What Are the Uses of Emtricitabine and Tenofovir?

Lactic acidosis / severe hepatomegaly with steatosis using nucleoside analogs alone (including tenofovir difufurate fumarate, one of the components of emtricitabine tenofovir) or combined with other anti-reversal During viral drug treatment, lactic acidosis and severe hepatomegaly with steatosis have been reported, including fatal cases. Most of these cases occur in women. Obesity and long-term exposure to nucleosides may be risk factors. Special care should be taken when administering nucleoside analogs in patients with known risk factors for liver disease; however, cases have been reported in patients without known risk factors. Any patient with clinical or laboratory results suggesting lactic acidosis or significant liver toxicity (which may include hepatomegaly and steatosis, even if the aminotransferase is not significantly elevated) should be discontinued with emtricitabine and nofovir.
Patients with co-infection with HIV-1 and HBV are advised that all HIV-1 infected persons be tested for hepatitis B virus (HBV) before starting antiretroviral therapy. Emtricitabine tenofovir is not approved for the treatment of chronic HBV infection. The safety and efficacy of emtricitabine tenofovir in patients with HBV and HIV-1 infection have not been proven. Patients with HBV and HIV-1 co-infection have reported severe acute hepatitis B exacerbations after discontinuing emtricitabine and tenofovir. Hepatitis B exacerbation in some patients with HBV infection treated with emtricitabine is accompanied by liver decompensation and liver failure. Patients with co-infection with HIV-1 and HBV who subsequently discontinue emtricitabine and tenofovir must be closely monitored for liver function, including clinical and laboratory follow-up, and for at least several months after discontinuation of treatment. If conditions are right, patients may need to restart anti-HBV treatment.
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 (tubular injury with severe hypophosphatemia) (see [ Adverse reactions]: Post-marketing experience).
It is recommended that creatinine clearance be calculated for all patients before starting treatment and when clinically appropriate during treatment with emtricitabine tenofovir. Patients at risk for renal impairment, including those who have previously experienced renal events when receiving adefovir dipivoxil, should be monitored regularly to calculate creatinine clearance and serum phosphorus.
It is recommended that all patients with creatinine clearance of 30 to 49 mL / min be adjusted for the interval between dosing of emtricitabine and tenofovir and monitor renal function closely (see [Dosage and Administration]). In patients with impaired renal function receiving emtricitabine tenofovir treated according to dose guidelines, no safety or efficacy data are currently available, so the potential efficacy and nephrotoxicity of emtricitabine tenofovir treatment should be considered The potential risks are assessed. Patients with creatinine clearance less than 30 mL / min or who need hemodialysis should not take emtricitabine tenofovir.
If nephrotoxic agents have been used recently or recently, treatment with emtricitabine and tenofovir should be avoided.
Emtricitabine tenofovir combined with other drugs is a fixed-dose combination of emtricitabine and tenofovir dipivofurate fumarate. Emtricitabine tenofovir should not be treated with emtricitabine, tenofovir disoproxil fumarate, or a fixed-dose combination (efavirenz / emtricitabine / tenofovir fumarate) Pirfurate, rilpivirine / emtricitabine / tenofovir disoproxil fumarate). Due to the similarity between emtricitabine and lamivudine, emtricitabine and tenofovir should not be combined with other lamivudine-containing drugs including lamivudine, or fixed-dose combination drugs (lamivudine Combination of zirconium / zidovudine, abacavir sulfate / lamivudine and abacavir sulfate / lamivudine / zidovudine).
Emtricitabine and tenofovir should not be used in combination with adefovir dipivoxil.

Emtricitabine tenofovir tablets, emtricitabine tenofovir is suitable for combination with other antiretroviral drugs to treat HIV-1 infection in adults and children 12 years of age or older. When starting to use this product to treat HIV-1 infection, the following factors should be considered: · This product is not recommended as a component of the trinucleoside treatment regimen; · This product should not be used with emtricitabine, tenofovir II Pirfurate, lamivudine, or a fixed-dose combination containing the three; combined use; · In patients who have been treated, the use of this product should be based on laboratory test results and patient treatment history. ^[1] .

Drug Name: Emtricitabine tenofovir tablets

Hanyu Pinyin: Enqutabin Tinuofuwei Pian

Emtricitabine Tenofovir Tablets Caution

Emtricitabine tenofovir tablets ingredients

This product is a compound preparation. Each tablet contains 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate.

