Proguanil and Atovaquone interacts in the following cases:
In patients with severe renal impairment (creatine clearance <30 mL/min) alternatives to Malarone for treatment of acute P. falciparum malaria should be recommended whenever possible.
The safety of atovaquone and proguanil hydrochloride when administered concurrently for use in human pregnancy has not been established and the potential risk is unknown.
Animal studies showed no evidence for teratogenicity of the combination. The individual components have shown no effects on parturition or pre- and post-natal development. Maternal toxicity was seen in pregnant rabbits during a teratogenicity study.
The use of atovaquone/proguanil in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.
The proguanil component of atovaquone/proguanil acts by inhibiting parasitic dihydrofolate reductase. There are no clinical data indicating that folate supplementation diminishes drug efficacy. For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements should be continued while taking atovaquone/proguanil.
The atovaquone concentrations in milk, in a rat study, were 30% of the concurrent atovaquone concentrations in maternal plasma. It is not known whether atovaquone is excreted in human milk.
Proguanil is excreted in human milk in small quantities.
Atovaquone/proguanil should not be taken by breast-feeding women.
Dizziness has been reported. Patients should be warned that if affected they should not drive, operate machinery or take part in activities where this may put themselves or others at risk.
In clinical trials of atovaquone/proguanil for prophylaxis of malaria, 357 children or adolescents 11 to ≤40 kg body weight received atovaquone/proguanil tablets. Most of these were residents of endemic areas and took atovaquone/proguanil for about 12 weeks. The rest were travelling to endemic areas, and most took atovaquone/proguanil for 2-4 weeks.
Open label clinical studies investigating the treatment of children weighing between ≥5 kg and <11 kg have indicated that the safety profile is similar to that in children weighing between 11 kg and 40 kg, and adults.
There are limited long term safety data in children. In particular, the long-term effects of atovaquone/proguanil on growth, puberty and general development have not been studied.
In clinical trials of atovaquone/proguanil for treatment of malaria, the most commonly reported adverse reactions were abdominal pain, headache, anorexia, nausea, vomiting, diarrhoea and coughing.
In clinical trials of atovaquone/proguanil for prophylaxis of malaria, the most commonly reported adverse reactions were headache, abdominal pain and diarrhoea.
The following table provides a summary of adverse reactions that have been reported to have a suspected (at least possible) causal relationship to treatment with atovaquone-proguanil in clinical trials and spontaneous post-marketing reports. The following convention is used for the classification of frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).
| System Organ Class | Very Common | Common | Uncommon | Rare | Not known2 |
|---|---|---|---|---|---|
| Blood and lymphatic disorders | Anaemia Neutropenia1 | Pancytopenia | |||
| Immune system disorders | Allergic reactions | Angioedema3 Anaphylaxis Vasculitis3 | |||
| Metabolism and nutrition disorders | Hyponatraemia1 Anorexia | Elevated amylase levels1 | |||
| Psychiatric disorders | Abnormal dreams Depression | Anxiety | Hallucinations | Panic attack Crying Nightmares Psychotic disorder | |
| Nervous system disorders | Headache | Insomnia Dizziness | Seizure | ||
| Cardiac disorders | Palpitations | Tachycardia | |||
| Gastrointestinal disorders | Nausea1 Vomiting Diarrhoea Abdominal pain | Stomatitis | Gastric intolerance3 Oral ulceration3 | ||
| Hepatobiliary disorders | Elevated liver enzymes1 | Hepatitis Cholestasis3 | |||
| Skin and subcutaneous tissue disorders | Pruritus Rash | Hair loss Urticaria | Stevens-Johnson syndrome Erythema multiforme Blister Skin exfoliation Photosensitivity reactions | ||
| General disorders and administration site conditions | Fever | ||||
| Respiratory, thoracic and mediastinal disorders | Cough |
1 Frequency taken from atovaquone label. Patients participating in clinical trials with atovaquone have received higher doses and have often had complications of advance Human Immunodeficiency Virus (HIV) disease. These events may have been seen at a lower frequency or not at all in clinical trials with atovaquone-proguanil.
2 Observed from post-marketing spontaneous reports and the frequency is therefore unknown.
3 Observed with proguanil.
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