VIREAD (tenofovir disoproxil fumarate) Tablets part 2
WARNINGS AND PRECAUTIONS:
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 m L/m in (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent. Coadministration with Other Products: VIREAD should not be used in combination with the fixed-dose combination products TRUVADA® (emtricitabine/tenofovir disoproxil fumarate) or ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate) since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with HEPSERA® (adefovir dipivoxil) (See Drug Interactions).Patients Coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD (tenofovir disoproxil fumarate) should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. Decreases in Bone Mineral Density: Bone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. In HIV-infected subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the study and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD (See Adverse Reactions). The bone effects of VIREAD have not been studied in patients with chronic HBV infection.
ADVERSE REACTIONS: Clinical Trials in Patients with Chronic Hepatitis B:
Treatment-Emergent Adverse Reactions: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in >5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile (frequency, nature, or severity of adverse reactions) was observed in subjects continuing treatment with VIREAD for up to 96 weeks in these studies.
The overall incidence of on-treatment ALT elevations (defined as serum ALT >2 x baseline and >10 x ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT elevations generally occurred within the first 4-8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication. Grade 3/4 laboratory abnormalities were similar in nature and frequency in subjects continuing treatment for up to 96 weeks in these studies. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: allergic reaction, including angioedema, lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The following adverse reactions listed above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.