PRODUCT INFORMATION. WELLVONE suspension is for oral administration and contains atovaquone 750 mg in 5 ml.

Transcription

1 PRODUCT INFORMATION WELLVONE SUSPENSION NAME OF DRUG: Atovaquone DESCRIPTION: The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4- naphthoquinone, with a molecular formula C 22 H 19 ClO 3 and a relative molecular mass of It is an extremely insoluble yellow crystalline powder. Solubility at 25 C in water and 0.1 M hydrochloric acid is <2x10-4 mg/ml; in 0.1 M sodium hydroxide it is 1.7 mg/ml. WELLVONE suspension is for oral administration and contains atovaquone 750 mg in 5 ml. PHARMACOLOGY: Mode of Action Atovaquone is a hydroxy-1,4-naphthoquinone, an analogue of ubiquinone, with antipneumocystis activity. Atovaquone belongs to a therapeutic class with a novel mechanism of action. It is a selective and potent inhibitor of the eukaryotic mitochondrial electron transport chain in a number of parasitic protozoa. 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. Microbiology Atovaquone has potent antiprotozoal activity, both in vitro and in animal models, particularly against the parasitic protozoa Pneumocystis carinii (IC µm), Toxoplasma gondii (IC µm) and Plasmodium species (eg P. falciparum IC nm). Pharmacokinetics in adults: Atovaquone is a highly lipophilic compound with a low aqueous solubility. It is 99% bound to plasma proteins. The bioavailability of the drug demonstrates a relative decrease with single doses above 750 mg and multiple doses over 750 mg, and shows considerable interindividual variability. Average absolute bioavailability of a 750 mg single dose of atovaquone suspension administered with food to adult HIV positive males is 47%. The bioavailability of atovaquone is increased greatly when administered with food than in the fasting state. In healthy volunteers, a standardised breakfast (23 g fat; 610 kcal) increased Issue4 1

2 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 C max was increased 3.4 fold. The mean (±SD) AUC values for suspension were (±115.0) µg/ml.hr fasted and (±319.8) µg/ml.hr with food. Significant differences in the bioavailability of atovaquone have been observed between healthy volunteers, asymptomatic HIV-infected volunteers and people with AIDS. In separate studies using the tablet formulation, steady state atovaquone plasma concentrations in people with AIDS ranged from one third to one half of the levels achieved in asymptomatic HIVinfected volunteers. For example, in volunteers with AIDS a dose of 3000 mg once daily produced a mean (±SD) maximum steady-state plasma concentration of 16.2 ± 6.6 µg/ml, compared with asymptomatic HIV-infected volunteers who achieved 48.8 ± 21.6 µg/ml. In a safety and pharmacokinetics study in which patients with PCP received treatment with 750 mg atovaquone suspension twice daily the mean (±SD) steady state plasma concentration (C avg,ss ) was 22.0 (± 10.1) µg/ml. Twelve of eighteen patients (67%) achieved a C avg,ss level of 15 µg/ml after 21 days of treatment. The mean C avg,ss for the 1500 mg once daily treatment regimen was slightly lower at 17.6 µg/ml (±8.1; n = 9). On pharmacokinetic grounds, the daily dose of 1500 mg might be taken as a single daily dose or divided between two daily doses. Previous study with the tablet formulation showed average steady state plasma concentrations of 15 µg/ml are predictive of high (> 90%) successful treatment rate (See Clinical Studies), therefore it is important to use twice daily dosing for Wellvone suspension to provide a higher plasma atovaquone concentration. The dependence of the absorption of atovaquone on a concomitant meal should be noted. In healthy volunteers and people 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. Pharmacokinetics in children: There are no studies on the use of Wellvone suspension in children. Studies using Wellvone tablets showed in children with AIDS, the pharmacokinetics of atovaquone appear to be similar to adults with AIDS. In 3 HIV positive children receiving atovaquone at a dose of 40 mg/kg/day, which approximates to the adult dose, maximum steady state concentrations ranged between 13 and 22 µg/ml. The average half-life is 2.6 days. CLINICAL STUDIES A comparative study of atovaquone with trimethoprim-sulphamethoxazole for the oral treatment of mild to moderate PCP was conducted in AIDS patients receiving 750 mg atovaquone tablets three times daily for 21 days, the mean steady-state atovaquone concentration was 13.0 μg/ml (n=133). Analysis of this data established a relationship between plasma atovaquone concentration and successful treatment. The dosing regimen for atovaquone suspension has been selected to achieve average plasma atovaquone concentrations of approximately 20 μg/ml because this concentration was previously shown to be well tolerated and associated with the highest treatment success rates (see table below). Steady-State Plasma Atovaquone Concentration (μg/ml) Successful Treatment* Number of Successes/ % Issue4 2

