1, African Church close, off Coker Road, Ilupeju, Lagos, Nigeria
Tel: 01-773-1473, 01-8179648, 08033160649
Micro Labs Ltd, 92, Sipcot Hosur 635 126 (TM) India
Dosage Form, Composition & NAFDAC Registration Number (NRN)
Tablet (NRN: 04-9504): Artesunate 100 mg, Sulfadoxine 500 mg, Pyrimethamine 25 mg.
Pack size: Combi pack of 3 tablets of Sulfadoxine/Pyrimethamine and 6 tablets of Artesunate
CHEMISTRY: sulfadoxine is N1-(5,6-dimethoxypyrimidin-4-yl)-sulphanilamide, Pyrimethamine is 4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine, and Artesunate is (3R,5aS,6R,8aS,9R,1OS,12R,12aR)-Decahydro-3,6.9·tnmethyl-3,12-epoxy-12H-pyrano[4,3-j] 1,2-benzodioxepm-10-ol,hydrogen succinate;
Artesunate and its active metabolite dihydroartemisinin are potent blood schizonticides, active against the ring stage of the parasite. It is effective against P. falciparum resistant to all other antimalarial drugs. It does not have hypnozoiticidal activity. It reduces gametocyte carriage rate. The functional group responsible for antimalarial activity of artesunate is endoperoxide bond. Release of an active oxygen species from this bond kills the parasite if accumulated in the erythrocytic cells. It also suppresses the production or activity of antioxidant enzymes in the erythrocytes.
Sulphadoxine and pyrimethamine combination is an antimalarial agent, which acts by reciprocal potentiation of its two components, achieved by a sequential blockade of two enzymes involved in the biosynthesis of folinic acid within the parasites. They are blood schizonticidal agents and are active against the asexual erythrocytic forms of susceptible plasmodia Trophozoites and schizonts are rapidly eliminated from the blood. The pre-erythrocytic stages are also affected, and the gametocytes are rendered non-infective in the mosquito.
Pyrimethamine is a folic acid antagonist and has a mechanism of action similar to that of trimethoprim. By binding to and reversibly inhibiting dihydrofolate reductase, pyrimethamine inhibits the reduction of dihydrofolic acid to tetrahdrofolic acid (folinic acid). Pyrimethamine interferes with the synthesis of tetrahydrofolic acid in malarial parasites at a point immediately succeeding that where sulphonamides act
Sulphadoxine, like other sulphonamides, is a structural analog of p-aminobenzoic acid (PABA) and competitively inhibits dihydrofolic acid synthesis by inhibiting dihydropteroate synthetase, which is necessary or the conversion of PABA to folic acid
The combination of sulphadoxine and pyrimethamine results in a synergistic action against susceptible plasmodia. The risk of resistance development is reduced by this means. This attacks the different development stages of the parasite.
Pharmacokinetic data in humans are sparse, with no data demonstrating the rate or extent of absorption or the systemic distribution of artesunate. The oral formulation is probably hydrolysed completely before entering the systemic circulation. Peak serum levels occur within one hour of an oral dose of artesunate and persist for up to 4 hours Dihydroartemisinin has a plasma elimination half-life of less than 2 hours, which may slow the development of resistance to artesunate.
Both sulphadoxine and pyrimethamine are well absorbed from the GI tract. Like other sulphonamides, sulphadoxine is widely distributed in the body Pyrimethamine is distributed mainly to the kidneys, lungs, liver and spleen. Plasma protein binding is about 90% for both pyrimethamine and sulphadoxine. About 5% of sulphadoxine appears in the blood as acetylated metabolite, about 2-3% as the glucuronide.
Pyrimethamine is transformed to several metabolites. Both sulphadoxine and the pyrimethamine are excreted mainly by the kidneys. The apparent elimination half-life of sulphadoxine ranged from 100 to 231 hours with a mean of 169 hours, whereas pyrimethamine half-lives ranged from 54 to 148 hours with a mean of 111 hours.
The combination is indicated for the treatment of malaria.
The drug is contraindicated in patients with prior hypersensitivity to artesunate or artemisinin derivatives, pyrimethamine or sulphonamides. The drug is also contraindicated in patients with severe renal insufficiency, marked liver parenchymal damage or blood dyscrasias, patients with documented megaloblastic anemia due to folate deficiency, Infants
Oral artesunate should not be used during the first trimester of pregnancy. Treatment must be immediately discontinued upon the appearance or any skin reactions or mucocutaneous signs or symptoms such as pruritus, erythema, rash, urogenital lesions or pharyngitis, and a medical practitioner consulted as these may be indicative of a life-threatening reaction to the drug.
