NATULAN 50 mg HARD CAPSULES

Introduction

Package Leaflet:information for the patient

Natulan 50 mg hard capsules

procarbazine

Read all of this leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Natulan and what is it used for
2. What you need to know before you take Natulan
3. How to take Natulan
4. Possible side effects

5 Storage of Natulan

1. Contents of the pack and further information

1. What is Natulan and what is it used for

Natulan contains the active substance procarbazine. Procarbazine is a medicine used to treat cancer (a cytotoxic systemic medicine). It works by killing cancer cells. This is also known as "chemotherapy".

Adults Natulan is indicated in combination chemotherapy for the treatment of Hodgkin's lymphoma. This medicine is also indicated as part of combination chemotherapy in other advanced lymphomas and brain tumors.

Children and adolescents Natulan, when combined with other anti-cancer treatments, is indicated for the treatment of Hodgkin's lymphoma in children between 2 and 18 years old.

2. What you need to know before you take Natulan

Do not take Natulan

• if you are allergic to procarbazine or any of the other ingredients of this medicine (listed in section 6).
• if you have a severe disorder of bone marrow function (bone marrow depression) and severe alterations in the number of white blood cells and platelets in the blood
• if kidney and/or liver function is severely impaired.
• during pregnancy or breastfeeding

Warnings and precautions

Talk to your doctor or pharmacist before starting Natulan.

• Procarbazine may have effects on your blood and immune system. Blood cells are produced in your bone marrow. These cells are of three types:
• • red cells, which carry oxygen in the body,
  • white cells, which fight infections, and
  • platelets, which allow blood to clot.
• After receiving this medicine, the value of blood cell count will decrease. Therefore, your doctor will monitor your blood counts before, during, and after administration of this medicine.
• Prior to treatment, liver and kidney function will be evaluated and monitored periodically during treatment.
• During treatment with this medicine, fever, bleeding, or superficial bleeding on the skin may occur due to the reduction of blood cells. If this happens, you should immediately inform your doctor.
• If you experience gastrointestinal discomfort with nausea and vomiting, consult your doctor immediately.

Children and adolescents

Natulan is always administered to children and adolescents at the same dose as for adults in combination with other anti-cancer medicines. Your doctor will determine the necessary dose for your child.

Other medicines and Natulan

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Some medicines may alter the effect of Natulan, or Natulan may affect the efficacy of other medicines administered at the same time.

Procarbazine enhances the effect of the following drugs:

• Oral anti-diabetic agents (medicines for diabetes taken orally) and insulin: as these may reduce your blood sugar level more than usual when used with this medicine, low blood sugar levels may occur.
• Antihistamines (for the treatment of allergic discomfort)
• Barbiturates (sleep inducers and narcotics)
• Blood pressure lowering medicines
• Narcotics
• Phenothiazines (medicines for the treatment of mental disorders or tranquilizers)

As procarbazine is a weak monoamine oxidase (MAO) inhibitor, interactions are possible with drugs that induce a reaction of the autonomic nervous system such as:

• sympathomimetics (to stimulate the autonomic nervous system)
• anti-asthmatics (for the treatment of asthma)
• anti-inflammatory nasal drops/sprays
• medicines that increase blood pressure
• tricyclic antidepressants (amitriptyline, imipramine)
• serotonin reuptake inhibitors (SSRIs, for the treatment of depression, e.g., sertraline)

Allopurinol may prolong the effect of procarbazine.

No interaction studies have been performed with medicines such as ketoconazole or rifampicin, so caution should be exercised when using them in combination with procarbazine.

Taking Natulan with food, drinks, and alcohol

Simultaneous intake of procarbazine and foods with high tyramine content may cause hypertensive crises. Therefore, cheese, cheese spread, yogurt, drinks containing methylxanthine (coffee, black tea, cola), alcoholic beverages (beer, wine, vermouth, sherry, port), chocolate, dry sausages (salami), meat, liver, yeast or yeast extracts, broad beans, beans, overripe fruit, avocado, bananas, figs, herring, smoked or marinated meats or fish, as well as meats or fish that are no longer fresh, should be avoided.

Alcohol and alcoholic beverages combined with procarbazine may cause a reaction that involves hot flashes, including skin redness, particularly on the face (flushing), increased heart rate, sweating, decreased blood pressure, headache, and difficulty breathing (disulfiram syndrome). Therefore, alcohol consumption should be completely avoided during the entire therapy.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist.