3 Number in Group 0 to <5 0/6 0 5 to <10 18/ to <15 30/ to <20 18/ to <25 18/ >25 6/6 100 Successful treatment was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Atovaquone Suspension Open Label Study In an open-label PCP treatment study with atovaquone suspension, dosing regimens of 1000 mg once daily, 750 mg twice daily, 1500 mg once daily and 1000 mg twice daily were administered to AIDS patients with PCP. The average steady-state plasma atovaquone concentration (± SD), achieved at 750 mg twice daily dose, given with meals was 22.0 ± 10.1 μg/ml (n=18). Sixty-seven percent (12/18) and sixty-one percent (11/18) achieved plasma atovaquone concentration of 15 μg/ml and 20 μg/ml, respectively. Sixty-two percent of patients treated with Wellvone suspension in this trial were successfully treated, regardless of the dosing regimen used. The small number of patients enrolled in each cohort precludes precise inferences about the relative efficacy of Wellvone suspension compared to the tablet formulation. The outcome of treatment is shown below: Outcome of Therapy Atovaquone Suspension: Number of Patients (% of Total) 1000 mg once daily (n = 22) Therapy Success* 14 (63.6%) Therapy Failure 750 mg twice daily (n = 24) 12 (50.0%) 1500 mg once daily (n = 11) 1000 mg twice daily (n = 12) Total (n = 69) 8 (72.7%) 9 (75.0%) 43 (62.3%) - Lack of Response 6 (27.3%) 7 (29.2%) 2 (18.2%) 2 (16.7%) 17 (24.6%) - Unevaluable 2 (9.1%) 2 (8.3%) 1 (9.1%) 1 (8.3%) 6 (8.7%) - Adverse Experience 0 (0.0%) 3 (12.5%) 0 (0.0%) 0 (0.0%) 3 (4.3%) * Defined as an improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Comparative Study Atovaquone tablets versus trimethoprim-sulphamethoxazole (TMP- SMX): A double-blind, randomised, multicentre efficacy and safety study was conducted in 408 adult AIDS patients with mild to moderate PCP. Eighty-six patients without histological confirmation of PCP were excluded from the efficacy analyses but were included in the safety analyses (see ADVERSE REACTIONS, Tables 1 and 2). Of the 322 patients with histologically confirmed PCP, 160 received atovaquone (three 750 mg tablets, tds) and 162 received TMP- SMX (320 mg TMP and 1600 mg SMX, tds). Treatment was administered for 21 days. Sixty-two percent of patients on atovaquone and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes. The outcome of treatment is shown below. The failure rate due to lack of response was significantly larger for patients receiving atovaquone Issue4 3