Emtricitabine Tenofovir Tablets Traits

This product is a light blue film-coated tablet that appears white or off-white after removing the coating.

Emtricitabine Tenofovir Tablets Indications

Emtricitabine tenofovir is suitable for use in combination with other antiretroviral drugs to treat HIV-1 infection in adults and children over 12 years of age.
When starting this product to treat HIV-1 infection, the following factors should be considered:
· This product is not recommended as a component of the trinucleoside treatment regimen;
· This product should not be combined with emtricitabine, tenofovir disoproxil, lamivudine, or a fixed-dose combination containing the three;
· For patients who have been treated, the use of this product should be performed in accordance with the results of laboratory tests and the history of treatment of patients.

Emtricitabine Tenofovir Tablet Specifications

Emtricitabine tenofovir is a tablet. Each tablet contains 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

Emtricitabine Tenofovir Tablets dosage

For adults and children over 12 years of age and children weighing 35 kg or more, the recommended dose of this product is oral once daily, one tablet at a time, with food or alone.
Adjusted dose for patients with impaired renal function. When given emtricitabine or tenofovir disoproxil fumarate in patients with moderate to severe renal impairment, drug exposure increased significantly (see Tenofovir disoproxil maleate drug instruction sheet "). For patients with a baseline creatinine clearance of 30 to 49 mL / min, the interval between dosing of emtricitabine and tenofovir should be adjusted according to the recommendations in Table 1. The recommended dosing interval is based on a model of pharmacokinetic data for a single dose in non-HIV infected patients. In patients with moderate to severe renal impairment, no clinical evaluation of the safety and efficacy of these dosing interval adjustment recommendations has been performed, so the clinical response to treatment and renal function should be closely monitored in these patients (see [Warning] ).
For patients with mild renal impairment, there is no need to adjust the dose (creatinine clearance 50 ~ 80 mL / min). For children with renal impairment, no data are available on the recommended dosage.
Table 1 Dose adjustment for patients with changes in creatinine clearance http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201608221311560392.png
a. Use ideal (lean) weight calculations.

Periodic monitoring of calculated creatinine clearance and serum phosphorus concentration in patients with mild renal impairment (see [Warning]).

Emtricitabine tenofovir tablets adverse reactions

Clinical trial experience Clinical trial empirical study 934 for adult subjects is a positive control clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, the most common adverse reactions in the study (The incidence is greater than or equal to 10%, any severity) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal nightmares and rash. The incidence of adverse reactions (grades 2 to 4) in the treatment of 5% or more subjects in any treatment group in this study is shown in Table 2.
Discoloration of the skin, manifested by hyperpigmentation of the palms and / or soles, is usually mild and asymptomatic. The mechanism and clinical significance are unknown.
Study 934-Adverse Reactions in Treatment: In Study 934, 511 subjects without antiretroviral therapy received emtricitabine (FTC) + tenofovir disoproxil fumarate (TDF ) Combined with efavirenz (EFV) (N = 257) or zidovudine (AZT) / lamivudine (3TC) with efavirenz (N = 254) for 144 weeks. The average age of the subjects was 40 years (20-73 years), and the majority of the subjects were male (88%). Overall, 65% are white, 17% are black, and 13% are Hispanic. Adverse reactions observed in this study were generally compared with other studies in subjects who received or did not use emtricitabine and / or tenofovir disoproxil fumarate The results observed afterwards were consistent (Table 2).
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a. The incidence of adverse reactions is based on adverse events in all treatments, whether or not they are related to the study drug.
b. From week 96 to 144 of the trial, subjects who received emtricitabine + tenofovir disoproxil fumarate combined with efavirenz received emtricitabine tenofovir combined with efavivir Gallon.
c. Rash events include dermatosis, exfoliative rash, systemic rash, maculopapular, maculopapular, prurigo, and vesicular rash.
Laboratory anomalies: The laboratory anomalies observed in this trial were basically the same as those observed in other trials with emtricitabine and / or tenofovir disoproxil fumarate (Table 3).
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a. From week 96 to 144 of the trial, subjects who received emtricitabine + tenofovir disoproxil fumarate combined with efavirenz were replaced by emtricitabine tenofovir combined with efavivir Gallon.