Pregnancy

Procarbazine may cause genetic damage and may harm the fetus. You should not use this medicine during pregnancy unless your doctor considers it clearly necessary. If you receive this treatment, you should ask your doctor to explain the risk of possible adverse effects of the treatment for your child, and genetic counseling is recommended.

Women must not become pregnant during treatment with procarbazine.

If you become pregnant during treatment, genetic counseling is recommended.

Breastfeeding

This medicine should not be administered during breastfeeding. If you need treatment with procarbazine during breastfeeding, you should stop breastfeeding.

Fertility

Before starting treatment with procarbazine, both male and female patients should be informed about the risk of permanent infertility (sterility).

Men treated with procarbazine should use contraceptive methods during treatment and up to 3 months after the end of treatment. Due to the possibility of irreversible infertility after treatment with procarbazine, you should consult your doctor regarding sperm preservation.

Women should not become pregnant during treatment with procarbazine. They should use recognized contraceptive methods during treatment and up to 6 months after the end of treatment with this medicine.

Driving and using machines

As procarbazine can cause nausea and vomiting, it may indirectly affect the ability to drive and use machines. If you feel dizzy or drowsy, do not drive or work with machinery until these effects have disappeared.

3. How to take Natulan

As a rule, procarbazine should only be prescribed by doctors with sufficient medical-oncological or hematological experience and according to an adequate chemotherapy protocol for their disease. This applies in particular to its use in children and adolescents.

Follow the instructions for administration of this medicine exactly as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Dosage

Dosage of procarbazine in combination with other chemotherapeutic agents:

The usual dose in most combinations is 100 mg/m2/day for 10 to 14 days of each cycle of 4 to 6 weeks. The dose should be adjusted according to the chemotherapy protocol used.

Dosage of procarbazine as monotherapy:

Adults

Start with 50 mg on the first day, then progressively increase by 50 mg each day until a dose of 250 to 300 mg/day is reached.

Treatment should be continued with a dose of 250 or 300 mg/day until the most complete possible remission is achieved, after which a maintenance dose will be administered. A dose of 50 to 150 mg/day will be administered as a maintenance dose. Treatment should be continued until a total dose of at least 6 g has been administered.

Pediatric population (2 to 18 years)

The dose used in most published clinical trials was analogous to that used in adults (100 mg/m2/day for up to 14 days). The available data are limited. The dosage in children should be adapted individually and with strict clinical control.

The dose should be adjusted according to:

• The chemotherapy protocol used.
• The functional state of the bone marrow.
• Previous chemotherapy and radiotherapy cycles.
• The myelosuppressive effect (reduction of blood cells) of other cytostatics used.
• Treatment should be temporarily interrupted if the white blood cell count is below 3,000 mm3 and/or platelets are below 80,000 mm3, and it may be restarted when levels recover. The patient's hematological status should be determined at least every 3 or 4 days.

Special populations

Patients with hepatic and renal impairment:

Procarbazine should be used with caution in patients with hepatic or renal impairment and is contraindicated in case of severe impairment (see section 4.3). Liver and kidney function should be determined weekly.

Elderly patients:

Procarbazine should be administered with caution in elderly patients. Patients in this group should be closely monitored to identify signs of early failure or intolerance to treatment.

Method of administration

Procarbazine capsules are for oral administration. The capsules should not be opened, broken, or chewed. The capsules should be taken whole, with a glass of water, with or without food.

If you take more Natulan than you should

If you or anyone else takes too much of this medicine, tell your doctor immediately or go to the casualty department of the nearest hospital. Please remember to take this medicine pack or this leaflet with you.

Especially in patients with limited bone marrow reserve, an overdose of procarbazine may cause severe functional impairment or deterioration of the bone marrow. In this case, supportive treatment measures, such as antibiotic treatment and platelet replacement, may be required in a specialized oncology intensive care unit, depending on the severity of the symptoms.

The following events have been reported in association with procarbazine overdose: dizziness, nausea, vomiting, diarrhea, decreased blood pressure, palpitations, tremors, hallucinations, depression, bone marrow failure, convulsions, coma, and cramps.

