obeying rules of caution during 14 days after discontinuing medication

» Caution in taking alcohol or other CNS depressants

» Caution if drowsiness occurs, especially when driving or doing things requiring alertness

» Avoiding immunizations unless approved by physician; other persons in patient’s household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
Diabetics: Checking urine or blood sugar levels

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

Carrying medical identification card

Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, hypertensive crisis, and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially anemia, excessive CNS stimulation, immunosuppression, infection, leukopenia, thrombocytopenia, hemolytic anemia, missing menstrual periods, pneumonitis, gastrointestinal toxicity, hepatotoxicity, peripheral neuropathy, stomatitis, allergic reaction, hypertensive crisis, and orthostatic hypotension

Physician or nurse can help in dealing with side effects

General Dosing Information
Patients receiving procarbazine should be under supervision of a physician experienced in cancer chemotherapy.

A variety of dosage schedules and regimens of procarbazine, alone or in combination with other antitumor agents, are used. The prescriber may consult medical literature as well as the manufacturer’s literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and appearance or severity of toxicity.

Although dosages are based on the patient’s actual weight, use of estimated lean body weight is recommended in obese patients or those with weight gain due to edema, ascites, or other abnormal fluid retention {01}.

It is recommended that procarbazine therapy be discontinued promptly if any of the following occur {01}:

• Allergic reaction

• Central nervous system signs or symptoms, such as paresthesias, neuropathies, or confusion

• Diarrhea

• Hemorrhage or bleeding tendencies

• Leukopenia (< 4000 white blood cells per cubic millimeter)

• Stomatitis

• Thrombocytopenia (< 100,000 platelets per cubic millimeter)
Therapy may be resumed at a lower dosage when the clinical and laboratory examinations are satisfactory.

Because of the risk of enhanced bone marrow toxicity, an interval of at least 1 month (based on bone marrow studies) is recommended before starting procarbazine therapy after a patient has received radiation or chemotherapy with medications that depress bone marrow function.

After dosage is stopped, monoamine oxidase (MAO) inhibitor effects of this medication may persist for up to 2 weeks after withdrawal (time required for regeneration of enzyme). During this period, food and drug contraindications must be observed.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of procarbazine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Diet/Nutrition
Foods and beverages containing tyramine or other high pressor amines, such as aged cheese; beer; reduced-alcohol and alcohol-free beer and wine; red and white wines; sherry; liqueurs; yeast/protein extracts; fava or broad bean pods; smoked or pickled meats, poultry, or fish; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; and any overripe fruit, when used concurrently with MAO inhibitors, may cause sudden and severe hypertensive reactions. The reactions are usually limited to a few hours and are easily treated with phentolamine. The severity depends on the amount of tyramine ingested, rate of gastric emptying, and length of the interval between the dose of MAO inhibitor and ingestion of tyramine. When MAO inhibitors are discontinued, dietary restrictions must continue for at least 2 weeks. Other foods, such as yogurt, sour cream, cream cheese, cottage cheese, chocolate, and soy sauce, if eaten when fresh and in moderation, are considered unlikely to cause serious problems.

For treatment of hypertensive crisis
Recommended treatment includes:

• Discontinuing MAO inhibitor.
• Lowering blood pressure immediately with intravenous administration of 5 mg of phentolamine, with care being taken to inject slowly, to prevent excessive hypotensive effect.
• Reducing fever by external cooling.

Combination chemotherapy
Procarbazine may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, procarbazine is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses):    —carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP).
—cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP).
—cyclophosphamide, vincristine, procarbazine, and prednisone (COPP).
—mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.

Oral Dosage Forms

PROCARBAZINE HYDROCHLORIDE CAPSULES USP

Note: The doses and strength are expressed in terms of procarbazine base, not the hydrochloride salt.

Usual adult dose
Lymphomas, Hodgkin’s
Initial: Oral, 2 to 4 mg (base) per kg of body weight (to the nearest 50 mg) a day in single or divided doses for the first week, followed by 4 to 6 mg per kg of body weight a day until leukopenia, thrombocytopenia, or maximum response occurs {01}.

Note: If hematologic toxicity occurs, the medication is withdrawn until the toxicity is resolved, then treatment may be resumed with 1 to 2 mg (base) per kg of body weight a day {01}.
Maintenance: Oral, 1 to 2 mg (base) per kg of body weight a day {01}.

Usual pediatric dose
Lymphomas, Hodgkin’s
Initial: Oral, 50 mg (base) per square meter of body surface area a day for the first week, followed by 100 mg per square meter of body surface area a day until leukopenia, thrombocytopenia, or maximum response occurs.
Note: If hematologic toxicity occurs, the medication is withdrawn until the toxicity is resolved, then treatment may be resumed with 50 mg (base) per square meter of body surface area a day {01}.

Maintenance: Oral, 50 mg (base) per square meter of body surface area a day {01}.

Note: This dosage schedule is a guideline only. Undue toxicity in the form of tremors, coma, and seizures has occurred; therefore, dosage must be individualized based on clinical response and appearance of toxicity {01}.

Strength(s) usually available
U.S.—

50 mg (base) (Rx) [Matulane]

Canada—

50 mg (base) (Rx) [Natulan]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
• Avoid alcoholic beverages.
• May cause drowsiness.
• Avoid certain foods as directed.

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