In addition to the adverse events in the above-mentioned study 934, other adverse reactions with a incidence of 25% in clinical trials of combination therapy with emtricitabine or tenofovir disoproxil fumarate combined with other antiretroviral drugs These include anxiety, joint pain, increased cough, indigestion, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia and rhinitis.
In addition to the laboratory abnormalities in study 934 above, clinical trials of combination therapy with emtricitabine or tenofovir disoproxil fumarate in combination with other antiretroviral drugs showed grade 3/4 biliary redness Laboratories with elevated serum levels (> 2.5xULN), increased pancreatic amylase (> 2.0 x ULN), elevated or decreased blood glucose (40 or> 250 mg / dL), and elevated serum lipase (> 2.0 x ULN) The percentage of anomalies is up to 3%.
Emtricitabine in children aged 12 years and older: In the two larger open-label, uncontrolled children's clinical trials (N = 116), except for the adverse effects reported in adults In addition, anemia and hyperpigmentation were observed in 7% and 32% of subjects treated with emtricitabine (3 months to under 18 years), respectively. For additional information, see Emtricitabine Instruction Manual Information.
Tenofovir disoproxil fumarate: In a child clinical trial of subjects 12 and 18 years of age, children treated with tenofovir disoproxil fumarate received The adverse reactions observed in the subjects were similar to the results of adult clinical trials (see [Caution] and [Cautions]).
Post-marketing experience:
The following adverse reactions were found during the use of tenofovir disoproxil fumarate after its approval. No additional adverse effects were found during the use of emtricitabine. Since the post-marketing response is a voluntary report and the source population is unknown, it is not possible to reliably estimate its frequency or establish a causal relationship with drug exposure.
Allergic reactions to diseases of the immune system, including angioedema;
Metabolic and nutritional diseases;
Lactic acidosis, hypokalemia, hypophosphatemia;
Breathing, chest and mediastinal disorders;
Gastrointestinal diseases pancreatitis, increased amylase and abdominal pain;
Hepatobiliary diseases fatty liver, hepatitis, elevated liver enzymes (most common AST, ALT, GGT);
Skin and subcutaneous tissue disorders rashes;
Musculoskeletal and connective tissue diseases rhabdomyolysis, osteomalacia (expressed as bone pain, which may cause fractures), muscle weakness, myopathy;
Renal and urinary diseases Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal tubular disease, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, elevated creatinine, Proteinuria, polyuria;
Systemic disease and weakness at the site of administration;
The following adverse reactions (listed under the heading of the above-mentioned body system) may be caused by proximal tubular lesions: rhabdomyolysis, osteomalacia, hypokalemia, myasthenia, myopathy, hypophosphatemia.

Emtricitabine Tenofovir Tablets Taboo

It is contraindicated in patients known to have an allergic reaction to tenofovir, tenofovir disoproxil fumarate, emtricitabine, or any of the excipients.

