DRUGS & SUPPLEMENTS
WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS
Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Tenofovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including Tenofovir. If appropriate, resumption of anti-hepatitis B therapy may be warranted .
WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS
See full prescribing information for complete boxed warning.
Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Tenofovir. Hepatic function should be monitored closely in these patients. If appropriate, resumption of anti-hepatitis B therapy may be warranted. (5.1)
1 INDICATIONS AND USAGE
Tenofovir is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.
1.1 HIV-1 Infection
Tenofovir® 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.
The following points should be considered when initiating therapy with Tenofovir for the treatment of HIV-1 infection:
1.2 Chronic Hepatitis B
Tenofovir is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.
The following points should be considered when initiating therapy with Tenofovir for the treatment of HBV infection:
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more)
For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg Tenofovir tablet once daily taken orally, without regard to food.
For patients unable to swallow Tenofovir tablets, the oral powder formulation (7.5 scoops) may be used.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established.
2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age
For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of Tenofovir is 8 mg of Tenofovir per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
Tenofovir oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir DF. Tenofovir oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer Tenofovir oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer Tenofovir oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).
Tenofovir is also available as tablets in 150, 200, 250, and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
Tables 1 and 2 contain dosing recommendations for Tenofovir oral powder and tablets based on body weight. Weight should be monitored periodically and the Tenofovir dose adjusted accordingly.
Chronic Hepatitis B
Safety and efficacy of Tenofovir in patients younger than 12 years of age have not been established.
2.3 Dose Adjustment for Renal Impairment in Adults
Significantly increased drug exposures occurred when Tenofovir was administered to subjects with moderate to severe renal impairment . Therefore, the dosing interval of Tenofovir tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment; therefore, clinical response to treatment and renal function should be closely monitored in these patients . There are no data to recommend use of Tenofovir tablets 150, 200, or 250 mg or Tenofovir oral powder in patients with renal impairment.
No dose adjustment of Tenofovir tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment .
The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients.
No data are available to make dose recommendations in pediatric patients with renal impairment.
3 DOSAGE FORMS AND STRENGTHS
Tenofovir is available as tablets or as an oral powder.
Tenofovir tablets 150 mg contain 150 mg of tenofovir DF, which is equivalent to 123 mg of tenofovir disoproxil. The tablets are triangle shaped, white, film coated, and debossed with "GSI" on one side and "150" on the other side.
Tenofovir tablets 200 mg contain 200 mg of tenofovir DF, which is equivalent to 163 mg of tenofovir disoproxil. The tablets are round shaped, white, film coated, and debossed with "GSI" on one side and "200" on the other side.
Tenofovir tablets 250 mg contain 250 mg of tenofovir DF, which is equivalent to 204 mg of tenofovir disoproxil. The tablets are capsule shaped, white, film coated, and debossed with "GSI" on one side and "250" on the other side.
Tenofovir tablets 300 mg contain 300 mg of tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond shaped, light blue, film coated, and debossed with "GILEAD" and "4331" on one side and with "300" on the other side.
The oral powder consists of white, taste-masked, coated granules containing 40 mg of tenofovir DF, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop. Each level scoop contains 1 gram of oral powder.
5 WARNINGS AND PRECAUTIONS
5.1 Exacerbation of Hepatitis after Discontinuation of Treatment
Discontinuation of anti-HBV therapy, including Tenofovir, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue Tenofovir 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.
5.2 New Onset or Worsening Renal Impairment
Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported with the use of Tenofovir .
It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Tenofovir. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Tenofovir, and periodically during Tenofovir therapy.
Dosing interval adjustment of Tenofovir and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min . No safety or efficacy data are available in patients with renal impairment who received Tenofovir using these dosing guidelines, so the potential benefit of Tenofovir therapy should be assessed against the potential risk of renal toxicity.
Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) . 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 tenofovir DF. 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 at-risk patients.
5.3 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 tenofovir DF, alone or in combination with other antiretrovirals. Treatment with Tenofovir 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).
5.4 Coadministration with Other Products
Tenofovir 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 should not be administered in combination with HEPSERA .
5.5 Patients Coinfected with HIV-1 and HBV
Due to the risk of development of HIV-1 resistance, Tenofovir 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. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with Tenofovir.
5.6 Bone Effects
Bone Mineral Density:
In clinical trials in HIV-1 infected adults, Tenofovir was associated with slightly greater decreases in bone mineral density 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 .
