Date of approval.
Date of revision.
Emtricitabine Tenofovir Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
WARNING: Severe acute worsening of hepatitis B after treatment
Emtricitabine tenofovir tablets are not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of emtricitabine tenofovir tablets have not been established in patients co-infected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HIV-1 and HBV who discontinued emtricitabine tenofovir tablets. Therefore, patients with HBV infection who discontinue emtricitabine tenofovir tablets should be closely monitored for liver function, including clinical and laboratory follow-up for at least several months. If conditions are appropriate, patients may be permitted to initiate anti-hepatitis B virus therapy (see [Precautions]).
Drug Name]
Generic Name: Emtricitabine Tenofovir Tablets
English Name: Emtricitabine and Tenofovir Disoproxil Fumarate Tablets
Hanyu Pinyin: Enqutabin Tinuofuwei Pian
Ingredients
This product is a compound preparation. Each tablet contains 200mg of Emtricitabine and 300mg of Tenofovir Disoproxil Fumarate.
Properties
This product is light blue film-coated tablets, white or off-white after removing the coating.
Indications
Emtricitabine tenofovir is indicated for use in combination with other anti-retroviral drugs for the treatment of HIV-1 infection in adults and children 12 years of age and older.
When starting this product for the treatment of HIV-1 infection, the following factors should be considered.
● It is not recommended that this product be used as a component of a triple nucleoside regimen.
● This product should not be combined with emtricitabine, tenofovir dipivoxil, propofol tenofovir, lamivudine, or a fixed-dose combination containing all three.
● In patients who have received treatment, this product should be administered in accordance with laboratory findings and the patient’s treatment history.
Specification
Each tablet contains 200mg emtricitabine and 300mg tenofovir disoproxil fumarate (as C8H10FN3O3S and C19H30N5O10P-C4H4O4, respectively).
Dosage]
The recommended dose for adults and pediatric patients 12 years of age or older who weigh 35 kg or more is one tablet orally once daily with food or alone.
Dose adjustment in patients with renal impairment
Drug exposure is significantly increased when emtricitabine or tenofovir disoproxil fumarate is given in patients with moderate to severe renal impairment (see “Emtricitabine or Tenofovir Disoproxil Fumarate Drug Guide”). For patients with baseline creatinine clearance between 30 and 49 mL/min, the dosing interval for emtricitabine tenofovir should be adjusted as recommended in Table 1. The dosing interval recommended here is based on modeled pharmacokinetic data from a single dose in non-HIV-infected patients. The safety and efficacy of these proposed dosing interval adjustments have not been clinically evaluated in patients with moderate to severe renal impairment, and clinical response to therapy and renal function should be closely monitored in these patients (see [Precautions]).
In patients with mild renal impairment, no dose adjustment is necessary (creatinine clearance 50 to 80 mL/min). For pediatric patients with renal impairment, no available data for the recommended dose are provided.
Table 1 Dose adjustment for patients with altered creatinine clearance
Creatinine clearance (mL/min)a³5030 to 49<30
(including patients requiring hemodialysis) The recommended dosing interval should not be taken every 24 hours every 48 hours for emtricitabine tenofovir a. Calculated using ideal (lean) body weight.
In patients with mild renal impairment, estimated creatinine clearance, serum phosphorus, urine glucose and urine protein should be monitored regularly (see [Precautions]).
[Adverse Reactions].
Clinical trial experience
Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared with the incidence in clinical trials of another drug, and may not reflect the actual observed incidence.
Clinical Trial Experience in Adult Subjects
Study 934 was a positive controlled clinical trial of efavirenz, emtricitabine and tenofovir disoproxil fumarate, and the most common adverse reactions (incidence greater than or equal to 10%, of any severity) in the study were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, unusual nightmares and rash. The incidence of on-treatment adverse reactions (grades 2 to 4) that occurred in greater than or equal to 5% of subjects in either treatment group in this study is shown in Table 2.
Skin discoloration, manifested as hyperpigmentation of the palms of the hands and/or feet, was usually mild and asymptomatic. The mechanism and clinical significance of this is unknown.
Study 934-Adverse reactions seen on treatment: in Study 934, 511 subjects without antiretroviral therapy received either emtricitabine (FTC) + tenofovir disoproxil fumarate (TDF) in combination with efavirenz (EFV) (N=257) or zidovudine (AZT)/lamivudine (3TC) in combination with efavirenz (N=254) 144 weeks. The mean age of the subjects was 40 years (20-73 years) and the majority of subjects were male (88%). Overall, 65% were white, 17% were black and 13% were Hispanic. The adverse reactions observed in this study were generally consistent with those observed in other studies conducted in subjects treated or untreated with emtricitabine and/or tenofovir disoproxil fumarate (Table 2).
Table 2 Adverse reactions (Grade 2 to 4) occurring in selected treatments with an incidence of ³5% in either treatment group in Study 934a (weeks 0 to 144)
FTC+TDF+EFVbAZT/3TC+EFVN=257N=254 Gastrointestinal disorders Diarrhea 9%5% Nausea 9%7% Vomiting 2%5% Systemic and administration site disorders Fatigue 9%8% Infections and infestations Sinusitis 8%4% Upper respiratory tract infections 8%5% Nasopharyngitis 5%3% Neurological disorders Headache 6%5% Dizziness 8%7% Psychiatric disorders Depression 9% 7% Insomnia5%7% Skin and subcutaneous tissue disorders Rash eventsc7%9% a. The incidence of adverse reactions is based on all adverse events occurring during treatment, whether or not they are related to the study drug.
b. Subjects receiving emtricitabine + tenofovir disoproxil fumarate combined with efavirenz were changed to receive emtricitabine tenofovir combined with efavirenz at weeks 96 through 144 of the trial.
c. Rash events included rash, exfoliative rash, generalized rash, maculopapular rash, maculopapular rash, itchy rash, and blistering rash.
In addition to the adverse events described above in Study 934, other adverse events with a 5% incidence in clinical trials receiving emtricitabine or tenofovir disoproxil fumarate in combination with other anti-retroviral agents included anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, sensory abnormalities, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.
Laboratory abnormalities.
The laboratory abnormalities observed in this trial were generally consistent with those observed in other trials conducted with emtricitabine and/or tenofovir disoproxil fumarate (Table 3).
