FUZEON 90mg / ml powder+solvent for injection medication leaflet

Fuzeon 90 mg/ml powder and solvent for solution for injection

Each vial contains 108 mg enfuvirtide.

Each ml of reconstituted solution contains 90 mg enfuvirtide.

Excipient with known effect: sodium. Contains less than 1 mmol sodium (23 mg) per dose, that is tosay essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White to off-white lyophilised powder.

Fuzeon is indicated in combination with other antiretroviral medicinal products for the treatment of

HIV-1 infected patients who have received treatment with and failed on regimens containing at leastone medicinal product from each of the following antiretroviral classes: protease inhibitors, non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors, or who haveintolerance to previous antiretroviral regimens (see section 5.1).

In deciding on a new regimen for patients who have failed an antiretroviral regimen, carefulconsideration should be given to the treatment history of the individual patient and the patterns ofmutations associated with different medicinal products. Where available, resistance testing may beappropriate (see sections 4.4 and 5.1).

Fuzeon should be prescribed by physicians who are experienced in the treatment of HIV infection.

Adults and adolescents ≥ 16 years: The recommended dose of Fuzeon is 90 mg twice daily injectedsubcutaneously into the upper arm, anterior thigh or abdomen.

In case a Fuzeon dose is missed, patients should be instructed to administer the dose as soon aspossible. However, if it is less than 6 hours before the next regular dose, the missed dose should beskipped.

Elderly: There is no experience in patients > 65 years old.

Children ≥ 6 years and adolescents: The experience in children is limited (see section 5.2). In clinicaltrials the dosage regimen in Table 1 below was used:

Table 1: Paediatric Dosing

Weight (kg) Dose per bid injection Injection volume(mg/dose) (90 mg enfuvirtideper ml)11.0 to 15.5 27 0.3 ml15.6 to 20.0 36 0.4 ml20.1 to 24.5 45 0.5 ml24.6 to 29.0 54 0.6 ml29.1 to 33.5 63 0.7 ml33.6 to 38.0 72 0.8 ml38.1 to 42.5 81 0.9 ml≥42.6 90 1.0 ml

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

Renal impairment: No dose adjustment is required for patients with renal impairment including thosereceiving dialysis (see sections 4.4 and 5.2).

Hepatic impairment: No data are available to establish a dose recommendation for patients withhepatic impairment (see sections 4.4 and 5.2).

Fuzeon is only to be administered by subcutaneous injection. For instructions on reconstitution beforeadministration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Patients should be informed that Fuzeon is not a cure for HIV-1 infection.

Animal studies have shown that enfuvirtide may impair some immune functions (see section 5.3). Inclinical 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 tothe use of Fuzeon has not been confirmed by subsequent epidemiological data.

Hypersensitivity reactions have occasionally been associated with therapy with enfuvirtide and in rarecases hypersensitivity reactions have recurred on rechallenge. Events included rash, fever, nausea andvomiting, chills, rigors, low blood pressure and elevated serum liver transaminases in variouscombinations, and possibly primary immune complex reaction, respiratory distress andglomerulonephritis. Patients developing signs/symptoms of a systemic hypersensitivity reaction shoulddiscontinue enfuvirtide treatment and should seek medical evaluation immediately. Therapy withenfuvirtide should not be restarted following systemic signs and symptoms consistent with ahypersensitivity reaction considered related to enfuvirtide. Risk factors that may predict theoccurrence 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 withsignificant underlying liver disorders. Patients with chronic hepatitis B and C and treated withantiretroviral 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 additionof Fuzeon did not increase the incidence of hepatic events. In case of concomitant antiviral therapy forhepatitis 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 antibodiesthat cross-react with HIV gp41. This may result in a false positive HIV test with the anti-HIV ELISAtest.

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

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the timeof institution of combination antiretroviral therapy (CART), an inflammatory reaction toasymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, oraggravation of symptoms. Typically, such reactions have been observed within the first few weeks ormonths of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/orfocal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptomsshould be evaluated and treatment instituted when necessary.

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

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported 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, jointstiffness or difficulty in movement.

Interaction studies have only been performed in adults.