4 while the failure rate due to adverse experiences was significantly larger for pateints receiving TMP-SMX. Outcome of Therapy # Number of Patients (% of Total) Atovaquone tablets (n=160) TMP-SMX (n=162) % of Total n % of Total n Therapy Success* Therapy Failure Lack of Response Adverse Experience Unevaluable 17 a 7 a 14 b Required Alternate PCP Therapy During Study * Defined as an improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. # During 21 day treatment period or during the 8 week follow-up period. a P < 0.01; b P = Mortality rates assessed during the 21 treatment period or during the 8 week follow-up period were significantly different between groups (P=0.03). Of the 13 patients treated with atovaquone who died, four died of PCP and five died with a combination of bacterial infections and PCP. Bacterial infections did not appear to be a factor in any of the four deaths among TMP-SMX-treated patients. In the intent-to- treat analysis (n=408 patients), the mortality rate was 8% and 3.4%, respectively, in the atovaquone and TMP-SMX arms (P=0.051). A correlation between plasma atovaquone concentrations and death was demonstrated. For those patients for whom plasma atovaquone levels were available at day 4, five (63%) of the eight patients with concentrations <5 μg/ml died during the study. However, only one (2.0%) of the 49 patients with day 4 plasma atovaquone levels 5 μg/ml died. Comparative Study Atovaquone versus Pentamidine: An open-label, randomised, multicentre efficacy and safety study was conducted in 174 adult AIDS patients. Thirty-nine patients without histological confirmation of mild or moderate PCP were excluded from the efficacy analyses (see ADVERSE REACTIONS, Tables 3 and 4). Approximately 80% of patients had a history of intolerance to TMP or sulphur containing antibiotics (primary therapy group) or were experiencing intolerance to TMP-SMX (salvage treatment group). Of the 134 patients with histologically confirmed PCP, 70 were randomised to receive atovaquone (three 750 mg tablets, tds for 21 days) and 64 to pentamidine (single daily iv infusion of 3 to 4 mg/kg for 21 days). The therapeutic outcome is shown below. Outcome of Therapy Primary Treatment Atovaquone tablets (n=56) Pentamidine i.v. (n=53) Salvage Treatment Atovaquone tablets (n=14) Pentamidine i.v. (n=11) %* (n) %* (n) %* (n) %* (n) Therapy success 57 (32) 40 (21) 93 (13) 64 (7) Issue4 4

5 Therapy Failure Lack of response Adverse Experience Unevaluable a 11 (16) (2) (6) (9) (19) (4) (0) (0) (1) (0) (3) (1) Required alternate PCP therapy during study 34 c (19) 55 (29) - (0) 36 b (4) * Percentage of total a P < 0.01, b P=0.03, c P=0.04 During the 21 day treatment period and follow-up period (8 weeks), mortality rates were similar between the treatment groups; 14% for either atovaquone and pentamidine groups. The mortality rate was similar for the intent-to treat analysis. In patients for whom day 4 plasma atovaquone levels were available, 3 (60%) of 5 that had concentrations <5 μg/ml, died during the study period. However, only 2 (9%) of 21 of patients with day 4 plasma atovaquone 5 μg/ml died. INDICATIONS: Wellvone Suspension is indicated for: Acute treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) (difference of alveolar and arterial oxygen tensions [(A-a) DO 2 ] 45 mmhg (6 kpa) and oxygen tension in arterial blood (Pa0 2 ) 60 mmhg (8 kpa) breathing room air) in adult patients with AIDS who are intolerant of trimethoprim/sulphamethoxazole therapy. CONTRA-INDICATIONS: Wellvone suspension is contra-indicated in individuals with known hypersensitivity to atovaquone or to any components of the formulation. Issue4 5

6 PRECAUTIONS: Atovaquone has not been systematically evaluated I) in patients failing other PCP therapy, ii) for the treatment of severe episodes of PCP [(A-a) DO 2 > 45 mmhg (6 kpa)], or iii) as a prophylactic agent for PCP. Absorption of atovaquone is limited but can be significantly increased when the drug is taken with food. In clinical studies using atovaquone tablets, atovaquone plasma concentrations have been shown to correlate generally with the likelihood of successful treatment and survival. There is limited efficacy data on atovaquone suspension that examined the correlation between plasma concentration and treatment success rate. Gastro-intestinal disorders may further reduce absorption of orally administered drugs and patients may not achieve plasma levels of atovaquone associated with response to therapy. Therefore, alternative therapies should be considered for such patients and for patients who have difficulty taking WELLVONE with food. The prescriber must be aware that diarrhoea at the start of treatment has been shown to be correlated with higher incidences of therapy failures and a lower survival rate. Therefore, alternative therapies should be considered for such patients. Patients with pulmonary disease should be carefully evaluated for causes of disease other than PCP and treated with additional agents as appropriate. Atovaquone is not expected to be effective therapy for concurrent bacterial, viral, fungal or mycobacterial diseases. The concomitant administration of atovaquone and rifampicin is not recommended. A potential drug interaction has been reported for concomitant administration of zidovudine and rifabutin with atovaquone (see Interactions with Other Drugs). Carcinogenicity, mutagenicity and impairment of fertility Oncogenicity studies in mice showed an increased incidence of hepatocellular adenomas and carcinomas at all dose levels tested. Studies in rats at dose of up to 500 mg/kg/day were negative. There was no evidence that atovaquone was mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and in mouse bone marrow micronucleus assays for chromosome damage in vivo. There are no data on the effect of atovaquone on human fertility. Data from animal studies show that atovaquone does not affect reproductive potential or performance at oral doses up to 1000 mg/kg. In dosage range of 600 to 1200 mg/kg in rabbits gave indications of maternal and embryotoxic effects. At these doses maternal toxicity was observed, as demonstrated by weight loss, decrease in food consumption and foetal loss, was accompanied by both lower foetal body weight and foetal length. There were no teratogenic effects observed even at maternally toxic doses. Use in Pregnancy (Category B2) There is no information on 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. Issue4 6

