750 mg/5 ml oral suspension
Each ml of suspension contains 150 mg atovaquone.
A unit dose of 5 ml contains 750 mg atovaquone.
For the full list of excipients, see section 6.1.
Wellvone oral suspension is a bright yellow liquid.
Wellvone Suspension is indicated for:
Acute treatment of mild to moderate Pneumocystis pneumonia (PCP, caused by Pneumocystis jiroveci
, formerly classified as P. carinii
) (alveolar - arterial oxygen tension difference [(A-a) DO2
45 mmHg (6 kPa) and oxygen tension in arterial blood (PaO2
) ≥ 60 mmHg (8 kPa) breathing room air) in patients who are intolerant of co-trimoxazole therapy (see section 4.4).
The importance of taking the full prescribed dose of Wellvone with food
should be stressed to patients. The presence of food, particularly high fat food, increases bioavailability two to three fold.
Dosage in adultsPneumocystis
The recommended oral dose is 750 mg twice a day (1 x 5 ml morning and evening) administered with food each day for 21 days.
Higher doses may be more effective in some patients (see section 5.2).
Dosage in Children
Clinical efficacy has not been studied.
Dosage in Older people
There have been no studies of Wellvone in the elderly (see section 4.4).
Renal or hepatic impairment
Wellvone has not been specifically studied in patients with significant hepatic or renal impairment (see section 5.2 for pharmacokinetics in adults). If it is necessary to treat such patients with Wellvone, caution is advised and administration should be closely monitored.
Wellvone Suspension is contra-indicated in individuals with known hypersensitivity to atovaquone or to any of the excipients listed in section 6.1.
Diarrhoea at the start of treatment has been shown to be associated with significantly lower atovaquone plasma levels. These in turn correlated with a higher incidence of therapy failures and a lower survival rate. Therefore, alternative therapies should be considered for such patients and for patients who have difficulty taking Wellvone with food.
Patients receiving concurrent tetracycline should be closely monitored (see section 4.5).
The concomitant administration of atovaquone and efavirenz or boosted protease-inhibitors should be avoided whenever possible (see section 4.5).
The concomitant administration of atovaquone and rifampicin or rifabutin is not recommended (see section 4.5).
Concurrent use of metoclopramide is not recommended. Another antiemetic treatment should be given (see section 4.5).
Atovaquone can increase the levels of etoposide and its metabolite (see section 4.5).
The efficacy of Wellvone has not been systematically evaluated i) in patients failing other PCP therapy, including co-trimoxazole, ii) for treatment of severe episodes of PCP [(A-a) DO2
> 45 mmHg (6kPa)], iii) as a prophylactic agent for PCP, or iv) versus intravenous pentamidine for treatment of PCP.
No data are available in non-HIV immuno-compromised patients suffering with PCP.
No clinical experience of atovaquone treatment has been gained in elderly patients. Therefore use in the elderly should be closely monitored.
Patients with pulmonary disease should be carefully evaluated for causes of disease other than PCP and treated with additional agents as appropriate. Wellvone is not expected to be effective therapy for other fungal, bacterial, mycobacterial or viral diseases.
As experience is limited, care should be taken when combining other drugs with Wellvone.
Concomitant administration of rifampicin or rifabutin is not recommended as it is known to reduce plasma concentrations of atovaquone levels by approximately 50% and 34%, respectively, (see section 4.4).
Concomitant treatment with metoclopramide has been associated with a significant decrease (about 50%) in plasma concentrations of atovaquone (see section 4.4).Another antiemetic treatment should be given.
When given with efavirenz or boosted protease-inhibitors, atovaquone concentrations have been observed to decrease as much as 75%. This combination should be avoided whenever possible (see section 4.4).
Concomitant treatment with tetracycline has been associated with decreases in plasma concentrations of atovaquone.