Emtricitabine Tenofovir Tablets Notes

Drug interactions Caution should be taken when co-administering noroxysine emtricitabine tenofovir with noroxysine, and patients receiving the combination should closely monitor the adverse reactions associated with inosine. In patients who experience inosine-related adverse reactions, inosine should be discontinued.
When combined with tenofovir disoproxil fumarate, the maximum serum concentration (Cmax_) and the area under the plasma concentration time curve (AUC) of didanosine sustained-release tablets or enteric preparations increased significantly (see Pharmacokinetics). The mechanism of this interaction is unclear. Higher inosine concentrations may cause adverse reactions associated with inosine, including pancreatitis and neuropathy. A decrease in CD4 + cell count was observed in patients receiving tenofovir disoproxil fumarate and didanosine 400 mg daily.
In patients weighing> 60 kg, the dose of didanosine should be reduced to 250 mg when used in combination with emtricitabine and tenofovir. In adult or pediatric patients weighing <60 kg, there is currently no Suggested data for glycoside dose adjustment. When administered in combination, emtricitabine tenofovir and didanosine enteric solvent can be administered on a fasting state or concurrently with light food (<400 Kcal, 20% fat). Noroxyinosine sustained-release tablets and emtricitabine tenofovir should be administered in a fasting state.
Atazanavir Atazanavir can increase tenofovir concentration (see [Pharmacokinetics]). The mechanism of this interaction is unclear. In patients receiving atazanavir and emtricitabine tenofovir, their adverse reactions related to emtricitabine tenofovir should be monitored. Emtricitabine tenofovir should be discontinued in patients with adverse reactions related to emtricitabine tenofovir.
Tenofovir reduces AUC and atazanavir (see [Pharmacokinetics]). When combined with emtricitabine and tenofovir, it is recommended that 300 mg of atazanavir be co-administered with 100 mg of ritonavir. In the absence of ritonavir, atazanavir should not be administered in combination with emtricitabine and tenofovir.
Lopinavir / ritonavir Lopinavir / ritonavir can increase tenofovir concentration (see [Pharmacokinetics]). The mechanism of this interaction is unclear. In patients receiving lopinavir / ritonavir and emtricitabine tenofovir, their adverse reactions related to emtricitabine tenofovir should be monitored. Emtricitabine tenofovir should be discontinued in patients with adverse reactions related to emtricitabine tenofovir.
The drugs that affect renal function, emtricitabine and tenofovir, are mainly cleared by the kidney through a combination of glomerular filtration and active tubular clearance (see [Pharmacokinetics]). No drug interactions due to competition for renal clearance were observed. However, the combination of emtricitabine tenofovir with drugs that are actively cleared through the renal tubules can increase the concentration of emtricitabine, tenofovir, and / or a combination drug. Such drugs include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that reduce kidney function may also increase serum concentrations of emtricitabine and / or tenofovir.
Bone Mineral Density Decrease BMD assessment should be considered in HIV-1 infected adults and children 12 years of age and older who are at risk for pathological fractures or osteoporosis or bone loss. Although the effects of calcium and vitamin D supplementation have not been studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, an appropriate consultation should be performed.
Tenofovir disoproxil fumarate: A 144-week trial in newly treated adult subjects showed that the bone mineral density (BMD) of the lumbar spine and hip was decline. At week 144, patients receiving tenofovir disoproxil fumarate + lamivudine + efavirenz compared to subjects receiving stavudine + lamivudine + efavirenz The average percentage decrease in the subject's lumbar spine bone mineral density relative to the baseline value was significantly higher. Changes in hip bone mineral density were similar in the two treatment groups. In both treatment groups, most of the decline in bone mineral density occurred during the first 24 to 48 weeks of the trial, and remained stable until the 144th week. 28% of subjects treated with tenofovir disoproxil fumarate and 21% of control subjects lost at least 5% of bone mineral density in the lumbar spine or bone minerals in the hip Density loss is at least 7%. Four subjects in the tenofovir disoproxil fumarate group and six subjects in the control group reported clinically relevant fractures (except fingers and toes). Biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum carboxy-terminal peptide, urine amino-terminal peptide) in the tenofovir disoproxil fumarate group significantly increased, suggesting bone Increased conversion. Subjects in the tenofovir disoproxil fumarate group also had higher serum parathyroid hormone levels and 1,25 vitamin D levels.
In a clinical trial (Study No. 321) of children aged 12 years and older with HIV-1 infection, bone effects were similar to those of adult subjects. Under normal circumstances, BMD increases rapidly in this age group. In this trial, the average rate of bone increase in the tenofovir disoproxil fumarate group was lower than in the placebo group. Within 48 weeks, 6 subjects in the tenofovir disoproxil fumarate group and 1 subject in the placebo group experienced a significant loss of BMD (greater than 4%) in their lumbar spine. In the 28 subjects who received tenofovir disoproxil fumarate for 96 weeks, their lumbar and systemic Z-scores decreased by -0.341 and -0.458, respectively. Bone growth (height) does not appear to be affected. In pediatric subjects over 12 years of age treated with tenofovir disoproxil fumarate, bone turnover markers indicate increased bone turnover, which is consistent with the effects observed in adults.
The effects of changes in bone mineral density and biochemical markers associated with tenofovir disoproxil fumarate on long-term bone health and future fracture risk remain unclear. For additional information, see Tenofovir disoproxil fumarate prescription information.
Cases of osteomalacia associated with tenofovir disoproxil fumarate (associated with proximal tubule lesions and possibly causing fractures) have been reported (see [Adverse Reactions]).
Redistribution of fat In patients receiving antiretroviral therapy, redistribution / accumulation of body fat has been observed to include concentric obesity, increased back fat (buffalo's back), peripheral weight loss, facial weight loss, enlarged chest, and Cushing-like appearance. The mechanism and long-term consequences of these phenomena are currently unclear. Causality has not yet been established.
Immune reconstitution syndrome has been reported in patients receiving antiretroviral combination therapy including emtricitabine tenofovir. In the early stages of antiretroviral therapy, patients with immune system responses may develop refractory or residual opportunistic infections (such as Mycobacterium avian tuberculosis, cytomegalovirus, pneumocystis pneumonia (PCP), or tuberculosis). The inflammatory response requires further evaluation and treatment.
In addition, autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have been reported during the course of immune reconstruction. However, the time of onset is more diverse and treatment may be started It happened within a few months.
Early virological failure Clinical trials in subjects with HIV-1 infection have proven to be compatible with the inclusion of two nucleoside reverse transcriptase inhibitors (NRTI) and a non-nucleoside reverse transcriptase inhibitor or an HIV-1 protease inhibitor Compared with the triple drug treatment regimens, some medication regimens that contain only three nucleoside reverse transcriptase inhibitors are generally less effective. Particular consideration should be given to reports of early virological failures and high resistance alternatives. Therefore, the use of trinucleoside treatment should be used with caution. Patients treated with the trinucleoside regimen should be carefully monitored and considered to improve therapy.