Table 3 Significant laboratory abnormalities (0 to 144 weeks) in subjects with an incidence of ³1% in either treatment group in Study 934
FTC+TDF+EFVaAZT/3TC+EFVN=257N=254 All ≥ grade 3 laboratory abnormalities 30% 26% Fasting cholesterol (>240 mg/dL) 22% 24% Creatine kinase
(Males: >990U/L)
(Females: >845U/L) 9%7% Serum amylase (>175U/L) 8%4% Alkaline phosphatase (>550U/L) 1%0% AST
(Males: >180 U/L)
(Females: >170 U/L) 3%3%ALT
(Male: >215 U/L)
(Female: >170 U/L) 2%3% Hemoglobin (<8.0 mg/ dL)
0%4% hyperglycemia (>250 mg/dL) 2%1% hematuria (>75 RBC/HPF) 3%2% glycosuria (≥3+) <1%1% neutrophils (<750/mm3) 3%5% fasting triglycerides (>750 mg/dL) 4%2% Weeks 96 through 144 of this trial, subjects receiving emtricitabine + tenofovir disoproxil fumarate combined with efavirenz subjects were switched to receive emtricitabine tenofovir combined with efavirenz.
In addition to the laboratory abnormalities described above in Study 934, clinical trials receiving emtricitabine or tenofovir disoproxil fumarate in combination with other anti-retroviral agents showed grade 3/4 elevations of bilirubin (>2.5´ULN), elevated pancreatic amylase (>2.0´ULN), elevated or decreased glucose (<40 or >250 mg/dL ), and elevated serum lipase (>2.0´ULN) in up to 3% of laboratory abnormalities.
Clinical trials in pediatric subjects 12 years of age (and older)
Emtricitabine: In the two larger open-label, uncontrolled pediatric clinical trials (N=116), in addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32% of subjects treated with emtricitabine in children (3 months of age to less than 18 years of age), respectively. For additional information, please refer to the Emtricitabine Instructions information.
Tenofovir disoproxil fumarate: In a pediatric clinical trial in subjects 12 years of age or older and younger than 18 years of age, adverse reactions observed in pediatric subjects treated with tenofovir disoproxil fumarate were similar to the results of the adult clinical trial (see [Precautions]).
Postmarketing Experience.
The following adverse reactions were identified during post-approval use of tenofovir disoproxil fumarate. No additional adverse reactions were identified during post-approval use of emtricitabine. Because postmarketing reactions are voluntarily reported and the population size of their source is unknown, it is not possible to reliably estimate their frequency or establish a causal relationship between them and drug exposure.
Immune System Disorders
Allergic reactions, including angioedema.
Metabolic and nutritional disorders
lactic acidosis, hypokalemia, hypophosphatemia.
Respiratory, thoracic, and mediastinal disorders
Respiratory distress.
Gastrointestinal disorders
Pancreatitis, increased amylase and abdominal pain.
Hepatobiliary disorders
Fatty liver, hepatitis, elevated liver enzymes (most commonly AST, ALT, GGT).
Skin and subcutaneous tissue disorders
Skin rashes.
Musculoskeletal and connective tissue disorders
rhabdomyolysis, osteochondrosis (manifested by bone pain, which may result in fractures), myasthenia gravis, myopathy.
Renal and urinary disorders
acute renal failure, renal failure, acute tubular necrosis, Fanconi’s syndrome, proximal tubular lesions, interstitial nephritis (including acute cases), nephrogenic uremia, renal insufficiency, elevated creatinine, proteinuria, polyuria.
systemic and administration site diseases
Weakness.
The following adverse reactions (already listed under the above body system headings) may be caused by proximal renal tubular lesions: rhabdomyolysis, osteochondrosis, hypokalemia, myasthenia, myopathy, hypophosphatemia.
[Contraindication
Contraindicated in patients with known hypersensitivity to tenofovir, tenofovir dipivoxil fumarate, emtricitabine, or any of the excipients.
[Precautions].
HBV infection
Testing for chronic hepatitis B virus (HBV) is recommended for all populations prior to initiating treatment with emtricitabine tenofovir. Emtricitabine tenofovir is not approved for the treatment of chronic HBV infection, and the safety and efficacy of emtricitabine tenofovir in patients with HBV infection have not been demonstrated. severe acute worsening of hepatitis B has been reported in patients with HBV and HIV-1 co-infection after interruption of emtricitabine tenofovir therapy. Some HBV-infected patients treated with emtricitabine had worsening hepatitis B with hepatic dysregulation and liver failure. Patients infected with HBV who subsequently discontinue emtricitabine tenofovir therapy must be closely monitored for liver function, including clinical and laboratory follow-up, for at least several months after discontinuation of therapy. If conditions are appropriate, patients may need to restart anti-hepatitis B virus therapy. Vaccination should be administered to HBV-uninfected individuals.
Emerging or more severe renal impairment
Emtricitabine and tenofovir are eliminated primarily through the kidneys. Renal impairment has been reported with tenofovir disoproxil fumarate, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) (see [Adverse Reactions]).
It is recommended that estimated creatinine clearance be assessed in all populations prior to initiation of therapy and when clinically appropriate during tenofovir treatment with emtricitabine. Among patients at risk for renal dysfunction (including those who have experienced renal events while previously treated with HEPSERATM), it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of emtricitabine tenofovir therapy and periodically during emtricitabine tenofovir therapy.
Concomitant use of emtricitabine tenofovir with nephrotoxic agents, such as high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs), or use too close together should be avoided (see [Drug Interactions]). Cases of acute renal failure after initiation of high-dose or multiple NSAID therapy have been reported in HIV-infected patients with stable performance on tenofovir disoproxil fumarate therapy and with risk factors for renal dysfunction. Some patients require hospitalization and renal replacement therapy. If patients are at risk for renal dysfunction, alternatives to NSAIDs should be considered if necessary.
Persistent or worsening bone pain, extremity pain, fractures, and/or muscle pain or muscle weakness may be clinical manifestations of proximal renal tubular lesions and should prompt patients at risk to undergo renal function evaluation.
Treatment of HIV-1 infection
It is recommended that the dosing interval for emtricitabine tenofovir be adjusted in all patients with an estimated creatinine clearance of 30-49 mL/min and that renal function be closely monitored (see [Dosage]). There are no available safety or efficacy data in patients with renal impairment receiving emtricitabine tenofovir according to this dosing guideline, so the potential utility of emtricitabine tenofovir therapy and the potential risk of nephrotoxicity should be evaluated. Emtricitabine tenofovir should not be administered to patients with an estimated creatinine clearance of less than 30 mL/min or who require hemodialysis.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, has been reported with nucleoside analogs including tenofovir disoproxil fumarate and emtricitabine (a component of emtricitabine tenofovir) alone or in combination with other anti-retroviral agents. Emtricitabine tenofovir therapy should be withheld if a patient develops clinical or laboratory test abnormalities suggestive of lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if transaminases are not significantly elevated).
