Roche Products Limited

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4.4       Special warnings and precautions for use

Animal studies have shown that enfuvirtide may impair some immune functions (see section 5.3). In clinical trials, an increased rate of some bacterial infections, most notably a higher rate of pneumonia, was seen in patients treated with Fuzeon; however, an increased risk of bacterial pneumonia related to the use of Fuzeon has not been confirmed by subsequent epidemiological data.

An increased rate of some bacterial infections, most notably a higher rate of pneumonia, has been seen in patients treated with Fuzeon. Patients should be monitored closely for signs and symptoms of pneumonia. (See section 4.8)

5.1     Pharmacodynamic properties

This medicinal product has been authorised under “Exceptional Circumstances”. This means that  for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 108 mg enfuvirtide.

Each1 ml of reconstituted solution contains 90 mg enfuvirtide.

Excipient(s):

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'. For a full list of excipients, see section 6.1.

4.8     Undesirable effects

Infections and Infestations

Common (≥1/100, <1/10): - sinusitis, skin papilloma, influenza, pneumonia, ear infection.

Blood and Lymphatic System Disorders

Common (≥1/100, <1/10): - lymphadenopathy.

Metabolism and Nutrition Disorders

Common (≥1/100, <1/10): - appetite decreased, anorexia, hypertriglyceridaemia, diabetes mellitus.

Psychiatric Disorders

Common ((≥1/100, <1/10): - anxiety, nightmare, irritability.

Nervous System Disorders

Very Common (≥1/10): - peripheral neuropathy.

Common (≥1/100, <1/10): -hypoaesthesia, disturbance in attention, tremor.

Eye Disorders

Common (≥1/100, <1/10): - conjunctivitis.

Ear and Labyrinth disorders

Common (≥1/100, <1/10): - vertigo.

Respiratory, Thoracic and Mediastinal Disorders

Common (≥1/100, <1/10): - nasal congestion.

Gastrointestinal Disorders

Common (≥1/100, <1/10): - pancreatitis, gastro-oesophageal reflux disease.

Skin and Subcutaneous Tissue Disorders

Common (≥1/100, <1/10): - dry skin, eczema seborrhoeic, erythema, acne.

Musculoskeletal, Connective Tissue and Bone Disorders

Common (≥1/100, <1/10): - myalgia.

Renal and Urinary Disorders

Common (≥1/100, <1/10): - Calculus renal.

General Disorders and Administration Site Conditions

Common (≥1/100, <1/10): - influenza like illness, weakness.

Investigations

Very Common (≥1/10): - weight decreased

Common (≥1/100, <1/10): - blood triglycerides increased, haematuria present.

6.3     Shelf life

After reconstitution: Store in a refrigerator (2°C – 8°C).

6.4     Special precautions for storage

This medicinal product does not require any special storage conditions.After reconstitution: Store in a refrigerator (2°C – 8°C). Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted medicinal product, see section 6.3.

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4.2     Posology and method of administration

Renal impairment: No dose adjustment is required for patients with renal impairment including creatinine clearance above 35 ml/min. and  No data are available to establish a dose recommendation for patients with creatinine clearance below 35 ml/min or those receiving dialysis. (See sections 4.4 and 5.2).

4.4       Special warnings and precautions for use

There is no experience in patients with reduced hepatic function. Data is limited  Enfuvirtide clearance is not significantly altered or in patients with moderate to severe renal impairment and only limited data, in patients with moderate renal impairment and in patients maintained on dialysis. Fuzeon should be used with caution in these populations. (See sections 4.2 and 5.2)

5.2     Pharmacokinetic properties

Renal Insufficiency: AA specific pharmacokinetic study has not been conducted in patients with renal impairment or those receiving dialysis. However analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is not affected to any clinically relevant extent in patients with mild to moderate renal impairmentcreatinine clearance above 35 ml/min. The results ofIn a renal impairment study indicate clearanceAUC of enfuvirtide was increased on average reduced by 3843-62% in patients with severe renal impairment and by 14-28% in patients withor end stage renal disease maintained on dialysis compared to patients with normal renal function. Haemodialysis did not significantly alter enfuvirtide clearance. Less than 13% of the dose was removed during haemodialysis. No dose adjustment is required for patients with impaired renal function.

Paediatric Patients: The pharmacokinetics of enfuvirtide have been studied in 9037 paediatric patients.

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4.4       Special warnings and precautions for use

Osteonecrosis:

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

4.8       Undesirable effects

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

10.       DATE OF REVISION OF THE TEX

Updated to: 24 January 2007

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2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient(s):

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free". For a full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Fuzeon is a whiteWhite to off-white lyophilised powder.

4.2       Posology and method of administration

Children ³ 6 years and adolescents: The experience in children is based on a very limited number of children. (See section 5.2). In ongoing clinical trials the dosage regimen in table 1 below is being used.

No data are available to establish dose recommendations of Fuzeon in children below the age of 6 years.

Fuzeon is not recommended for use in children below age 6 due to insufficient data on safety and efficacy (see section 5.2).

4.4       Special warnings and precautions for use

Animal studies have shown that enfuvirtide may impair some immune functions (See section 5.3).

4.5       Interaction with other medicinal products and other forms of interaction

Interactions studies have only been performed in adults.

4.8       Undesirable effects

These events are then designated frequency estimation ("very common" (³ 1/10), or "common" (³ 1/100, < 1/10)).

5.1       Pharmacodynamic properties

This medicinal product has been authorised under "Exceptional Circumstances". This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

5.3       Preclinical safety data

Studies in guinea pigs indicated a potential for enfuvirtide to produce delayed contact hypersensitivity.  In a rat model on the resistance to influenza infection, an impairment of IFN-g production was observed. The resistance to influenza and streptococcal infection in rats was only weakly compromised. In vitro studies have shown that enfuvirtide may act as an agonist on the formyl peptide receptor, a receptor on leucocytes believed to be important for the early defense against infection.

6.4       Special precautions for storage

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.6       Special precautions for disposal

Any unused product should be disposed of in accordance with local requirements.

10.       DATE OF REVISION OF THE TEXT

Updated to: 24 October 2006