Natulan (Capsules) Instructions for Use

Marketing Authorization Holder

Leadiant Biosciences, Ltd. (United Kingdom)

Manufactured By

Haupt Pharma Amareg, GmbH (Germany)

Contact Information

Pharma Riace Ltd. (United Kingdom)

ATC Code

L01XB01 (Procarbazine)

Active Substance

Procarbazine (Rec.INN registered with WHO)

Dosage Form

Natulan

Capsules 50 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin, oval, ivory-colored; the capsule contents are a fine-grained powder, white or white with a yellowish tint.

Excipients: starch, talc, magnesium stearate, mannitol.

Capsule shell composition: gelatin, titanium dioxide, iron oxide (E172).

50 pcs. – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antineoplastic drug, an alkylating compound from the methylhydrazine group. The mechanism of action of procarbazine has not been precisely studied. The drug inhibits the synthesis of proteins, DNA, and RNA by disrupting transmethylation processes – the transfer of methyl radicals from methionine to transfer RNA (tRNA). The absence of normally functioning tRNA causes disruption of DNA, RNA, and protein synthesis (it is an S-phase specific agent). An important component of the mechanism of action is the formation of hydrogen peroxide as a result of auto-oxygenation. Hydrogen peroxide, interacting with sulfhydryl groups of tissue proteins, promotes tighter spiralization of the DNA molecule and complicates transcription processes.

It blocks MAO activity, which causes the accumulation of tyramine and, as a consequence, an increase in norepinephrine content in the endings of the sympathetic nervous system and an increase in blood pressure.

Pharmacokinetics

Absorption and Distribution

After oral administration, it is rapidly and completely absorbed from the gastrointestinal tract. C_max is reached within 30-60 minutes. Penetrates the blood-brain barrier.

Metabolism and Excretion

Metabolized in the liver and kidneys to form active metabolites. T_1/2 is 10 minutes.

It is excreted mainly by the kidneys (70% is excreted in the urine within 24 hours, mainly as N-isopropylterephthalic acid, less than 5% unchanged) and by the lungs as methane and carbon dioxide.

Indications

• Hodgkin’s disease (lymphogranulomatosis);
• Non-Hodgkin lymphomas;
• Reticulosarcoma;
• Chronic lymphocytic leukemia;
• Brill-Symmers disease;
• Malignant brain tumors (neuroblastoma and medulloblastoma).

ICD codes

Dosage Regimen

It is administered orally, after meals. When choosing the dose and regimen for the drug in each individual case, one should refer to specialized literature.

In monotherapy, the initial dose of Natulan is 50 mg with a subsequent daily increase of 50 mg up to a daily dose of 250-300 mg. Frequency of administration is 1-3 times/day, daily for 15-20 days or until the development of leukopenia and thrombocytopenia. Upon development of a therapeutic effect, the dose is gradually reduced to a maintenance dose, usually to 150-50 mg/day. The total course dose is typically 4-7 g.

In combination with other antineoplastic drugs, Natulan is prescribed at a dose of 100 mg/m² daily for 10-14 days.

Adverse Reactions

From the hematopoietic system: leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, bleeding and hemorrhage.

From the digestive system: nausea, vomiting, anorexia, dysphagia, dry mouth, diarrhea, constipation, abdominal pain, stomatitis, impaired liver function, cholestatic jaundice.

From the central and peripheral nervous system: headache, dizziness, paresthesia, peripheral neuropathy, increased excitability, hypomanic and manic states, convulsions, hallucinations, depression, nightmares, increased fatigue, confusion, coma, weakness; rarely – ataxia.

From the sensory organs: diplopia, nystagmus, photophobia, optic nerve edema, intraocular hemorrhage, hearing loss.

From the cardiovascular system: decreased blood pressure, tachycardia, syncope.

From the respiratory system: pneumonitis, pleurisy, cough.

From the urinary system: impaired renal function, hematuria, amenorrhea, azoospermia.

Dermatological reactions: dermatitis, skin itching, rash, urticaria, alopecia, hyperpigmentation, sensation of hot flushes or facial redness.

From the musculoskeletal system: arthralgia, myalgia, tremor.

Other: immunosuppression (addition of infections), fever, gynecomastia, risk of secondary malignant tumors, allergic reactions.

Contraindications

• Bone marrow hypoplasia;
• Severe impairment of renal and/or liver function;
• Pheochromocytoma;
• Pregnancy;
• Lactation period;
• Hypersensitivity to the drug components.

With caution, the drug should be used in cases of arrhythmias and other cardiovascular diseases, diabetes mellitus, hyperthyroidism, cerebrovascular diseases, paranoid schizophrenia and other conditions accompanied by increased excitability, epilepsy, alcoholism, parkinsonism, chickenpox, herpes zoster, other systemic infections, chronic viral diseases, prior cytotoxic or radiation therapy, history of sympathectomy, and in elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation (breastfeeding).

Men and women of childbearing potential should use reliable methods of contraception during treatment with Natulan and for at least 3 months after.

Use in Hepatic Impairment

Contraindicated in cases of severe hepatic impairment.

Use in Renal Impairment

Contraindicated in cases of severe renal impairment.

Geriatric Use

With caution, the drug should be used in elderly patients.

Special Precautions

Treatment with Natulan should be carried out under the supervision of a physician experienced in the use of antineoplastic drugs.

During therapy with procarbazine, careful monitoring of hematological (before starting treatment, then every 3-4 days) and biochemical (before starting treatment, then once a week) blood parameters is necessary.

If disorders of the nervous system (paresthesia, peripheral neuropathy, confusion), leukopenia (<4000/µl), thrombocytopenia (<100,000/µl), allergic reactions, stomatitis, diarrhea, increased bleeding tendency or bleeding occur, treatment with Natulan should be stopped immediately.

During treatment, the consumption of alcohol, hypnotics (barbiturates, benzodiazepines) and sympathomimetic agents is contraindicated. Foods high in tyramine (aged cheeses, wine, beer, yeast/protein extracts, yogurt, bananas) should be excluded from the diet.

Effect on ability to drive vehicles and operate machinery

During treatment with Natulan, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: nausea, vomiting, enteritis, diarrhea, decreased blood pressure, tremor, convulsions, coma, pronounced suppression of bone marrow hematopoiesis, impaired liver function.

Treatment: induction of vomiting or gastric lavage (within the first hour after overdose), symptomatic therapy, monitoring of vital functions (during signs of overdose and for at least 2 weeks after the patient’s condition normalizes).

Drug Interactions

Concomitant use of other myelotoxic drugs and radiation therapy may cause additive suppression of bone marrow function.

Natulan increases the activity of sympathomimetics, barbiturates, antihistamines, narcotics, hypotensive drugs, tricyclic antidepressants, and phenothiazine.

Concomitant use of Natulan potentiates the action of hypoglycemic agents and anticonvulsant drugs.

Concomitant use of NSAIDs increases the risk of bleeding.

Natulan is incompatible with ethyl alcohol (a disulfiram-like reaction may develop).

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.