Co-administration with other drugs
Emtricitabine tenofovir is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. Do not combine emtricitabine tenofovir with other drugs containing emtricitabine or tenofovir disoproxil fumarate, or with propofol tenofovir, including efavirenz/emtricitabine/tenofovir disoproxil fumarate, rilpivirine/emtricitabine/tenofovir disoproxil fumarate, emtricitabine/propofol tenofovir, emtricitabine, everolimus/cobicistat/emtricitabine/propofol tenofovir, rilpivirine/emtricitabine/propofol tenofovir, emtricitabine, propofol tenofovir, or tenofovir dipivoxil fumarate in combination. Because of the similarity between emtricitabine and lamivudine, do not co-administer FTC/TDF with other drugs containing lamivudine, including lamivudine/zidovudine, lamivudine/lategravir, abacavir sulfate/lamivudine, dotilapamil, or abacavir sulfate/lamivudine/zidovudine. Emtricitabine tenofovir should not be used in combination with adefovir.
Bone effects of tenofovir disoproxil fumarate
Bone mineral density
In clinical trials in HIV-1 infected adults and in clinical trials in HIV-1 uninfected individuals, tenofovir disoproxil fumarate was associated with a slight increase in bone mineral density (BMD) reduction and an increase in biochemical markers of bone metabolism, indicating an increase in bone turnover relative to controls (see [Adverse Reactions] and Tenofovir Disoproxil Fumarate Prescribing Information). In addition, serum parathyroid hormone levels and 1,25 vitamin D levels were higher in subjects treated with tenofovir disoproxil fumarate.
Clinical trials evaluating tenofovir disoproxil fumarate were conducted in pediatric and adolescent subjects. Under normal conditions, BMD was rapidly elevated in pediatric patients. The bone effect in HIV-1 infected subjects aged 2 years to less than 18 years was similar to that observed in adult subjects, showing increased bone turnover. The increase in systemic BMD was smaller in HIV-1-infected pediatric subjects treated with tenofovir disoproxil fumarate relative to controls. Similar trends were observed in adolescent subjects with chronic hepatitis B infection aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) was shown to be unaffected. For more information, please consult the Tenofovir disoproxil fumarate prescribing information.
The impact of tenofovir disoproxil fumarate-related changes in BMD and biochemical markers on long-term bone health and future fracture risk is unknown. BMD assessment should be considered in adult and pediatric patients with pathologic fractures or other risk factors for osteoporosis or bone loss. Although no studies have been conducted on the effects of calcium and vitamin D supplementation, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, an appropriate consultation should be performed.
Mineralization defects
Cases of osteochondrosis (associated with proximal renal tubular lesions manifesting as bone pain or pain in the extremities, possibly resulting in fracture) have been reported in association with the use of tenofovir disoproxil fumarate (see [Adverse Reactions]). Arthralgia and muscle pain or muscle weakness have been reported in cases of proximal renal tubular lesions. Hypophosphatemia and osteochondrosis secondary to proximal renal tubulopathy should be considered in patients at risk for renal dysfunction and with persistent or worsening bone or muscle symptoms during treatment with tenofovir disoproxil fumarate-containing products (see [Precautions]).
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome has been previously reported in patients receiving anti-retroviral combination therapy including emtricitabine tenofovir. During the initial phase of anti-retroviral combination therapy, immune system-responsive patients are at risk of developing an inflammatory response to recalcitrant or residual opportunistic infections such as Mycobacterium avium tuberculosis infection, cytomegalovirus, Yersinia pneumonia (PCP), or tuberculosis, for which further evaluation and treatment are warranted.
In addition, autoimmune dysregulation (e.g. Graves’ disease, polymyositis and Guillain-Barre syndrome) has been reported to occur during immune reconstitution, however, the onset is more diverse and may also occur within a few months after initiation of treatment.
Early virologic failure
Clinical trials in HIV-1-infected subjects have demonstrated the overall lesser utility of certain drug regimens containing only three nucleoside reverse transcriptase inhibitors compared to triple drug regimens containing two nucleoside reverse transcriptase inhibitors (NRTIS) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) or one HIV-1 protease inhibitor. In particular, early virologic failure and high resistance substitution have been reported. Thus, triple nucleoside regimens should be used with caution. Patients treated with triple nucleoside regimens should be carefully monitored and improved therapy should be considered.
For pregnant and lactating women
U.S. Pregnancy Classification Category B
Risk Summary
Emtricitabine tenofovir has been evaluated in a limited number of women during pregnancy and the postpartum period. The available human and animal data suggest that emtricitabine tenofovir does not increase the risk of major birth defects overall compared to background rates. However, no adequate and well-controlled trials have been conducted in pregnant women. Because human studies do not exclude the possibility of harm, emtricitabine tenofovir should be used in pregnancy only if truly needed.
Clinical considerations
As of July 2011, the ARV Pregnancy Registry has received reports of prospective studies of 764 and 1219 cases of exposure to emtricitabine-containing and tenofovir-containing regimens in early pregnancy, 321 and 455 cases in mid-pregnancy, and 140 and 257 cases in late pregnancy, respectively. In early pregnancy, the birth defect rate was 18/764 (2.4%) in the emtricitabine-containing therapy group compared with 27/1219 (2.2%) in the tenofovir-containing therapy group; in mid/late pregnancy, the birth defect rate was 10/461 (2.2%) in the emtricitabine-containing therapy group compared with 15/714 (2.1%) in the tenofovir-containing therapy group. In the US reference population of pregnant women, the background rate of birth defects was 2.7%. No correlation between emtricitabine or tenofovir and overall birth defects was observed in the APR.
Animal data
Emtricitabine: Embryonic and fetal toxicity studies showed no increase in the incidence of fetal variation and malformations in mice and rabbits exposed to emtricitabine at approximately 60 and 120 times higher than the recommended daily human dose, respectively.
Tenofovir disoproxil fumarate: Reproduction studies were conducted in rats and rabbits at doses up to 14 and 19 times higher than human doses based on body surface area comparisons, respectively, and showed no evidence of impaired fertility or harm to embryos due to tenofovir.
Breastfeeding women: The Centers for Disease Control and Prevention recommends that HIV-1-infected women should not breastfeed their infants to avoid the risk of postnatal HIV-1 transmission. Human studies have shown that both tenofovir and emtricitabine are secreted into human milk. Because the risk of infant exposure to low levels of emtricitabine and tenofovir is unknown, mothers should be asked not to breastfeed if they are being treated with emtricitabine tenofovir.
Emtricitabine
Breast milk samples obtained from 5 HIV-1 infected women showed that emtricitabine was secreted into human milk. Breastfed infants whose mothers are receiving emtricitabine are at risk of developing resistance to emtricitabine. Other risks associated with emtricitabine are not known for breastfed infants whose mothers are receiving emtricitabine.
Tenofovir disoproxil fumarate
Breast milk samples obtained from 5 HIV-1 infected women showed that tenofovir was secreted into human milk. Risks associated with tenofovir, including the risk of resistance to emtricitabine, are not known for breastfed infants whose mothers are being treated with tenofovir disoproxil fumarate.
[Pediatric Dosage].
