Tenofovir Disoproxil Fumarate Hetero

Tenofovir Disoproxil Fumarate Hetero

tenofovir disoproxil fumarate

Manufacturer:

Hetero

Distributor:

Hind Wing
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Tenofovir disoproxil fumarate.
Description
Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil.
Tenofovir disoproxil fumarate is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl] adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P · C4H4O4 and a molecular weight of 635.52.
Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.
Tenofovir disoproxil fumarate tablets are for oral administration.
In this monograph, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
Excipients/Inactive Ingredients: Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, pregelatinized starch and magnesium stearate. The tablets are coated with opadry II light blue which contains lactose monohydrate, hypromellose, titanium dioxide, triacetin and FD&C blue #2 / indigo carmine aluminum lake.
Action
Pharmacology: Mechanism of Action: Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology as follows].
Pharmacokinetics: The pharmacokinetics of TDF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption: TENOFOVIR DISOPROXIL FUMARATE is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from TENOFOVIR DISOPROXIL FUMARATE in fasted subjects is approximately 25%. Following oral administration of a single dose of TENOFOVIR DISOPROXIL FUMARATE 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg·hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a TENOFOVIR DISOPROXIL FUMARATE dose range of 75 to 600 mg and are not affected by repeated dosing.
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
Distribution: In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination: In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of TENOFOVIR DISOPROXIL FUMARATE, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of TENOFOVIR DISOPROXIL FUMARATE 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption: Administration of TENOFOVIR DISOPROXIL FUMARATE 300 mg tablets following a high-fat meal (~700 to 1,000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of TENOFOVIR DISOPROXIL FUMARATE with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg·hr/mL following multiple doses of TENOFOVIR DISOPROXIL FUMARATE 300 mg once daily in the fed state, when meal content was not controlled.
Specific Populations: Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Gender: Tenofovir pharmacokinetics are similar in male and female subjects.
Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Renal Impairment: The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see New Onset or Worsening Renal Impairment under Precautions]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (Table 1). (See Table 1.)

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Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of TENOFOVIR DISOPROXIL FUMARATE have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in TENOFOVIR DISOPROXIL FUMARATE dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions: At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.
TENOFOVIR DISOPROXIL FUMARATE has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 2 and 3 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TENOFOVIR DISOPROXIL FUMARATE on the pharmacokinetics of coadministered drug.
TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.
No clinically significant drug interactions have been observed between TENOFOVIR DISOPROXIL FUMARATE and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir. (See Table 2.)

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No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TENOFOVIR DISOPROXIL FUMARATE: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine. (See Table 3.)

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Microbiology: Mechanism of Action: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Activity against HIV: Antiviral Activity: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies, tenofovir was not antagonistic with HIV-1 NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine), NNRTIs (efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 μM to 2.2 μM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).
Resistance: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.
In Trial 903 of treatment-naïve subjects (TENOFOVIR DISOPROXIL FUMARATE+3TC+EFV versus d4T+3TC+EFV), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of EFV and 3TC resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the TENOFOVIR DISOPROXIL FUMARATE arm and in 2/49 (4%) of analyzed patient isolates in the d4T arm. Of the 8 subjects whose virus developed K65R in the TENOFOVIR DISOPROXIL FUMARATE arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the TENOFOVIR DISOPROXIL FUMARATE arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to TENOFOVIR DISOPROXIL FUMARATE were not identified in this trial.
In Trial 934 of treatment-naïve subjects (TENOFOVIR DISOPROXIL FUMARATE+FTC+EFV versus AZT/3TC+EFV), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of EFV resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to FTC and 3TC, was observed in 2/19 of analyzed subject isolates in the TENOFOVIR DISOPROXIL FUMARATE+FTC group and in 10/29 of analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross Resistance: Cross resistance among certain HIV-1 NRTIs has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to FTC and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three AZT-associated RT substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Trials 902 and 907 conducted in treatment-experienced subjects (TENOFOVIR DISOPROXIL FUMARATE + Standard Background Therapy (SBT) compared to placebo + SBT), 14/304 (5%) of the TENOFOVIR DISOPROXIL FUMARATE-treated subjects with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 RT gene.
The virologic response to TENOFOVIR DISOPROXIL FUMARATE therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Trials 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross resistance of TENOFOVIR DISOPROXIL FUMARATE to pre-existing AZT resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. TENOFOVIR DISOPROXIL FUMARATE-treated subjects whose HIV-1 expressed 3 or more AZT resistance-associated substitutions that included either the M41L or L210W RT substitution showed reduced responses to TENOFOVIR DISOPROXIL FUMARATE therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to TENOFOVIR DISOPROXIL FUMARATE therapy. Subjects whose virus expressed an L74V substitution without AZT resistance-associated substitutions (N=8) had reduced response to TENOFOVIR DISOPROXIL FUMARATE. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to TENOFOVIR DISOPROXIL FUMARATE was not reduced in subjects with HIV-1 that expressed the abacavir/FTC/3TC resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Trials 902 and 907 Phenotypic Analyses: Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to TENOFOVIR DISOPROXIL FUMARATE and response to TENOFOVIR DISOPROXIL FUMARATE therapy. Table 4 summarizes the HIV-1 RNA response by baseline TENOFOVIR DISOPROXIL FUMARATE susceptibility. (See Table 4.)