Emtricitabine Tenofovir Tablets for pregnant and lactating women

US pregnancy classification B:
Antiretroviral Pregnancy Registry: To monitor the fetal outcome of pregnant women exposed to emtricitabine tenofovir, an antiretroviral pregnancy registry (APR) has been established. Medical staff are welcome to call + 011-910-256-0238 (the pay phone of the other party) to register patients, or contact the registration office by fax: +1 011-910-256-0637 or visit the website www.apregistry.com.
Risk Summary Emtricitabine tenofovir was evaluated in a limited number of pregnant and postpartum women. Available human and animal data indicate that emtricitabine tenofovir does not generally increase the risk of major birth defects compared to background rates. However, adequate and well-controlled trials have not been conducted in pregnant women. Because human studies cannot rule out the possibility of causing harm, emtricitabine tenofovir can only be used during pregnancy if it is really needed.
Clinical considerations As of July 2011, the antiretroviral pregnancy registry has received 764 and 1219 cases in the first trimester, 321 and 455 cases in the second trimester, and 140 and 257 cases in the third trimester respectively. Prospective study of tabinovir and tenofovir-containing therapy. In the first trimester, the birth defect rate was 18/764 (2.4%) in the emtricitabine-containing group and 27/1219 (2.2%) in the tenofovir-containing group; The rate of birth defects was 10/461 (2.2%) in the metformin group and 15/714 (2.1%) in the tenofovir-containing group. Among pregnant women in the US reference population, the background rate for birth defects was 2.7%. No association between emtricitabine or tenofovir and overall birth defects was observed in APR.
Animal data Emtricitabine: Embryo and fetal toxicity studies have shown that when mice and rabbits are exposed to emtricitabine approximately 60 times and 120 times higher than the recommended human daily dose, respectively, the incidence of fetal variation and deformities It has not increased.
Tenofovir disoproxil fumarate: A reproductive study was performed in rats and rabbits, and the doses based on body surface area comparisons were 14 and 19 times the highest in humans, respectively. The results showed no evidence of tenofovir Causes damage to fertility or damage to the embryo.
Breastfeeding women: The Centers for Disease Control and Prevention recommends that HIV-1 infected women should not breastfeed their babies to avoid the risk of HIV-1 transmission after birth. Human studies have shown that both tenofovir and emtricitabine are secreted into human milk. Because infants' exposure to low levels of emtricitabine and tenofovir is unknown, mothers should be asked not to breastfeed if they are receiving emtricitabine tenofovir.
Emtricitabine breast milk samples obtained from five HIV-1 infected women showed that emtricitabine was secreted into human milk. While the mother of a breastfed infant is receiving emtricitabine, the infant may be at risk for developing resistance to emtricitabine. For breastfeeding babies whose mothers are receiving emtricitabine, other risks associated with emtricitabine are unknown.
Tenofovir disoproxil fumarate breast milk samples obtained from five HIV-1 infected women showed that tenofovir was secreted into human milk. For breastfed infants whose mothers are receiving tenofovir disoproxil fumarate, the risks associated with tenofovir, including the risk of resistance to emtricitabine, are unclear.