The possibility of an adverse drug reaction should be considered in patients developing a rash, Jaundice, fever or severe generalized malaise during treatment with sulphadoxine-pyrimethamine This combination should not be used in premature or newborn infants in the first two months of life because of the immaturity of their enzyme systems. Pyrimethamine has been reported to cause aplastic anaemia if used between courses of antineoplastic agents. This should be borne in mind when using sulphadoxine pyrimethamine combination.
They are mainly pertaining to sulphadoxine-pyrimethamine. Fatalities associated with the administration of sulphadoxine and pyrimethamine have occurred due to severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Discontinue sulphadoxine and pyrimethamine prophylaxis at the first appearance of skin rash, if a significant reduction in the count of any formed blood elements is noted or upon the occurrence of active bacterial or fungal infections.
Care should be exercised in patients with hepatic and particularly renal impairment and dosage adjustments made if necessary Excessive exposure to the sun must be strictly avoided.
Administer with caution to patients with possible folate deficiency and to those with severe allergy or bronchial asthma. As with some sulphonamide drugs. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. Perform a urinalysis with microscopic examination and renal function test during therapy for patients who have impaired renal function.
Because sulphadoxine and pyrimethamine contains a sulphonamide the drug shares the toxic potentials of the sulphonamides, and the usual precautions and contraindications to sulphonamide therapy should be observed, including maintenance of an adequate fluid intake to prevent crystalluria.
Patients who develop signs suggestive of sulphonamide or pyrimethamine sensitivity should never receive drugs containing these substances again. These signs include skin rashes, evidence of haemolysis including dark urine and purpura and presumptive signs of bone marrow depression such as sore throat and mouth ulcers.
USAGE IN PREGNANCY AND LACTATION:
little experience has been gained with the use of artesunate m pregnancy. Oral artesunate should not be used during the first trimester of pregnancy.
Sulphadoxine and pyrimethamine therapy is contraindicated during pregnancy at term as there is possibility that use of sulphadoxine plus pyrimethamine may produce kernicterus in the neonate.
There are no adequate and well controlled studies of sulphadoxine pyrimethamine in pregnant women. However, due to the teratogenic effect shown in animals and because pyrimethamine plus sulphadoxine may interfere with folic acid metabolism, use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Women of child bearing potential who are travelling to areas where malaria is endemic should be advised against becoming pregnant. In addition, they should be advised to practice contraception during treatment with and for three months after the last dose Pyrimethamine may interfere with folic acid metabolism and if pyrimethamine is given during pregnancy, folic acid supplementation may be required Sulphadoxine may cause kernicterus in babies during the first month or lite by displacing bilirubin from plasma albumin. Sulphadoxine should therefore be avoided during the last month of pregnancy.
Sulphadoxine and pyrimethamine therapy is contraindicated in the nursing period because sulphonamides cross the placenta and are excreted m breast milk, which may result in kernicterus.
Usage in paediatrics: Do not give to infants Artemisinin derivatives are to be given to children over 6 months of age
Hence the combipack is indicated for children over 6 months of age.
Usage in geriatrics: Although no specific studies have been performed to establish the use of sulphadoxine- Pyrimethamine m the elderly, it has been used extensively and the dosage requirements and side-effects appear to be similar to those of younger adults
Artesunate has a minimal effect on hepatic cytochrome P450 activity and does not appear to influence the metabolism of mefloquine, a drug likely to be used in combination with artesunate.
Artersunate does not inhibit the formation of carboxy-primaquine, a metabolite of primaquine.
Chloroquine - There have been reports that may indicate an increase in incidence and severity of adverse reactions when chloroquine is used with sulphadoxine and pyrimethamine tablets as compared with the use of the sulphadoxine and pyrimethamine tablets alone.
Quinine - The tablets are compatible with quinine and with antibiotics.
Antifolic drugs - Do not use antifolic drugs (e.g. sulphonamides or trimethoprim-sulfamethoxazole combinations, methotrexate, anticonvulsants) while the patient is receiving sulphadoxine and pyrimethamine tablets for antimalarial prophylaxis. It can result in increased impairment of folic acid metabolism which leads to haematological side effects.
Antidiabetic agents- The tablets have not been reported lo interfere with antidiabetic agents. However, the hypoglycaemic effect of some sulfonylureas is enhanced by sulphonamides.
