ATOP 250/100

Indications

• Adjunct in the treatment of non-falciparum malaria caused by Plasmodium vivax
• Adjunct in the treatment of non-falciparum malaria caused by Plasmodium ovale
• Treatment of mild to moderate Pneumocystis pneumonia in combination with clindamycin

Mechanism of action

Proguanil is a prodrug that is metabolized in the liver to its active form, cycloguanil. Cycloguanil inhibits dihydrofolate reductase, an enzyme required for the synthesis of tetrahydrofolate, which is necessary for the production of nucleic acids in the malaria parasite. This inhibition leads to the impairment of nucleic acid synthesis, ultimately resulting in the death of the parasite.

Pharmacodynamics

The pharmacodynamic effects of proguanil are primarily related to its antimalarial activity. The drug demonstrates a rapid onset of action against the malaria parasite, effectively reducing parasitemia and alleviating symptoms associated with malaria infection. Its effectiveness is enhanced when used in combination with other antimalarial agents, particularly those targeting different stages of the parasite's lifecycle.

Pharmacokinetics

Proguanil is well absorbed from the gastrointestinal tract, with peak plasma concentrations usually reached within 1 to 3 hours after oral administration. It undergoes extensive hepatic metabolism, mainly to cycloguanil, which has a longer half-life. The elimination half-life of proguanil itself is approximately 8 to 12 hours, while cycloguanil has a half-life of about 12 to 20 hours. The drug is predominantly eliminated through the urine, with both unchanged drug and metabolites present. In cases of renal impairment, caution is advised as elimination may be prolonged.

Contra-indications

• Hypersensitivity to proguanil or any component of the formulation
• Severe renal impairment
• Severe hepatic impairment
• Known G6PD deficiency (without expert advice)

Adverse effects

• Drowsiness
• Dizziness
• Nausea
• Vomiting
• Abdominal pain
• Rash
• Malaise
• Headache
• Psychosis
• Tremor
• Seizures
• Thrombocytopenia
• Neutropenia
• Pancreatitis
• Liver function abnormalities
• Haemolysis in G6PD-deficient patients

Interactions

• Antimalarials (refer to Appendix 1 in BNF)
• Warfarin (may enhance anticoagulant effect)
• Other nephrotoxic or hepatotoxic agents
• Potential interactions with drugs that induce or inhibit cytochrome P450 enzymes

Precautions

• Caution in patients with G6PD deficiency
• Caution in patients with history of psychiatric disorders
• Monitor renal and hepatic function
• Avoid in pregnancy unless benefits outweigh risks
• Screen for G6PD deficiency before treatment

Pregnancy

Manufacturer advises to avoid use, particularly in the first trimester, unless the potential benefit outweighs the risk due to teratogenicity observed in animal studies.

Breast-feeding

No specific information available; potential risk of haemolysis in G6PD-deficient infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• {'form': 'Tablet', 'strength': '100 mg'}
• {'form': 'Tablet', 'strength': '200 mg'}
• {'form': 'Oral suspension', 'strength': None}

Indications

• Pneumocystis jirovecii pneumonia (in patients intolerant to co-trimoxazole)
• Prophylaxis of Pneumocystis jirovecii pneumonia

Dosage

Children: Child: 2 mg/kg once daily (max. per dose 100 mg).

Adults: 750 mg once daily with food.

Mechanism of action

Atovaquone is a selective inhibitor of the mitochondrial electron transport chain in protozoa, leading to a disruption in ATP production, which is crucial for their survival and replication.

Pharmacodynamics

Atovaquone exhibits antiprotozoal activity against Pneumocystis jirovecii by inhibiting its mitochondrial respiratory chain. The drug is effective in treating mild to moderate cases of Pneumocystis pneumonia.

Pharmacokinetics

Atovaquone is well absorbed when taken with food, particularly high-fat meals, which significantly enhance its bioavailability. It has a long half-life, allowing for once-daily dosing, and is primarily eliminated through feces. Its metabolism does not involve significant liver enzymes, thus reducing the risk of drug interactions.

Adverse effects

• Agranulocytosis
• Haemolytic anaemia
• Headache
• Hepatic disorders
• Hypoalbuminaemia
• Insomnia
• Nausea
• Photosensitivity reaction
• Psychosis
• Severe cutaneous adverse reactions (SCARs)
• Skin reactions
• Tachycardia
• Vomiting

Interactions

• efavirenz: Severe (decreases exposure)
• rifabutin: Severe (decreases exposure)
• rifampicin: Severe (decreases exposure)
• metoclopramide: Unknown (decreases concentration)
• nirmatrelvir boosted with ritonavir: Unknown (decreases concentration)
• tetracycline: Unknown (decreases concentration)

Precautions

• Use with caution in significant hepatic impairment
• Caution in renal impairment, monitor closely
• Monitor for blood disorders
• Dapsone syndrome: discontinue immediately if occurs

Pregnancy

Manufacturer advises avoid unless potential benefit outweighs risk-no information available.

Breast-feeding

Manufacturer advises avoid. Significant amount in milk, risk to infant very small unless infant is G6PD deficient.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral suspension
• Oral liquid formulations

Indications

• Prevention of malaria
• Treatment of acute malaria
• Suppressive treatment of *P. vivax* malaria

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Proguanil inhibits the dihydrofolate reductase of plasmodia, blocking the biosynthesis of purines and pyrimidines necessary for DNA synthesis and cell multiplication. This inhibition leads to failure of nuclear division during the schizont formation in both erythrocytes and liver.

Pharmacodynamics

Proguanil, as a biguanide derivative, is converted into cycloguanil, which exerts its antimalarial effects by inhibiting the parasitic dihydrofolate reductase enzyme. It possesses causal prophylactic and suppressive activity against *P. falciparum* and is effective in treating acute infections while also suppressing clinical attacks of *P. vivax* malaria. Its action, however, is comparatively slower than that of 4-aminoquinoline derivatives.

Pharmacokinetics

Proguanil is well absorbed from the gastrointestinal tract, with its absorption potentially affected by the presence of antacids. It is metabolized in the liver to the active metabolite cycloguanil, which has a longer half-life and is responsible for the drug's therapeutic effects. The pharmacokinetics of proguanil can be influenced by factors such as liver function and the presence of other medications.

Interactions

• oral antacids: Unknown (decreases absorption)
• efavirenz: Unknown (affects exposure)

Pregnancy

Proguanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Proguanil is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Proguanil hydrochloride tablets

Mechanism of action

Proguanil 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.

Pharmacodynamics

Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against <i>P. falciparum</i> and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.