Clinical trials evaluating Tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected .
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. 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.
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 the use of Tenofovir . Arthralgias 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 products containing tenofovir DF.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including Tenofovir. During the initial phase of combination antiretroviral treatment, 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.
5.8 Early Virologic Failure
Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Adverse Reactions from Clinical 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.
Clinical Trials in Adult Patients with HIV-1 Infection
More than 12,000 subjects have been treated with Tenofovir 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 1544 subjects have received Tenofovir 300 mg once daily in clinical trials; over 11,000 subjects have received Tenofovir in expanded access programs.
The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Study 903 −Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received Tenofovir (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) 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. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 4.
Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with Tenofovir (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the Tenofovir and stavudine treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 5.
Study 934 – Treatment-Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either Tenofovir + EMTRIVA® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6).
Changes in Bone Mineral Density
In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving Tenofovir + lamivudine + efavirenz (−2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (−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 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 trial 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 Tenofovir 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) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the Tenofovir group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range .
Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).
Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).
A summary of moderate to severe treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8.
Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the Tenofovir and placebo-treated groups. A summary of Grades 3–4 laboratory abnormalities is provided in Table 9.
Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection
Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with Tenofovir (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with Tenofovir were consistent with those observed in clinical trials in adults.
Eighty-nine pediatric subjects (2 to less than 12 years of age) received Tenofovir in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score .
Changes in Bone Mineral Density:
Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the Tenofovir compared to the placebo treatment group. Six Tenofovir treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with Tenofovir for 96 weeks. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the Tenofovir and the d4T or AZT treatment groups. Total body BMD gain was less in the Tenofovir compared to the d4T or AZT treatment groups. One VIREAD-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with Tenofovir for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected .
Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease
Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with Tenofovir during the 48-week double-blind period experienced nausea: 9% with Tenofovir versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with Tenofovir included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.
During the open-label phase of treatment with Tenofovir (weeks 48–384) in Studies 0102 and 0103, 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks.
Laboratory Abnormalities: A summary of Grades 3–4 laboratory abnormalities through Week 48 is provided in Table 10. Grades 3–4 laboratory abnormalities were similar in subjects continuing Tenofovir treatment for up to 384 weeks in these trials.
The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between Tenofovir (2.6%) and HEPSERA (2%). ALT flares 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.
The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with Tenofovir were consistent with those observed in other hepatitis B clinical trials in adults.
Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease
In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with Tenofovir or other antiviral drugs for up to 48 weeks . Among the 45 subjects receiving Tenofovir, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both Tenofovir and decompensated liver disease may have an impact on renal function, the contribution of Tenofovir to renal impairment in this population is difficult to ascertain.
One of 45 subjects experienced an on-treatment hepatic flare during the 48-week trial.
Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B
Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with Tenofovir (N=52) or placebo (N=54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with Tenofovir were consistent with those observed in clinical trials of Tenofovir in adults.
In this study, both the Tenofovir and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the Tenofovir group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to Tenofovir were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving Tenofovir for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected .
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Tenofovir. 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.
Immune System Disorders
allergic reaction, including angioedema
Metabolism and Nutrition Disorders
lactic acidosis, hypokalemia, hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders
pancreatitis, increased amylase, abdominal pain
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
Renal and Urinary Disorders
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
General Disorders and Administration Site Conditions
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
7 DRUG INTERACTIONS
This section describes clinically relevant drug interactions with Tenofovir. Drug interactions trials are described elsewhere in the labeling.
Coadministration of Tenofovir and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
When administered with Tenofovir, Cmax and AUC of didanosine increased significantly . The mechanism of this interaction is unknown. 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 with didanosine 400 mg daily.
In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with Tenofovir. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with Tenofovir. When coadministered, Tenofovir and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of Tenofovir and didanosine, please refer to the full prescribing information for didanosine.
7.2 HIV-1 Protease Inhibitors
Tenofovir decreases the AUC and Cmin of atazanavir . When coadministered with Tenofovir, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenofovir should not be coadministered with atazanavir without ritonavir.
Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations . Tenofovir DF is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir DF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving Tenofovir concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions. Tenofovir should be discontinued in patients who develop VIREAD-associated adverse reactions.
7.3 Hepatitis C Antiviral Agents
Coadministration of Tenofovir and EPCLUSA® (sofosbuvir/velpatasvir) or HARVONI® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure .