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

Influence of enfuvirtide on metabolism of concomitant medicinal products: In an in-vivo humanmetabolism study enfuvirtide, at the recommended dose of 90 mg twice daily, did not inhibit themetabolism of substrates by CYP3A4 (dapsone), CYP2D6 (debrisoquine), CYP1A2 (caffeine),

CYP2C19 (mephenytoin), and CYP2E1 (chlorzoxazone).

Influence of concomitant medicinal products on enfuvirtide metabolism: In separate pharmacokineticinteraction studies, co-administration of ritonavir (potent CYP3A4 inhibitor) or saquinavir incombination with a booster dose of ritonavir or rifampicin (potent CYP3A4 inducer) did not result inclinically significant changes of the pharmacokinetics of enfuvirtide.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Animal studies donot indicate harmful effects with respect to foetal development. Enfuvirtide should be used duringpregnancy 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. It is recommended thatwomen living with HIV do not breast-feed their infants in order to avoid transmission of HIV and anypossible undesirable effects in breast-fed infants.

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

Safety data mainly refer to 48-week data from studies TORO 1 and TORO 2 combined (seesection 5.1). Safety results are expressed as the number of patients with an adverse reaction per100 patient-years of exposure (except for injection site reactions).

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

Table 2 presents events seen at a higher rate among patients receiving Fuzeon + OB regimen thanamong patients on the OB alone regimen with an exposure adjusted increase of at least 2 patients withevent per 100 patient-years. A statistically significant increase was seen for pneumonia andlymphadenopathy. Most adverse reactions were of mild or moderate intensity. Adverse reactions arelisted according to MedDRA system organ class and frequency category. Frequency categories aredefined 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

System organ class Adverse reaction

Frequency

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

Common Lymphadenopathy

Common Appetite decreased, anorexia,hypertriglyceridaemia, blood triglyceridesincreased, diabetes mellitus

Common Anxiety, nightmare, irritability

Very common Peripheral neuropathy

Common Hypoaesthesia, disturbance in attention, tremor

Common Conjunctivitis

Ear and labyrinth disorders

Common Vertigo

Common Nasal congestion

Common Pancreatitis, gastro-oesophageal reflux disease

Common Dry skin, eczema seborrhoeic, erythema, acne

Musculoskeletal, connective tissue and bonedisorders

Common Myalgia

Renal and Urinary Disorders

Common Nephrolithiasis, haematuria

General disorders and administration siteconditions

Very common Weight decreased

Common Influenza like illness, asthenia

c. Description of selected adverse 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 Fuzeonadministration and were associated with mild to moderate pain or discomfort at the injection sitewithout limitation of usual activities. The severity of the pain and discomfort did not increase withtreatment duration. The signs and symptoms generally lasted equal to or less than 7 days. Infections atthe injection site (including abscess and cellulitis) occurred in 1.5% of patients.

Table 3: Summary of individual signs/symptoms characterising local injection site reactionsin studies TORO 1 and TORO 2 combined (% of patients)n=663

Withdrawal Rate due to ISRs 4%

Event Category Fuzeon % of Event % of Event+Optimised comprising comprisingbackgrounda Grade 3 reactions Grade 4 reactions

Pain/discomfort 96.1% 11.0%b 0%b

Erythema 90.8% 23.8%c 10.5%c

Induration 90.2% 43.5%d 19.4%d

Nodules and cysts 80.4% 29.1%e 0.2%e

Pruritus 65.2% 3.9%f NA

Ecchymosis 51.9% 8.7%g 4.7%gaAny severity grade.bGrade 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 significantdisability/incapacity, or life-threatening, or medically significant.cGrade 3= ≥ 50 mm but < 85 mm average diameter; Grade 4= ≥ 85 mm average diameter.dGrade 3= ≥ 25 mm but < 50 mm average diameter; Grade 4= ≥ 50 mm average diameter.eGrade 3= ≥ 3 cm; Grade 4= If draining.fGrade 3= refractory to topical treatment or requiring oral or parenteral treatment; Grade 4= not defined.gGrade 3= > 3 cm but ≤ 5 cm; Grade 4= > 5 cm.