During recovery and for at least two weeks thereafter, both the blood count and liver function should be monitored at regular intervals. Infection prophylaxis should be considered. Furthermore, the decision to continue specific treatment should be made based on blood values.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone: 91 562 04 20 (indicating the medicine and the amount ingested).

If you forget to take Natulan

Do not take a double dose to make up for forgotten doses. If you forget to take this medicine once, you should continue taking it as described in the dosing instructions without taking an additional dose.

However, you should talk to your doctor, especially if you forget to take several doses. Your doctor will decide how to proceed with taking the medicine.

If you stop taking Natulan

Procarbazine often causes nausea and vomiting. Do not stop treatment with Natulan, even if you start to feel unwell. If this happens, you should immediately inform your doctor. He will take the necessary measures to make the unwanted symptoms that accompany therapy more bearable.

Tell your doctor if you vomit shortly after taking Natulan. He will then decide whether you should take an additional dose or wait until the next regular dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following list of adverse reactions includes all known adverse reactions during treatment with procarbazine. Natulan is a medicine that can kill cancer cells but also attacks normal cells, so it can have a series of side effects.

Your doctor will not give you Natulan unless he is convinced that your cancer poses a greater risk to you than the possible side effects of treatment. Your doctor will examine you regularly and treat any side effects whenever possible.

Tell your doctor immediately if you notice any of the following serious side effects:

The most frequent serious reactions of procarbazine are hair loss (alopecia), gastrointestinal disorders such as weight loss (anorexia), nausea, and vomiting, and bone marrow depression (reduction of blood cells).

Due to its effects on different types of white blood cells, many cancer medicines, including procarbazine, cause a deep suppression of normal immunity, and patients may have a much higher risk of developing serious and diverse infections.

The assessment of side effects is based on the following frequencies:

Frequent: affects less than 1 in 10 patients treated

• infections;
• decrease in blood cell count (red cells, platelets, white cells);
• anorexia (loss of appetite);
• nausea;
• vomiting;
• alopecia;

Uncommon: affects more than 1 in 1000 patients

• hypersensitivity (including anaphylaxis, angioedema)

Frequency not known (cannot be estimated from the available data)

• sepsis, herpes zoster, pneumonia, urinary tract infection, nasopharyngitis;
• acute myeloid leukemia, myelodysplastic syndrome, secondary primary neoplasms;
• bone marrow failure, abnormal blood cell count (decrease or increase) (red cells, white cells, platelets);
• depression, confusion;
• seizures, peripheral neuropathy, paresthesia, headaches;
• visual disturbances (including blurred vision and visual impairment);
• bleeding;
• pulmonary diseases, dyspnea, cough;
• stomatitis, constipation, diarrhea, abdominal pain;
• hepatotoxicity, hepatitis, jaundice (increased bilirubin);
• Stevens-Johnson syndrome, toxic epidermal necrolysis, skin rash, urticaria;
• osteonecrosis, myalgia;
• azoospermia (sometimes permanent), sterility;
• pain, fever, fatigue, general malaise, feeling of lack of energy or vitality.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines (www.notificaRAM.es). By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Natulan

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of the month shown.

Do not store above 25°C.

Store in the original package to protect from moisture.

Medicines should not be disposed of via wastewater or household waste. Return the containers and any unused medicine to a pharmacy for disposal. Ask your pharmacist how to dispose of containers and any unused medicine. This will help protect the environment.

6. Container Content and Additional Information

Natulan Composition

The active ingredient is: procarbazine

Each hard capsule contains 58.3 mg of procarbazine hydrochloride (corresponding to 50 mg of procarbazine).

The other components are:

Capsule content: mannitol (E 421), talc, corn starch, magnesium stearate.

Capsule shell: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172).

Product Appearance and Container Content

Natulan are hard capsules of a yellowish-beige color available in brown glass bottles with an HDPE screw cap with a desiccant that contain 50 hard capsules.

Marketing Authorization Holder and Manufacturer

Leadiant GmbH

Liebherrstasse 22

80538 Munich

Germany

Further information about this medicinal product can be obtained by contacting the local representative of the marketing authorization holder:

Medicare Pharma, S.L.,

Ctra. Fuencarral, 22,

28108, Alcobendas,

Madrid

Date of the last revision of thisleaflet:August 2024

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

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