Emtricitabine tenofovir should only be administered to pediatric patients aged 12 years or older and weighing greater than or equal to 35 kg. The safety and efficacy of emtricitabine tenofovir in pediatric patients younger than 12 years of age or weighing less than 35 kg have not been established (see [Precautions], [Adverse Reactions], [Pharmacokinetics]).
Geriatric Use]
Clinical trials of emtricitabine and tenofovir disoproxil fumarate did not enroll sufficient numbers of subjects aged 65 years or older to determine whether their response was different from that of younger subjects. In general, doses should be selected with caution in older patients, keeping in mind that they have a higher chance of decreased hepatic, renal, or cardiac function, concurrent disease, or being treated with other medications.
[Drug Interactions].
Drug interaction trials have not been conducted using emtricitabine tenofovir tablets. Separate drug interaction trials have been conducted with emtricitabine and tenofovir disoproxil fumarate (a component of emtricitabine tenofovir tablets). This section describes clinically relevant drug interactions observed in trials using emtricitabine and tenofovir disoproxil fumarate (see [Pharmacokinetics]).
Dehydroinositide
Caution should be exercised when co-administering emtricitabine tenofovir with dehydroinositide, and patients receiving the combination should be closely monitored for adverse reactions associated with dehydroinositide. Dehydroinosine should be discontinued in patients who have experienced adverse reactions associated with dehydroinosine.
When tenofovir disoproxil fumarate was co-administered with dehydroinosine, the Cmax and AUC of dehydroinosine were significantly increased (see [Pharmacokinetics]). The mechanism of this interaction has not been clarified. Higher concentrations of dehydroinosine have the potential to cause adverse reactions associated with dehydroinosine, including pancreatitis and neuropathy. Decreases in CD4+ cell counts were observed in patients receiving tenofovir disoproxil fumarate and desoxymyosin 400 mg/day.
In patients weighing >60 kg, the dose of dehydroxymorphone should be reduced to 250 mg when co-administered with emtricitabine tenofovir. There are no data on the recommended dose adjustment of dehydroxymorphone in adult or pediatric patients weighing <60 kg. When co-administered, emtricitabine tenofovir and dehydroinositide enteric solvent may be administered in the fasted state or concomitantly with light food (<400kcal, 20% fat).
HIV-1 protease inhibitors
Tenofovir decreases the AUC and Cmin of atazanavir (see [Pharmacokinetics]). When co-administered with emtricitabine tenofovir, atazanavir 300 mg is recommended for concomitant administration with ritonavir 100 mg. In the absence of ritonavir, emtricitabine tenofovir should not be co-administered with atazanavir.
Lopinavir/ritonavir, atazanavir in combination with ritonavir, and dirinavir in combination with ritonavir have been shown to increase tenofovir concentrations (see [Pharmacokinetics]). Tenofovir disoproxil fumarate is a substrate for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is combined with inhibitors of these transporters, an increase in absorption may be observed. Patients receiving emtricitabine tenofovir in combination with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted dirinavir should be closely monitored for tenofovir-related adverse reactions. Emtricitabine tenofovir should be discontinued in patients who develop tenofovir-related adverse reactions.
Antiviral drugs for hepatitis C
Tenofovir disoproxil fumarate, emtricitabine tenofovir, sofosbuvir/velpatasvir, or leidiprevir/sofosbuvir co-administration all increase tenofovir exposure (see [Pharmacokinetics]).
Adverse reactions associated with tenofovir disoproxil fumarate should be monitored in patients co-administering emtricitabine tenofovir and sofosbuvir/velpatasvir.
Patients should be monitored for adverse reactions associated with tenofovir disoproxil fumarate if they are not using HIV-1 protease inhibitor/ritonavir or HIV-1 protease inhibitor/cobicistat drug combinations in combination with emtricitabine tenofovir and letepivir/sofosbuvir.
If a patient is co-administering emtricitabine tenofovir and ledipavir/sofosbuvir with an HIV-1 protease inhibitor/ritonavir or HIV-1 protease inhibitor/cobicistat drug combination in which the safety of increased tenofovir concentrations has not been confirmed, an alternative regimen to HCV or anti-retroviral therapy should be considered. If a combination is required, monitor for adverse effects associated with tenofovir disoproxil fumarate.
Drugs affecting renal function
Emtricitabine and tenofovir are cleared renally primarily by a combination of glomerular filtration and active renal tubular clearance (see [Pharmacokinetics]). No drug interactions due to competition for renal clearance have been observed; however, the combination of emtricitabine tenofovir with drugs that are actively cleared by the renal tubules can result in increased concentrations of emtricitabine, tenofovir, and/or the combined drugs. Such drugs include, but are not limited to, acyclovir, adefovir, cidofovir, ganciclovir, vaxilovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (see [Precautions]). Drugs that reduce renal function may also increase serum concentrations of emtricitabine and/or tenofovir.
Evaluation of Drug Interactions
The steady-state pharmacokinetics of emtricitabine and tenofovir were not affected by the combined dosing compared to dosing alone.
In vitro studies and clinical pharmacokinetic drug-drug interaction tests suggest that the potential for CYP-mediated interactions between emtricitabine and tenofovir and other drugs is low.
No clinically meaningful drug interactions were observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (Tables 4 and 5).
Similarly, no clinically meaningful drug interactions were observed between tenofovir disoproxil fumarate and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy subjects. (Tables 6 and 7).
Table 4 Drug interactions: changes in pharmacokinetic parameters of emtricitabine in the presence of combination drugsa
Combination drug Combination drug dose
(mg) Emtricitabine dose
(mg) Percentage change in pharmacokinetic parameters of N-emtricitabineb
(90% confidence interval) CmaxAUCCmin Tenofovir disoproxil fumarate 300 once daily
×7 days 200 once daily
×7 days 17 ⇔ ↑20
(↑12 to ↑29) Zidovudine 300 twice daily
×7 days 200 once daily
×7 days 27⇔⇔⇔ Indinavir 800 × 1200 × 112⇔⇔ NA Famciclovir 500 × 1200 × 112⇔⇔ NA Stavudine 40 × 1200 × 16⇔⇔ NAa. All trials of drug interactions were conducted in healthy volunteers.
b. ↑ = elevated; ⇔ = no effect; NA = not applicable
Table 5 Drug interactions: changes in pharmacokinetic parameters of the combined drugs in the presence of emtricitabinea
Combination drug Combination drug dose
(mg) Emtricitabine dose
(mg) N Percentage change in pharmacokinetic parameters of the combination drugb
(90% confidence interval) CmaxAUCCmin Tenofovir disoproxil fumarate 300 once daily
×7 days 200 once daily
×7 days17⇔⇔Zidovudine 300 twice daily
×7 days 200, 1 time daily
×7 days27↑17
(↑0 to ↑38) ↑13
(↑5 to ↑20) ⇔ indinavir 800 × 1200 × 112 ⇔ ⇔ NA famciclovir 500 × 1200 × 112 ⇔ ⇔ NA stavudine 40 × 1200 × 16 ⇔ ⇔ NAa. All trials of drug interactions were conducted in healthy volunteers.