7 Use in Lactation It is not known whether atovaquone is excreted in human milk and breast feeding is not recommended. Renal impairment Atovaquone has not been specifically studied in patients with significant renal impairment. There is no theoretical reason for patients with renal impairment to be at increased risk (see PHARMACOLOGY, Pharmacokinetics in adults). Hepatic impairment Atovaquone has not been specifically studied in patients with impaired hepatic function. Elimination of atovaquone is substantially liver dependent. Use in children Experience with atovaquone tablets in the paediatric population shows it to be well tolerated, but data are limited to a pharmacokinetic and safety study (see Pharmacokinetics in children). There is no data from clinical studies using atovaquone suspension in the paediatric population. Use in the Elderly No clinical experience of atovaquone treatment has been gained in patients over 65 years of age. Therefore use in the elderly should be closely monitored reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population. Interactions with other Drugs: As experience is limited, care should be taken when combining other drugs with atovaquone. The causal relationship between the change in plasma concentrations of atovaquone and the administration of the drugs mentioned below is unknown. Concomitant treatment with metoclopramide and rifampicin has been associated with significant decreases in plasma concentrations of atovaquone (mean decreases of 4.0 and 7.6 µg/ml, respectively). Concomitant administration of tetracycline with atovaquone is associated with approximately 40% lower plasma atovaquone concentration. Caution should be exercised in prescribing either of these drugs with atovaquone until the potential interaction has been further studied. Concomitant administration of rifabutin and WELLVONE has been associated with a moderate reduction in the steady state plasma concentrations of both atovaquone (on average by 34%) and rifabutin (on average by 19%). In clinical trials of atovaquone, small decreases in plasma concentrations of atovaquone (mean <3 µg/ml) were associated with concomitant administration of paracetamol, benzodiazepines, aciclovir, opiates, cephalosporins, anti-diarrhoeals and laxatives. The causal relationship between the change in plasma concentrations of atovaquone and the administration of these drugs is unknown. 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 atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy. There are no data available for other antiretrovirals. Issue4 7

8 In clinical trials of atovaquone 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 H 2 -antagonists. Atovaquone is highly bound to plasma proteins and caution should be used when administering concurrently with other highly plasma protein bound drugs with narrow therapeutic indices. e.g. warfarin. There is no plasma protein binding interaction between atovaquone and quinine, or phenytoin in vitro. Concomitant administration of WELLVONE and indinavir results in a significant decrease in the Cmin of indinavir (23% decrease ; 90% CI 8-35%). Caution should be exercised in prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir. ADVERSE REACTIONS: Patients participating in clinical trials with atovaquone have often had complications of advanced Human Immunodeficiency Virus (HIV) disease and therefore the causal relationship between the adverse experiences and atovaquone is difficult to evaluate. No life-threatening or fatal adverse experiences have been specifically attributed to atovaquone. Table 1 summarises common adverse experiences (frequency 10%) reported in a pharmacokinetic study of atovaquone suspension for the treatment of PCP in adult patients with AIDS. Issue4 8