Emtricitabine Tenofovir Tablets for Children

Emtricitabine and tenofovir fumarate can only be used on children 12 years of age or older and weighing 35 kg (77 lb) or more A fixed-dose combination tablet of dipyrfurate, and the safety and efficacy of tenofovir disoproxil fumarate in children younger than 12 years and weighing less than 35 kg have not been established.

Emtricitabine Tenofovir Tablets

The clinical trials of emtricitabine and tenofovir disoproxil fumarate did not enroll a sufficient number of subjects 65 years of age or older to determine whether their response was comparable to that of younger subjects different. In general, elderly patients should be careful when choosing a dose, keeping in mind that their liver, kidney, and heart function are reduced, and they are more likely to have a disease or be treated with other drugs.

Emtricitabine Tenofovir Tablets Drug Interactions

Compared with the single drug, the steady-state pharmacokinetics of emtricitabine and tenofovir were not affected by the combined drug.
In vitro studies and clinical pharmacokinetic drug interaction tests have shown that there is little chance of CYP-mediated interactions between emtricitabine and tenofovir and other drugs.
Tenofovir disoproxil fumarate will affect the pharmacokinetic parameters of atazanavir. Tenofovir disoproxil fumarate can only be administered in combination with atazanavir (300 mg atazanavir / 100 mg ritonavir) after elevated concentrations (see Tables 4 and 5).
No clinically significant drug interactions between emtricitabine, famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine were observed (see Tables 4 and 5) ).
Similarly, in the trials performed in healthy subjects, tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, and rafavi Clinically significant differences between mifudine, lopinavir / ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir / ritonavir, and tacrolimus Drug interactions (see Tables 6 and 7).
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a. increase = ; decrease = ; no effect = ; NA = not applicable b. Reyataz prescription information c. In HIV-infected subjects, add tenofovir disoproxil fumarate to aza Navir 300 mg + ritonavir 100 mg, the results showed that the AUC and L values of atazanavir were 2.3 times and 4 times higher than those observed when atazanavir 400 mg was used alone.
d. When administered alone or in combination with tenofovir disoproxil fumarate, the R isomer (activity), S isomer, and overall methadone exposure levels were comparable.
e. Each subject maintains his stable methadone dose. No pharmacodynamic changes (opioid toxicity or withdrawal signs or symptoms) have been reported.
f. When administered alone or in combination with tenofovir disoproxil fumarate, the exposure levels of ethinyl estradiol and 17-deacetylnorgestimate (pharmacologically active metabolite) are comparable.
g. Because no clinically relevant increases in AUC and Cmin are expected, no dose adjustment is necessary when tenofovir fumarate fumarate is combined with ritonavir-enhanced saquinavir.
HIV-negative subjects receiving long-term methadone maintenance therapy or oral contraceptives or a single ribavirin treatment after tenofovir disoproxil fumarate are given multiple times. The generational kinetics are similar to those observed in previous trials, suggesting that there are no clinically significant drug interactions between these drugs and tenofovir disoproxil fumarate.
The changes in the pharmacokinetics of didanosine when tenofovir disoproxil fumarate combined with didanosine may have clinical significance. Table 8 summarizes the effect of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Co-administration of tenofovir disoproxil fumarate in combination with didanosine sustained-release tablets or enteric-coated capsules significantly increased didanosine (Cmax and AUC. Enteroxy-coated capsules of didanosine 250 mg When combined with tenofovir disoproxil fumarate, systemic exposure levels of didanosine are similar to when fasting 400 mg enteric capsules are used alone. The mechanism of this interaction is not yet clear. See [Note Matters] Regarding the use of didanosine and tenofovir disoproxil fumarate.
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Emtricitabine Tenofovir Tablets Overdose

If overdose occurs, the patient must be monitored for evidence of poisoning and, if necessary, standard supportive treatment should be used.
Emtricitabine: Clinical experience at therapeutic doses higher than Emtricitabine is limited. In a clinical pharmacological trial, 11 subjects received a single dose of emtricitabine at 1200 mg. No serious adverse reactions were reported.
Emtricitabine was administered for 3 hours within 1.5 hours after administration of emtricitabine. Dialysis treatment can clear about 30% of the dose of emtricitabine (blood flow rate: 400 mL / min; dialysate flow rate: 600 mL / min). Whether emtricitabine can be cleared by peritoneal dialysis is unclear.
Tenofovir disoproxil fumarate: clinical experience at 300 mg higher than tenofovir disoproxil fumarate is limited. In one trial, eight subjects received oral tenofovir disoproxil fumarate 600 mg for 28 days. No serious adverse reactions have been reported.
54%300 mg 410%