In patients receiving Tenofovir concomitantly with EPCLUSA, monitor for adverse reactions associated with tenofovir DF.
In patients receiving Tenofovir concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir DF.
In patients receiving Tenofovir 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 tenofovir DF.
7.4 Drugs Affecting Renal Function
Since tenofovir is primarily eliminated by the kidneys , coadministration of Tenofovir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
In the treatment of chronic hepatitis B, Tenofovir should not be administered in combination with HEPSERA (adefovir dipivoxil).
8 USE IN SPECIFIC POPULATIONS
Nursing mothers: Women infected with HIV should be instructed not to breastfeed.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tenofovir should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tenofovir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
8.3 Nursing Mothers
Nursing Mothers: 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. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Tenofovir.
8.4 Pediatric Use
Pediatric Patients 2 Years of Age and Older with HIV-1 infection
The safety of Tenofovir in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which Tenofovir was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials .
In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with Tenofovir (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (VIREAD N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label Tenofovir. At Week 48, 89% of subjects in the Tenofovir treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the Tenofovir group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the Tenofovir group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.
In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with Tenofovir (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the Tenofovir and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to Tenofovir and OBR.
Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of Tenofovir in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to Tenofovir..
Safety and effectiveness of Tenofovir in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.
Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B
In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with Tenofovir 300 mg (N=52) or placebo (N=54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with Tenofovir, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the Tenofovir group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving Tenofovir had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.
Safety and effectiveness of Tenofovir in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.
8.5 Geriatric Use
Clinical trials of Tenofovir 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.
8.6 Patients with Impaired Renal Function
It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis .
Limited clinical experience at doses higher than the therapeutic dose of Tenofovir 300 mg is available. In Study 901, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.
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, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Tenofovir is the brand name for tenofovir DF (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir DF 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 DF 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. It has the following structural formula:
Tenofovir DF 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 is available as tablets or as an oral powder.
Tenofovir tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir DF, which are equivalent to 123, 163, 204, and 245 mg of tenofovir disoproxil, respectively. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg tablets are coated with Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
Tenofovir oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir DF per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.
In this insert, all dosages are expressed in terms of tenofovir DF except where otherwise noted.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tenofovir DF is an antiviral drug.
The pharmacokinetics of tenofovir DF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Tenofovir is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from Tenofovir in fasted subjects is approximately 25%. Following oral administration of a single dose of Tenofovir 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 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.
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, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of Tenofovir 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 300 mg tablets following a high-fat meal (~700 to 1000 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 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 300 mg once daily in the fed state, when meal content was not controlled.
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.
Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 11). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of Tenofovir 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of Tenofovir 300 mg.
Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of Tenofovir 300 mg tablet were comparable to exposures achieved in HIV-1 infected adults and adolescents receiving once-daily doses of 300 mg.
Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment . 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 12). It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis .
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of Tenofovir 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 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 has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 13 and 14 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of Tenofovir on the pharmacokinetics of coadministered drug. Coadministration of Tenofovir with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of Tenofovir with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with Tenofovir, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.
No clinically significant drug interactions have been observed between Tenofovir and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.
No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with Tenofovir: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.
Mechanism of Action
Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase 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
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 nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, 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).
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2- to 4- fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.
In Study 903 of treatment-naïve subjects (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) , genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine 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 arm and in 2/49 (4%) of analyzed patient isolates in the stavudine arm. Of the 8 subjects whose virus developed K65R in the Tenofovir arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the Tenofovir arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to Tenofovir were not identified in this trial.
In Study 934 of treatment-naïve subjects (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz) , genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 of analyzed subject isolates in the Tenofovir + EMTRIVA group and in 10/29 of analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross resistance among certain reverse transcriptase inhibitors 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 emtricitabine and lamivudine. 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 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Studies 902 and 907 conducted in treatment-experienced subjects (VIREAD + Standard Background Therapy (SBT) compared to placebo + SBT) , 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had greater than 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 reverse transcriptase gene.
The virologic response to Tenofovir therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 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 to pre-existing zidovudine 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. VIREAD-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to Tenofovir 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 therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Tenofovir. 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 was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Studies 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 and response to Tenofovir therapy. Table 15 summarizes the HIV-1 RNA response by baseline Tenofovir susceptibility.
