- proguanil hydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
PosologyThe dosage for the prophylaxis and treatment of acute, uncomplicated P. falciparum malaria in children is based on body weight.PROPHYLAXIS
Dosage in adults and children weighing 11-40 kg
|Body Weight Range (kg)||Atovaquone (mg)||Proguanil (mg)||No of Tablets|
|11-20||62.5||25||One Reprapog tablet|
|21-30||125||50||Two Reprapog tablets|
|31-40||187.5||75||Three Reprapog tablets|
|>40||250||100||Subjects of >40 kg should receive ONE tablet daily containing 250 mg atovaquone and 100 mg proguanil hydrochloride.|
Dosage in children weighing 5-11 kg
|Body Weight Range (kg)||Atovaquone (mg)||Proguanil (mg)||Dosage Regimen|
|5-8||125||50||Two Reprapog tablets daily for 3 consecutive days|
|9-10||187.5||75||Three Reprapog tablets daily for 3 consecutive days.|
Dosage in hepatic impairmentThere are no studies in children with hepatic impairment. However, a pharmacokinetic study in adults indicates that no dosage adjustments are needed in patients with mild to moderate hepatic impairment. Although no studies have been conducted in patients with severe hepatic impairment, no special precautions or dosage adjustment are anticipated (see section 5.2).
Dosage in renal impairmentThere are no studies in children with renal impairment. However, pharmacokinetic studies in adults indicate that no dosage adjustments are needed in those with mild to moderate renal impairment. Due to the lack of information regarding appropriate dosing, Reprapog is contraindicated for the prophylaxis of malaria in adults and children with severe renal impairment (creatinine clearance <30 mL/min; see sections 4.3 and 5.2).
Method of administrationThe daily dose should be taken once daily with food or a milky drink (to ensure maximum absorption) at the same time each day.If patients are unable to tolerate food Reprapog should be administered, but systemic exposure of atovaquone will be reduced. In the event of vomiting within 1-hour of dosing a repeat dose should be taken.Reprapog should preferably be swallowed whole. If difficulties are encountered when dosing young children, the tablets may be crushed and mixed with food or a milky drink just prior to administration.
PregnancyThe 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. In rabbits treated with atovaquone during pregnancy, embryotoxicity was observed only in the presence of maternal toxicity (see section 5.3).The use of Reprapog in pregnancy should only be considered if the expected benefit to the mother outweighs any potential risk to the foetus.The proguanil component of Reprapog 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 Reprapog.
Breast-feedingThe 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.Reprapog should not be taken by breast-feeding women.
FertilityNo data are available regarding the effects of the combination on fertility, but in animal studies the individual components atovaquone and proguanil have shown no effects on fertility.
|System Organ Class||Very Common||Common||Uncommon||Not known2|
|Blood and lymphatic disorders||Anaemia Neutropenia1||Pancytopenia|
|Immune system disorders||Allergic reactions||Angioedema3 Anaphylaxis (see section 4.4) Vasculitis3|
|Metabolism and nutrition disorders||Hyponatraemia1 Anorexia||Elevated amylase levels1|
|Psychiatric disorders||Abnormal dreams Depression||Anxiety||Panic attack Crying Hallucination Nightmares|
|Nervous system disorders||Headache||Insomnia Dizziness||Seizure|
|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|
Paediatric populationIn clinical trials with tablets containing atovaquone 62.5 mg/proguanil hydrochloride 25 mg for the prophylaxis of malaria, 357 children or adolescents 11 to ≤ 40 kg body weight received atovaquone/proguanil. Most of these were residents of endemic areas and took atorvaquone/proguanil tablets for about 12 weeks. The rest were travelling to endemic areas, and most took atorvaquone/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 atorvaquone/proguanil on growth, puberty and general development have not been studied.
Reporting of suspected adverse reactionsReporting 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 (www.mhra.gov.uk/yellowcard).
Mechanism of actionReprapog is a fixed dose combination of atovaquone and proguanil hydrochloride, which acts as a blood schizonticide and also has activity against hepatic schizonts of Plasmodium falciparum. Atovaquone and proguanil hydrochloride interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil. Proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may contribute to the antimalarial synergy seen when atovaquone and proguanil are used in combination.
MicrobiologyAtovaquone has potency against Plasmodium spp (in vitro IC50 against P. falciparum 0.23-1.43 ng/mL).
ResistanceIn in vitro studies with more than 30 P. falciparum isolates, resistance had been detected against chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates), and halofantrine (48% of isolates) and not against atovaquone (0% of isolates).However, regarding in vivo data, cases of failures to respond to atovaquone/proguanil associated with resistance of P. falciparum strains have been published. The mechanism of resistance has not been entirely elucidated. It may include involvement of point mutations in the target gene of atovaquone, P. falciparum mitochondrial cytochrome b gene.The prevalence of resistance may vary geographically and with time. Information on resistance can be obtained from official guidelines such as public health authorities' and WHO guidelines.
ProphylaxisThe efficacy in non-immune paediatric travellers has not been directly established, but may be assumed through extrapolation by the results on safety and efficacy in studies of up to 12 weeks in paediatric residents (semi-immune) of endemic areas, and from results of safety and efficacy in both semi-immune and non-immune adults.Data in the paediatric population are available from two trials that primarily evaluated the safety of atovaquone/proguanil paediatric tablets in (non-immune) travellers to endemic areas. In these trials, a total of 93 travellers weighing <40 kg were given atovaquone/proguanil and 93 received another prophylactic antimalarial regimen (81 chloroquine/proguanil and 12 mefloquine). The majority of travellers went to Africa and the mean duration of stay was between 2-3 weeks. There were no cases of malaria recorded in any subjects who took part in these studies.
