Tenofovir Disoproxil Fumarate Teva Adverse Reactions

Summary of the safety profile: HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving tenofovir disoproxil fumarate (see Precautions).
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated adult patients discontinued treatment due to the gastrointestinal events.
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients. the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%). Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see Precautions).
Tabulated summary of adverse reactions: Assessment of adverse reactions for tenofovir disoproxil fumarate is based on safety data from clinical studies and postmarketing experience. All adverse reactions are presented in Table 1.
HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil fumarate 300 mg (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil fumarate 300 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. After an initial decline of approximately -4.9 ml/min (using Cockcroft-Gault equation) or -3.9 ml/min/1.73 m² (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil fumarate treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) and -0.74 ml/min/1.73 m² per year (using MDRD equation).
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was assessed in a double-blind active controlled study in which adult patients received treatment with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22) for 48 weeks.
In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of ≥0.5 mg/dl or confirmed serum phosphate of <2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the tenofovir disoproxil fumarate group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil fumarate group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥0.5 mg/dl or confirmed serum phosphate of <2 mg/dl.
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil fumarate group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) in the entecavir group.
Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see Precautions).
Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil fumarate were identified from a randomised, double-blind study in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 240 weeks.
The adverse reactions with suspected (at least possible) relationship to treatment are listed as follows by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). (See Table 1.)

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Description of selected adverse reactions: HIV-1 and hepatitis B: Renal impairment: As tenofovir disoproxil fumarate may cause renal damage monitoring of renal function is recommended (see Precautions and Summary of the safety profile as previously mentioned). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil fumarate discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil fumarate discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil fumarate discontinuation (see Precautions).
Lactic acidosis: Cases of lactic acidosis have been reported with tenofovir disoproxil fumarate alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil fumarate treatment, including fatal outcomes.
HIV-1: Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Precautions).
Immune reactivation syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Precautions).
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see Precautions).
Hepatitis B: Exacerbations of hepatitis during treatment: In studies with nucleoside-naïve patients, on-treatment ALT elevations >10 times ULN (upper limit of normal) and >2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥2 log₁₀ copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see Precautions).
Exacerbations of hepatitis after discontinuation of treatment: In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see Precautions).
Other special population(s): Elderly: Tenofovir disoproxil fumarate has not beenstudied 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 (see Precautions).
Patients with renal impairment: Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with tenofovir disoproxil fumarate (see Dosage & Administration and Precautions). The use of tenofovir disoproxil fumarate is not recommended in paediatric patients with renal impairment.
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.