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 (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose
No case of overdose has been reported. The highest dose administered to 12 patients in a clinical trial was 180 mg as a single dose subcutaneously. These patients did not experience any adverse reactions that were not seen with the recommended 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 of general supportive measures.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antivirals, ATC code: J05AX07

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

Antiviral activity in vitro: The susceptibility to enfuvirtide of 612 HIV recombinants containing the env genes from HIV RNA samples taken at baseline from patients in Phase III studies gave a geometric mean EC 50 of 0.259 μg/ml (geometric mean + 2SD = 1.96 μg/ml) in a recombinant phenotype HIV entry assay. Enfuvirtide also inhibited HIV-1 envelope mediated cell-cell fusion. Combination studies of enfuvirtide with representative members of the various antiretroviral classes exhibited additive to synergistic antiviral activities and an absence of antagonism. The relationship between the in vitro susceptibility of HIV-1 to enfuvirtide and inhibition of HIV-1 replication in humans has not been established.

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

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

In Vivo resistance to enfuvirtide: