Pill Identifier App

DARAPRIM 25MG TABLETS

Active substance: PYRIMETHAMINE

View full screen / Print PDF » Download PDF ⇩

Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Daraprim 25mg Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Pyrimethamine 25.0 mg
For excipients see 6.1.

3.

PHARMACEUTICAL FORM
Tablet
Each tablet is white and round with the marking GS A3A.

4

CLINICAL PARTICULARS

4.1

Therapeutic Indications
Toxoplasmosis
Treatment is not normally required for asymtomatic or mild toxoplasma
infection. Daraprim, in conjunction with a sulphonamide, is effective in the
treatment of the following conditions associated with toxoplasma infections:
Toxoplasmic encephalitis and other manifestations in immune deficient
individuals including those with AIDS.
Ocular infections where there is considered to be a risk of visual damage.
Proven foetal infection following maternal infection during pregnancy.
For the treatment of toxoplasmosis, Daraprim should not be used as
monotherapy. It must be combined with a synergistic agent, normally an orally

administered sulphonamide as recommended in section 4.2 Posology and
Method of Administration.

4.2.

Posology and method of administration

Toxoplasmosis treatment:
Daraprim should be given concurrently with sulphadiazine or another
appropriate sulphonamide. Data on the extent to which other combinations
might be better than pyrimethamine alone are limited. For patients who are
intolerant of sulphonamides however, consideration should be given to
substituting the sulphonamide for another agent such as clindamycin.
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 should be administered. Folic acid is
likely to be less effective than calcium folinate.
Daraprim treatment should generally be given for 3 to 6 weeks and not less
than three weeks in immunosuppressed patients. If further therapy is
indicated, a period of two weeks should elapse between treatments.
There have been no dose response studies of pyrimethamine in the treatment
of toxoplasmosis. The following recommendations are therefore for guidance
only.
Dosage for Toxoplasmic encephalitis and other manifestations in immunedeficient patients (adults and children over 5 years)
Daraprim :
A loading dose of 100 mg – 200 mg daily should be given for the first 2 - 3
days of treatment.
The optimal dose subsequently for the treatment of toxoplasmic encephalitis in
AIDS patients is not fully established but is generally in the range 25mg75mg/day. Doses up to 100mg/day have been used successfully. The duration
of treatment of the acute infection will depend on the clinical response and
tolerability, but should normally be not less than three to six weeks.
Maintenance treatment is required indefinitely in immunocompromised
patients if relapses are to be avoided. There is insufficient evidence to
establish the optimal dose regimen, but doses of 25-100mg daily have been
employed successfully.
Sulphadiazine 2 - 6 g per day in divided doses.

Dosage for treatment of ocular infections (adults and children over 5 years)
Daraprim:
A loading dose of 100mg for 1-2 days followed by maintenance doses of 2550mg daily. The optimal maintenance dose has not been clearly established.
Sulphadiazine: 2-4g daily in divided doses.


Dosage for treatment of foetal toxoplasmosis during pregnancy

See Section 4.4 Special Warnings and Precautions for Use and Section 4.6
Pregnancy and Lactation
Daraprim:
Sulphadiazine

25 - 50 mg daily
2 - 4 g daily in divided doses

Children under 5 years
There is insufficient data to provide specific dose recommendations in
children. This formulation is not suitable for children under 5 years.
Use in the elderly
There is no definitive information on the effect of Daraprim on elderly
individuals. It is theoretically possible that elderly patients might be more
susceptible to folate depression associated with the daily administration of
Daraprim in the treatment of toxoplasmosis, and folate supplements are
therefore essential (See section 4.2 Special Warnings and Precautions for
Use).

4.3.

Contraindications
Daraprim should not be given to patients with a history of pyrimethamine
sensitivity.
Daraprim should not be used during the first trimester of pregnancy. (See
Section 4.6 Fertility, Pregnancy and Lactation).
Breast-feeding should be avoided during toxoplasmosis treatment. (See
Section 4.6 Fertility, Pregnancy and Lactation).

