FUZEON Powder and solvent for solution for injection Ref.[8773] Active ingredients: Enfuvirtide

Fuzeon must be taken as part of a combination regimen. Please also refer to the respective summary of product characteristics of the other antiretroviral medicinal products used in the combination. As with other antiretrovirals, enfuvirtide should optimally be combined with other antiretrovirals to which the patient’s virus is sensitive (see section 5.1).

Patients should be informed that Fuzeon is not a cure for HIV-1 infection. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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.

Hypersensitivity reactions have occasionally been associated with therapy with enfuvirtide and in rare cases hypersensitivity reactions have recurred on rechallenge. Events included rash, fever, nausea and vomiting, chills, rigors, low blood pressure and elevated serum liver transaminases in various combinations, and possibly primary immune complex reaction, respiratory distress and glomerulonephritis. Patients developing signs/symptoms of a systemic hypersensitivity reaction should discontinue enfuvirtide treatment and should seek medical evaluation immediately. Therapy with enfuvirtide should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction considered related to enfuvirtide. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified.

Liver disease

The safety and efficacy of enfuvirtide has not been specifically studied in patients with significant underlying liver disorders. Patients with chronic hepatitis B and C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. Few patients included in the phase III trials were co-infected with hepatitis B/C. In these the addition of Fuzeon did not increase the incidence of hepatic events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Administration of Fuzeon to non-HIV-1 infected individuals may induce anti-enfuvirtide antibodies that cross-react with HIV gp41. This may result in a false positive HIV test with the anti-HIV ELISA test.

There is no experience in patients with reduced hepatic function. Data is limited in patients with moderate to severe renal impairment, and in patients maintained on dialysis. Fuzeon should be used with caution in these populations (see sections 4.2 and 5.2).

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology 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.

Interaction studies have only been performed in adults.

No clinically significant pharmacokinetic interactions are expected between enfuvirtide and concomitantly given medicinal products metabolised by CYP450 enzymes.

Influence of enfuvirtide on metabolism of concomitant medicinal products

In an in-vivo human metabolism study enfuvirtide, at the recommended dose of 90 mg twice daily, did not inhibit the metabolism of substrates by CYP3A4 (dapsone), CYP2D6 (debrisoquine), CYP1A2 (caffeine), CYP2C19 (mephenytoin), and CYP2E1 (chlorzoxazone).

Influence of concomitant medicinal products on enfuvirtide metabolism

In separate pharmacokinetic interaction studies, co-administration of ritonavir (potent CYP3A4 inhibitor) or saquinavir in combination with a booster dose of ritonavir or rifampicin (potent CYP34A inducer) did not result in clinically significant changes of the pharmacokinetics of enfuvirtide.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Animal studies do not indicate harmful effects with respect to foetal development. Enfuvirtide should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is not known whether enfuvirtide is secreted in human milk. Mothers should be instructed not to breast-feed if they are receiving enfuvirtide because of the potential for HIV transmission and any possible undesirable effects in breast-fed infants.

No studies on the effects on the ability to drive and use machines have been performed. There is no evidence that enfuvirtide may alter the patient’s ability to drive and use machines, however, the adverse event profile of enfuvirtide should be taken into account (see section 4.8).

a. Summary of the safety profile

Safety data mainly refer to 48-week data from studies TORO 1 and TORO 2 combined (see section 5.1). Safety results are expressed as the number of patients with an adverse reaction per 100 patient-years of exposure (except for injection site reactions).

The most frequently reported events were injection site reactions, diarrhoea and nausea. The addition of Fuzeon to background antiretroviral therapy generally did not increase the frequency or severity of most adverse reactions.

b. Tabulated list of adverse reactions

Table 2 presents events seen at a higher rate among patients receiving Fuzeon + OB regimen than among patients on the OB alone regimen with an exposure adjusted increase of at least 2 patients with event per 100 patient-years. A statistically significant increase was seen for pneumonia and lymphadenopathy. Most adverse reactions were of mild or moderate intensity. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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).

Table 2. Adverse reactions attributed to treatment with Fuzeon in studies TORO 1 and TORO 2 combined:

Infections and infestations

Common: Sinusitis, skin papilloma, influenza, pneumonia, ear infection

Blood and lymphatic system disorders

Common: Lymphadenopathy

Metabolism and nutrition disorders

Common: Appetite decreased, anorexia, hypertriglyceridaemia, blood triglycerides increased, diabetes mellitus

Psychiatric disorders

Common: Anxiety, nightmare, irritability

Nervous system disorders

Very common: Peripheral neuropathy

Common: Hypoaesthesia, disturbance in attention, tremor

Eye disorders

Common: Conjunctivitis

Ear and labyrinth disorders

Common: Vertigo

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

Gastrointestinal disorders

Common: Pancreatitis, gastro-oesophageal reflux disease

Skin and subcutaneous tissue disorders

Common: Dry skin, eczema seborrhoeic, erythema, acne

Musculoskeletal, connective tissue and bone disorders

Common: Myalgia

Renal and Urinary Disorders

Common: Nephrolithiasis, haematuria

General disorders and administration site conditions

Very common: Weight decreased

Common: Influenza like illness, asthenia

c. Description of selected adverse reactions

Injection site reactions

Injection site reactions (ISRs) were the most frequently reported adverse reaction and occurred in 98% of the patients (Table 3). The vast majority of ISRs occurred within the first week of Fuzeon administration and were associated with mild to moderate pain or discomfort at the injection site without limitation of usual activities. The severity of the pain and discomfort did not increase with treatment duration. The signs and symptoms generally lasted equal to or less than 7 days. Infections at the injection site (including abscess and cellulitis) occurred in 1.5% of patients.

Table 3. Summary of individual signs/symptoms characterising local injection site reactions in studies TORO 1 and TORO 2 combined (% of patients):

^a Any severity grade.
^b Grade 3= severe pain requiring analgesics (or narcotic analgesics for ≤72 hours) and/or limiting usual activities; Grade 4= severe pain requiring hospitalisation or prolongation of hospitalisation, resulting in death, or persistent or significant disability/incapacity, or life-threatening, or medically significant.
^c Grade 3= ≥50 mm but <85 mm average diameter; Grade 4= ≥85 mm average diameter.
^d Grade 3= ≥25 mm but <50 mm average diameter; Grade 4= ≥50 mm average diameter.
^e Grade 3= ≥3 cm; Grade 4= If draining.
^f Grade 3= refractory to topical treatment or requiring oral or parenteral treatment; Grade 4= not defined.
^g Grade 3= >3 cm but ≤5 cm; Grade 4= >5 cm.

In addition there have been a small number of hypersensitivity reactions attributed to enfuvirtide and in some cases recurrence has occurred upon re-challenge (see section 4.4).

Other adverse reactions

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

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).

As a peptide, enfuvirtide can cause cutaneous amyloidosis at the injection site.

Laboratory abnormalities

The majority of patients had no change in the toxicity grade of any laboratory parameter during the study except for those listed in Table 4. Through week 48, eosinophilia [greater than the Upper Limit of Normal of >0.7 × 10⁹/l] occurred at a higher rate amongst patients in the Fuzeon containing group (12.4 patients with event per 100 patient-years) compared with OB alone regimen (5.6 patients with event per 100 patient-years). When using a higher threshold for eosinophilia (>1.4 × 10⁹/l), the patient exposure adjusted rate of eosinophilia is equal in both groups (1.8 patients with event per 100 patient- years).

Table 4. Exposure adjusted Grade 3 & 4 laboratory abnormalities among patients on Fuzeon+OB and OB alone regimens, reported at more than 2 patients with event per 100 patient years:

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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.