Procarbazine Capsules USP 50mg Taj Pharma

1. Name of the medicinal product

Procarbazine Capsules USP 50mg Taj Pharma

2. Qualitative and quantitative composition

Each capsule contains:
Procarbazine Hydrochloride USP
Equivalent to Procarbazine                50mg
Excipients                                            q.s.
Colours: Approved colours use for capsule shells.

For a full list of excipients, see section 6.1

3. Pharmaceutical form

Capsules.

4. Clinical particulars

4.1 Therapeutic indications

The main indication is Hodgkin’s disease (lymphadenoma).

Procarbazine may also be useful in other advanced lymphomata and a variety of solid tumours which have proved resistant to other forms of therapy.

Children

Procarbazine is indicated in the treatment of Hodgkin’s lymphoma in children aged 2-18, when associated with other antineoplastic drugs in an appropriate protocol.

4.2 Posology and method of administration

In combination chemotherapeutic regimens:

Procarbazine is usually administered concomitantly with other appropriate cytostatic drugs in repeated four- to six-weekly cycles. In most such combination chemotherapy regimens currently in use (eg. the so-called MOPP schedule with mustine, Vincristine and Prednisone) Procarbazine is given daily on the first 10 – 14 days of each cycle in a dosage of 100mg per sq. metre of body surface (to nearest 50mg).

As sole therapeutic agent: Adults:

Treatment should begin with small doses which are increased gradually up to a maximum daily dose of 250 or 300mg divided as evenly as possible throughout the day.

Initial dosage scheme

Further procedure:

Treatment should be continued with 250 or 300mg daily until the greatest possible remission has been obtained, after which a maintenance dose is given.

Maintenance dose:

50 -150mg daily. Treatment should be continued until a total dose of at least 6g has been given. Otherwise, a negative result is not significant.

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 of treatment.

Children:

The pro m2 dose used in most published trials was analogous to the dose used in adults (100 mg/ m2 for up to 14 days).

The dose should be adjusted according to:

• The chemotherapy protocol used
• The functional state of the bone marrow
• Previous chemo- and radiotherapy cycles
• The myelosuppressive effect of other cytostatics used

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.

Procarbazine capsules are for oral administration.

4.3 Contraindications

Pre-existing severe leucopenia or thrombocytopenia from any cause; severe hepatic or renal damage.

Procarbazine should not be used in the management of non-malignant disease.

Procarbazine is contraindicated during the first trimester of pregnancy and during breast-feeding (see section 4.6).

Hypersensitivity to the active substance (Procarbazine) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Procarbazine should be given only under the supervision of a physician who is experienced in cancer chemotherapy and having facilities for regular monitoring of clinical and haematological effects during and after administration.

Introduction of therapy should only be effected under hospital conditions.

Caution is advisable in patients with hepatic or renal dysfunction and Procarbazine should be avoided in patients with severe hepatic or renal disease. Its use should be avoided if creatinine clearance is less than 10mL/min. Caution is also advised in cardiovascular or cerebrovascular disease, phaeochromocytoma, or epilepsy.

Regular blood counts are of great importance due to the possibility of bone-marrow suppression. If during the initial treatment the total white cell count falls to 3,000 per mm³ or the platelet count to 80,000 per mm³, treatment should be suspended temporarily until the leucocyte and/or platelet levels recover, when therapy with the maintenance dose may be resumed.

Treatment should be interrupted on the appearance of allergic skin reactions.

Live vaccines should not be given during or within at least 6 months of treatment with immunosuppressive chemotherapy or radiotherapy for malignant disease.

4.5 Interaction with other medicinal products and other forms of interaction

Procarbazine is a weak MAO inhibitor and therefore interactions with certain foodstuffs and drugs, although very rare, must be borne in mind. Thus, owing to possible potentiation of the effect of barbiturates, narcotic analgesics (especially Pethidine), drugs with anticholinergic effects (including phenothiazine derivatives and tricyclic antidepressants), other central nervous system depressants (including anaesthetic agents) and anti-hypertensive agents, these drugs should be given concurrently with caution and in low doses.

