Consumer medicine information

Daraprim Tablets

Pyrimethamine

BRAND INFORMATION

Brand name

Daraprim Tablets

Active ingredient

Pyrimethamine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Daraprim Tablets.

What is in this leaflet?

Please read this leaflet carefully before you take Daraprim tablets.

This leaflet answers some common questions about Daraprim tablets. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the expected benefits of you taking Daraprim tablets against the risks this medicine could have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What are Daraprim tablets used for?

Daraprim tablets are used:

  • to treat toxoplasmosis infections when taken with another antibiotic called a sulphonamide together with a folic acid supplement.

Daraprim belongs to a group of medicines called antiprotozoals, which are used against infections of the blood caused by the parasites called Plasmodium which causes a disease called toxoplasmosis.

Daraprim tablets work by disrupting the way that proteins and genetic material are made inside the parasites.

Your doctor may have prescribed Daraprim tablets for another reason. Please ask your doctor why Daraprim has been prescribed for you.

Daraprim tablets are not addictive.

Before you take Daraprim tablets

Do not take if:

You must not take Daraprim tablets if:

  • you have ever had an allergic reaction to pyrimethamine or any of the ingredients listed toward the end of this leaflet. (See “Ingredients”).
  • the expiry date (EXP) printed on the pack has passed.
  • the packaging is torn or shows signs of tampering.

Tell your doctor if:

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines.
  • you have kidney, liver or blood disease (anaemia).
  • you have previously been diagnosed as having a low level of folic acid in your blood.
  • you are taking or likely to be taking any of the following medicines:
    - anti-infectives (e.g. trimethoprim or co-trimoxazole, zidovudine)
    - sleeping tablets (e.g. lorazepam)
    - anti-cancer medicines (e.g. methotrexate, daunorubicin, cytosine arabinoside)
    - blood thinning tablets (e.g. warfarin)
    - antimalarial medicines (e.g. quinine, proguanil).
  • you are taking any other medicines, including medicines you buy without a prescription.
  • you are breastfeeding, pregnant or trying to become pregnant.
    If you take Daraprim tablets while you are pregnant, folic acid supplementation may be required.

How do I take Daraprim tablets?

How much to take

Take Daraprim tablets as directed by your doctor or pharmacist.

Your doctor will tell you how many tablets to take and how often to take them. You will also find this information on the label of your medicine.

How to take it

Take Daraprim tablets with a glass of water.

How long to take it for

Your doctor will tell you how long to take Daraprim tablets.

Do not stop taking Daraprim tablets, or change the dose without first checking with your doctor.

What do I do if I take too much? (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, if you think you or anyone else may have taken too much Daraprim tablets, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Daraprim tablets

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.

Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use Daraprim tablets to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how Daraprim tablets affects you.

What are the side effects?

Check with your doctor as soon as possible if you think you are experiencing any side effects or allergic reactions due to taking Daraprim tablets, even if the problem is not listed below.

Like other medicines, Daraprim tablets can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

The most commonly reported side effects:

  • nausea
  • colic
  • vomiting
  • diarrhoea
  • blood abnormalities.

Less commonly reported side effects:

  • headache
  • giddiness
  • dry mouth or throat
  • fever
  • a feeling of general discomfort
  • dermatitis
  • abnormal colour of the skin
  • depression.

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

  • Wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash (hives) or fainting. These could be a symptom of an allergic reaction.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

How do I store Daraprim tablets?

Keep this medicine where children cannot reach it, such as in a locked cupboard.

Keep Daraprim tablets in a cool place, where they stay below 30°C and are protected from light.

Do not leave in a car, on window sill or in bathroom.

Keep Daraprim tablets in the blister pack until it is time to take them.

Return any unused or expired medicine to your pharmacist.

Product description

What Daraprim tablets look like

Daraprim tablets are white, scored and marked "GS A3A".

Daraprim tablets are available in blister packs containing 50 tablets.

Ingredients

Daraprim tablets contain the active ingredient pyrimethamine 25mg.

Daraprim tablets also contain lactose, maize starch, hydrolysed starch, docusate sodium and magnesium stearate.

Daraprim tablets contain lactose.

Supplier

Your Daraprim tablets are supplied by:

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition.

This leaflet was prepared on April 2016.

Daraprim tablets: AUST R 97456.

BRAND INFORMATION

Brand name

Daraprim Tablets

Active ingredient

Pyrimethamine

Schedule

S4

 

Name of the medicine

Pyrimethamine.

Excipients.

Lactose, maize starch, hydrolysed starch, docusate sodium and magnesium stearate.

Description

Chemical name: 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine. Molecular formula: C12H13ClN4. MW: 248.7. CAS: 58-14-0. It is practically insoluble in water; slightly soluble in ethanol and dilute HCl.

