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Wellvone 750mg / 5ml oral suspension

1. Name Of The Medicinal Product

Wellvone 750 mg/5 ml oral suspension

2. Qualitative And Quantitative Composition

Each ml of suspension contains 150 mg atovaquone

A unit dose of 5 ml contains 750 mg atovaquone.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral suspension.

Wellvone oral suspension is a bright yellow liquid

4. Clinical Particulars

4.1 Therapeutic Indications

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)

4.2 Posology And Method Of 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 pneumonia:

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 the Elderly

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.

4.3 Contraindications

Wellvone Suspension is contra-indicated in individuals with known hypersensitivity to atovaquone or to any components of the formulation.

4.4 Special Warnings And Precautions For Use

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.

The concomitant administration of atovaquone and rifampicin or rifabutin is not recommended (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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As experience is limited, care should be taken when combining other drugs with Wellvone.

Concomitant administration of rifampicin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively, and could result in sub therapeutic plasma concentrations in some patients (see section 4.4).

Concomitant treatment with tetracycline or metoclopramide has been associated with significant decreases in plasma concentrations of atovaquone. Caution should be exercised in prescribing these drugs with Wellvone until the potential interaction has been further studied.

In clinical trials of Wellvone small decreases in plasma concentrations of atovaquone (mean < 3 g/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. No data are available regarding potential interactions of Wellvone and other protease inhibitor drugs.

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-antagonists.

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.

4.6 Pregnancy And Lactation

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.

4.7 Effects On Ability To Drive And Use Machines

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.

4.8 Undesirable Effects

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 (

Blood and the lymphatic system disorders

Common: anaemia, neutropenia

Metabolism and nutrition disorders

Common: hyponatraemia

Psychiatric disorders

Common: insomnia

Nervous system disorders

Common: headache

Gastrointestinal disorders

Very common: nausea

Common: diarrhoea, vomiting

Hepatobiliary disorders

Common: elevated liver enzymes levels

Immune System Disorders

Common: hypersensitivity reactions including angioedema, bronchospasm and throat tightness

Skin and subcutaneous tissue disorders

Very common: rash, pruritus

Common: urticaria

Not known: erythema multiforme, Stevens-Johnson Syndrome

General disorders and administration site conditions

Common: fever

Investigations

Uncommon: elevated amylase levels

4.9 Overdose

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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 protozoaand 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.

Microbiology

Atovaquone has potent activity against Pneumocystic sp, both in vitro and in animal models, (IC50 0.5-8?g/mL).

5.2 Pharmacokinetic Properties

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 0.620.19 l/kg and 0.150.09 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) g/ml.h fasted and 800.6 (319.8) g/ml.h with food.

In a safety and pharmacokinetic study in patients with PCP, the following results were obtained:

Dose regimen

750 mg twice daily

1000 mg twice daily

Number of Patients

18

9

C avg, ss (range)

22 g/ml (6-41)

25.7 g/ml (15-36)

% of patients with C avg, ss >15 g/ml

67%

100%

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 [respectively for the 750 mg tid and 1500 mg bid doses: 24.8 (7-40) and 23.4 g/ml (7-35). Moreover, for both doses a Cavg, ss >15 g/ml was reached in 87.5% of patients.

Average steady state concentrations above 15 g/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.

5.3 Preclinical Safety Data

Carcinogenicity

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.

Reproductive toxicity

In the dosage range of 600 to 1200 mg/kg studies in rabbits gave indications of maternal and embryotoxic effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzyl alcohol

Xanthan Gum

Poloxamer 188

Saccharin Sodium

Purified water

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.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

After first opening, the suspension may be stored for up to 21 days.

6.4 Special Precautions For Storage

Do not store above 25C.

Do not freeze.

6.5 Nature And Contents Of Container

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.

6.6 Special Precautions For Disposal And Other Handling

Do not dilute

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd

trading as

GlaxoSmithKline UK

Stockley Park West

Uxbridge, Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0271

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 25 March 1997

Date of last renewal: 21 May 2006

10. Date Of Revision Of The Text

15 April 2010





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