TreatmentAn open-label, randomised, parallel-group trial was undertaken in Gabon in 200 children weighing ≥5 kg and <11 kg with confirmed, uncomplicated P. falciparum malaria. Treatment was with atovaquone/proguanil paediatric tablets or amodiaquine suspension. In the intent-to-treat population, the 28-day cure rate was 87% in the atovaquone/proguanil group (87/100 subjects). In the per-protocol population, the 28-day cure rate was 95% in the atovaquone/proguanil group (87/92 subjects). The parasitological cure rates for the atovaquone/proguanil group were 88% and 95% for the ITT and PP populations, respectively.
|62.5 mg/25 mg||125 mg/50 mg||187.5 mg/75 mg||250mg/100 mg|
|[Weight Category]||[11-20 kg]||[21-30 kg]||[31-40 kg]||Adult (>40 kg)|
|Atovaquone (μg/mL) No. Subjects||2.2 + 1.1 (0.2-5.8) n=87||3.2 + 1.8 (0.2-10.9) n=88||4.1 + 1.8 (0.7-8.8) n=76||2.1 + 1.2 (0.1-5.7) n=100|
|Proguanil (ng/mL) No. Subjects||12.3 + 14.4 (<5.0-14.3) n=72||18.8 + 11.2 (<5.0-87.0) n=83||26.8 + 17.1 (5.1-55.9) n=75||26.8 + 14.0 (5.2-73.2) n=95|
|Cycloguanil (ng/mL) No. Subjects||7.7 + 7.2 (<5.0-43.5) n=58||8.1 + 6.3 (<5.0-44.1) n=69||8.7 + 7.3 (6.4-17.0) n=66||10.9 + 5.6 (5.0-37.8) n=95|
AbsorptionAtovaquone is a highly lipophilic compound with low aqueous solubility. Although there are no atovaquone bioavailability data in healthy subjects, in HIV-infected patients, the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 21% (90% CI: 17%-27%).Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. Patients are recommended to take Reprapog tablets with food or a milky drink (see section 4.2).Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.
DistributionApparent volume of distribution of atovaquone and proguanil is a function of bodyweight.Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.Following oral administration, the volume of distribution of atovaquone and proguanil is approximately 8.8 L/kg.Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults and children (> 5 kg) ranged from 20 to 79 L/kg.In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the other.
BiotransformationThere is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450 isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites cycloguanil and 4-chlorophenylbiguanide are also excreted in the urine.During administration of atovaquone/proguanil at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.
EliminationThe elimination half-life of atovaquone is 1-2 days in children.The elimination half-lives of proguanil and cycloguanil are each about 12-15 hours in children.Oral clearance for atovaquone and proguanil increases with increased body weight and is about 70% higher in a 40 kg subject relative to a 20 kg subject. The mean oral clearance in paediatric and adult patients weighing 5 to 40 kg ranged from 0.5 to 6.3 L/h for atovaquone and from 8.7 to 64 L/h for proguanil.
Pharmacokinetics in renal impairmentThere are no studies in children with renal impairment.In adult patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function.Atovaquone Cmax and AUC are reduced by 64% and 54%, respectively, in adult patients with severe renal impairment (<30 mL/min/1.73 m2).In adult patients with severe renal impairment, the elimination half-lives for proguanil (t½ 39 hours) and cycloguanil (t½ 37 hours) are prolonged, resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and 4.4).
Pharmacokinetics in hepatic impairmentThere are no studies in children with hepatic impairment.In adult patients with mild to moderate hepatic impairment, there is no clinically significant change in exposure to atovaquone when compared to healthy patients.In adult patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC, with no change in elimination half-life, and there is a 65-68% decrease in Cmax and AUC for cycloguanil.No data are available in adult patients with severe hepatic impairment (see section 4.2).
Repeat dose toxicityFindings in repeat dose toxicity studies with atovaquone/proguanil hydrochloride combination were entirely proguanil related and were observed at doses providing no significant margin of exposure in comparison with the expected clinical exposure. However, as proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in the combination, these findings are considered of little relevance to the clinical situation.
Reproductive toxicity studiesIn rats and rabbits there was no evidence of teratogenicity for the combination. No data are available regarding the effects of the combination on fertility or pre- and post-natal development, but studies on the individual components have shown no effects on these parameters. In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria. Adverse foetal effects in rabbits, including decreased foetal body lengths, increased early resorptions and post-implantation losses, were observed only in the presence of maternal toxicity. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit foetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.
MutagenicityA wide range of mutagenicity tests have shown no evidence that atovaquone or proguanil have mutagenic activity as single agents.Mutagenicity studies have not been performed with atovaquone in combination with proguanil.Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil (a dihydrofolate antagonist) were significantly reduced or abolished with folinic acid supplementation.
CarcinogencityOncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular adenomas and carcinomas. No such findings were observed in rats and mutagenicity tests were negative. These findings appear to be due to the inherent susceptibility of mice to atovaquone and are considered of no relevance in the clinical situation.Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice.Oncogenicity studies on proguanil in combination with atovaquone have not been performed.
Tablet corePoloxamerMicrocrystalline CelluloseLow-substituted Hydroxypropyl Cellulose Povidone K30Sodium Starch Glycolate (Type A)Magnesium StearateSilica colloidal anhydrous
CoatingHypromelloseTitanium dioxide (E171) MacrogolIron Oxide Red (E172)