Local anaesthetics - Drugs containing the para-aminobenzoic acid nucleus (e.g. some local anaesthetics) competitively antagonize the effects of sulphonamides.
Goitrogens, diuretics, hypoglycemic agents - The sulphonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulphonamides. Cross-sensitivity may exist with these agents.
PABA - Although the clinical importance is unclear, p-aminobenzoic acid (PABA) reportedly interferes with the action of pyrimethamine and probably should not be used m patients receiving pyrimethamine.
Lorazepam - Mild hepatotoxicity has been reported m some patients receiving pyrimethamine and lorazepam concomitantly.
Artesunate and other related artemisinin derivatives have been widely used in China, with no reports of any serious adverse reactions.
Drug induced fever can occur. Neurotoxicity has been observed in animal studies but not m humans. In view of the uncertainty about toxic effects, caution should be exercised when more than one 3 day treatment is given. Cardiotoxicity has been observed following administration of high doses.
In healthy volunteers, a reversible reduction in reticulocyte counts was the dose limiting adverse effect of artesunate, occurring with doses of 16.88 mg/Kg.
Possible drug related adverse effects include dizziness, itching, vomiting, abdominal pain, flatulence, headache, bodyache diarrhoea, tinnitus and increased hair loss, macular rash, reduction in neutrophil counts and convulsions. However, it is likely that many of these effects are disease-related rather than drug-induced.
Occasional skin rash and pruritus has been observed with artesunate
There were no clinically important local or systemic adverse effects observed in 346 patients treated with intravenous artesunate. Electrocardiography was undertaken in a total of 82 patients. Slight sinus bradycardia occurred in a few patients and transient first degree atrioventricular block was observed in 1 patient. Slight elevations in hepatic transaminases were also reported, but these were more likely to be related to the disease than to the treatment per se.
Sulphadoxine and pyrimethamine generally is well tolerated.
Adverse effects include:
CNS - Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo, Insomnia, apathy, fatigue, muscle weakness, nervousness.
GI - Glossitis, stomatitis, nausea, emesis, abdominal pains, hepatitis, hepatocellular necrosis, diarrhoea, pancreatitis.
Hematologic - Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, eosinophilia.
Hypersensitivity- Erythema multiforme, Stevens-Johnson syndrome, generalized skin eruptions, toxic epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, arthralgia, allergic myocarditis.
Hepatic - Adverse hepatic effects, possibly secondary to sulphonamide hypersensitivity, have been reported in patients receiving sulphadoxine and pyrimethamine. In some patients adverse hepatic effects have been associated with severe cutaneous reactions to the combination Abnormal liver function tests, jaundice, hepatomegaly, and hepatitis which can be fatal, have been reported with the combination.
Miscellaneous - Pulmonary infiltrates, drug fever, chills, toxic nephrosis with oliguria and anuria, periarteritis nodosa, LE phenomenon.
Dosage & Administration
Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.
If anorexia or vomiting occurs during the therapy, these adverse effects may be minimized by taking the drug with meals.
The recommended dose of artesunate is 4 mg/Kg bodyweight daily for 3 days.
The dosage for sulphadoxine-pyrimethamine is as follows:
The recommended dosage is single dose of 25 mg/Kg of sulphadoxine and 1.25 mg/Kg of pyrimethamine.
Suggested guidelines for sulphadoxine-pyrimethamine dosage as per age group and weight are as follows:
|Age||Body Weight||Sulphadoxine 500 mg + Pyrimethamine 25 mg tablet|
|2 - 11 months||5 - 10 kg||0.50|
|1 - 2 years||10.1 - 14 kg||0.75|
|3 - 5 years||14.1 - 20 kg||1.00|
|6 - 8 years||20.1 - 30 kg||1.50|
|9 - 11 years||30.1 - 40 kg||2.00|
|12 - 13 years||40.1 - 50 kg||2.50|
|14 years||>50 kg||3.00|
No data available for overdosage of artesunate.
Symptoms - Acute intoxication may be manifested by anorexia, vomiting and CNS stimulation (including convulsions), followed by megaloblastic anemia, leukopenia, thrombocytopenia, glossitis and crystalluria.
Treatment - In acute intoxication, emesis and gastric lavage followed by purges may be of benefit. Adequately hydrate the patient to prevent renal damage.
Monitor the renal and hematopoietic systems for >1 month after overdosage.
If the patient is having convulsions, the use of a parenteral barbiturate is indicated.
Administer folinic acid (leucovorin) 5 to 15 mg lM daily for >3 days for depressed platelet or white blood cell counts.