The co-administration of atovaquone at doses of 45 mg/kg/day in children (n=9) with acute lymphoblastic leukaemia for prophylaxis of PCP was found to increase the plasma concentrations (AUC) of etoposide and its metabolite etoposide catechol by a median of 8.6% and 28.4% (respectively compared to the co-administration of etoposide and sulfamethoxazole-trimethoprim). Caution should be advised in patients receiving concomitant therapy with etoposide (see section 4.4).
In clinical trials of Wellvone small decreases in plasma concentrations of atovaquone (mean < 3 µg/ml) were associated with concomitant administration of paracetamol, benzodiazepines, acyclovir, opiates, cephalosporins, anti-diarrhoeals and laxatives. The causal relationship between the change in plasma concentrations of atovaquone and the administration of the drugs mentioned above is unknown.
Clinical trials have evaluated the interaction of Wellvone Tablets with:
Zidovudine - Zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of Wellvone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine.
Didanosine (ddI) - ddI does not affect the pharmacokinetics of atovaquone as determined in a prospective multidose drug interaction study of atovaquone and ddI. However, there was a 24% decrease in the AUC for ddI when co-administered with atovaquone which is unlikely to be of clinical significance.
Nevertheless, the modes of interaction being unknown, the effects of atovaquone administration on zidovudine and ddI may be greater with atovaquone suspension. The higher concentrations of atovaquone possible with the suspension might induce greater changes in the AUC values for zidovudine or ddI than those observed. Patients receiving atovaquone and zidovudine should be regularly monitored for zidovudine associated adverse effects.
Concomitant administration of Wellvone and indinavir results in a significant decrease in the Cmin
of indinavir (23% decrease; 90% CI 8-35%) and the AUC (9% decrease; 90% CI 1-18%). Caution should be exercised on the potential risk of failure of indinavir treatment if co-administered with atovaquone.
In clinical trials of Wellvone the following medications were not associated with a change in steady state plasma concentrations of atovaquone: fluconazole, clotrimazole, ketoconazole, antacids, systemic corticosteroids, non-steroidal anti-inflammatory drugs, anti-emetics (excluding metoclopramide) and H2
Atovaquone is highly bound to plasma proteins and caution should be used when administering Wellvone concurrently with other highly plasma protein bound drugs with narrow therapeutic indices. Atovaquone does not affect the pharmacokinetics, metabolism or extent of protein binding of phenytoin in vivo
. In vitro
there is no plasma protein binding interaction between atovaquone and quinine, phenytoin, warfarin, sulfamethoxazole, indometacin or diazepam.
There is no information on the effects of atovaquone administration during human pregnancy. Atovaquone should not be used during pregnancy unless the benefit of treatment to the mother outweighs any possible risk to the developing foetus.
Insufficient data are available from animal experiments to assess the possible risk to reproductive potential or performance.
It is not known whether atovaquone is excreted in human milk, and therefore breast feeding is not recommended.
There have been no studies to investigate the effect of Wellvone on driving performance or the ability to operate machinery but a detrimental effect on such activities is not predicted from the pharmacology of the drug.
Patients participating in clinical trials with atovaquone have often experienced undesirable effects consistent with the course of advanced Human Immunodeficiency Virus (HIV) disease or of concomitant therapy. The following adverse reactions have been observed and reported to have a suspected (at least possible) causal relationship to treatment with atovaquone with the following frequencies:
The following convention is used for frequencies: 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); very rare (< 1/10 000); not known (cannot be estimated from the available data).
| Blood and the lymphatic system disorders
|| anaemia, neutropenia
| Metabolism and nutrition disorders
| Psychiatric disorders
| Nervous system disorders
| Gastrointestinal disorders
| Very common:
|| diarrhoea, vomiting
| Hepatobiliary disorders
|| elevated liver enzymes levels
| Immune System Disorders
|| hypersensitivity reactions including angioedema, bronchospasm and throat tightness
| Skin and subcutaneous tissue disorders
| Very common:
|| rash, pruritus
| Not known:
|| erythema multiforme, Stevens-Johnson Syndrome
| General disorders and administration site conditions
|| elevated amylase levels
Reporting of suspected adverse reactions
Reporting 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 at: www.mhra.gov.uk/yellowcard
There is insufficient experience to predict the consequences or suggest specific management of atovaquone overdose. However, in the reported cases of overdosage, the observed effects were consistent with known undesirable effects of the drug. If overdosage occurs, the patient should be monitored and standard supportive treatment applied.
Pharmacotherapeutic group: Antiprotozoals,
ATC Code: P01A X06.
Mode of Action
Atovaquone is a selective and potent inhibitor of the eukaryotic mitochondrial electron transport chain in a number of parasitic protozoa and the parasitic fungus P. jiroveci
. The site of action appears to be the cytochrome bc1 complex (complex III). The ultimate metabolic effect of such blockade is likely to be inhibition of nucleic acid and ATP synthesis.
Atovaquone has potent activity against Pneumocystic
sp, both in vitro
and in animal models, (IC50
Atovaquone is a highly lipophilic compound with a low aqueous solubility. It is 99.9% bound to plasma proteins. The bioavailability of the drug demonstrates a relative decrease with single doses above 750 mg, and shows considerable inter-individual variability. Average absolute bioavailablility of a 750 mg single dose of atovaquone suspension administered with food to adult HIV positive males is 47% (compared to 23% for Wellvone tablets). Following the intravenous administration, the volume of distribution and clearance were calculated to be 0.62±0.19 l/kg and 0.15±0.09 ml/min/kg, respectively.
The bioavailability of atovaquone is greater when administered with food than in the fasting state. In healthy volunteers, a standardized breakfast (23 g fat; 610 kCal) increased bioavailability two to three-fold following a single 750 mg dose. The mean area under the atovaquone plasma concentration-time curve (AUC) was increased 2.5 fold and the mean Cmax
was increased 3.4 fold. The mean (±SD) AUC values for suspension were 324.3 (±115.0) µg/ml.h fasted and 800.6 (±319.8) µg/ml.h with food.
In a safety and pharmacokinetic study in patients with PCP, the following results were obtained:
750 mg twice daily
1000 mg twice daily
Number of Patients
C avg, ss (range)
22 µg/ml (6-41)
25.7 µg/ml (15-36)
% of patients with C avg, ss >15 µg/ml
In a small safety and pharmacokinetic study of two higher dosing regimens [750 mg three times daily (n=8) and 1500 mg twice daily (n=8)] in HIV infected volunteers with severity criteria comparable to patients with PCP, similar Cavg were reached with the two doses [for the 750 mg tid and 1500 mg bid doses: 24.8 (7-40) and 23.4 µg/ml (7-35) respectively]. Moreover, for both doses a Cavg, ss >15 µg/ml was reached in 87.5% of patients.
Average steady state concentrations above 15 µg/ml are predictive of a high (>90%) success rate.
In healthy volunteers and patients with AIDS, atovaquone has a half-life of 2 to 3 days.
In healthy volunteers there is no evidence that the drug is metabolised and there is negligible excretion of atovaquone in the urine, with parent drug being predominantly (>90%) excreted unchanged in faeces.
Oncogenicity studies in mice showed an increased incidence of hepatocellular adenomas and carcinomas without determination of the no observed adverse effect level. 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 not predictive of a risk in the clinical situation.
In the dosage range of 600 to 1200 mg/kg studies in rabbits gave indications of maternal and embryotoxic effects.
Tutti Frutti Flavour (Firmenich 51.880/A) containing sweet orange oil, concentrated orange oil, propylene glycol, benzyl alcohol, vanillin, acetic aldehyde, amyl acetate and ethyl butyrate.
After first opening, the suspension may be stored for up to 21 days.
Do not store above 25°C.
Do not freeze.
A 240 ml high density polyethylene bottle with child resistant polypropylene closure, containing 226 ml of atovaquone suspension.
A 5 ml measuring spoon (polypropylene) is included.
Do not dilute
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Glaxo Wellcome UK Ltd
Stockley Park West
Date of first authorisation: 23 August 1994
Date of latest renewal: 25 May 2006.