9 Table 1 Treatment-Emergent Adverse Experience ATQ Suspension 1000 mg once daily (n = 30) Non-drug related Adverse Events ATQ Suspension 750 mg twice daily (n = 26) ATQ Suspension 1500 mg once daily (n = 13) ATQ Suspension 1000 mg twice daily (n = 13) Total (n = 82) Total Drug related Adverse Events (n=82) Body as a whole Fever 6 (20%) 11 (42%) 4 (31%) 6 (46%) 27 (33%) 3 (4%) Headache 5 (17%) 4 (15%) 2 (15%) 1 (8%) 12 (15%) 0 (0%) Abdominal pain 4 (13%) 4 (15%) 1 (8%) 2 (15%) 11 (13%) 2 (2%) Asthenia 2 (7%) 3 (12%) - 3 (23%) 8 (10%) 0 (0%) Gastrointestinal System Nausea 8 (27%) 10 (38%) 3 (23%) 4 (31%) 25 (30%) 8 (10%) Diarrhoea 6 (20%) 11 (42%) 2 (15%) 4 (31%) 23 (28%) 16 (20%) Vomiting 4 (13%) 4 (15%) 3 (23%) 1 (8%) 12 (15%) 2 (2%) Oral Monilia 3 (10%) 3 (12%) - 3 (23%) 9 (11%) 0 (0%) Dyspepsia 7 (23%) - 1 (8%) - 8 (10%) 1 (1%) Central Nervous System Insomnia 6 (20%) 2 (8%) (10%) 3 (4%) Respiratory System Sinusitis 1 (3%) 4 (15%) - 4 (31%) 9 (11%) 0 (0%) Skin and Appendages Rash including 10 (33%) 8 (31%) 3 (23%) 2 (15%) 23 (28%) 14(17%) maculopapular rash Sweat 4 (13%) 4 (15%) 2 (15%) 2 (15%) 12 (15%) 2 (2%) Table 2 summarises common adverse experiences (frequency 5%), regardless of attributability, reported in a comparative study of atovaquone tablets and trimethoprimsulphamethoxazole for the treatment of PCP in adult patients with AIDS. Laboratory test abnormalities (frequency 5%) during the treatment period are summarised in Table 3. Issue4 9

10 Table 2 Treatment-Emergent Adverse Experience Number of Patients with Treatment Emergent Adverse Experience Atovaquone tablets (n=203) Trimethoprim & Sulphamethoxazole (n=205) % of total (n) % of total (n) Rash (including maculopapular) 23 (47) 34* (69) Nausea 21 (43) 44* (90) Diarrhoea 19 (39) 7 (15) Headache 16 (33) 22 (44) Vomiting 14 (29) 35 (72) Fever 14 (28) 25 (52) Insomnia 10 (20) 9 (18) Asthenia 8 (17) 8 (16) Pruritus 5 (11) 9 (18) Monilia, Oral 5 (11) 10 (21) Abdominal Pain 4 (9) 7 (15) Constipation 3 (7) 17* (35) Dizziness 3 (7) 8* (17) No. Patients Discontinuing Therapy due to an Adverse Experience 9 (19) 24* (50) No. Patients Reporting at least one Adverse Experience * P< 0.05 Table 3 Laboratory Test Abnormality 63 (127) 65 (134) Patients Developing a Laboratory Test Abnormality (% of Total) Atovaquone tablets Trimethoprim/ Sulphamethoxazole Anaemia (Hb < 8.0 g/dl) 6 7 Neutropenia (ANC < 750 cells/mm 3 ) 3 9 Elevated ALT (> 5 x ULN) 6 16 Elevated AST (> 5 x ULN) 4 14 Elevated Alkaline Phosphatase (> 2.5 x ULN) 8 6 Elevated Amylase (> 1.5 x ULN) 7 12 Hyponatraemia (< 0.96 x LLN) 7 26 ULN = upper limit of normal range. LLN = lower limit of normal range. Nine percent of patients discontinued atovaquone as the result of an adverse experience. Of the most common adverse experiences, only rash, which occurred at a rate of 23 % was shown to be related to plasma atovaquone concentration. The most common reasons for discontinuation of atovaquone were rash and vomiting. The incidence of adverse experiences with atovaquone suspension at the recommended dose was similar to that seen with the tablet formulation. Issue4 10

