Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Patients with HIV-1 harbouring mutations
Truvada should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1).

Overall HIV-1 infection prevention strategy

Truvada is not always effective in preventing the acquisition of HIV-1. The time to onset of protection after commencing Truvada is unknown.

Truvada should only be used for pre-exposure prophylaxis as part of an overall HIV-1 infection prevention strategy including the use of other HIV-1 prevention measures (e.g. consistent and correct condom use, knowledge of HIV-1 status, regular testing for other sexually transmitted infections).

Risk of resistance with undetected HIV-1 infection:
Truvada should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV negative (see section 4.3). Individuals should be re-confirmed to be HIV-negative at frequent intervals (e.g. at least every 3 months) using a combined antigen/antibody test while taking Truvada for pre-exposure prophylaxis.

Truvada alone does not constitute a complete regimen for the treatment of HIV-1 and HIV-1 resistance mutations have emerged in individuals with undetected HIV-1 infection who are only taking Truvada.

If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV-1 are suspected, use of Truvada should be delayed for at least one month and HIV-1 status reconfirmed before starting Truvada for pre-exposure prophylaxis.

Importance of adherence:
The effectiveness of Truvada in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in blood (see section 5.1). HIV-1 uninfected individuals should be counselled at frequent intervals to strictly adhere to the recommended Truvada daily dosing schedule.

Patients with hepatitis B or C virus infection

HIV-1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).


The safety and efficacy of Truvada for pre-exposure prophylaxis in patients with HBV or HCV infection has not been established.

In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. See also under Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir below.

Tenofovir disoproxil is indicated for the treatment of HBV and emtricitabine has shown activity against HBV in pharmacodynamic studies but the safety and efficacy of Truvada have not been specifically established in patients with chronic HBV infection.

Discontinuation of Truvada therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue Truvada should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease

The safety and efficacy of Truvada have not been established in patients with significant underlying liver disorders. The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for Truvada in patients with hepatic impairment (see sections 4.2 and 5.2).

HIV-1 infected 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.

Renal and bone effects in adults

Renal effects
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (see section 4.8).

Renal monitoring
Prior to initiating Truvada for the treatment of HIV-1 infection or for use in pre-exposure prophylaxis, it is recommended that creatinine clearance is calculated in all individuals.

In individuals without risk factors for renal disease, it is recommended that renal function (creatinine clearance and serum phosphate) is monitored after two to four weeks of use, after three months of use and every three to six months thereafter.

In individuals at risk for renal disease more frequent monitoring of renal function is required.

See also under Co-administration of other medicinal products below.
Renal management in HIV-1 infected patients
If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 50 mL/min in any patient receiving Truvada, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should be given to interrupting treatment with Truvada in patients with creatinine clearance decreased to < 50 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L). Interrupting treatment with Truvada should also be considered in case of progressive decline of renal function when no other cause has been identified.

Renal safety with Truvada has only been studied to a very limited degree in HIV-1 infected patients with impaired renal function (creatinine clearance < 80 mL/min). Dose interval adjustments are recommended for HIV-1 infected patients with creatinine clearance 30-49 mL/min (see section 4.2).
Limited clinical study data suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Furthermore, in a small clinical study, a subgroup of patients with creatinine clearance between 50 and 60 mL/min who received tenofovir disoproxil in combination with emtricitabine every 24 hours had a 2-4-fold higher exposure to tenofovir and worsening of renal function (see section 5.2). Therefore, a careful benefit-risk assessment is needed when Truvada is used in patients with creatinine clearance < 60 mL/min, and renal function should be closely monitored. In addition, the clinical response to treatment should be closely monitored in patients receiving Truvada at a prolonged dosing interval. The use of Truvada is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) and in patients who require haemodialysis since appropriate dose reductions cannot be achieved with the combination tablet (see sections 4.2 and 5.2).

Renal management in pre-exposure prophylaxis
Truvada has not been studied in HIV-1 uninfected individuals with creatinine clearance < 60 mL/min and is therefore not recommended for use in this population. If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 60 mL/min in any individual receiving Truvada for pre-exposure prophylaxis, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should be given to interrupting use of Truvada in individuals with creatinine clearance decreased to < 60 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L). Interrupting use of Truvada should also be considered in case of progressive decline of renal function when no other cause has been identified.

Bone effects
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil- induced proximal renal tubulopathy (see section 4.8).

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Treatment of HIV-1 infection
Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil in randomized controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients.
These BMD decreases generally improved after treatment discontinuation.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Overall in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or with a history of bone fractures.

Pre-exposure prophylaxis
In clinical studies of HIV-1 uninfected individuals, small decreases in BMD were observed. In a study of 498 men, the mean changes from baseline to week 24 in BMD ranged from -0.4% to -1.0% across hip, spine, femoral neck and trochanter in men who received daily Truvada prophylaxis (n = 247) vs.
placebo (n = 251).


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 (hyperlactatemia, hyperlipasemia). 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 etiology, 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 are 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

HIV-1 infected patients receiving Truvada 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.

Co-administration of other medicinal products

Use of Truvada should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use with nephrotoxic agents is unavoidable, renal function should be monitored weekly.


Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in HIV-1 infected patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If Truvada is co-administered with an NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in HIV-1 infected patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function is required in these patients (see section 4.5). In HIV-1 infected patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

Truvada should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidine analogues, such as lamivudine (see section 4.5). Truvada should not be administered concomitantly with adefovir dipivoxil.

Use with ledipasvir and sofosbuvir, sofosbuvir and velpatasvir or sofosbuvir, velpatasvir and voxilaprevir
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat).

The safety of tenofovir disoproxil when co-administered with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

Co-administration of tenofovir disoproxil and didanosine
Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.5).

Triple nucleoside therapy
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV-1 infected patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. There is close structural similarity between lamivudine and emtricitabine and similarities in the pharmacokinetics and pharmacodynamics of these two agents. Therefore, the same problems may be seen if Truvada is administered with a third nucleoside analogue.

Elderly

Truvada has not been studied in individuals over the age of 65 years. Individuals over the age of 65 years are more likely to have decreased renal function, therefore caution should be exercised when administering Truvada to older people.

Excipients

Truvada 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 medicine 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

No studies on the effects on the ability to drive and use machines have been performed. However, individuals should be informed that dizziness has been reported during treatment with both emtricitabine and tenofovir disoproxil.