Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Patients co-infected with HIV and hepatitis B or C virus

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of Gendevra in patients co-infected with HIV-1 and hepatitis C virus (HCV) have not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of Gendevra therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Gendevra should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Liver disease

The safety and efficacy of Gendevra in patients with significant underlying liver disorders have not been established.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life-style. For lipids, there is in some cases, evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).
Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of 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 include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii 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 these events can occur many months after initiation of treatment.

Opportunistic infections

Patients receiving Gendevra or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

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.

Nephrotoxicity

Post-marketing cases of renal impairment, including acute renal failure and proximal renal tubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapy with Gendevra and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of Gendevra should be considered.

Patients with end stage renal disease on chronic haemodialysis

Gendevra should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh the potential risks (see section 4.2). In a study of Gendevra in HIV-1 infected adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Although there were no new safety issues identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co-administration of other medicinal products

Some medicinal products should not be co-administered with Gendevra (see sections 4.3 and 4.5).
Gendevra should not be co-administered with other antiretroviral medicinal products (see section 4.5).

Gendevra should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection (see section 4.5).

Contraception requirements
Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 µg ethinyloestradiol and containing drospirenone or norgestimate as the progestogen or should use an alternative reliable method of contraception (see sections 4.5 and 4.6). The use of Gendevra with oral contraceptives containing other progestogens should be avoided (see section 4.5). Plasma concentrations of drospirenone are expected to be increased following co-administration with Gendevra and clinical monitoring is recommended due to the potential for hyperkalaemia (see section 4.5).

Pregnancy

Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposures (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, therapy with Gendevra should not be initiated during pregnancy, and women who become pregnant during therapy with Gendevra should be switched to an alternative regimen (see section 4.6).

Paediatric population

Reductions in BMD (≥ 4%) of the spine and total-body-less-head (TBLH) have been reported in patients aged between 7 to < 12 years weighing at least 25 kg receiving Genvoya for 48 weeks in study GS-US-292-0106 (see section 4.8). The long-term effects of changes in BMD on the growing bone, including the risk of fracture, are uncertain. A multidisciplinary approach is recommended to decide the appropriate monitoring during treatment.

Excipients

Gendevra contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Gendevra may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with Gendevra.