934HIV-1903303
934511+/14496144 +381880)86%59%23%CD4+245/mm3 (21191),HIV-1 RNA5.01 logic /mL (3.566.54)CD4+200/mm)41%CD4+<200/mm51%>100, 000/mL481449
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a.4896HIV-1 RNA <400/mL)4896
b.48144HIV-1 RNA<400/mL
c.48144<400/mL
d.
48+/84%73%HIV-1 RNA <400/mL (14471%58%)48HIV-1 RNA <400/mL/+/80%70%48HIV-1 RNA <50/mL14464%56%)48+CD4+190/mm,/158/mm3 (144312271/mm)
48+7/5CDCC144106

Emtricotinofovir pirfurate tablets are compound preparations of the antiviral drug emtricitabine and tenofovir disoproxil fumarate.
Mechanism of action Emtricitabine: Emtricitabine is a synthetic cytosine nucleoside analog, which is phosphorylated by cell enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits HIV-1 reverse transcriptase (RT) activity by competing with the natural substrate 5'-triphosphate deoxycytidine and integrating into newly synthesized viral DNA to terminate the chain. Emtricitabine 5'-triphosphate on mammalian DNA polymerase a,
The inhibitory activities of 0, e and mitochondrial DNA polymerase y were weak.
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is a non-cyclic nucleoside phosphorylated diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate is first converted to tenofovir by diesterase hydrolysis, and then tenofovir diphosphate is formed by phosphorylation of cellular enzymes. Tenofovir diphosphate competes with the natural substrate 5'-triphosphate deoxyadenosine and then integrates with DNA to terminate the DNA strand, thereby inhibiting HIV-1 reverse transcriptase activity. Tenofovir diphosphate has weak inhibitory activity on mammalian DNA polymerases a, 0 and mitochondrial DNA polymerase y.
Antiviral activity Emtricitabine and tenofovir dipivofurate fumarate: The combined antiviral activity of emtricitabine and tenofovir was evaluated by cell culture. The results show that emtricitabine and tenofovir have Synergistic antiviral effect.
Emtricitabine: Emtricitabine was evaluated in laboratory and clinically isolated HIV-1 virus strains in lymphoblastoid cell lines, MAGI-CCR5 cell line and peripheral blood mononuclear cells. Emtricitabine has an EC ₅₀ value between 0.013-0.64 uM (0.0003-158 ug / mL). Emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tazacitadine, zidovudine), non-nucleoside reverse transcriptase inhibitors (tiladol Trials of combination of wedin, efavirenz, nevirapine), and protease inhibitors (ampunavir, nelfinavir, ritonavir, saquinavir) have shown additive to synergistic effects. Emtricitabine showed antiviral activity against HIV-1 subtypes A, B, C, D, E, F, and G (EC ₅₀ values between 0.007 to 0.075 uM) in cell culture, And showed specific activity against HIV-2 toxic strain (EC ₅₀ value between 0.007-1.5 uM).
Tenofovir disoproxil fumarate: tenofovir has been evaluated for laboratory- and clinically isolated HIV-1 in lymphoblastoid cell lines, primary monocytes / macrophages, and peripheral blood lymphocytes Antiviral activity of the virus strain. EC5 of Tenofovir. The value is between 0.04-8. 5 uM. Tenofovir and nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-reverse transcriptase inhibition In combination trials of agents (deslavide, efavirenz, nevirapine) and protease inhibitors (ampunavir, indinavir, nelfinavir, ritonavir, and saquinavir) have shown Add to synergy. Tenofovir showed antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G, and 0 in cell culture (EC ₅₀ between 0.5-2. 2 uM) And showed specific activity against HIV-2 toxic strains (EC ₅₀ values between 1.6-5.5 uM).
Drug-resistant emtricitabine and tenofovir disoproxil fumarate were screened in cell cultures to isolate HIV-1 isolates that were less sensitive to the combination of emtricitabine and tenofovir. Genotype analysis of the virus strain revealed that M184V / I and / or K65R amino acid substitutions occurred in viral reverse transcriptase.