4.4.

Special warnings and precautions for use

During pregnancy and in other conditions predisposing to folate deficiency, a
folate supplement should be given. The co-administration of a folate
supplement is necessary for treatment of toxoplasmosis (see section 4.2
Posology & Method of Administration). Full blood counts should be carried
out weekly during therapy and for a further two 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.
Caution should be exercised in administering Daraprim to patients with a
history of seizures; large loading doses should be avoided in such patients (see
section 4.8 Undesirable Effects).
When a sulphonamide is given an adequate fluid intake should be ensured to
minimise the risk of crystalluria.
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 renally impaired subjects. Due
to lack of data on the theoretical possibility of active metabolites with
prolonged treatment, caution should be exercised in renally impaired patients.
It is not known if Daraprim is dialyzable. Since Daraprim is co-administered
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 for metabolism of pyrimethamine. Data on the use
of pyrimethamine in patients with liver disease are limited. Daraprim in
combination with sulphonamides has been used effectively to treat
toxoplasmosis in a patient with mild hepatic disease. There are no general
recommendations for dosage reductions for liver-impaired states but
consideration should be given to dose adjustment for individual cases.

4.5.

Interactions with other medicinal products and other forms of interaction
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 (eg. methotrexate). 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. Megaloblastic anaemia has been reported occasionally in
individuals who took pyrimethamine in excess of 25 mg weekly concurrently
with a trimethoprim/sulphonamide combination.
Convulsions have occurred after concurrent administration of methotrexate
and pyrimethamine to children with central nervous system leukaemia. Also,
seizures have occasionally been reported when pyrimethamine was used in
combination with other antimalarial drugs.
The concurrent administration of lorazepam and Daraprim may induce
hepatotoxicity.
In vitro data suggest that antacid salts and the anti-diarrhoeal agent kaolin
reduce the absorption of pyrimethamine.
The high protein binding exhibited by pyrimethamine may prevent protein
binding by other compounds (eg. quinine or warfarin). This could affect the
efficacy or toxicity of the concomitant drug depending on the levels of
unbound drug.

4.6.

Fertility, Pregnancy and lactation
Pregnancy
Pyrimethamine in combination with sulphonamide has been used for many
years in the treatment of toxoplasmosis during pregnancy. These infections
carry a high risk to the foetus. Pyrimethamine crosses the placenta and,
although there is a theoretical risk of foetal abnormalities from all folate
inhibitors given during pregnancy, there have been no reports that have shown
with any certainty that pyrimethamine is associated with human teratogenicity.
Nevertheless, caution should be exercised in the administration of
pyrimethamine. A folate supplement should be given to pregnant women
receiving Daraprim.
Consideration should be given to the treatment of all suspected cases of
acquired toxoplasmosis in pregnancy. The risks associated with the
administration of Daraprim must be balanced against the dangers of abortion
or foetal malformation due to the infection.

Treatment with pyrimethamine and sulfadiazine during pregnancy is indicated
in the presence of confirmed placental or foetal infection or when the mother
is at risk of serious sequelae. However, in view of the theoretical risk of foetal
abnormality arising from the use of Daraprim in early pregnancy, its use in
combination therapy should be restricted to the second and third trimesters.
Alternative therapy is therefore advised in the first trimester of pregnancy and
until diagnosis has been confirmed.
Lactation
Pyrimethamine enters human breast milk. It has been estimated that over a 9day period an average weight infant would receive about 45% of the dose
ingested by the mother. In view of the high doses of pyrimethamine and
concurrent sulphonamides needed in toxoplasmosis treatment, breast feeding
should be avoided for the duration of treatment.
4.7.

Effects on ability to drive and use machines
Not known.

4.8.