In addition there have been a small number of hypersensitivity reactions attributed to enfuvirtide andin 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

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

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

The majority of patients had no change in the toxicity grade of any laboratory parameter during thestudy except for those listed in Table 4. Through week 48, eosinophilia [greater than the Upper Limitof Normal of > 0.7 x 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 withevent per 100 patient-years). When using a higher threshold for eosinophilia (>1.4 x 109/l), the patientexposure 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 per100 patient years

Laboratory Parameters Fuzeon+OB regimen OB alone regimen

Grading Per 100 patient years Per 100 patient yearsn 663 334(Total Exposure patient years) (557.0) (162.1)

ALAT

Gr. 3 (>5-10 x ULN) 4.8 4.3

Gr. 4 (>10 x ULN) 1.4 1.2

Gr. 3 (6.5-7.9 g/dL) 2.0 1.9

Gr. 4 (<6.5 g/dL) 0.7 1.2

Creatinine phosphokinase

Gr. 3 (>5-10 x ULN) 8.3 8.0

Gr. 4 (>10 x ULN) 3.1 8.6

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

The highest dose administered to 12 patients in a clinical trial was 180 mg as a single dosesubcutaneously. These patients did not experience any adverse reactions that were not seen with therecommended dose. In an Early Access Program study, one patient was administered 180 mg of

Fuzeon as a single dose on one occasion. He did not experience an adverse reaction as a result.

There is no specific antidote for overdose with enfuvirtide. Treatment of overdose should consist ofgeneral supportive measures.

Pharmacotherapeutic group: : Other antivirals, ATC code: J05AX07

Mechanism of Action: Enfuvirtide is a member of the therapeutic class called fusion inhibitors. It is aninhibitor of the structural rearrangement of HIV-1 gp41 and functions by specifically binding to thisvirus protein extracellularly thereby blocking fusion between the viral cell membrane and the targetcell membrane, preventing the viral RNA from entering into the target cell.

Antiviral activity in vitro: The susceptibility to enfuvirtide of 612 HIV recombinants containing theenv genes from HIV RNA samples taken at baseline from patients in Phase III studies gave ageometric mean EC 50 of 0.259 µg/ml (geometric mean + 2SD = 1.96 µg/ml) in a recombinantphenotype HIV entry assay. Enfuvirtide also inhibited HIV-1 envelope mediated cell-cell fusion.

Combination studies of enfuvirtide with representative members of the various antiretroviral classesexhibited additive to synergistic antiviral activities and an absence of antagonism. The relationshipbetween the in vitro susceptibility of HIV-1 to enfuvirtide and inhibition of HIV-1 replication inhumans has not been established.

Antiretroviral drug resistance: Incomplete viral suppression may lead to the development of drugresistance to one or more components of the regimen.

In Vitro resistance to enfuvirtide: HIV-1 isolates with reduced susceptibility to enfuvirtide have beenselected in vitro which harbour substitutions in amino acids (aa) 36-38 of the gp41 ectodomain. Thesesubstitutions were correlated with varying levels of reduced enfuvirtide susceptibility in HIV site-directed mutants.

In Vivo resistance to enfuvirtide: In phase III clinical studies HIV recombinants containing the envgenes from HIV RNA samples taken up to week 24 from 187 patients showed > 4 fold reducedsusceptibility to enfuvirtide compared with the corresponding pre-treatment samples. Of these,185 (98.9%) env genes carried specific substitutions in region of aa 36 - 45 of gp41. The substitutionsobserved in decreasing frequency were at aa positions 38, 43, 36, 40, 42 and 45. Specific singlesubstitutions at these residues in gp41 each resulted in a range of decreases from baseline inrecombinant viral susceptibility to enfuvirtide. The geometric mean changes ranged from 15.2 fold for

V38M to 41.6 fold for V38A. There were insufficient examples of multiple substitutions to determineany consistent patterns of substitutions or their effect on viral susceptibility to enfuvirtide. Therelationship of these substitutions to in vivo effectiveness of enfuvirtide has not been established.

Decrease in viral sensitivity was correlated to the degree of pre-treatment resistance to backgroundtherapy. (see Table 6).