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Activity against HBV: Antiviral Activity: The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 μM, with CC50 (50% cytotoxicity concentration) values >100 μM. In cell culture combination antiviral activity studies of tenofovir with HBV NrtIs entecavir, lamivudine, and telbivudine, and with the HIV-1 NRTI emtricitabine, no antagonistic activity was observed.
Resistance: Cumulative TENOFOVIR DISOPROXIL FUMARATE genotypic resistance has been evaluated annually for up to 384 weeks in Trials 0102, 0103, 0106, 0108, and 0121 with the paired HBV rt amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of TENOFOVIR DISOPROXIL FUMARATE monotherapy and remained viremic with HBV DNA ≥400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of TENOFOVIR DISOPROXIL FUMARATE monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Trials 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on TENOFOVIR DISOPROXIL FUMARATE monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 5); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to TENOFOVIR DISOPROXIL FUMARATE (genotypic and phenotypic analyses). (See Table 5.)

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Cross Resistance: Cross resistance has been observed between HBV NrtIs.
In cell-based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine (3TC) and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating TENOFOVIR DISOPROXIL FUMARATE therapy in Trials 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV NrtIs: 14 with adefovir resistance- associated substitutions (rtA181S/T/V and/or rtN236T), 135 with 3TC resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and 3TC resistance-associated substitutions. Following up to 384 weeks of TENOFOVIR DISOPROXIL FUMARATE treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with 3TC-resistant HBV, and 2 of the 3 subjects with both adefovir- and 3TC-resistant HBV achieved and maintained virologic suppression (HBV DNA <400 copies/mL [69IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
Indications/Uses
HIV-1 Infection: TENOFOVIR DISOPROXIL FUMARATE is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults [see Immune Reconstitution Syndrome under Precautions].
Chronic Hepatitis B: TENOFOVIR DISOPROXIL FUMARATE is indicated for the treatment of chronic hepatitis B virus (HBV) in adults.
Dosage/Direction for Use
Testing Prior to Initiation of TENOFOVIR DISOPROXIL FUMARATE for Treatment of HIV-1 Infection or Chronic Hepatitis B: Prior to or when initiating TENOFOVIR DISOPROXIL FUMARATE, test patients for HBV infection and HIV-1 infection. TENOFOVIR DISOPROXIL FUMARATE alone should not be used in patients with HIV-1 infection [see Patients Coinfected with HIV-1 and HBV under Precautions].
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 [see New Onset or Worsening Renal Impairment under Precautions].
Recommended Tablet Dosage in Adults: The recommended dosage of TENOFOVIR DISOPROXIL FUMARATE in adults is one 300 mg tablet taken orally once daily without regard to food.
Dosage Adjustment in Patients with Renal Impairment: Significant increase in drug exposures occurred when TENOFOVIR DISOPROXIL FUMARATE was administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 6 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of TENOFOVIR DISOPROXIL FUMARATE tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min) [see Patients Coinfected with HIV-1 and HBV and Renal Impairment under Precautions, and Pharmacology: Pharmacokinetics under Actions]. (See Table 6.)