Pharmacology

Pyrimethamine is an inhibitor of the enzyme dihydrofolate reductase (DHFR). It blocks the reduction of dihydrofolic acid to tetrahydrofolic acid which is an essential coenzyme in the production of nucleic acids, thereby leading to disruption of protein synthesis and nuclear division. The affinity of pyrimethamine for protozoal DHFR is much greater than that for the mammalian enzyme. Sulphonamides act synergistically with pyrimethamine by arresting production of dihydrofolic acid from para-aminobenzoic acid. This results in sequential blockade of the folate pathway of Toxoplasma which, in contrast to man, is unable to utilise preformed folate.

Pharmacokinetics.

Peak plasma levels are found between 2 and 4 hours after oral administration of a 100 mg dose of pyrimethamine and the plasma half-life is approximately 90 hours. 87% of pyrimethamine is bound to plasma proteins and its pKa is 7.34.
Pyrimethamine is secreted in breast milk.

Indications

Toxoplasmosis.

Daraprim in combination with a sulphonamide is effective in the treatment of congenital and acquired infections.

Contraindications

Daraprim should not be given to individuals with a history of pyrimethamine sensitivity or any of the components of the preparation.
Daraprim should not generally be used during the first trimester of pregnancy (see Precautions, Use in pregnancy).
Since Daraprim is to be taken in conjuction with another drug for the indications listed, the relevant prescribing information for the synergistic agent should also be considered.

Precautions

Depression of haematopoesis.

Therapeutic doses of Daraprim have been shown to depress haematopoiesis in about 25% of patients. The likelihood of leucopenia, anaemia or thrombocytopenia developing is reduced by concurrent administration of calcium folinate.
Pancytopenia, responsive to folate treatment, has been reported very rarely in patients with probable pre-existing folate deficiency. Fatalities have occurred in the absence of folate treatment.

Prevention of haematological toxicity.

In the treatment of toxoplasmosis, all patients receiving Daraprim should be given a folate supplement to reduce the risk of bone marrow depression. Whenever possible calcium folinate, 6 mg daily, should be administered; or alternatively folic acid, 5 mg daily, should be given. Full blood counts should be carried out weekly during therapy and for a further 2 weeks after treatment is stopped. In immunosuppressed patients, full blood counts should be carried out twice weekly. Should signs of folate deficiency develop treatment must be discontinued and high doses of calcium folinate administered. Calcium folinate should be used because folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitors.
Daraprim may exacerbate folate deficiency in subjects predisposed to this condition through disease or malnutrition. Accordingly, a calcium folinate supplement should be given to such individuals. In patients with megaloblastic anaemia due to folate deficiency the risks versus benefits of administering Daraprim require careful consideration.

Seizures.

Caution should be exercised in administering Daraprim to patients with a history of seizures; large loading doses should be avoided in such patients (see Adverse Effects).

Risk of crystalluria.

When a sulphonamide is given an adequate fluid intake should be ensured to minimise the risk of crystalluria.

Precautions applicable to sulphonamides.

Since pyrimethamine is administered with a sulphonamide for the conditions indicated the general precautions applicable to sulphonamides should be observed.

Use in renal impairment.

The kidney is not the major route of excretion of pyrimethamine and excretion is not significantly altered in patients with renal failure. There are, however, no substantial data on the use of Daraprim in patients with renal impairment, therefore Daraprim should be given with caution. Since Daraprim is coadministered with a sulphonamide, care should be taken to avoid accumulation of the sulphonamide in renally impaired patients.

Use in hepatic impairment.

The liver is the main route of metabolism of pyrimethamine. Data on the use of pyrimethamine in patients with liver disease are limited. Daraprim should be given with caution to patients with hepatic impairment.There are no general recommendations for dosage reductions for liver impaired states but consideration should be given to dose adjustments for individual cases.

Use in pregnancy.

(Category B3)
Pyrimethamine should not be used during the first trimester of pregnancy. Pyrimethamine may interfere with folic acid metabolism and animal experiments have shown that administration of very high doses of pyrimethamine during organ development may give rise to birth defects typical of folic acid antagonism.
The risks associated with the administration of Daraprim must be balanced against the dangers of abortion or foetal malformation due to the infection.
Concurrent administration of folinic acid is advocated when pyrimethamine is used for the treatment of toxoplasmosis during pregnancy.

Use in lactation.

Pyrimethamine enters human breast milk. In view of the high doses of pyrimethamine and concurrent sulphonamides needed in toxoplasmosis treatment, breastfeeding should be discontinued for the duration of treatment.

Cognitive and motor performance.

No studies on the effects on the ability to drive and use machinese have been performed. Some patients may experience dizziness or convulsions, therefore, caution is recommended (see Adverse Effects).

Lactose.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take medicine.

