Pharmacological properties of the drug Procarbazine
Alkylating cytostatic of the methylhydrazine class. Suppresses the process of mitotic cell division, probably acting on already formed DNA, as well as on DNA synthesis (purine methylation, DNA fragmentation). Since cross-resistance to other cytostatics is not observed, procarbazine is effective against tumors that are not amenable to treatment with other cytostatics. Procarbazine is quickly and completely absorbed from the digestive tract. The maximum concentration in blood plasma is achieved 30–60 minutes after oral administration. Penetrates into the CSF. It is believed that procarbazine or its toxic metabolites cross the placental barrier and into breast milk. Procarbazine is rapidly metabolized in the liver and kidneys. The effectiveness of procarbazine is attributed in part to hydrogen peroxide and hydroxyl radicals formed during its oxidation. About 70% of the dose is excreted in the urine within 24 hours.
Procarbazine
International name of the medicinal substance:
Procarbazine The list of drugs containing the active substance Procarbazine is given after the description.
Pharmacological action:
Antitumor agent, alkylating compound (from the group of methylhydrazines).
It disrupts the processes of transmethylation: the transfer of methyl radicals from methionine to transfer RNA (tRNA). The absence of a normally functioning t-RNA causes a disruption in the synthesis of DNA, RNA and proteins. An important component in the mechanism of action is the formation of hydrogen peroxide (the result of autooxygenation). Hydrogen peroxide, interacting with sulfhydryl groups of tissue proteins, promotes tighter spiralization of the DNA molecule and hinders transcription processes. Blocks the activity of MAO, which causes the accumulation of tyramine and an increase in the concentration of adrenaline in the endings of the sympathetic nervous system and an increase in blood pressure. Pharmacokinetics:
Quickly and completely absorbed from the gastrointestinal tract, penetrates the BBB. TCmax after oral administration - 30-60 minutes. Penetrates through the BBB. Metabolized in the liver to form active metabolites. T1/2 - 10 min. It is excreted by the kidneys - 70%, with less than 5% unchanged, and by the lungs - in the form of methane and carbon dioxide.
Indications:
Lymphogranulomatosis, malignant reticulosis, reticulosarcoma, Waldenström's disease, lymphosarcoma, Brill-Simmers disease, polycythemia vera, melanoma, myeloma, lung cancer, brain tumors, malignant thymoma, non-Hodgkin's lymphoma.
Contraindications:
Hypersensitivity, alcoholism, arrhythmias, CHF, ischemic heart disease, liver and/or renal failure, inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia), thyrotoxicosis, diabetes mellitus, epilepsy, parkinsonism, acute infectious diseases of a viral, fungal or bacterial nature (including including chickenpox, herpes zoster), pregnancy, lactation.
Side effects:
From the nervous system: central nervous system stimulation, hypomanic and manic states;
weakness, increased fatigue; peripheral neuropathy, paresthesia, ataxia. From the digestive system: nausea, vomiting, diarrhea, abdominal pain; stomatitis, hepatotoxicity, cholestatic jaundice. From the hematopoietic organs and hemostasis system: leukopenia, thrombocytopenia, hemolytic anemia. From the cardiovascular system: hypertensive crisis, orthostatic hypotension. Other: alopecia, amenorrhea, azoospermia, immunosuppression, superinfection. Allergic reactions. Interaction:
Increases the activity of adrenergic stimulants, barbiturates, antidepressants and antipsychotic drugs (neuroleptics).
Incompatible with ethanol, may cause intolerance to the latter. Ethanol, anticoagulants, antiepileptic drugs, antidepressants, oral hypoglycemic drugs, beta-blockers, adrenergic stimulants, rauwolfia alkaloids enhance the effects of the drug. Special instructions:
During treatment you should refrain from drinking ethanol-containing drinks.
Treatment should be carried out under the control of the blood picture. When prescribing to patients who have previously been treated with cytostatics or a course of radiation therapy, caution must be exercised (the risk of toxic effects on the bone marrow is increased). Preparations containing the active substance Procarbazine:
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The information provided in this section is intended for medical and pharmaceutical professionals and should not be used for self-medication. The information is provided for informational purposes only and cannot be considered official.