b. ↑ = elevated; ⇔ = no effect; NA = not applicable
Table 6 Drug interactions: changes in pharmacokinetic parameters of tenofovir in the presence of co-administered drugsa
Combination drug Combination drug dose (mg) N% Change in tenofovir pharmacokinetic parametersb
(90% CI) CmaxAUCCmin atazanavirc400 once daily
´14 days3314
(8 to 20)24
(21 to 28) 22
(15 to 30) Atazanavir/
Ritonavir c300/100 once daily 1234
(20 to 51) 37
(30 to 45) 29
(21 to 36) Direnavir/
Ritonavird300/100 twice daily1224
(8 to 42) 22
(10 to 35) 37
(19 to 57) Indinavir 800 three times daily
´7 days1314
(¯3 to 33) ÛÛ Lepidipavir/
Sofosbuvir e,f90/400
Once daily for 10 days 24↑47
(↑37 to ↑58) ↑35
(↑29 to ↑42) ↑47
(↑38 to ↑57) Ledipavir/
Sofosbuvir e,g23↑64
(↑54 to ↑74) ↑50
(↑42 to ↑59) ↑59
(↑49 to ↑70) Lediprevir/
Sofosbuvir h90/400
1 time daily for 14 days15↑79
(↑56 to ↑104) ↑98
(↑77 to ↑123) ↑163
(↑132 to ↑197) Lediprevir/
Sofosbuvir i90/400
1 time daily for 10 days14↑32
(↑25 to ↑39) ↑40
(↑31 to ↑50) ↑91
(↑74 to ↑110) Lediprevir/
Sofosbuvirj90/400 once daily
´10 days2961
(51 to 72) 65
(59 to 71) 115
(105 to 126) Lopinavir/
Ritonavir 400/100 twice daily
´14 days 24Û32
(25 to 38) 51
(37 to 66) Saquinavir/
Ritonavir 1000/100 twice a day
Twice´ 14 days 35ÛÛ23
(16 to 30) Sofosbuvir k400 single dose 16 ↑25
(↑8 to ↑45) ÛÛ sofosbuvir/
Vipatasvir l400/100 once daily 2455
(43 to 68) 30
(24 to 36)39
(31 to 48) Sofosbuvir/
Vipatasvir m400/100 once daily 2955
(45 to 66)39
(33 to 44)52
(45 to 59) Sofosbuvir/
Vipatasvir n400/100 once daily 1577
(53 to 104) 81
(68 to 94) 121
(100 to 143) Sofosbuvir/
Vipatavir o400/100 once daily 2436
(25 to 47) 35
(29 to 42) 45
(39 to 51) Sofosbuvir/
Vipatavir p400/100 once daily 2444
(33 to 55) 40
(34 to 46) 84
(76 to 92) Sofosbuvir/
Vipatavir q400/100 once daily 3046
(39 to 54) 40
(34 to 45) 70
(61 to 79) Tacrolimus 0.05 mg/kg
Twice daily´7 days 2113
(1 to 27) ÛÛ tipranavir/
Ritonavir r500/100 twice daily22¯23
(¯32 to ¯13)¯2
(¯9 to ¯5)7
(¯2 to ¯17) 750/200 twice daily
(23 doses) 20¯38
(¯46 to ¯29)2
(¯6 to ¯10) 14
(¯1 to ¯27) Subjects received tenofovir disoproxil fumarate 300 mg once daily
Increased = ↑; decreased = ↓; no effect = ⇔
Reyataz Prescribing Information
Prezista Prescribing Information
Data from concomitant administration of Ledipavir/Sofosbuvir. Similar results were obtained with staggered dosing (12 hours apart).
Comparison based on exposure under atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate dosing conditions.
Exposure-based comparisons under dirinavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate administration conditions.
A study of the combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate with ledipavir/sofosbuvir.
A study of the combination of emtricitabine/ribivirine/tenofovir disoproxil fumarate with ledipavir/sofosbuvir.
A study of the combination of emtricitabine/tenofovir disoproxil fumarate + dolutegravir with ledipavir/sofosbuvir.
A study of the combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate with sofosbuvir.
Exposure-based comparison when administered as atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate.
Exposure-based comparison when administered as dirinavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate.
A study of efavirenz/emtricitabine/tenofovir disoproxil fumarate in combination with sofosbuvir/vipatasvir.
A study of the combination of efavirenz/cobicistat/emtricitabine/tenofovir disoproxil fumarate with sofosbuvir/vipatavir.
A study of the combination of emtricitabine/ribivirine/tenofovir disoproxil fumarate with sofosbuvir/vipatasvir.
Administered as raltegravir + emtricitabine/tenofovir disoproxil fumarate.
Aptivus prescribing information.
No effects on the following pharmacokinetic parameters of the coadministered drugs were seen with emtricitabine tenofovir: abacavir, desoxymetamol (dispersible tablets), emtricitabine, entecavir, and lamivudine.
Table 7 Drug interactions: changes in pharmacokinetic parameters of the combination drugs in the presence of tenofovir
Combination drug Combination drug dose
(mg) N Percentage change in pharmacokinetic parameters of the combination druga
(90% confidence interval) CmaxAUCCmin Abacavir 300, 1 time 8↑12
(↓1 to ↑26) ⇔ NA atazanavirb400 once daily
×14 days 34↓21
(↓27 to ↓14) ↓25
(↓30 to ↓19) ↓40
(↓48 to ↓32) atazanavirb atazanavir/ritonavir 300/100 once daily
×42 days10↓28
(↓50 to ↑5) ↓25c
(↓42 to ↓3) ↓23c
(↓46 to ↑10) Dirinavirdirinavir/ritonavir
300/100, once daily 1216
(¯6 to 42) 21
(¯5 to 54) 24
(¯10 to ¯69) Desoxymyxin e 250, 1 dose, with tenofovir disoproxil fumarate and light food f 33 ¯20g
(¯32 to ¯7)ÛgNA emtricitabine 200 once daily
×7 days 17⇔⇔↑20
(↑12 to ↑29) indinavir 800 3 times daily
×7 days12↓11
(↓30 to ↑12) ⇔⇔ entecavir 1 once daily
×10 days 28 ⇔ ↑13
(↑11 to ↑15) ⇔ lamivudine 150 twice daily
×7 days 15 ↓24
(↓34 to ↓12) ⇔⇔ saquinavir saquinavir/ritonavir
1000/100.