Interactions

Daraprim, by its mode of action, may further depress folate metabolism in patients receiving treatment with other folate inhibitors or agents associated with myelosuppression, including co-trimoxazole, trimethoprim, proguanil, zidovudine, or cytostatic agents (e.g. methotrexate).
Occasional reports suggest that individuals taking pyrimethamine may develop megaloblastic anaemia should a trimethoprim/ sulphonamide combination be prescribed concurrently.
The concurrent administration of lorazepam and pyrimethamine may induce hepatotoxicity.
Daraprim may cause exacerbation of the myelosuppressive effects of cytostatic agents, especially those of the antifolate methotrexate.
Convulsions have occurred after concurrent administration of methotrexate and pyrimethamine to children with CNS leukaemia and cases of fatal bone marrow aplasia have been associated with the administration of daunorubicin, cytosine arabinoside and pyrimethamine to individuals suffering from acute myeloid leukaemia. Also, seizures have occasionally been reported when pyrimethamine was used in combination with antimalarial drugs.
In vitro data suggest that antacid salts and the antidiarrhoeal agent kaolin reduce the absorption of pyrimethamine.

High protein bound compounds.

Pyrimethamine may displace other drugs from protein binding sites, causing elevated concentrations of unbound drugs; this may be of particular clinical concern for drugs that are both highly protein bound and have a narrow therapeutic index.

Adverse Effects

Since a concurrent sulphonamide is to be taken with pyrimethamine for the indications listed, the relevant prescribing information for the sulphonamide should be consulted for sulphonamide associated adverse events.
It is important to note that the frequency categories assigned for each adverse event below are only estimates as suitable data for accurately calculating incidence were not available. Adverse events may vary in their incidence according to the indication and the possible contribution of concomitant sulphonamides to the occurrence of these events is unknown. In addition some events may be related to the underlying disease.
Adverse reactions are ranked under headings of frequency using the following convention: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10,000 to < 1/1000; very rare < 1/10,000.

Blood and lympathic system disorders.

Very common: anaemia. Common: leucopenia, thrombocytopenia. Very rare: pancytopenia.

Metabolism and nutrition disorders.

Very rare: hyperphenylalaninemia (reported in neonates treated for congenital toxoplasmosis).

Psychiatric disorders.

Uncommon: depression. Very rare: insomnia (when pyrimethamine has been given at weekly doses above those recommended).

Nervous system disorders.

Very common: headache. Common: dizziness. Very rare: convulsions (predominantly in patients treated for toxoplasmosis) (see Precautions, Cognitive and motor performance (ability to perform tasks that require judgement, motor or cognitive skills)).

Vascular disorders.

Very rare: circulatory collapse (in patients treated with higher than recommended doses).

Respiratory, thoracic and mediastinal disorders.

Very rare: pneumonia with cellular and eosinophilic pulmonary infiltration (observed when pyrimethamine was administered once weekly in associated with sulfadoxine).

Gastrointestinal disorders.

Very common: vomiting, nausea, diarrhoea, colic. Uncommon: dry mouth, dry throat. Very rare: buccal ulceration.

Skin and subcutaneous tissue disorders.

Very common: rash. Uncommon: abnormal skin pigmentation, dermatitis.

Renal and urinary disorders.

Very rare: haematuria.

General disorders and administration site condition.

Uncommon: fever, malaise.
Precipitation of a grand mal attack in one patient predisposed to epilepsy has been reported but the clinical significance has not been defined.

Dosage and Administration

Toxoplasmosis.

Daraprim should be given concurrently with sulphadiazine or other sulphonamides. See Table 1.
Treatment should be given for 3 to 6 weeks. If further therapy is indicated, a period of 2 weeks should elapse between treatments.
The risk of administering sulphadiazine or other sulphonamides to neonates should be weighed against their therapeutic benefit.

Overdosage

Symptoms and signs.

Vomiting and convulsions occur in cases of severe, acute overdoses. Ataxia, tremor and respiratory depression can also occur.
Chronic excess doses can result in bone marrow depression (e.g. megaloblastic anaemia, leucopenia, thrombocytopenia) resulting from folic acid deficiency.

Treatment.

Adequate fluids should be given to ensure optimal diuresis. Routine supportive treatment including maintenance of a clear airway and control of convulsions should be given.
To counteract possible folate deficiency, calcium folinate (9 to 15 mg by intramuscular injection every 6 hours) should be given until signs of toxicity have subsided.
There may a delay of 7 to 10 days before the full leucopenic side effects become evident, therefore calcium folinate therapy should be continued for the period at risk.

Presentation

Tablets, 25 mg (white, round, biconvex, scored, marked GS/A3A, plain on reverse): 50's (Al/Al strip pack*, PVC/PVDC/Al blister pack).
*Not currently marketed in Australia.

Storage

Store below 30°C. Protect from light.

Poison Schedule

S4.