Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg. ( 1.1 ) for the treatment of chronic hepatitis B in adults and pediatric patients 2 years and older weighing at least 10 kg.
( 1.2 )
1.1HIV-1 Infection
Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg.
1.2Chronic Hepatitis B
Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 2 years of age and older weighing at least 10 kg.
Contraindications
None. None. ( 4 )
Warnings and precautions
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs. ( 5.2 ) HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.
( 5.3 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.4 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.5 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
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5.1Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection
All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating tenofovir disoproxil fumarate [see Dosage and Administration ( 2.1 )] . Discontinuation of anti-HBV therapy, including tenofovir disoproxil fumarate, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue tenofovir disoproxil fumarate 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, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.2New 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 tenofovir disoproxil fumarate [see Adverse Reactions ( 6.2 )] . Prior to initiation and during use of tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.
In patients with chronic kidney disease, also assess serum phosphorus. Dosing interval adjustment of tenofovir disoproxil fumarate tablets and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [see Dosage and Administration ( 2.4 )] . No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity.
Tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions ( 7.1 ) ] . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy.
Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.
5.3 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, 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 tenofovir disoproxil fumarate. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir disoproxil fumarate.
5.4Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneu mocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.5Bone Loss and Mineralization Defects Bone Mineral Density
In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions ( 6.1 )] . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate.
Clinical trials evaluating tenofovir disoproxil fumarate in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir disoproxil fumarate-treated HIV-1 infected pediatric subjects as compared to the control groups.
Similar trends were observed in chronic HBV-infected pediatric subjects 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials [see Adverse Reactions ( 6.1 )]. The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown.
The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
If bone abnormalities are suspected, appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with tenofovir disoproxil fumarate use [see Adverse Reactions ( 6.2 )] . Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.
Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions ( 5.2 )] .
5.6Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with t
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Interactions
Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. ( 7.2 ) Coadministration decreases atazanavir concentrations. When coadministered with tenofovir disoproxil fumarate, use atazanavir given with ritonavir. ( 7.2 ) Coadministration of tenofovir disoproxil fumarate with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations.
Monitor for evidence of tenofovir toxicity. ( 7.2 ) Consult Full Prescribing Information prior to and during treatment for important drug interactions. ( 7.2 )
7.1Drugs Affecting Renal Function
Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology ( 12.3 ) ] . Coadministration of tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions ( 5.2 ) ].
Drugs that decrease renal function may increase concentrations of tenofovir. In the treatment of chronic hepatitis B, tenofovir disoproxil fumarate should not be administered in combination with HEPSERA (adefovir dipivoxil).
7.2Established and Significant Interactions Table
12 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with TDF [see Clinical Pharmacology ( 12.3 )]. T ab l e 12 Established and Significant a D rug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration b Clinical Comment NRTI: didanosine ↑ didanosine Patients receiving tenofovir disoproxil fumarate tablets and didanosine should be monitored closely for didanosine-associated adverse reactions.
Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with tenofovir disoproxil fumarate.
In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with tenofovir disoproxil fumarate. When coadministered, tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). HIV-1 Protease Inhibitors : atazanavir ↓ atazanavir When coadministered with tenofovir disoproxil fumarate tablets, atazanavir 300 mg should be given with ritonavir 100 mg. lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir ↑ tenofovir Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for TDF-associated adverse reactions.
Discontinue tenofovir disoproxil fumarate tablets in patients who develop TDF-associated adverse reactions. Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) for adverse reactions associated with TDF. ledipasvir/sofosbuvir Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF.
In patients receiving tenofovir disoproxil fumarate tablets concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with TDF. a This table is not all inclusive b ↑=Increase, ↓=Decrease
Adverse reactions
The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions ( 5.1 )] . New Onset or Worsening Renal Impairment [see Warnings and Precautions ( 5.2 )] . Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . Bone Loss and Mineralization Defects [see Warnings and Precautions ( 5.5 )] .
Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions ( 5.6 )] . In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) were rash, diarrhea, nausea, headache, pain, depression, and asthenia. ( 6.1 ) In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). ( 6.1 ) In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (incidence greater than or equal to 10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.
( 6.1 ) In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Adults More than 12,000 subjects have been treated with tenofovir disoproxil fumarate alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs.
A total of 1,544 subjects have received tenofovir disoproxil fumarate tablets 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate in expanded access programs. The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral- naïve subjects received tenofovir disoproxil fumarate (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea.
Table 4 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 4 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) Tenofovir disoproxil fumarate + 3 T C+EFV d4T+3TC+EFV N=299 N=301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophyc 1% 8% Peripheral neuropathy d 1% 5% a.
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d. Peripheral neuropathy includes peripheral neuritis and neuropathy. La b o r a tory Abnormalities: Table 5 provides a list of laboratory abnormalities (Grades 3−4) observed in Trial 903.
With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the tenofovir disoproxil fumarate group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms. Table 5 Grades 3 to 4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 903 (0 to 144 Weeks) Tenofovir Disoproxil Fumarate + 3TC + EFV d 4T + 3TC + EFV N=299 N=301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (>240 mg/dL) 19% 40% Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12% Serum Amylase (>175 U/L) 9% 8% AST (M: >180 U/L; F: >170 U/L) 5% 7% ALT (M: >215 U/L; F: >170 U/L) 4% 5% Hematuria (>100 RBC/HPF) 7% 7% Neutrophils (<750/mm 3 ) 3% 1% Fasting Triglycerides (>750 mg/dL) 1% 9% Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks.
Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of d4T-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 tenofovir disoproxil fumarate group and 6 subjects in the d4T 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) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir disoproxil fumarate group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions ( 5.5 )] .
In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + tenofovir disoproxil fumarate tablets (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
Table 6 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 6 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Trial 934 (0 to 144 Weeks) Tenofovir disoproxil fumarate tablets b + FTC+EFV A ZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash eventc 7% 9% Headache 6% 5% Insomnia 5% 7% Nasopharyngitis 5% 3% Vomiting 2% 5% a.
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of tenofovir disoproxil fumarate + FTC with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. La b o r a tory Abnormalities: Laboratory abnormalities observed in this trial were generally
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Composition
Active ingredients
TENOFOVIR DISOPROXIL FUMARATE 300MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
