Procarbazine

PROCARBAZINE

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use

Indication (uses)

  • Used for the treatment of stage III and stage IV Hodgkin’s disease. procarbazine
  • It is a part of MOPP (nitrogen mustard, vincristine, Procarbazine, Prednisone regimen).
  • Non-Hodgkin’s lymphoma
  • Gliomas

Pharmacological classification

Anti-cancer drug (methyl hydrazine derivative) used for the treatment of stage III and stage IV Hodgkin’s disease.

Brand names

Matulane

Dosage form

  • Supplied as capsules containing 50 mg of Procarbazine.

Mechanism of action

Procarbazine is a unique anti neoplastic agent with multiple sites of action. It inhibits incorporation of small DNA precursors as well as RNA and protein synthesis. Procarbazine can directly damage DNA through an alkylation reaction. Procarbazine is not cross-resistant with other alkylating agents.

 Dosage

  • Below mentioned dosing guidelines are applicable when Procarbazine is used as a single agent.
  • The dosage of Procarbazine should be appropriately reduced when used in combination with other drugs.
  • In the MOPP regimen, the Matulane dose is 100 mg/m2 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.

Dosage in Adults

  • Single or divided doses of 2 to 4 mg/kg/day for the first week.
  • The daily dose should be maintained at 4 to 6 mg/kg/day until a maximum therapeutic response is achieved or until WBC count falls below 4000/mm3 or platelets fall below 100000/mm3.
  • The dose should be maintained at 1 to 2 mg/kg/day after the maximum response is achieved.
  • Upon evidence of hematologic or other toxicities, therapy should be discontinued until satisfactory recovery is achieved. Therapy may then be resumed after recovery at 1 to 2 mg/kg/day.

Dosage in pediatric patients

  • 50 mg/m2 of the body surface area per day is recommended for the first week.
  • Maintenance dose at 100 mg/m2 of the body surface area until the maximum therapeutic response is achieved or until thrombocytopenia or leukopenia occurs.
  • Upon evidence of hematologic or other toxicities, therapy should be discontinued until satisfactory recovery is achieved. Therapy may then be resumed after recovery.

Renal dose adjustments

  • Data not available. Dose adjustments may be required.

Hepatic dose adjustments

  • Data not available. Dose adjustments may be required.

Geriatric dose adjustments

  • Data not available. Dose adjustments may be required.

Overdosage

  • Symptoms of Overdosage are:
    • Nausea
    • Vomiting
    • Enteritis
    • Diarrhea
    • Hypotension
    • Tremors
    • Convulsions
    • 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.

Side effects or adverse effects

Side effects specific to Procarbazine

  • Common side effects in adult patients
    • Nausea
    • Vomiting
  • Common side effects in pediatric patients
    • Undue toxicity
    • Tremors
    • Coma
    • Convulsions
  • Common side effects (observed in all population group (but not in all subjects of a group))
    • Leukopenia, anemia, and thrombopenia occur frequently.
    • Nausea and vomiting are the most commonly reported side effects.
  • 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 lung cancer, 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. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use.

Other side effects associated with cancer therapy

  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below-mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anti-cancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and haemorrhage due to a decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to the reduction in the number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout, and Urate stones may develop in the urinary tract.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.

Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above-mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

Warnings

  • 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 Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) 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.

Precautions

  • Undue toxicity may occur if Matulane (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 Matulane. 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.

Contraindications

Matulane 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.

Pregnancy & breast feeding warnings

  • Pregnancy
    • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing:
    • It is not known whether Matulane 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.

Interactions

Drug – 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 Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided.
  • Because of the potential for increased risk of infections, avoid the concomitant use of Procarbazine with TNF blockers.
  • Live vaccines may be administered concurrently with Procarbazine only if the benefits outweigh the risks.
  • Concomitant use of Procarbazine with following drugs/medicines should be strictly avoided.
    • Dextromethorphan and nortryptiline as it increases the risk of serotonin syndrome.
    • Almotriptan as it increases the risk of serotonin syndrome.
    • 5-hydroxy tryptophan as it increases the risk of serotonin syndrome
    • Phenylephrine, Phenylpropanolamine, Benzphetamine, Phentermine, Atomoxetine, Selegiline, Levodopa and Rasagiline as it may cause dangerously high blood pressure and even death.
    • Pseudoephedrine as it may cause dangerously high blood pressure and even death.
    • Hydrocodone, Codeine, Oxycodone and Pentazocine as it increase the risk of serious side effects such as respiratory depression, low blood pressure, fainting, coma, and even death.
    • Deutetrabenazine (Tetrabenazine) may cause excitation and hypertension in patients treated with monoamine oxidase inhibitors (MAOIs).
    • Morphine as it increases the risk of serious side effects such as respiratory depression, low blood pressure, fainting, coma, and even death.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Certolizumab as it increases the risk of infections.
    • Influenza virus vaccine (live, trivalent) as it increases the risk of infections.
    • Small pox vaccine as it increases the risk of infections.
    • Measles virus vaccine as it increases the risk of infections.
    • Mumps virus vaccine as it increases the risk of infections.
    • Polio virus vaccine (live, trivalent) as it increases the risk of infections.
    • Varicella virus vaccine as it increases the risk of infections.
    • Typhoid vaccine (live) as it increases the risk of infections.
    • BCG vaccine as it increases the risk of infections.
    • Yellow fever vaccine as it increases the risk of infections.
    • Zoster vaccine (live) as it increases the risk of infections.
    • Tofacitinib as it increases the risk of infections.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Alefacept as it increases the risk of infections.
    • Alemtuzumab as it increases the risk of infections.
    • Azathioprine as it increases the risk of infections.
    • Canakinumab as it increases the risk of infections.
    • Cladribine as it increases the risk of infections.
    • Denosumab as it increases the risk of infections.
    • Efalizumab as it increases the risk of infections.
    • Ocrelizumab as it increases the risk of infections.
    • Omacetaxine as it increases the risk of infections.
    • Ustekinumab as it increases the risk of infections.

Click here to go to Procarbazine forums.

Reference

  • Highlights of prescribing information: 1
By |2017-12-20T12:58:49+00:00September 2nd, 2017|medicines|1 Comment

About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

One Comment

  1. Rashmi Sharma February 8, 2018 at 11:00 am - Reply

    Your work is great .

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