2 times daily × 14 days 32↑22
(↑6 to ↑41)↑29h
(↑12 to ↑48) ↑47h
(↑23 to ↑76) Ritonavir⇔⇔↑23
(↑3 to ↑46) Tacrolimus 0.05mg/kg twice daily
×7 days21⇔⇔⇔Tiranavir iTiranavir/Ritonavir, 500/100 twice daily22¯17
(¯26 to ¯6) ¯18
(¯25 to ¯9) ¯21
(¯30 to ¯10) Tiranavir/ritonavir, 750/200 twice daily
(23 doses) 20¯11
(¯16 to ¯4) ¯9
(¯15 to ¯3) ¯12
(¯22 to ¯0) elevated = ↑; decreased = ↓; no effect = ⇔; NA = not applicable
Reyataz Prescribing Information
The addition of tenofovir disoproxil fumarate to atazanavir 300 mg + ritonavir 100 mg in HIV-infected subjects showed that the AUC and Cmin values of atazanavir were 2.3-fold and 4-fold higher, respectively, than those observed with atazanavir 400 mg alone
Prezista Prescribing Information
VidexEC prescribing information for subjects receiving desoxymyelone enteric-coated capsules
373kcal, 8.2g fat
compared to the fasting state when dehydroinosine (enteric) 400 mg was administered alone
Because clinically relevant increases in AUC and Cmin are not expected, no dose adjustment is required when tenofovir disoproxil fumarate is combined with saquinavir augmented by ritonavir
Aptivus Prescribing Information
Tenofovir disoproxil fumarate may have clinically significant pharmacokinetic changes induced by dehydroinositide when co-administered with dehydroinositide. Tenofovir disoproxil fumarate has been shown to significantly increase the Cmax and AUC of dehydroinosine when co-administered with dehydroinosine enteric-coated capsules. The systemic exposure levels of dehydroxymyosin in combination with tenofovir disoproxil fumarate in dehydroxymyosin 250 mg enteric capsules were similar to those of 400 mg enteric capsules alone in the fasted state. The mechanism of this interaction has not been clarified. See [Precautions] for the use of dehydroxymyosin with tenofovir disoproxil fumarate.
[Drug Overdose].
If an overdose occurs, the patient must be monitored for evidence of toxicity and, if necessary, standard supportive therapy protocols should be used.
Emtricitabine: There is limited clinical experience at higher than therapeutic doses of emtricitabine. A single dose of 1200 mg of emtricitabine was administered to 11 subjects in a clinical pharmacology trial. No serious adverse reactions were reported.
A 3-hour hemodialysis session was initiated within 1.5 hours of emtricitabine administration, and dialysis treatment cleared approximately 30% of the emtricitabine dose (blood flow rate: 400 mL/min; dialysate flow rate: 600 mL/min). Whether emtricitabine is cleared by peritoneal dialysis is not known.
Tenofovir disoproxil fumarate: Clinical experience at therapeutic doses higher than 300 mg of tenofovir disoproxil fumarate is limited. In one trial, eight subjects received oral tenofovir disoproxil fumarate 600 mg for 28 days. There were no reports of serious adverse reactions. The possible effects of higher doses are not known.
Tenofovir was effectively cleared by hemodialysis with an extraction factor of approximately 54%. After a single dose of tenofovir disoproxil fumarate 300 mg, a single 4-hour hemodialysis session cleared approximately 10% of the administered tenofovir dose.
Pharmacology and Toxicology
Entefovir dipivoxil tablets are a combination of the antiviral drug emtricitabine and tenofovir dipivoxil fumarate. For additional information on mechanism of action, antiviral activity, resistance and cross-resistance, please refer to the prescribing information for emtricitabine and tenofovir disoproxil fumarate.
Mechanism of action
Emtricitabine: Emtricitabine is a synthetic cytosine analog that is phosphorylated by cytosolic enzymes to produce emtricitabine 5′-triphosphate. emtricitabine 5′-triphosphate inhibits HIV-1 reverse transcriptase (RT) activity by competing with the natural substrate 5′-deoxycytidine triphosphate and integrating into newly synthesized viral DNA to cause strand termination. emtricitabine 5′-triphosphate is active against mammalian The inhibitory activity of emtricitabine 5′-triphosphate was weak against mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is a non-cyclic nucleoside phosphorylated diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate is first hydrolyzed by diesterase to tenofovir and then phosphorylated by cytosolic enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV 1 reverse transcriptase by competing with the natural substrate 5′-deoxyadenosine triphosphate and then terminating the DNA strand after integration with DNA. Tenofovir diphosphate has weak inhibitory activity against mammalian DNA polymerases α and β and mitochondrial DNA polymerase γ.
Antiviral activity
Emtricitabine and tenofovir disoproxil fumarate: The combined antiviral activity of emtricitabine and tenofovir was evaluated by cell culture and showed no antagonistic effect of emtricitabine and tenofovir.
Emtricitabine: The antiviral activity of emtricitabine was evaluated in lymphoblastoid cell lines, MAGI-CCR5 cell lines and peripheral blood mononuclear cells against laboratory and clinically isolated HIV-1 virus strains. The EC50 values of emtricitabine ranged from 0.0013 to 0.64 μM (0.0003 to 0.158 μg/mL). No antagonistic effects were found in trials of emtricitabine in combination with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir). Emtricitabine showed antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F and G (EC50 values between 0.007 and 0.075 μM) and showed activity specific to HIV-2 virulent strains (EC50 values between 0.007 and 1.5 μM).
Tenofovir disoproxil fumarate: The antiviral activity of tenofovir was evaluated in lymphoblastoid cell lines, primary monocytes/macrophages and peripheral blood lymphocytes against laboratory and clinically isolated HIV-1 viral strains. The EC50 values of tenofovir ranged from 0.04 to 8.5 μM. No antagonistic effects were observed in trials of tenofovir in combination with nucleoside reverse transcriptase inhibitors (abacavir, dehydroinositide, lamivudine, stavudine, zalcitabine, zidovudine), non-reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine) and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir). Tenofovir in cell culture showed antiviral activity against HIV 1 subtypes A, B, C, D, E, F, G and O (EC50 values between 0.5 and 2.2 μM) and showed activity specific to HIV 2 virulent strains (EC50 values between 1.6 and 5.5 μM).
Drug resistance
Emtricitabine and tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir were screened in cell culture, and genotypic analysis of these strains revealed the presence of M184V/I and/or K65R amino acid substitutions in the viral reverse transcriptase. In addition, tenofovir increased the K70E substitution in HIV-1 reverse transcriptase, resulting in reduced susceptibility to tenofovir.