Activity against HBV
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 greater than 100 µM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.
Cumulative Tenofovir genotypic resistance has been evaluated annually for up to 384 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of Tenofovir monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of Tenofovir monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 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 monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 16); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to Tenofovir (genotypic and phenotypic analyses).
Cross resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.
In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine 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 therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 384 weeks of Tenofovir treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir- and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.
Impairment of Fertility
There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
13.2 Animal Toxicology and/or Pharmacology
Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2−20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
14 CLINICAL STUDIES
14.1 Clinical Efficacy in Adults with HIV-1 Infection
Treatment-Naïve Adult Patients
Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing Tenofovir administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18−64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3−956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417−5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 17.
Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the Tenofovir and stavudine arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the Tenofovir arm and 283 cells/mm3 for the stavudine arm.
Through 144 weeks, 11 subjects in the Tenofovir group and 9 subjects in the stavudine group experienced a new CDC Class C event.
Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + Tenofovir administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + Tenofovir with efavirenz. Subjects had a mean age of 38 years (range 18−80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2−1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56−6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.
Through Week 48, 84% and 73% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + Tenofovir group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + Tenofovir group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Treatment-Experienced Adult Patients
Study 907 was a 24-week, double-blind, placebo-controlled multicenter trial of Tenofovir added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label Tenofovir for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23−1385), median baseline plasma HIV-1 RNA of 2340 (range 50−75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years; 85% were male, 69% Caucasian, 17% Black, and 12% Hispanic.
The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.
At 24 weeks of therapy, there was a higher proportion of subjects in the Tenofovir arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the Tenofovir group and −5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the Tenofovir group.
Through Week 24, one subject in the Tenofovir group and no subjects in the placebo arm experienced a new CDC Class C event.
14.2 Clinical Efficacy in Adults with Chronic Hepatitis B
HBeAg-Negative Chronic Hepatitis B
Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years; 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy, and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.
HBeAg-Positive Chronic Hepatitis B
Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years; 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.
The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.
The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).
Treatment Beyond 48 Weeks
In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to Tenofovir and HEPSERA, respectively) were eligible to roll over to open-label Tenofovir with no interruption in treatment.
In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384. Among subjects randomized to Tenofovir followed by open-label treatment with Tenofovir, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with Tenofovir, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384. At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.
In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384. Among subjects randomized to Tenofovir, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with Tenofovir, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384. At Week 384, HBsAg loss and seroconversion were 11% and 8%, respectively, in subjects initially randomized to Tenofovir and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.
Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with Tenofovir monotherapy were available for analysis at baseline, Week 48, and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label Tenofovir without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0−4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5−6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.
Patients with Lamivudine-Resistant Chronic Hepatitis B
Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of Tenofovir compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). One hundred forty-one adult subjects were randomized to the Tenofovir treatment arm. The mean age of subjects randomized to Tenofovir was 47 years (range 18−73); 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to Tenofovir had HBV DNA <400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to Tenofovir, 10 of 65 subjects (15%) experienced HBeAg loss and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the Tenofovir monotherapy and the comparator arms.
Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
Patients with Chronic Hepatitis B and Decompensated Liver Disease
Tenofovir was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of Tenofovir compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).
Forty-five adult subjects (37 males and 8 females) were randomized to the Tenofovir treatment arm. At baseline, 69% subjects were HBeAg-negative and 31% were HBeAg-positive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL, and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥0.5 mg/dL or confirmed serum phosphorus of <2 mg/dL .
At 48 weeks, 31/44 (70%) and 12/26 (46%) VIREAD-treated subjects achieved an HBV DNA <400 copies/mL (69 IU/mL), and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.
16 HOW SUPPLIED/STORAGE AND HANDLING
Tenofovir tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir DF, which is equivalent to 123 mg of tenofovir disoproxil, and are debossed with "GSI" on one side and with "150" on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0404-1)
Tenofovir tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir DF, which is equivalent to 163 mg of tenofovir disoproxil, and are debossed with "GSI" on one side and with "200" on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0405-1)
Tenofovir tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir DF, which is equivalent to 204 mg of tenofovir disoproxil, and are debossed with "GSI" on one side and with "250" on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0406-1)
Tenofovir tablets, 300 mg, are almond-shaped, light-blue, film-coated tablets containing 300 mg of tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil, and are debossed with "GILEAD" and "4331" on one side and with "300" on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0401-1)
Tenofovir oral powder consists of white, coated granules containing 40 mg of tenofovir DF, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop. (NDC 61958-0403-1)
Store Tenofovir tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F).