Undesirable effects
Since a concurrent sulphonamide is to be taken with pyrimethamine for the
indications listed the relevant sulphonamide data sheet/SPC or published
literature 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.
The following convention has been used for the classification of undesirable
effects in terms of frequency:very common ≥1/10,
common ≥1/100 and <1/10,
uncommon ≥1/1000 and <1/100,
rare ≥1/10,000 and <1/1000,
very rare <1/10,000.
Blood and lymphatic system disorders

Very common:Anaemia
Common:
Leucopenia, thromboctopenia
Very rare:
Pancytopenia
Daily therapeutic doses of pyrimethamine have been shown to depress
haematopoesis in some 25-50% of patients. The likelihood of inducing
leucopenia, anaemia or thrombocytopenia is reduced by concurrent
administration of calcium folinate. Pancytopenia, responsive to folate, has
been reported in patients with probable pre-existing folate deficiency.
Fatalities have occurred in the absence of folate treatment.
Nervous system disorders
Very common:Headache
Common:
Giddiness
Very rare:
Convulsions
Convulsions were reported predominantly in patients treated for
toxoplasmosis.
Respiratory, thoracic and mediastinal Disorders
Very rare:

Pneumonia with cellular and eosinophilic pulmonary
infiltration

Observed when pyrimethamine was administered once weekly in association
with sulfadoxine.
Gastrointestinal disorders
Very common:Vomiting, nausea, diarrhoea
Very rare:
Colic, buccal ulceration
Skin and subcutaneous tissue disorders
Very common:Rash
Uncommon: Abnormal skin pigmentation
Very rare:
Dermatitis
General disorders and administrative site conditions
Uncommon:

Fever

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 the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9.

Overdose
Symptoms and signs:Vomiting and convulsions occur in cases of severe, acute overdoses. Ataxia, tremor
and respiratory depression can also occur. There have been isolated cases with fatal
outcomes following acute overdose of pyrimethamine.
Chronic excess doses can result in bone marrow depression (eg. megaloblastic
anaemia, leucopenia, thrombocytopenia) resulting from folic acid deficiency.
Management:Routine supportive treatment, including maintenance of a clear airway and control of
convulsions.
Adequate fluids should be given to ensure optimal diuresis.
To counteract possible folate deficiency, calcium folinate 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.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Pyrimethamine is an antiparasitic agent.
Group: diaminopyrimidines
ATC code: P01B D01
Mode of Action:
The antiparasitic action of pyrimethamine is due to its specific activity on folic
acid metabolism in the Plasmodium and Toxoplasma parasites. In this respect
it competitively inhibits the dihydrofolate reductase enzyme with an affinity
far greater for the protozoal than for the human enzyme.

5.2.

Pharmacokinetic properties
Absorption:
Pyrimethamine is rapidly absorbed from the gastrointestinal tract after
administration. Time to peak plasma concentration is 2 to 4 hours in healthy
volunteers. Peak plasma concentrations vary widely between individuals and
can range from 260 to 1411ng/ml after daily doses of 25mg. A similar degree
of inter-patient variability in serum levels has been noted in patients with
AIDS.

Distribution:
The volume of distribution for pyrimethamine is approximately 2L/kg. In
patients with HIV infection, population pharmacokinetic analysis has indicated
that the mean volume of distribution (corrected for bioavailability) is 246 ±
64L.
About 87% of the drug is bound to plasma proteins. Pyrimethamine has been
shown to reach the cerebrospinal fluid of patients with AIDS given daily
doses, achieving concentrations approximately one fifth of those in serum.
Metabolism and elimination:
Pyrimethamine is predominantly eliminated by metabolism, with up to 30%
recovered in the urine as parent compound over a period of several weeks. The
mean elimination half-life is 85 hours (ranging from 35 to 175 hours). In
AIDS patients, the total clearance is 1.28 ± 0.41 L/h resulting in an elimination
half life of 139 ± 34h . Data are lacking on the nature of the metabolites of
pyrimethamine, their route/rate of formation and elimination in man and any
pharmacological activity, particularly after prolonged daily dosing.
Multiple dose studies indicate that steady state is achieved in 12 to 20 days
with daily dosing. It is theoretically possible that metabolic pathways might be
saturable, leading to excessive accumulation of the drug in some patients.
However, it has been demonstrated that plasma levels are approximately
proportional to dose at steady state so this appears unlikely. Genetic variation
in the exposure to pyrimethamine has been reported but these data are
unsubstantiated.
Some studies in patients with AIDS have indicated shorter half lives than
those noted above: these are very likely to be a consequence of inappropriate
sampling and analytical techniques. However, if there are patients in whom the
half-life is particularly short, steady state therapeutic levels might be
inadequate.