In a clinical trial conducted in first-time treated subjects (Study 934), HIV-1 strains isolated from all subjects with confirmed ART failure were analyzed for drug resistance. These subjects had HIV-1 RNA greater than 400 copies/mL at week 144 or early termination. the highest incidence of efavirenz-associated resistance variation was observed, and the incidence of this variation was similar between treatment groups. M184V amino acid substitution was observed in 2 of 19 analyzed samples isolated from the emtricitabine + tenofovir disoproxil fumarate treatment group and in 10 of 29 analyzed samples isolated from the zidovudine/lamivudine treatment group, and this amino acid substitution was associated with emtricitabine and lamivudine resistance. Standard genotypic analysis of subjects over the course of 144 weeks of study 934 did not detect the production of K65R or K70E substitutions in HIV 1 strains.
Emtricitabine: HIV-1 virus strains resistant to emtricitabine were screened by cell culture and in vivo in humans. Genotypic analysis of these strains showed that their reduced susceptibility to emtricitabine was associated with a base substitution at codon 184 on the HIV-1 reverse transcriptase gene, which resulted in the replacement of methionine with valine or isoleucine (M184V/I).
Tenofovir disoproxil fumarate: HIV-1 strains with reduced susceptibility to tenofovir were isolated by cell culture. These viral strains showed K65R substitution of the reverse transcriptase and a 2- to 4-fold reduction in susceptibility to tenofovir.
Among subjects receiving initial treatment, 8/47 (17%) of the tenofovir disoproxil fumarate-treated group developed K65R substitution during 144 weeks of treatment; seven of these cases occurred during the first 48 weeks of treatment and one occurred at week 96. Among subjects previously treated with tenofovir disoproxil fumarate, 14/304 (5%) failed treatment within 96 weeks with viral strains whose susceptibility to tenofovir decreased more than 1.4-fold (median 2.7-fold). Genotypic analysis of viral strains that developed resistance showed a K65R amino acid substitution in HIV-1RT.
Cross-resistance
Emtricitabine and tenofovir disoproxil fumarate: cross-resistance has been identified between some NRTIs. Strains of M184V/I and/or K65R substitution have been screened from cell cultures following the combination of emtricitabine and tenofovir, and such mutant strains have been found in strains isolated from patients who failed treatment with tenofovir in combination with emtricitabine or lamivudine, and tenofovir in combination with abacavir and dehydroxymethyldeoxyinosine. Thus, cross-resistance can arise in patients carrying viruses containing one or both of these (substitution) gene mutations.
Emtricitabine: Emtricitabine-resistant virus strains (M184V/I) are cross-resistant to lamivudine, but they remain susceptible in cell culture to NRTI dehydroxylinosine, stavudine, tenofovir, and zidovudine, as well as to non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine). HIV-1 strains containing K65R substitution isolated from patients treated with abacavir, dehydroinositide, tenofovir, and zalcitabine had reduced susceptibility to emtricitabine inhibition. HIV-1 viruses with reduced susceptibility to zidovudine and stavudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E substitutions) and dehydroxynucleoside (L74V substitution) maintained susceptibility to emtricitabine. HIV-1 strains containing the K103N substitution associated with non-nucleoside reverse transcriptase inhibitor resistance remain susceptible to emtricitabine.
Tenofovir disoproxil fumarate: K65R substitution in HIV-1 RT screened by tenofovir has also been screened in some HIV-1-infected patients treated with abacavir or dehydroinositide. HIV-1 isolates containing K65R and K70E substitutions showed decreased susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance to these NRTIs may occur in patients carrying K65R or K70E substitutions. HIV-1 strains isolated from 20 subjects with an average of three zidovudine-related reverse transcriptase amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in susceptibility to tenofovir. Subjects who developed L74V substitutions but no zidovudine resistance-associated substitutions (N=8) had a reduced efficacy response to tenofovir disoproxil fumarate. Limited data showed reduced efficacy responses in patients containing Y115F substitution (N=3), Q151M substitution (N=2) or T69 insertion (N=4).
Toxicological studies
Emtricitabine.
Genotoxicity: negative results in the Emtricitabine Ames test, mouse lymphoma test or mouse micronucleus test.
Reproductive toxicity: No effect on fertility was observed in male rats given approximately 140 times the human recommended dose of 200 mg/day of emtricitabine or in male/female mice given approximately 60 times the human recommended dose of emtricitabine. In the embryo-fetal toxicity test, no increase in the incidence of fetal abnormalities and malformations was observed in mice and rabbits exposed at approximately 60 and 120 times the recommended human dose (AUC), respectively. The fertility of offspring was normal in mice given approximately 60 times the recommended human dose (200 mg/day) daily (AUC) from prenatal (litter) to sexual maturity.
Carcinogenicity: No drug-related increase in tumor incidence was observed in long-term carcinogenicity tests with emtricitabine administered orally at doses up to 750 mg/kg/day in mice (equivalent to 26 times the human systemic exposure at a therapeutic dose of 200 mg/day) or 600 mg/kg/day in rats (equivalent to 31 times the human systemic exposure at a therapeutic dose).
Tenofovir disoproxil fumarate.
Genotoxicity: Tenofovir disoproxil fumarate showed positive results in the in vitro mouse lymphoma test and negative results in the Ames test with the mouse micronucleus test.
Reproductive toxicity: Tenofovir disoproxil fumarate was administered to male rats starting 28 days prior to mating and to females starting 15 days prior to mating until day 7 of gestation at a dose equivalent to 10 times the human dose (based on body surface area). No effects on fertility, mating ability or early embryonic development were observed, but changes in the motility cycle were observed in females. In the embryo-fetal toxicity test, no fertility impairment or fetal toxicity due to tenofovir was observed in rats and rabbits given 14 and 19 times the human administered dose (based on body surface area), respectively.
Carcinogenicity: In long-term carcinogenicity tests with oral administration of tenofovir disoproxil fumarate, exposure was up to approximately 16 times (mice) and 5 times (rats) the therapeutic dose for human HIV-1 infection. Female mice showed an increased incidence of hepatic adenomas at 16 times the human exposure. Rats had negative carcinogenicity test results at exposures up to 5 times the human therapeutic dose.
Other toxicity: In toxicology tests, tenofovir and tenofovir disoproxil fumarate were found to cause osteotoxicity in rats, dogs and monkeys given greater than or equal to 6 times human exposure (based on AUC). Osteotoxicity in monkeys was diagnosed as osteochondrosis. The osteochondrosis observed in monkeys was reversible when the tenofovir dose was reduced or discontinued. Osteotoxicity in rats and dogs was manifested by a reduction in bone mineral density. The mechanism causing osteo-toxicity is not known.
Nephrotoxicity was observed in all four species, where elevations in serum creatinine, urea nitrogen, glycosuria, proteinuria, phosphaturia and/or calciuria, and decreases in serum phosphate were observed to varying degrees. These toxicities were observed at exposures 2 to 20 times higher than human exposure (based on AUC). The relationship between renal abnormalities (particularly phosphaturia) and osteo-toxicity is unknown.