Cross-resistance: Due to its novel viral target enfuvirtide is equally active in vitro against both wild-type laboratory and clinical isolates and those with resistance to 1, 2 or 3 other classes ofantiretrovirals (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptaseinhibitors and protease inhibitors). Conversely, mutations in aa 36-45 of gp41 which give resistance toenfuvirtide would not be expected to give cross resistance to other classes of antiretrovirals.

Clinical Pharmacodynamic data

Studies in Antiretroviral Experienced Patients: The clinical activity of Fuzeon (in combination withother antiretroviral agents) on plasma HIV RNA levels and CD4 counts have been investigated in tworandomised, multicentre, controlled studies (TORO 1 and TORO 2) of Fuzeon of 48 weeks duration.995 patients comprised the intent-to-treat population. Patient demographics include a median baseline

HIV-1 RNA of 5.2 log10 copies/ml and 5.1 log10 copies/ml and median baseline CD4 cell count of88 cells/mm3 and 97 cells/mm3 for Fuzeon + OB and OB, respectively. Patients had prior exposure toa median of 12 antiretrovirals for a median of 7 years. All patients received an optimised background(OB) regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the patient's priortreatment history, as well as baseline genotypic and phenotypic viral resistance measurements.

The proportion of patients achieving viral load of <400 copies/ml at week 48 was 30.4% amongpatients on the Fuzeon + OB regimen compared to 12% among patients receiving OB regimen only.

The mean CD4 cell count increase was greater in patients on the Fuzeon + OB regimen than inpatients on OB regimen only (see Table 5).

Table 5 Outcomes of Randomised Treatment at Week 48 (Pooled Studies TORO 1 and

TORO 2, ITT)

Outcomes Fuzeon + OB OB Treatment 95% p-value90 mg bid (N=334) Difference Confidenc(N=661) e Interval

HIV-1 RNA -1.48 -0.63 LSM -1.073, - <.0001

Log Change from baseline -0.85 0.628(log *10 copies/ml)

CD4+ cell count +91 +45 LSM 25.1, 67.8 <.0001

Change from baseline 46.4(cells/mm3)#

HIV RNA >1 log below 247 (37.4%) 57 (17.1%) Odds Ratio 2.16, 4.20 <.0001

Baseline** 3.02

HIV RNA <400 copies/ml** 201 (30.4%) 40 (12.0%) Odds Ratio 2.36, 5.06 <.00013.45

HIV RNA <50 copies/ml** 121 (18.3%) 26 (7.8%) Odds Ratio 1.76, pct. 4.37 <.00012.77

Discontinued due to adverse 9% 11%reactions/intercurrentillness/labs†

Discontinued due to injection 4% N/Asite reactions†

Discontinued due to other 13% 25%reasons†φ§

* Based on results from pooled data of TORO 1 and TORO 2 on ITT population, week 48 viral load for subjects whowere lost to follow-up, discontinued therapy, or had virological failure replaced by their last observation (LOCF).

# Last value carried forward.

** M-H test: Discontinuations or virological failure considered as failures.† Percentages based on safety population Fuzeon+background (N=663) and background (N=334). Denominator fornon-switch patients: N=112.φ As per the judgment of the investigator.§ Includes discontinuations from loss to follow-up, treatment refusal, and other reasons.

Fuzeon + OB therapy was associated with a higher proportion of patients reaching <400 copies/ml (or<50 copies/ml) across all subgroups based on baseline CD4, baseline HIV-1 RNA, number of priorantiretrovirals (ARVs) or number of active ARVs in the OB regimen. However, subjects with baseline

CD4 >100 cells/mm3, baseline HIV-1 RNA <5.0 log10 copies/ml, ≤ 10 prior ARVs, and/or other active

ARVs in their OB regimen were more likely to achieve a HIV-1 RNA of <400 copies/ml(or <50 copies/ml) on either treatment (see Table 6).