11 Table 4 summarises common adverse experiences (frequency 5%), regardless of attributability, reported in a comparative study of atovaquone tablets and intravenous pentamidine for the treatment of PCP in adult patients with AIDS. Laboratory test abnormalities (frequency 5%) during the treatment period are summarised in Table 5. Table 4 Treatment- Emergent Adverse Experience Number of Patients with Treatment-Emergent Adverse Experience Atovaquone tablets (n=73) Pentamidine (n=71) % of total (n) % of total (n) Fever 40 (29) 25 (18) Nausea 22 (16) 37 (26) Rash 22 (16) 13 (9) Diarrhoea 21 (15) 31 (22) Insomnia 19 (14) 14 (10) Headache 18 (13) 28 (20) Vomiting 14 (10) 17 (12) Cough 14* (10) 1 (1) Abdominal Pain 10 (7) 11 (8) Pain 10 (7) 10 (7) Sweat 10 (7) 3 (2) Monilia, Oral 10 (7) 3 (2) Asthenia 8 (6) 14 (10) Dizziness 8 (6) 14 (10) Anxiety 7 (5) 10 (7) Anorexia 7 (5) 10 (7) Sinusitis 7 (5) 10 (7) Dyspepsia 5 (4) 10 (7) Rhinitis 5 (4) 7 (7) Taste Perversion 3 (2) 13* (9) Hypoglycaemia 1 (1) 15* (11) Hypotension 1 (1) 10* (7) No. Patients Discontinuing Therapy due to an Adverse Experience 7 (5) 41 # (29) No. Patients Reporting at least one Adverse Experience 63 (46) 72 (51) * P< # P< Issue4 11

12 Table 5 Laboratory Test Abnormality Patients Developing a Laboratory Test Abnormality (% of Total) Atovaquone tablets Pentamidine Anaemia (Hb< 8.0 g/dl) 4 9 Neutropenia (ANC< 750 cells/mm 3 ) 5 9 Hyponatremia (< 0.96 x LLN) Hyperkalaemia (> 1.18 x ULN) 0 5 Alkaline Phosphatase (> 2.5 x ULN) 5 2 Hyperglycaemia (< 1.8 x ULN) 9 13 Elevated AST (> 5 x ULN) 0 5 Elevated Amylase (> 1.5 x ULN) 8 4 Elevated Creatinine (> 1.5 x ULN) 0 7 ULN = upper limit of normal range. LLN = lower limit of normal range. Hypersensitivity reactions including angioedema, bronchospasm and throat tightness have also been commonly reported. Although experience is limited, adverse experiences reported in children with AIDS (Acquired Immune Deficiency Syndrome) do not appear to differ significantly from those of adults with AIDS receiving atovaquone. Effect on ability to drive and use machinery There have been no studies to investigate the effect of atovaquone 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. DOSAGE AND ADMINISTRATION: 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 adults Pneumocystis carinii pneumonia: The recommended oral dose of Wellvone suspension is 750 mg (5 ml) administered with food twice daily for 21 days (see Pharmacokinetics in Adults). For patients with difficulty in swallowing and unable to take two meals a day, the dose should be 1,500 mg (2 x 5 ml) with food once a day for 21 days. Dosage in children Experience with Wellvone in the paediatric population shows it to be well tolerated, but data are limited to a pharmacokinetic and safety study and at present there is insufficient data to recommend the use of atovaquone in children (see PRECAUTIONS, Use in Children:). Dosage in elderly There have been no studies of Wellvone in the elderly (see PRECAUTIONS, Use in the Elderly:). Issue4 12

13 OVERDOSAGE: Acute toxicity of atovaquone was not obvious in rats and mice given the highest practicable dose level. There is insufficient experience to predict the consequences, or suggest specific management, of atovaquone overdose. If overdose occurs the patient should be monitored and standard supportive treatment administered. PRESENTATION: Wellvone suspension is bright yellow with a sweet, fruity odour. Each 5 ml of suspension contains atovaquone 750 mg, benzyl alcohol, xanthan gum, poloxamer 188, saccharin sodium, tutti frutti flavour and purified water. Supplied in a plastic bottle with child-resistant screw cap and plastic spoon. Pack size 210 ml. Store below 25 C. Do not freeze. Shake well before use. Do not dilute. NAME AND ADDRESS OF SPONSOR: Glaxo Wellcome Australia Ltd A.C.N Mountain Highway Boronia Victoria 3155 TGA Approval: 27 November 1998 Date of Safety Related Notification: 29 August 2006 Wellvone is a trade mark of the Glaxo Wellcome Group of Companies. Wellvone suspension - Issue No. 4 Issue4 13