Keep the bottle tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients that Tenofovir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using Tenofovir.
Advise patients to avoid doing things that can spread HIV or HBV to others.
Inform patients that:
Gilead Sciences, Inc.
Foster City, CA 94404
COMPLERA, DESCOVY, EMTRIVA, EPCLUSA, GENVOYA, HARVONI, HEPSERA, ODEFSEY, SOVALDI, STRIBILD, TRUVADA, VEMLIDY, and Tenofovir are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.
© 2017 Gilead Sciences, Inc. All rights reserved.
(tenofovir disoproxil fumarate)
tablets and oral powder
Read this Patient Information before you start taking Tenofovir and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about Tenofovir?
Tenofovir can cause serious side effects, including:
Worsening of your Hepatitis B infection. Your hepatitis B Virus (HBV) infection may become worse (flare-up) if you take Tenofovir and then stop it. A "flare-up" is when your HBV infection suddenly returns in a worse way than before.
What is Tenofovir?
Tenofovir is a prescription medicine used:
What should I tell my healthcare provider before taking Tenofovir?
Before you take Tenofovir, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.
Tenofovir may affect the way other medicines work, and other medicines may affect how Tenofovir works.
Do not take Tenofovir if you also take:
Especially tell your healthcare provider if you take the following medications.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
How should I take Tenofovir?
What are the possible side effects of Tenofovir?
Tenofovir may cause serious side effects, including:
The most common side effects in all people who take Tenofovir are:
In some people with advanced HBV-infection, other common side effects may include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Tenofovir. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Tenofovir?
Keep Tenofovir and all medicines out of the reach of children.
General information about Tenofovir:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tenofovir for a condition for which it was not prescribed. Do not give Tenofovir to other people, even if they have the same condition you have. It may harm them.
Avoid doing things that can spread HIV-1 or HBV infection to others.
Do not share or re-use needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
A vaccine is available to protect people at risk for becoming infected with HBV. You can ask your healthcare provider for information about this vaccine.
This leaflet summarizes the most important information about Tenofovir. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Tenofovir that is written for health professionals.
For more information, go to www.viread.com or call Gilead Sciences, Inc. at 1-800-GILEAD-5 (1-800-445-3235).
What are the ingredients in Tenofovir?
Active Ingredient: Tenofovir
Tenofovir tablets: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
Tenofovir Oral Powder: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.
Tenofovir tablets 300 mg: Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
Tenofovir tablets 150, 200 and 250 mg: Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
Instructions for Use of Tenofovir oral powder
Read the Instructions for Use below before you give Tenofovir oral powder. Be sure you can understand and follow them. If you have any questions, ask your healthcare provider or pharmacist.
How do I prepare and give Tenofovir oral powder?
This Patient Information has been approved by the U.S. Food and Drug Administration.
Figure A Figure B Figure C
Manufactured for and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404
Revised: April 2017
COMPLERA, DESCOVY, GENVOYA, HARVONI, HEPSERA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, and Tenofovir are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.
© 2017 Gilead Sciences, Inc. All rights reserved.
PRINICPAL DISPLAY PANEL - 300 mg Bottle Label
fumarate) Tablets, 300 mg
PRINICPAL DISPLAY PANEL - 150 mg Bottle Label
PRINICPAL DISPLAY PANEL - 200 mg Bottle Label
PRINICPAL DISPLAY PANEL - 250 mg Bottle Label
PRINICPAL DISPLAY PANEL - 60 g Bottle Carton
(tenofovir disoproxil fumarate)
Oral Powder, 40 mg/scoop
Each level dosing scoop provides approximately
1g of the oral powder which contains 40 mg of
Tenofovir, which is
equivalent to 33 mg of tenofovir disoproxil.
60 g per bottle
PRINICPAL DISPLAY PANEL - 60 g Bottle Carton
Tenofovir pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Tenofovir available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Tenofovir destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Tenofovir Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Tenofovir pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Tenofovir?
Depending on the reaction of the Tenofovir after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tenofovir not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Tenofovir addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Tenofovir, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tenofovir consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
One visitor reported age
The information was verified by Dr. Arunabha Ray, MD Pharmacology