Table 6 Proportion of Patients achieving <400 copies/ml and <50 copies/ml at Week 48 bysubgroup (pooled TORO 1 and TORO 2, ITT)

Subgroups HIV-1 RNA < 400 copies/ml HIV-1 RNA < 50 copies/ml

Fuzeon + OB OB Fuzeon + OB OB90 mg bid (N=334) 90 mg bid (N=334)(N=661) (N=661)

BL HIV-1 RNA < 5.0 118/269 26/144 77/269 18/144log 110 copies/ml (43.9%) (18.1%) (28.6%) (12.5%)

BL HIV-1 RNA ≥ 5.0 83/392 14/190 44/392 8/190log 110 copies/ml (21.2%) (7.4%) (11.2%) (4.2%)

Total prior ARVs ≤ 100/215 29/120 64/215 19/120101 (46.5%) (24.2%) (29.8%) (15.8%)

Total prior ARVs > 101/446 11/214 57/446 7/214101 (22.6%) (5.1%) (12.8%) (3.3%)0 Active ARVs in 9/112 0/53 4/112 0/53background1,2 (8.0%) (0%) (3.5%) (0%)1 Active ARV in 56/194 7/95 34/194 3/95background1,2 (28.9%) (7.4%) (17.5%) (3.2%)≥ 2 Active ARVs in 130/344 32/183 77/334 22/183background1,2 (37.8%) (17.5%) (22.4%) (12.0%)1Discontinuations or virological failures considered as failures.2Based on GSS score.

The pharmacokinetic properties of enfuvirtide have been evaluated in HIV-1-infected adult andpaediatric patients.

Absorption: The absolute bioavailability after subcutaneous administration of enfuvirtide 90 mg in theabdomen was 84.3 ± 15.5%. Mean (± SD) Cmax was 4.59 ± 1.5 µg/ml, AUC was 55.8 ± 12.1 µg*hr/ml

The subcutaneous absorption of enfuvirtide is proportional to the administered dose over the 45 to180 mg dose range. Subcutaneous absorption at the 90 mg dose is comparable when injected intoabdomen, thigh or arm. In four separate studies (N = 9 to 12) the mean steady state trough plasmaconcentration ranged from 2.6 to 3.4 µg/ml.

Distribution: The steady state volume of distribution with intravenous administration of a 90 mg doseof enfuvirtide was 5.5 ± 1.1 l. Enfuvirtide is 92% bound to plasma proteins in HIV infected plasmaover a plasma concentration range of 2 to 10 µg/ml. It is bound predominantly to albumin and to alower extent to α-1 acid glycoprotein. In in vitro studies, enfuvirtide was not displaced from itsbinding sites by other medicinal products, nor did enfuvirtide displace other medicinal products fromtheir binding sites. In HIV patients, enfuvirtide levels in the cerebrospinal fluid have been reported tobe negligible.

Biotransformation: As a peptide, enfuvirtide is expected to undergo catabolism to its constituent aminoacids, with subsequent recycling of the amino acids in the body pool. In vitro human microsomalstudies and in in vivo studies indicate that enfuvirtide is not an inhibitor of CYP450 enzymes. Inin vitro human microsomal and hepatocyte studies, hydrolysis of the amide group of the C-terminusamino acid, phenylalanine results in a deamidated metabolite and the formation of this metabolite isnot NADPH dependent. This metabolite is detected in human plasma following administration ofenfuvirtide, with an AUC ranging from 2.4 to 15% of the enfuvirtide AUC.

Elimination: Clearance of enfuvirtide after intravenous administration 90 mg was 1.4 ± 0.28 l/h andthe elimination half-life was 3.2 ± 0.42 h. Following a 90 mg subcutaneous dose of enfuvirtide thehalf-life of enfuvirtide is 3.8 ± 0.6 h. Mass balance studies to determine elimination pathway(s) ofenfuvirtide have not been performed in humans.

Hepatic impairment: The pharmacokinetics of enfuvirtide have not been studied in patients withhepatic impairment.

Renal impairment: Analysis of plasma concentration data from patients in clinical trials indicated thatthe clearance of enfuvirtide is not affected to any clinically relevant extent in patients with mild tomoderate renal impairment. In a renal impairment study AUC of enfuvirtide was increased on averageby 43-62% in patients with severe or end stage renal disease compared to patients with normal renalfunction. Haemodialysis did not significantly alter enfuvirtide clearance. Less than 13% of the dosewas removed during haemodialysis. No dose adjustment is required for patients with impaired renalfunction.

Elderly: The pharmacokinetics of enfuvirtide have not been formally studied in elderly patients over65 years of age.

