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General: HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil fumarate therapy (see Co-infection with HIV-1 and hepatitis B as follows).
HIV-1: White 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.
Hepatitis B: Patients must be advised that tenofovir disoproxil fumarate has not been proven to prevent the risk of transmission of HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.
Co-administration of other medicinal products: Tenofovir Disoproxil Fumarate Teva Tablet should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
Tenofovir Disoproxil Fumarate Teva Tablet should not be administered concomitantly with adefovir dipivoxil.
Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see Interactions).
Triple therapy with nucleosides/nucleotides: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once-daily regimen.
Renal and bone effects in adult population: Renal effects: Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see Adverse Reactions).
Renal monitoring: It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil fumarate and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.
Renal management: If serum phosphate is <1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to <50 ml/min in any adult patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see Adverse Reactions, proximal tubulopathy).
Consideration should also be given to interrupting treatment with tenofovir disoproxil fumarate in adult 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 tenofovir disoproxil fumarate should also be considered in case of progressive decline of renal function when no other cause has been identified.
Co-administration and risk of renal toxicity: Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin , foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and 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 patients treated with tenofovir disoproxit fumarate and with risk factors for renal dysfunction. If tenofovir disoproxil fumarate is co-administered with an NSAID, renal function should be monitored adequately.
A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients (see Interactions). In patients with renal risk factors, the co-administration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products, which are secreted by the same renal pathway including transport proteins hOAT1 and 3 or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see Interactions).
Renal impairment: Renal safety with tenofovir disoproxil fumarate has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance <80 ml/min).
Adult patients with creatinine clearance <50 ml/min, including haemodialysis patients: There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function.
Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance <30 ml/min) and in patients who require haemodialysis use of tenofovir disoproxil fumarate is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored (see Dosage & Administration).
Bone effects: In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Adverse Reactions).
If bone abnormalities are suspected or detected then appropriate consultation should be obtained.
Liver disease: Safety and efficacy data are very limited in liver transplant patients.
There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a Child Pugh-Turcotte (CPT) score >9. These patients may beat higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.
Exacerbations of hepatitis: Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterized by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see Adverse Reactions). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may beat at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. 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 flares are especially serious, and sometimes fatal inpatients with decompensated liver disease.
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.
Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. 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. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see Exacerbations of hepatitis as previously mentioned.
Use with certain hepatitis C virus antiviral agents: Co-administration of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of 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 of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) 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 fumarate and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil fumarate.
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.
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.
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, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.
Use in Elderly: Tenofovir disoproxil fumarate has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate.
Tenofovir Disoproxil Fumarate Teva Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