Cytotoxics may reduce the absorption of phenytoin and cardiac glycosides.

Concomitant use of clozapine may increase the risk of agranulocytosis. Use with enzyme-inducing antiepileptics is associated with an increased risk of hypersensitivity reactions to procarbazine.

Intolerance to alcohol (Disulfiram-like reaction) may occur.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use of Procarbazine is contraindicated during the first trimester of pregnancy, and should be avoided throughout the remainder of the gestational period.

Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown. There are no adequate data from the use of Procarbazine in pregnant women, however isolated human foetal malformations have been reported following MOPP combination therapy.

Breast-feeding

Procarbazine is contraindicated during breast-feeding.

Fertility

Procarbazine has been reported to cause azoospermia and ovarian failure, which may be irreversible. It is extremely important that the patient is provided with appropriate information and advice, particularly as men may wish to have semen saved for use after Procarbazine treatment (see section 4.8).

4.7 Effects on ability to drive and use machines

Patients should be warned of the possibility of lethargy (see section 4.8 Undesirable effects).

4.8 Undesirable effects

Tabulated list of adverse reactions

Undesirable effects are listed by MedDRA System Organ Classes.

Assessment of undesirable effects is based on the following frequency groupings:

Very common: ≥1/10

Common: ≥1/100 to <1/10

Uncommon: ≥1/1,000 to <1/100

Rare: ≥1/10,000 to <1/1,000

Very rare: <1/10,000

Not known: cannot be estimated from the available data

Description of selected adverse reactions

Leucopenia and thrombocytopenia are almost always reversible and seldom require complete cessation of therapy.

Loss of appetite, nausea and vomiting are usually confined to the first few days of treatment and then tend to disappear.

Azoospermia and ovarian failure may be irreversible. It is extremely important that the patient is provided with appropriate information and advice, particularly as men may wish to have semen saved for use after Procarbazine treatment.

Procarbazine is carcinogenic and an increased incidence of acute myelogenous leukaemia has been reported in patients receiving MOPP chemotherapy for Hodgkins disease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs of overdosage include severe nausea and vomiting, dizziness, hallucinations, depression and convulsions; hypotension or tachycardia may occur.

The benefit of gastric decontamination is uncertain. Consider activated charcoal if the patient presents within 1 hour of ingestion of any amount (because of risk of myelosuppression at all doses).

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).

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Methylhydrazines, ATC Code: L01XB01

Procarbazine, a methylhydrazine derivative, is a cytostatic agent with weak MAO inhibitor properties. Its exact mode of action on tumour cells is unknown. It may be effective in patients who have become resistant to radiation therapy and other cytostatic agents.

Children:

Procarbazine in combination with other anti-tumour agents has been investigated in uncontrolled studies in children with brain tumours. Favourable partial responses, complete responses and survival rates have been documented. Paediatric data from randomised controlled clinical studies are limited.

5.2 Pharmacokinetic properties

Absorption

Procarbazine is readily absorbed from the gastrointestinal tract.

Distribution

Peak plasma levels are reached at 0.5-1 hour after oral administration. Procarbazine quickly equilibrates between the blood and cerebrospinal fluid (CSF). Peak CSF levels are achieved 30-90 minutes after oral administration.

Biotransformation

Procarbazine is rapidly metabolised, the primary circulating metabolite is the azo derivative while the major urinary metabolite has been shown to be N-isopropyl-terephthalamic acid.

Elimination

A plasma half-life of about 10 minutes has been reported.

Approximately 5% of procarbazine is excreted unchanged in the urine. The remainder is oxidised to N-isopropylterephthalamic acid and excreted in the urine, up to about 70% of a dose being excreted in 24 hours. Some of the drug is excreted as carbon dioxide and methane via the lungs.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, other that already included in other sections of the SPC.

6. Pharmaceutical particulars

6.1 List of excipients

Mannitol, Maize starch, Talc, Magnesium stearate, Gelatin, Titanium dioxide , Shellac, Propylene glycol, Ammonium hydroxide, Black iron oxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Three years.

6.4 Special precautions for storage

Store in a dry place. Do not store above 25°C

6.5 Nature and contents of container

Blister packs of 50 capsules.