Use of the drug Procarbazine
Therapy begins with low doses, which are gradually increased to a maximum daily dose of 250–300 mg. Start of treatment: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 150 mg, 4th day - 200 mg, 5th day - 250 mg, 6th and subsequent days - 250–300 mg. Treatment at a dose of 250–300 mg/day is continued until the most complete remission occurs, after which they switch to maintenance doses. If at the beginning of treatment the total number of leukocytes is less than 3000 per 1 mm3 or the number of platelets is less than 80,000 per 1 mm3, treatment should be temporarily suspended until the normal levels of leukocytes and platelets are restored, after which therapy is continued with maintenance doses. During maintenance therapy, the daily dose is 50–150 mg. Treatment should be continued until a total dose of 6 g is reached. For lymphogranulomatosis, the combination of procarbazine with other cytostatics, such as derivatives of nitrogen mustard and cyclophosphamide, vinca alkaloids and corticosteroids (MOPP/COPP regimen), has proven itself to be effective. With this combination therapy, good rates of both remission rates and five-year survival are achieved. When combining procarbazine with other cytostatics or radiation therapy, the above doses should be reduced.
Side effects of the drug Procarbazine
Like other cytostatics, procarbazine often causes side effects, although compared to other drugs in this group it is relatively well tolerated. The most pronounced side effects of procarbazine are anorexia, nausea, and sometimes vomiting (these symptoms are usually observed in the first days of treatment and then usually disappear), as well as leukopenia and thrombocytopenia. Changes in the blood system are almost always reversible and the need to completely stop treatment rarely occurs. Rarely, alopecia is observed, which is reversible in most cases. There are reports of neurological disorders (headache, paresthesia, neuropathy and ataxia), liver dysfunction (cholestatic jaundice), allergic skin reactions (rash, urticaria, itching), and in rare cases azoospermia occurs.
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According to the World Health Organization (WHO), adverse effects are classified according to their frequency as follows: very common (≥ 1/10), common (≥1/100, <1/10), uncommon (≥1/1000, < 1/100), rare (≥1/10000, <1/1000) and very rare (<1/10000); frequency unknown (the frequency of events cannot be determined from the available data).
Infectious and parasitic diseases:
often - infections;
uncommon - sepsis, herpes zoster, lower respiratory tract infection; rarely - conjunctivitis, cystitis, infection caused by Pneumocystis jirovecii ,
pneumonia caused by
Pneumocystis jirovecii ,
pneumonia, septic shock; very rarely - esophageal candidiasis, acquired immunodeficiency syndrome, atypical pneumonia.
Neoplasms (benign, malignant and unspecified):
frequency unknown*: acute myeloid leukemia, leukemia, myelodysplastic syndrome, additional primary malignancies.
Blood and lymphatic system disorders:
very often - anemia, leukopenia, thrombocytopenia; often - granulocytopenia. neutropenia, blood diseases, hematotoxicity; uncommon - bone marrow dysfunction, febrile neutropenia; rarely - pancytopenia, lymphopenia; very rarely - hemolytic anemia, hemophagocytic histiocytosis, eosinophilia.
Immune system disorders:
infrequently - hypersensitivity.
Metabolic and nutritional disorders:
infrequently - loss of appetite; rarely - hyperglycemia, diabetes mellitus, hemosiderosis; very rarely - tumor lysis syndrome; frequency unknown - dehydration, hypokalemia.
Mental disorders:
very rarely - personality change, affective disorder; frequency unknown - insomnia, hallucinations, depression, confusion, nightmares.
Nervous system disorders:
often
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neurotoxicity; uncommon - peripheral neuropathy, paresthesia, hypoesthesia; rarely - headache; very rarely - stroke, progressive multifocal leukoencephalopathy, autonomic neuropathy, fainting, encephalopathy; frequency unknown - dizziness, ataxia, dysgeusia, tremor, coma, weakness; diplopia, nystagmus.
Visual disorders:
frequency unknown - photophobia, intraocular hemorrhage.
Hearing and labyrinth disorders:
rarely - ototoxicity; frequency unknown - hypacusia.
Cardiac disorders:
uncommon - cardiovascular toxicity, cardiac dysfunction; rarely - myocardial infarction, cardiovascular diseases, congestive heart failure; very rarely - sinus arrhythmia, pericarditis; frequency unknown - tachycardia.
Vascular disorders:
uncommon - thrombosis; rarely - hypotension, hemorrhage, Raynaud's syndrome; very rarely - phlebitis.
Disorders of the respiratory system, chest and mediastinal organs:
often - disruption of the respiratory system; Uncommon: respiratory tract infection, pulmonary toxicity, pulmonary dysfunction; rarely - respiratory failure, pulmonary embolism, pneumonitis; very rarely - difficulty breathing, aspiration pneumonia, interstitial lung disease, pulmonary fibrosis; frequency unknown - shortness of breath.