[Pharmacokinetics].
Emtricitabine tenofovir: One tablet of emtricitabine tenofovir taken on an empty stomach was shown to be bioequivalent to one capsule of emtricitabine (200 mg) plus one tablet of tenofovir dipivoxil fumarate (300 mg) in healthy subjects (N=39).
Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 9. Following oral administration of emtricitabine, emtricitabine was rapidly absorbed and reached peak blood concentrations 1 to 2 hours after dosing. In vitro experiments have shown that emtricitabine binds to human plasma proteins at concentrations ranging from 0.02 to 200 mg/mL at less than 4% and independent of concentration. Following administration of radiolabeled emtricitabine, approximately 86% of the dose was excreted in the urine and 13% in the form of metabolites. Metabolites of emtricitabine include 3′-sulfoxide diastereoisomers and glucuronide conjugates. Emtricitabine is eliminated by a combination of both glomerular filtration and active renal tubular absorption. The plasma half-life of emtricitabine is approximately 10 hours after a single oral dose.
Tenofovir disoproxil fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 9. Following oral administration of tenofovir disoproxil fumarate, the time to peak for tenofovir was 1.0 ± 0.4 hours. In vitro experiments showed tenofovir binding to human plasma proteins in the concentration range of 0.01 to 25 μg/mL at less than 0.7% and independent of concentration. Tenofovir is excreted in the urine as a prototype drug at approximately 70 to 80% of the dose when administered intravenously. Tenofovir is eliminated by a combination of both glomerular filtration and active tubular absorption. The final elimination half-life of tenofovir after a single oral dose of tenofovir disoproxil fumarate is approximately 17 hours.
Table 9 Single-dose pharmacokinetic parameters of emtricitabine and tenofovir in adultsa
Emtricitabine tenofovir oral bioavailability in fastingb (%) 92 (83.1 to 106.4) 25 (NC to 45.0) Plasma final elimination half-lifeb (h) 10 (7.4 to 18.0) 17 (12.0 to 25.7) Cmaxc (µg/mL) 1.8 ± 0.72d 0.30 ± 0.09 AUCc (µg -hr/mL) 10.0±3.12d2.29±0.69CL/Fc (mL/min) 302±941043±115CLrenalc (mL/min) 213±89243±33a. NC=not calculated
b. Median value (range)
c. Mean (± standard deviation)
d. The data are obtained under steady-state conditions.
Effect of food on oral absorption
Emtricitabine tenofovir may be taken with food or alone. Administration of emtricitabine tenofovir after a high-fat diet (784kcal; 49g fat) or a light diet (373kcal; 8g fat) prolongs the time to peak tenofovir Cmax by approximately 0.75 hours. The AUC and Cmax of tenofovir increased by an average of approximately 35% and 15% after administration following a high-fat or light diet compared to fasting dosing. In previous safety and efficacy studies, tenofovir was administered in the fed state. The systemic exposure (AUC and Cmax) of emtricitabine was not affected whether emtricitabine tenofovir was taken with a high-fat or light diet.
Special Populations
Race
Emtricitabine: No race-related pharmacokinetic differences were observed with emtricitabine.
Tenofovir disoproxil fumarate: With the exception of Caucasians, there are insufficient racial and ethnic data to adequately determine possible pharmacokinetic differences between these populations following administration of tenofovir disoproxil fumarate.
Gender
The pharmacokinetics of emtricitabine and tenofovir were similar in male and female subjects.
Pediatric Patients
Emtricitabine tenofovir should not be used in pediatric patients younger than 12 years of age or weighing less than 35 kg (less than 77lb).
Emtricitabine: Steady-state emtricitabine pharmacokinetics were measured in 27 HIV-1-infected pediatric subjects aged 13 to 17 years who received doses ranging from 6 mg/kg daily to a maximum of 240 mg oral solution or one 200 mg capsule; 26 of the 27 subjects in this age group received 200 mg emtricitabine capsules. The mean (± standard deviation) Cmax and AUC were 2.7 ± 0.9 µg/mL and 12.6 ± 5.4 µg-hr/mL, respectively. exposures achieved by pediatric subjects aged 12 years (inclusive) to less than 18 years (inclusive) were similar to those achieved by adults receiving 200 mg once daily.
Tenofovir disoproxil fumarate: Steady-state tenofovir pharmacokinetics were evaluated in eight HIV-1-infected pediatric subjects (12 years of age and older, up to 18 years of age). Mean (± standard deviation) Cmax and AUCtau were 0.38 ± 0.13 µg/mL and 3.39 ± 1.22 µg-hr/mL, respectively. tenofovir exposure reached by pediatric patients receiving 300 mg oral tenofovir disoproxil fumarate daily was similar to that reached by adults receiving 300 mg tenofovir disoproxil fumarate daily. exposure was similar.
Elderly Patients
The pharmacokinetics of emtricitabine and tenofovir have not been adequately evaluated in elderly patients (65 years of age and older).
Patients with impaired renal function
The pharmacokinetics of emtricitabine and tenofovir were altered in subjects with impaired renal function (see [Precautions]). In adult subjects with creatinine clearance less than 50 mL/min, Cmax and AUC0-¥ were increased for both emtricitabine and tenofovir. In adult patients with estimated creatinine clearance of 30 to 49 mL/min, adjustment of the dosing interval for emtricitabine tenofovir is recommended. No data are available on the recommended dose for pediatric patients with impaired renal function. Emtricitabine tenofovir is contraindicated in patients with an estimated creatinine clearance of less than 30 mL/min and in patients with end-stage renal disease requiring dialysis (see [DOSAGE]).
Patients with impaired hepatic function
The pharmacokinetics of tenofovir were studied following a single dose of tenofovir disoproxil fumarate 300 mg in non-HIV-infected subjects with moderate to severe hepatic impairment. Tenofovir pharmacokinetics were not substantially altered in subjects with impaired hepatic function compared to subjects without impaired hepatic function. Pharmacokinetic studies of emtricitabine tenofovir or emtricitabine have not been conducted in subjects with impaired hepatic function. However, since emtricitabine is not primarily metabolized by hepatic enzymes, the effect of impaired hepatic function on it is limited.
Storage]
Seal and store below 30℃.
Package】
High-density polyethylene bottle for oral solid medicine, plus a bag of silica gel desiccant in paper bag for solid medicine; 30 tablets/bottle x 1 bottle/box.
Expiration date
12 months.
Execution standard
【Approval number】
【Marketing license holder
Company name: Zhengda Tianqing Pharmaceutical Group Co.
Registered address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Manufacturer
Manufacturer: Zhengda Tianqing Pharmaceutical Group Co.
Production Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Postal Code: 222062
Telephone number: 0518-85804002
Fax number: 0518 -85806524
Web
Address: http://www.cttq.com
Health consultation telephone：4007885028