6.6 Special precautions for disposal and other handling

Handling guidelines:

Undamaged capsules present minimal risk of contamination, but in accordance with good hygiene requirements, direct handling should be avoided. As with all cytotoxics, precautions should be taken to avoid exposing staff during pregnancy.

Urine produced for up to 48 hours after a dose of procarbazine should be handled wearing protective clothing.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Procarbazine Capsules USP 50mg Taj Pharma

Package leaflet: Information for the patient

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 signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Procarbazine 50mg Capsules are and what they are used for
   2. What you need to know before you take Procarbazine 50mg Capsules
   3. How to take Procarbazine 50mg Capsules
   4. Possible side effects
   5. How to store Procarbazine 50mg Capsules
   6. Contents of the pack and other information
2. What Procarbazine 50mg Capsules are and what they are used for

Procarbazine is one of the group of medicines known as alkylating agents, which interfere with the growth of certain types of cells in the body.

Procarbazine is used as one of the chemotherapy drugs in the treatment of some cancers.

In adults, Procarbazine is used on its own or in combination with other drugs in the treatment of cancers such as Hodgkin’s disease (a cancer of the lymph glands).

In children (aged 2-18 years), Procarbazine is used in combination with other drugs in the treatment of Hodgkin’s disease.

2. What you need to know before you take Procarbazine 50mg Capsules

Do not take Procarbazine 50mg Capsules:

• if you are allergic to procarbazine or any of the other ingredients of this medicine (listed in section 6)
• if you have anything wrong with your blood, in particular, too few white cells or platelets (your doctor will be able to advise you).
• if you suffer from any severe kidney or liver disorder
• if you have a non-cancerous tumour
• if you are in the first trimester of pregnancy
• if you are breast-feeding

Make sure your doctor knows if any of the above applies to you.

Warnings and precautions

Talk to your doctor before taking Procarbazine 50mg Capsules:

• if you suffer from any kidney or liver disorder
• if you have any disorder of the heart or circulation
• if you are, or could be, pregnant or may want to become pregnant in the future (for further information refer to the following sections of this leaflet: ‘Do not take Procarbazine 50mg Capsules’ and ‘Pregnancy, breast-feeding and fertility’)
• if you have a tumour on the adrenal gland (near the kidney), causing high blood pressure
• if you suffer from epilepsy
• if you have had a stroke

Some types of vaccinations should not be given to you during or within at least six months of treatment with chemotherapy drugs such as procarbazine. Your doctor will be able to advise you on this. If you need any other medical treatment or surgery whilst taking Procarbazine 50mg Capsules, remember to tell the doctor or dentist treating you that you are taking this medicine.

Try to avoid people with infections whilst taking procarbazine. Check with your doctor immediately if you get a cough, cold, or any other infection.

Other medicines and Procarbazine 50mg Capsules

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

In particular, check with your doctor or pharmacist if you are taking any of the following:

• strong painkillers (especially Pethidine)
• medicines for anxiety or difficulty in sleeping
• anticholinergic medicines, these include some medicines used for irritable bowel syndrome, asthma or incontinence
• medicines for depression
• medicines for high blood pressure or for your heart
• anaesthetic products
• medicines for epilepsy
• clozapine (an anti-psychotic medication)

It is safe to use plain Paracetamol or Aspirin without speaking to your pharmacist.

Procarbazine 50mg Capsules with food, drink and alcohol

Certain foods, drinks and medicines may cause an unpleasant reaction if taken whilst you are being treated with Procarbazine 50mg Capsules or during the two weeks after the course of treatment is completed. The most important foods and drinks that might cause such an effect are:

Mature cheeses (including processed cheeses), yeast or meat extracts (such as Marmite, Oxo and Bovril), broad bean pods, pickled herring, salami sausage, pepperoni sausage, bologna sausage, overripe fruit, alcoholic drinks (especially heavy red wines such as Chianti), non-alcoholic beers, lagers and wines and other foods which are not fresh, particularly if they have been fermented, pickled, smoked, ‘hung’ or ‘matured’.