5.3.

Preclinical safety data
Mutagenicity:
In microbial tests, pyrimethamine was found to be non-mutagenic in the Ames
Salmonella assay whereas DNA damage was seen in the Escherichia coli
repair assay.
Further in vitro data indicate that pyrimethamine induces mutagenic activity in
mouse lymphoma cells in the absence, but not in the presence of metabolic
activation.

Pyrimethamine also showed clastogenic activity in mammalian lymphocytes
in the absence of metabolic activation.
Following intraperitoneal administration, pyrimethamine has been shown to
induce chromosomal damage in male rodent germ cells although studies in
somatic cells (micronucleus tests) are either negative or inconclusive. Studies
following oral administration of pyrimethamine in rodents showed negative
results in female germ cells and in male and female bone marrow/peripheral
blood cells.
Carcinogenicity
A study in mice (dosed with either 500 or 1000 ppm pyrimethamine in the diet
for 5 days per week, for 78 weeks) showed no evidence of carcinogenicity in
females. Survival in the male mice did not allow for an assessment of
carcinogenicity in this sex.
A similar study in rats dosed at 200 or 400 ppm pyrimethamine showed no
evidence of carcinogenicity.
Teratogenicity
No changes in early development were seen in embryos from 15 mice given a
single intra-gastric dose of pyrimethamine (50mg/kg bodyweight) on the first
day of gestation. However development of mouse and rat embryos in culture
was severely hindered by pyrimethamine in a dose-dependent manner.
Pyrimethamine was teratogenic in rodents and in the Gottingen minipig in a
dose-dependent manner.
Other studies in rats dosed at either 1mg/kg or 10mg/kg bodyweight showed
some inhibition of developmental processes but no teratological effects.
Pyrimethamine was not teratogenic in rabbits at dose levels up to 100mg/kg
bodyweight/day administered on days 6 to 18 of pregnancy. Pyrimethamine
markedly reduced early stage cell division in rabbit embryos but implantation
and foetal development were normal.
Fertility
A study in rats dosed with 5mg/kg bodyweight/day for 6 weeks resulted in
reduced sperm concentrations and testis weights, but there were no effects on
fertility. Reversible arrest of spermatogenesis was shown in a study on mice
dosed with 200mg/kg/day for 50 days. However, this dose is far in excess of
human therapeutic doses.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Lactose Monohydrate
Maize Starch
Hydrolysed Starch
Docusate sodium
Magnesium stearate

6.2.

Incompatibilities
Not applicable

6.3.

Shelf life
5 years

6.4.

Special precautions for storage
Do not store above 30°C.
Store in the original container.

6.5

Nature and contents of container
Cold formed PVC/PVDC Aluminium Foil Blister
Lidding foil:
Aluminium foil 20 μm
Heat Seal Lacquer
Blister clear film:
PVC/PVDC 280 μm (nominally)
Pack size: 30 tablets

6.6.

Instructions for use/handling
Not applicable.

7

MARKETING AUTHORISATION HOLDER
The Wellcome Foundation Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
Trading as
GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex UB11 1BT

8.

MARKETING AUTHORISATION NUMBER(S)
PL 00003/5026R

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/09/1986 / 21/12/2005

10

DATE OF REVISION OF THE TEXT
04/09/2014

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide
(web2)