NATULAN^®

MIMS Revision Date: 01 October 2025

1 Name of Medicine

Procarbazine (as hydrochloride).

2 Qualitative and Quantitative Composition

Natulan contains the active component procarbazine (as the hydrochloride). Each capsule contains 50 mg procarbazine (as the hydrochloride).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsules (opaque ivory coloured with a white to yellowish fine granular powder).

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of Hodgkin's disease (multiple lymphadenoma); treatment of other malignant lymphomas including lymphosarcoma, reticulosarcoma, Brill-Symmers disease. Natulan is dissimilar to other cytostatic agents and may be effective in cases resistant to other drugs and X-rays.

4.2 Dose and Method of Administration

Initial dosage. Natulan is given by mouth, initially in small doses which are increased gradually to a maximum of 250 to 300 mg daily. Dosage is 50 mg on the first day, increasing by 50 mg daily up to 250 to 300 mg daily after 5 or 6 days. Dosage is maintained at this level until the greatest possible remission has occurred.
If during this time, leucopoenia of about 3,000/mm³ or thrombocytopaenia of about 80,000/mm³ occurs, treatment should be suspended until leucocyte and platelet levels recover and then recommenced.
Maintenance dosage. 50 to 150 mg daily until a total dose of 6 g has been given. Otherwise a negative result is not significant.
Special populations. Patients with hepatic and renal impairment. Procarbazine should be used with caution in patients with hepatic or renal impairment and is contraindicated if impairment is severe. The haematological status of the patient should be determined at least every 3 or 4 days and hepatic and renal function determined weekly (see Section 4.4 Special Warnings and Precautions for Use).
Elderly. Procarbazine should be used with caution in the elderly. Patients in this group should be observed very closely for signs of early failure or intolerance to treatment (see Section 4.4 Special Warnings and Precautions for Use).
Paediatric patients. The treatment and the maintenance doses of procarbazine should be determined only by a physician experienced in the use of potent antineoplastic drugs in children (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Patients with known hypersensitivity to the active substance or any of the listed excipients. If allergic skin reactions occur, treatment must be stopped.
Pre-existing leucopoenia or thrombocytopenia; severe hepatic or renal damage.
Pregnancy and breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.4 Special Warnings and Precautions for Use