These reactions are extremely rare and if you want to eat or drink anything on the list you could try a little at a time, until you are sure that it does not upset you. However, it is best to avoid alcohol altogether.

Pregnancy, breast-feeding and fertility

If you are pregnant, think you might be pregnant, are planning to become pregnant or are breast-feeding, you should tell your doctor.

Pregnancy

Procarbazine should not be taken during the first trimester of pregnancy. Its use should also be avoided throughout the remainder of the pregnancy period.

Breast-feeding

Do not take Procarbazine if you are breast-feeding.

Fertility

Procarbazine may cause infertility which might mean that you are not able to have children.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Procarbazine can cause drowsiness. If affected you should not drive or use machinery.

3. How to take Procarbazine 50mg Capsules

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Procarbazine is usually given in combination with other drugs and it is important that you (or your child) take each medicine at the right time. Sometimes treatment starts with a small dose (1 capsule per day) and is increased each day up to a maximum of six capsules per day.

If you take more Procarbazine 50mg Capsules than you should

If you swallow too many capsules or someone else accidentally takes your medicine, contact your doctor, pharmacist or nearest hospital straight away. Overdose can cause severe vomiting and feeling sick, dizziness, imagining sensations (hallucinations), depression, fits, low blood pressure and increased pulse rate.

If you forget to take Procarbazine 50mg Capsules

If you miss a dose, take it as soon as you remember unless your next dose is due within a couple of hours. In this case you should skip the missed dose, go back to your regular dosing schedule and check with your doctor. Do not take a double dose to make up for a forgotten capsule. The same applies if you forget to give a dose to your child at the right time.

After taking Procarbazine 50mg Capsules

Patients and carers should use gloves when handling urine or vomit produced for up to 48 hours after a dose of procarbazine has been taken.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

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

All medicines can cause allergic reactions although serious allergic reactions are very rare. Any sudden wheeziness, difficulty in breathing, swelling in any part of the body, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.

Procarbazine may cause the following side effects:

• Infertility, which might mean that you are not able to have children
• Skin rash or any unusual bleeding or bruising. If you (or your child) develop these side effects, check with your doctor as soon as possible
• Nausea and vomiting. Do not stop taking procarbazine if it makes you (or your child) sick in the first few days, as this side effect should disappear. However if it is very bad, or if vomiting occurs shortly after taking a dose, check with the hospital or your own doctor who will tell you what to do. It may be possible to reduce this unpleasant effect
• Liver disorder. If you (or your child) develop signs of liver disorder which include persistent vomiting, feeling sick, feeling tired and yellowing of the skin or the whites of the eyes (jaundice) you should stop treatment and contact your doctor immediately
• Loss of appetite, especially at the start of treatment. This usually improves after a few days
• Lowering of your white blood cell count. Common symptoms include infections, lack of energy, headache, fever and irritability
• Drowsiness and a lack of enthusiasm
• Inflammation of lung tissue. Symptoms include shortness of breath, cough, and a burning sensation in the chest.

Procarbazine in combination with other chemotherapy drugs has been associated with an increased occurrence of a rare cancer of the blood cells.

It is very important that you keep all hospital appointments whilst taking procarbazine so that your progress can be checked.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Procarbazine 50mg Capsules

Keep this medicine out of the sight and reach of children – preferably in a locked cupboard or medicine cabinet.

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

In order that Procarbazine 50mg Capsules are always clearly identified they should not be removed from their blister packaging until you are ready to take them. Do not mix loose Procarbazine 50mg Capsules with other loose capsules or tablets. Store in the original container in order to protect from moisture. Do not store above 25°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Procarbazine 50mg Capsules contain

The active substance is procarbazine hydrochloride. There is 50mg of procarbazine in each capsule. The other ingredients are mannitol, maize starch, talc and magnesium stearate. The capsule shells are made from gelatin, and also titanium dioxide, shellac, propylene glycol, ammonium hydroxide and black iron oxide.

What Procarbazine 50mg Capsules look like and contents of pack

Procarbazine 50mg Capsules are produced in blister strips, each pack contains 50 capsules.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).