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No data are available to make dosage recommendations in patients with creatinine clearance below 10 mL/min who are not on hemodialysis.
No data are available to make dosage recommendations in pediatric patients with renal impairment.
Overdosage
If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TENOFOVIR DISOPROXIL FUMARATE, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Contraindications
None.
Warnings
Post Treatment Acute Exacerbation of Hepatitis B: Severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including TENOFOVIR DISOPROXIL FUMARATE. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HBV-infected patients who discontinue anti-hepatitis B therapy, including TENOFOVIR DISOPROXIL FUMARATE. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection under Precautions].
Special Precautions
Severe 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 Testing Prior to Initiation of TENOFOVIR DISOPROXIL FUMARATE for Treatment of HIV-1 Infection or Chronic Hepatitis B under Dosage & Administration].
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 post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
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 TENOFOVIR DISOPROXIL FUMARATE.
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 and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [see Dosage Adjustment in Patients with Renal Impairment under Dosage & Administration]. 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 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 Drugs Affecting Renal Function under Interactions]. 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.
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.
Immune 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, Pneumocystis 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.
Coadministration with Other Products: TENOFOVIR DISOPROXIL FUMARATE should not be used in combination with other drugs containing tenofovir DF or Tenofovir alafenamide, including ATRIPLA, Complera, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, or VEMLIDY. TENOFOVIR DISOPROXIL FUMARATE should not be administered in combination with adefovir dipivoxil.
Bone 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. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TENOFOVIR DISOPROXIL FUMARATE.
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 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. 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 New Onset or Worsening Renal Impairment as previously mentioned].
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 TDF, alone or in combination with other antiretrovirals. Treatment with TENOFOVIR DISOPROXIL FUMARATE 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).
Risk of Adverse Reactions Due to Drug Interactions: The concomitant use of TENOFOVIR DISOPROXIL FUMARATE and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Established and Significant Interactions under Interactions].
See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TENOFOVIR DISOPROXIL FUMARATE; review concomitant medications during therapy with TENOFOVIR DISOPROXIL FUMARATE; and monitor for adverse reactions associated with the concomitant drugs.
Renal Impairment: The dosing interval for TENOFOVIR DISOPROXIL FUMARATE should be modified in adult patients with estimated creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage Adjustment in Patients with Renal Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions].
Use in Elderly: Clinical trials of TENOFOVIR DISOPROXIL FUMARATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TENOFOVIR DISOPROXIL FUMARATE during pregnancy.
Risk Summary: Available data show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data as follows). The rate of miscarriage for individual drugs is not reported. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%.
Published studies in HBV-infected subjects do not report an increased risk of adverse pregnancy-related outcomes with the use of TENOFOVIR DISOPROXIL FUMARATE during the third trimester of pregnancy (see Data as follows).
In animal reproduction studies, no adverse developmental effects were observed when TDF was administered at doses/exposures ≥ 14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of TENOFOVIR DISOPROXIL FUMARATE (see Data as follows).
Data: Human Data: Based on prospective reports exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens.
Prospective reports of overall major birth defects in pregnancies exposed to TDF are compared with a U.S. background major birth defect rate. Methodological limitations include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered TENOFOVIR DISOPROXIL FUMARATE from 28 to 32 weeks gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of TENOFOVIR DISOPROXIL FUMARATE in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in TENOFOVIR DISOPROXIL FUMARATE-exposed infants. Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to TENOFOVIR DISOPROXIL FUMARATE during late gestation.
Animal Data: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TENOFOVIR DISOPROXIL FUMARATE.
Lactation: Risk Summary: Based on published data, tenofovir has been shown to be present in human breast milk (see Data as follows). It is not known if tenofovir affects milk production or has effects on the breastfed child.
Treatment of HIV-1 infection: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking TENOFOVIR DISOPROXIL FUMARATE for the treatment of HIV-1.
Treatment of HBV infection: The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TENOFOVIR DISOPROXIL FUMARATE and any potential adverse effects on the breastfed infant from TENOFOVIR DISOPROXIL FUMARATE or from the underlying maternal condition.
Data: In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.
Adverse Reactions
The following adverse reactions are discussed in Precautions: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection; New Onset or Worsening Renal Impairment; Immune Reconstitution Syndrome; Bone Loss and Mineralization Defects; Lactic Acidosis/Severe Hepatomegaly with Steatosis.
Drug Interactions
Drugs Affecting Renal Function: Tenofovir is primarily eliminated by the kidneys [see Pharmacology: Pharmacokinetics under Actions]. 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 New Onset or Worsening Renal Impairment under Precautions]. 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).
Established and Significant Interactions: Table 7 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with TDF [see Pharmacology: Pharmacokinetics under Actions]. (See Table 7.)

Click on icon to see table/diagram/image
Caution For Usage
Do not use if seal over bottle opening is broken or missing.
Storage
Store in tightly closed containers below 30°C.
MIMS Class
ATC Classification
J05AF07 - tenofovir disoproxil ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
Tab 300 mg (light blue coloured, almond shaped, film coated, debossed with 'H' on one side and '123' on other side) x 30's.
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