Leonate Kit

Uses

Artesunate can quickly and reliably control the acute attack of malaria. It is suitable to salvage the patients with pernicious malaria and treat P. falciparum malaria and P. vivax malaria. It is effective against malaria caused by chloroquine resistant strain of plasmodium falciparum.

Treatment of Toxoplasmosis: Pyrimethamine is used for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination.

Treatment of Acute Malaria: Pyrimethamine is also used for the treatment of acute malaria. It should not be used alone to treat acute malaria. Fast-acting schizonticides such as chloroquine or quinine are used and preferable for the treatment of acute malaria. However, conjoint use of Pyrimethamine with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and suppression of susceptible strains of plasmodia.

Chemoprophylaxis of Malaria: Pyrimethamine is used for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas.

Leonate Kit is also used to associated treatment for these conditions: Acute Uncomplicated Plasmodium Falciparum Malaria, Malaria, Cerebral, Severe MalariaPlasmodium Infections, Toxoplasmosis, Acute Malaria

How Leonate Kit works

Artesunate is metabolized to the active DHA. the endoperoxide bridge of DHA reacts with heme, generating free radicals which inhibit protein and nucleic acid synthesis of the Plasmodium parasites during all erythrocytic stages. Reactions with these free radicals can also lead to alkylation of parasitic proteins such as a calcium adenosine triphosphatase and EXP1, a glutathione S-transferase.

Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

Dosage

Leonate Kit dosage

Adult: 5 days treatment: on the 1st day 2 tablets twice and 2nd day onward 1 tablet twice daily for remaining 4 days

Children:

• 1-3 years: 5 days treatment: on the 1st day ½ tablet twice and 2nd day onward ¼ tablet twice daily for remaining 4 days
• 4-5 years: 5 days treatment: on the 1st day 1 tablet twice and 2nd day onward ½ tablet twice daily for remaining 4 days
• 6-12 years: 5 days treatment: on the 1st day ½ tablet twice, 2nd day 1 tablet twice and 3rd day onward ½ tablet twice daily for remaining 3 days

Prophylmcis: 100 mg tablet once a week, from 1 week before entering malarial areas, to 4 weeks after leaving the area.

For Treatment of Toxoplasmosis: The dosage of Pyrimethamine for the treatment of toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic effect and a minimum of side effects. At the dosage required, there is a marked variation in the tolerance to the drug. Young patients may tolerate higher doses than older individuals. Concurrent administration offolinic acidis strongly recommended in all patients.

The adultstartingdose is 50 to 75 mg of the drug daily, together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g. sulfadoxine. This dosage is ordinarily continued for 1 to 3 weeks, depending on the response of the patient and tolerance to therapy. The dosage may then be reduced to about one half that previously given for each drug and continued for an additional 4 to 5 weeks.

The pediatric dosage of Pyrimethamine is 1 mg/kg/day divided into 2 equal daily doses; after 2 to 4 days this dose may be reduced to one half and continued for approximately 1 month. The usual pediatric sulfonamide dosage is used in conjunction with Pyrimethamine.

For Treatment of Acute Malaria: Pyrimethamine is NOT recommended alone in the treatment of acute malaria. Fast-acting schizonticides, such as chloroquine or quinine, are indicated for treatment of acute malaria. However, Pyrimethamine at a dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission control and suppression of non-falciparum malaria.Pyrimethamine is only recommended for patients infected in areas where susceptible plasmodia exist. Should circumstances arise wherein Pyrimethamine must be used alone in semi- immune persons, the adult dosage for acute malaria is 50 mg for 2 days; children 4 through 10 years old may be given 25 mg daily for 2 days. In any event, clinical cure should be followed by the once-weekly regimen described below for chemoprophylaxis. Regimens which include suppression should be extended through any characteristic periods of earlyrecrudescenceand late relapse, i.e., for at least 10 weeks in each case.

For Chemoprophylaxis of Malaria:

• Adults and pediatric patients over 10 years: 25 mg (1 tablet) once weekly
• Children 4 through 10 years:12.5 mg (½ tablet) once weekly
• Infants and children under 4 years: 6.25 mg (¼ tablet) once weekly.

Side Effects

Transient and reversible reticulocytopaenia, drug fever, rash, bradycardia, transient 1st-degree heart block and reversible elevation of serum transaminases.

Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur particularly when pyrimethamine is administered concomitantly with a sulfonamide. Consult the complete prescribing information for the relevant sulfonamide for sulfonamideassociated adverse events. With doses of pyrimethamine used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, neutropenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm.

Toxicity

Data regarding overdoses of artesunate are rare. Patients experiencing an overdose may present with pancytopenia, melena, seizures, multiorgan failure, and death. Treat overdose with symptomatic and supportive measures.

Precaution

Hepatic or renal insufficiency; Pregnancy and lactation.

The recommended dosage for chemoprophylaxis of malaria should not be exceeded. Pyrimethamine should be used with caution in patients with impaired renal or hepatic function or in patients with possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin, affecting folate levels

Interaction

Antimalarial potentiating action seen with mefloquine, primaquine and tetracycline. Additive effect with chloroquine. Antagonistic effect with pyrimethamine and sulphonamides.

Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. However, the concomitant use of other antifolic drugs or agents associated with myelosuppression including sulfonamides or trimethoprim-sulfamethoxazole combinations, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate), while the patient is receiving pyrimethamine, may increase the risk of bone marrow suppression. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored

Volume of Distribution

The volume of distribution of artesunate is 68.5L while the volume of distribution of DHA is 59.7L.

Elimination Route

The C_max of artesunate is 3.3µg/mL while the C_max of the active metabolite DHA is 3.1µg/mL. The AUC of artesunate is 0.7µg*h/mL while the AUC of DHA is 3.5µg*h/mL. After intravenous artesunate, DHA has a T_max of 0.5-15 minutes in adult patients and 21-64 minutes in pediatric patients. Intramuscular artesunate has a T_max of 8-12 minutes. Infants less than 6 months old will have a higher AUC due to an undeveloped UGT metabolic pathway.

Well absorbed with peak levels occurring between 2 to 6 hours following administration

Half Life

The elimination half life of artesunate is 0.3h with a range of 0.1-1.8h. The elimination half life of DHA is 1.3h with a range of 0.9-2.9h. Half life after intramuscular administration is 48 min in children and 41 min in adults.

96 hours

Clearance

The clearance of artesunate is 180L/h while the clearance of DHA is 32.3L/h.

Elimination Route

The main route of elimination in humans is unknown. In rats, a dose of artesunate is 56.1% eliminated in the urine and 38.5% in the feces.

Pregnancy & Breastfeeding use

Pregnancy category is not classified. FDA has yet not classified the drug into a specific pregnancy catagory.

Pregnancy Category C. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis.

There are no adequate and well-controlled studies in pregnant women. Pyrimethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy.

Nursing Mothers: Pyrimethamine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pyrimethamine and from concurrent use of a sulfonamide with Pyrimethamine for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Contraindication

Hypersensitivity.

Use of Pyrimethamine is contraindicated in patients with known hypersensitivity to pyrimethamine or to any component of the formulation. Use of the drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency.

Special Warning

Geriatric Use: Clinical studies of Pyrimethamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Innovators Monograph

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