Gastrointestinal disorders:
often - nausea, vomiting, gastrointestinal toxicity; infrequently - stomatitis, constipation; rarely - diarrhea, esophagitis; very rarely - gastric bleeding; frequency unknown - pain in the upper abdomen.
Disorders of the liver and biliary tract:
uncommon - hepatotoxicity; rarely - liver dysfunction, hepatitis, liver necrosis, liver steatosis; very rarely - jaundice.
Disorders of the skin and subcutaneous tissues:
very often - alopecia; uncommon - skin toxicity, rash; rarely - urticaria, drug rash; very rarely - acne, itching; frequency unknown - toxic epidermal necrolysis, toxic skin rash.
Musculoskeletal and connective tissue disorders:
infrequently - pain in the jaw; rarely - myalgia, osteonecrosis; very rarely - spondylitis, osteoporosis; frequency unknown - back pain.
Renal and urinary tract disorders:
infrequently
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disruption of the genitourinary system; rarely - toxic nephropathy, renal failure, renal dysfunction.
Disorders of the genital organs and breast:
frequency unknown - azoospermia, amenorrhea.
General disorders and disorders at the injection site:
often - inflammation of the mucous membrane, pain, pyrexia; infrequently - fatigue; very rarely - sudden death from cardiac arrest; frequency unknown - hyperpigmentation, discomfort, malaise, progression of the disease, lack of effect from taking the drug.
Laboratory and instrumental data:
often - a decrease in the level of leukocytes in the blood, a decrease in the level of neutrophils in the blood; infrequently - increased levels of gamma-glutamyltransferase, increased levels of transaminases; rarely - abnormal levels of creatinine in the blood; frequency unknown - weight loss.
Side effects in children
The overall spectrum of adverse reactions in children is largely consistent with the adverse reactions observed and reported in adults. Adverse reactions not reported in adults are listed below.
Infectious and parasitic diseases:
uncommon - chicken pox, bronchopneumonia, abscess, pneumococcal bacteremia, gastroenteritis; rarely - subphrenic abscess, tuberculous meningitis, bacterial sepsis, hepatitis B.
Neoplasms (benign, malignant and unspecified):
frequency unknown*: acute myeloid leukemia, leukemia, myelodysplastic syndrome, additional primary malignancies.
Blood and lymphatic system disorders:
rarely - autoimmune hemolytic anemia.
Immune system disorders:
rarely - Graves' disease.
Endocrine system disorders:
infrequently - hypothyroidism.
Metabolic and nutritional disorders:
rarely - hypernatremia.
Mental disorders:
rarely - abnormal behavior, confusion.
Nervous system disorders:
often - disorders of the nervous system; infrequently - convulsions; rarely - hemiparesis, monoparesis, drowsiness, areflexia.
Visual disorders:
rarely - decreased visual acuity.
Vascular disorders:
rarely - hot flashes.
Disorders of the respiratory system, chest and mediastinal organs:
infrequently - shortness of breath, respiratory arrest.
Gastrointestinal disorders:
infrequently - colitis; rarely - bloody vomiting.
Disorders of the liver and biliary tract:
rarely - liver failure.
Disorders of the skin and subcutaneous tissues:
rarely - allergic dermatitis.
Renal and urinary tract disorders:
infrequently - hemorrhagic cystitis.
Disorders of the genital organs and breast:
frequency unknown - azoospermia*.
General disorders and disorders at the injection site:
rarely - asthenia.
Laboratory and instrumental data:
uncommon - abnormal calcium levels in the blood, abnormal levels of magnesium in the blood; rarely - abnormal results of examination of the oculomotor nerve.
Surgical and medical procedures:
rarely - transfusion of red blood cells.
*: Long-term toxicity includes secondary tumors and toxicity to some organs. The number of patients suffering from delayed toxicity may increase over time.
Drug interactions Procarbazine
Procarbazine is a weak MAO inhibitor and potentiates the effect of concomitantly used sympathomimetics, barbiturates, antidepressants and antipsychotics, so it is necessary to use reduced doses of these drugs. Patients taking procarbazine may develop intolerance to alcohol, so during treatment it is necessary to refrain from drinking it. In rare cases, eating cheese during treatment with MAO inhibitors can cause an increase in blood pressure, and although a similar effect is not known with the use of procarbazine, for safety reasons patients should be advised to refrain from eating cheese during treatment.