Gender and Weight: Analysis of plasma concentration data from patients in clinical trials indicatedthat the clearance of enfuvirtide is 20% lower in females than males irrespective of weight and isincreased with increased body weight irrespective of gender (20% higher in a 100 kg and 20% lowerin a 40 kg body weight patient relative to a 70 kg reference patient). However, these changes are notclinically significant and no dose adjustment is required.

Race: Analysis of plasma concentration data from patients in clinical trials indicated that the clearanceof enfuvirtide was not different in Afro-Americans compared to Caucasians. Other PK studies suggestno difference between Asians and Caucasians after adjusting exposure for body weight.

Paediatric population: The pharmacokinetics of enfuvirtide have been studied in 37 paediatric patients.

A dose of 2 mg/kg bid (maximum 90 mg bid) provided enfuvirtide plasma concentrations similar tothose obtained in adult patients receiving 90 mg bid dosage. In 25 paediatric patients ranging in agefrom 5 to 16 years and receiving the 2 mg/kg bid dose into the upper arm, anterior thigh or abdomen,the mean steady-state AUC was 54.3 ± 23.5 µg*h/ml, Cmax was 6.14 ± 2.48 µg/ml, and Ctrough was2.93 ± 1.55 µg/ml.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and late embryonal development. Long-termanimal carcinogenicity studies have not been performed.

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-γ production wasobserved. The resistance to influenza and streptococcal infection in rats was only weaklycompromised. The clinical relevance of these findings is unknown.

Sodium carbonate

Mannitol

Sodium hydroxide

Hydrochloric Acid

Water for Injections

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

Powder5 years

Solvent5 years

Shelf life after reconstitution

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

Chemical and physical in-use stability has been demonstrated for 48 hours at 5°C when protected fromlight.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place incontrolled and validated aseptic conditions.

Keep the vial in the outer carton in order to protect from light. For storage conditions afterreconstitution of the medicinal product, see section 6.3.

This medicinal product does not require any special storage conditions.

Vial: 3 ml vial, colourless glass type 1

Closure: lyophilisate stopper, rubber (latex free)

Seal: aluminium seal with flip-off cap

Vial: 2 ml vial, colourless glass type 1

Closure: rubber stopper (latex free)

Seal: aluminium seal with flip-off cap

Pack sizes60 vials powder for solution for injection60 vials solvent60 3 ml syringes60 1 ml syringes180 alcohol swabs

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

Patients should be instructed on the use and administration of Fuzeon by a healthcare professionalbefore using for the first time.

Fuzeon must only be reconstituted with 1.1 ml of Water for Injections. Patients must be instructed toadd the water for injections and then gently tap the vial with their fingertip until the powder begins todissolve. They must never shake the vial or turn it upside down to mix—this will cause excessivefoaming. After the powder begins to dissolve they can set the vial aside to allow it to completelydissolve. The powder may take up to 45 minutes to dissolve into solution. The patient can gently rollthe vial between their hands after adding the water for injections until it is fully dissolved and this mayreduce the time it takes for the powder to dissolve. Before the solution is withdrawn foradministration, the patient should inspect the vial visually to ensure that the contents are fully insolution, and that the solution is clear and without bubbles or particulate matter. If there is evidence ofparticulate matter, the vial must not be used and should be discarded or returned to the pharmacy.

The solvent vials contain 2 ml Water for Injections, of which 1.1 ml must be withdrawn for thereconstitution of the powder. Patients should be instructed to discard the remaining volume in thesolvent vials.

Fuzeon contains no preservative. Once reconstituted, the solution should be injected immediately. Ifthe reconstituted solution cannot be injected immediately, it must be kept refrigerated until use andused within 24 hours. Refrigerated reconstituted solution should be brought to room temperaturebefore injection.

1 ml of the reconstituted solution should be injected subcutaneously in to the upper arm, abdomen oranterior thigh. The injection should be given at a site different from the preceding injection site andwhere there is no current injection site reaction. A vial is suitable for single use only; unused portionsmust be discarded.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/03/252/001

Date of first authorisation: 27 May 2003

Date of latest renewal: 27 May 2008

Detailed information on this medicinal product is available on the web site of the European Medicines

Agency: http://www.ema.europa.eu/