Identified precautions. It is recommended that procarbazine be given only under supervision of a physician experienced in the use of potent antineoplastic drugs.
Bone marrow depression may occur, and full blood count, liver and renal function tests should be performed prior to each cycle of administration of procarbazine.
The immunosuppressant effect of procarbazine may increase the risk of infections caused by pathogenic or opportunistic microorganism, may reduce the response to vaccines, and there is a possibility of generalised infection with live vaccines. Use of live vaccines should generally be avoided.
Secondary non-lymphoid malignancies such as acute myeloid leukaemia and lung cancer have occurred in patients with Hodgkin's disease receiving procarbazine in combination with other chemotherapy and/or radiation therapy. Discontinuation of treatment with procarbazine should be considered if the following situations occur:
Leucopenia, thrombocytopenia;
CNS symptoms such as paraesthesia, neuropathy or state of confusion;
Hypersensitivity reactions;
Diarrhoea;
Stomatitis;
Vomiting.
If allergic skin reactions occur, treatment should be interrupted. Intolerance to alcohol may develop and abstinence may be advisable during therapy.
Care is also advisable in patients with phaeochromocytoma, epilepsy, or cardiovascular or cerebrovascular.
Use in renal and hepatic impairment. The haematological status must be monitored twice a week and hepatic and renal function at least once a week. Increased toxicity has been reported in patients with decreased renal and/or hepatic function. Therapy initiation in hospital should be considered in these patients (see Section 4.2 Dose and Method of Administration). Procarbazine is contraindicated if impairment is severe (see Section 4.3 Contraindications).
Use in the elderly. There is no specific data in the elderly. The use of antineoplastic agents in the elderly should take into consideration age-related physiological changes including decline in renal and hepatic function, reduced haematopoietic reserve, and reduced gastrointestinal and cardiac function. Other factors to consider are comorbid conditions and potential drug interactions with associated medications. (See Section 4.2 Dose and Method of Administration.)
Paediatric use. Increased toxicity has been reported in children, including tremors, coma and convulsions (see Section 4.2 Dose and Method of Administration).
Effects on laboratory tests. No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Natulan is a weak monoamine oxidase inhibitor (MAOI); it may thus potentiate barbiturates, and sympathomimetic and psychotropic agents.
Patients should be advised to avoid cheese, yoghurt, bananas, and other foods high in sympathomimetic amines during treatment. Patients may become intolerant to alcohol, and abstinence is advised during the course of therapy.
Avoid concomitant use of: sympathomimetic drugs; decongestants.
Due to potentiation, the following drugs should be used with caution and in reduced dosage:
CNS depressants (anaesthetics, barbiturates, narcotic analgesics);
Drugs with anticholinergic effects (including tricyclic antidepressants);
Phenothiazines;
Antihypertensive agents.
Use of procarbazine with enzyme-inducing antiepileptics is associated with an increased risk of hypersensitivity reactions, possibly through a reactive intermediate generated by induction of the cytochrome P450 isoenzyme CYP3A subfamily. In patients with brain tumours who are treated with procarbazine, use with non-enzyme-inducing antiepileptics might be more appropriate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. Before starting treatment with procarbazine, both male and female patients must be informed about the risk of sterility. Permanent azoospermia and sterility have been reported.
Use in pregnancy. (Category D)
Contraindicated (see Section 4.3 Contraindications).
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying text above should be consulted for further details.
Procarbazine is teratogenic in animal studies. There have been reports of malformations in babies born to women exposed to procarbazine, miscarriages, premature births and underweight babies. Women of childbearing potential must not become pregnant during treatment with procarbazine.
Use in lactation. It is not known whether procarbazine enters breast milk, but mothers should not breast feed when taking the drug (see Section 4.3 Contraindications).
Contraception. During treatment, both men and women should be informed of recognised methods of contraception. These contraceptive measures should be taken for up to 6 months for males and 9 months for females after the end of treatment.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned of the possibility of dizziness and somnolence (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Gastrointestinal upsets and bone marrow depression are most prominent. Anorexia and nausea occur in most cases, sometimes with vomiting; these symptoms are usually confined to the first few weeks of treatment. Leucopenia and thrombocytopenia are almost always reversible and seldom require complete cessation of therapy. Alopecia may occur, this is reversible in the majority of cases. There have also been reports of neurological disorders (headache, paresthesias, neuropathy and ataxia), disturbances of liver function (cholestatic jaundice) and allergic skin reactions (rash, urticaria, pruritus) and azoospermia.
The adverse reactions are listed below, based on experience from clinical trial and post marketing surveillance safety data. Within the MedDRA system organ classification, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10), common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infection and infestations. Common. Infection.
Not known. Sepsis, herpes zoster, pneumonia, influenza, urinary tract infection, nasopharyngitis.
Neoplasm benign, malignant and unspecified. Not known. Acute myeloid leukaemia, myelodysplastic syndrome, second primary malignancies.
Blood and lymphatic system disorders. Common. Thrombocytopenia, leucopenia, anaemia.
Not known. Bone marrow failure, pancytopenia, febrile neutropenia, eosinophilia.
Immune system disorders. Uncommon. Hypersensitivity (including anaphylaxis, angioedema).
Metabolism and nutrition disorders. Common. Anorexia.
Psychiatric disorders. Not known. Insomnia, depression, confusion, mental status changes, lethargy.
Nervous system disorders. Not known. Seizures, neuropathy peripheral, paraesthesia, hypoaesthesia, dizziness, headache, tremor, somnolence.
Eye disorders. Not known. Visual disturbance (including vision blurred and visual impairment).
Cardiac disorders. Not known. Congestive heart failure, cardiac disorder.
Vascular disorders. Not known. Thrombosis, hypotension, haemorrhage.
Respiratory, thoracic and mediastinal disorders. Not known. Interstitial lung disease, pleural effusion, pneumonitis, dyspnoea, oropharyngeal pain, cough.
Gastrointestinal disorder. Common. Nausea, vomiting, loss of appetite.
Not known. Stomatitis, constipation, diarrhoea, abdominal pain upper, abdominal pain, abdominal discomfort, dyspepsia.
Hepato-biliary disorders. Not known. Hepatotoxicity, hepatitis, jaundice, abnormal liver function tests.
Skin and subcutaneous tissue disorders. Common. Alopecia.
Not known. Stevens-Johnson syndrome; toxic epidermal necrolysis, toxic skin eruption, rash generalised, rash, urticaria, pruritus.
Musculoskeletal, connective tissue, and bone disorders. Not known. Osteonecrosis, myalgia, back pain, arthralgia, pain in jaw, bone pain.
Renal and urinary disorders. Not known. Renal failure, acute kidney injury.
Reproductive system and breast disorders. Not known. Permanent azoospermia, ovarian failure.
General disorders and administration site conditions. Not known. Pain, pyrexia, fatigue, malaise, asthenia.
*Late toxicity includes secondary malignancies (acute myeloid leukemia, non-lymphoid leukemia, non-Hodgkin's lymphoma), solid tumours (lung, GI tract, pancreas, liver, head and neck, breast, ovarian, cutaneous, teratoma testes). The number of patients suffering from late toxicities may increase over time.
Paediatric population. Although the safety profile between paediatric patients and adults is expected to be similar, increased toxicity has been reported in children (see Section 4.4 Special Warnings and Precautions for Use).
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The following ADRs have been reported with overdose of procarbazine: nausea, vomiting, enteritis, diarrhoea, hypotension, tachycardia, tremors, dizziness, hallucinations, depression, bone marrow suppression, convulsions, coma.
Treatment. Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
General supportive treatment should be performed, with prophylactic treatment against possible infection, and frequent blood counts weekly for at least 3 weeks, or more frequently if unwell or clinically symptomatic from myelosuppression (evidence of bleeding or infection).
Consider further haematological monitoring after 3 weeks only if white cells and platelets not recovering (discuss with haematologist/ oncologist).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Natulan is a derivative of methylhydrazine with cytostatic properties.
Clinical trials. No data available.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

Genotoxicity. No data available.
Carcinogenicity. No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, maize starch, purified talc, magnesium stearate, iron oxide yellow, titanium dioxide and gelatin.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store bottle below 30°C in a dry place. *Not currently marketed in Australia.
Store blister pack below 25°C in a dry place.

6.5 Nature and Contents of Container

Glass type III coloured (amber) bottle of 50 capsules. *Not currently marketed in Australia.
Al/ Al foil blister pack of 50 capsules.

6.6 Special Precautions for Disposal

Urine produced for up to 48 hours after a dose of procarbazine should be handled wearing protective clothing.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Procarbazine hydrochloride is a white to pale yellow crystalline powder with a slight odour.
Procarbazine is sensitive to oxidation. It is very soluble in water and methanol and freely soluble in chloroform and diethyl ether.
Chemical structure.

N-1(1-methylethyl)-4-[(2-methylhydrazino)methyl]benzamide monohydrochloride.
Molecular formula: C₁₂H₁₉N₃O.HCl.
Molecular weight: 257.59.
CAS number. 366-70-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Date of Revision

22 August 2025

Summary Table of Changes