In a clinical trial (Research 934) conducted in first-time subjects, resistance analysis was performed on HI V-1 virus strains isolated from all subjects who demonstrated failure of antiviral therapy. These subjects had HIV-1 RNA greater than 400 copies / mL at 144 weeks or early discontinuation. The incidence of resistance mutations associated with efavirenz was highest, and the incidence was similar among treatment groups. Among the 19 analysis samples isolated from the emtricitabine + tenofovir disoproxil fumarate treatment group, M184V amino acid substitutions were observed in 2 cases, while 29 in the zidovudine / lamivudine treatment group were isolated. Ten cases were observed in the sample analyzed, and this amino acid substitution was associated with emtricitabine and lamivudine resistance. During the 144-week period of Study 934, subjects were subjected to standard genotyping, and no K65R substitution was detected in the HIV-1 strain.
Emtricitabine: An HIV-1 strain that has developed resistance to emtricitabine has been screened in cells and humans. Genotype analysis of these strains showed that their reduced sensitivity to emtricitabine was related to base substitution at the codon 184 of the HIV-1 reverse transcriptase gene, which resulted in methionine being replaced by valine Or isoleucine (M184V / I) replacement.
Tenofovir disoproxil fumarate: An HIV-1 strain with reduced sensitivity to tenofovir was isolated by cell culture. The K65R substitutions occurred in the reverse transcriptase of these strains, and their sensitivity to tenofovir decreased by two to four times.
Among subjects receiving treatment for the first time, 8/47 (17%) of K65R replacement occurred in the tenofovir disoproxil fumarate treatment group during the 144-week treatment period; 7 of these occurred in the treated group. In the first 48 weeks, one case occurred at week 96. Among subjects previously treated with tenofovir disoproxil fumarate, 14/304 (5%) failed treatment within 96 weeks, and the sensitivity of the strain to tenofovir declined more than 1. 4 times (median value 2.7 times). Genotyping of drug-resistant virus strains revealed that HIV-1 reverse transcriptase gene substitutions resulted in K65R amino acid substitutions.
Cross-resistance Emtricitabine and tenofovir disoproxil fumarate: Cross-resistance has been identified between some nucleoside reverse transcriptase inhibitors (NRTI). M184V / I and / or K65R replacement virus strains have been screened from cell culture when emtricitabine was combined with tenofovir. Such variant virus strains were combined with lamivudine or emtricitabine in tenofovir Medications, as well as virus strains isolated from patients who failed treatment with tenofovir in combination with abacavir and inosine, were also found. Therefore, cross-resistance can develop in patients who carry a virus containing one or two of these (substitution) gene mutations.
Emtricitabine: Emtricitabine-resistant virus strain (M184V / I) has cross-resistance to lamivudine and tacitabine, but it is resistant to inosine, stavudine in cell culture , Tenofovir, zidovudine, and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine) remain sensitive. K65R-replaced HIV-1 strains isolated from patients treated with abacavir, didanosine, tenofovir, and zalcitabine have reduced sensitivity to the inhibitory effects of emtricitabine. HIV-1 viruses with reduced susceptibility to zidovudine and stavudine (M41L, D67N, K70R, L210W, T215Y / F, K219Q / E replacement) and didanosine (L74V replacement) remain sensitive to Emtricita Bin sensitivity. HIV-1 strains containing K103N substitutions associated with resistance to non-nucleoside reverse transcriptase inhibitors remain sensitive to emtricitabine.
Tenofovir disoproxil fumarate: an average of 3 zidovudine-associated reverse transcriptase amino acid substitutions (M41L, D67N, K70R, L210ff, T215Y / F or K219Q / E / N) HIV-1 strains were 3.1 times less sensitive to tenofovir. Subjects who produced L74V replacements without zidovudine resistance-related replacements (N = 8) had a reduced response to the efficacy of tenofovir disoproxil fumarate. Limited data show that patients with Y115F replacement (N = 3), Q151M replacement (N = 2), or T69 insertion (N = 4) all have a reduced response.
Emtricitabine for toxicology:
Genetic toxicity: Emtricitabine Ames test, mouse lymphoma test, mouse micronucleus test results were negative.
Reproductive toxicity: Male rats were given approximately 140 times the exposure of 200 mg / day of the recommended dose of emtricitabine, or males and female mice were given approximately 60 times the exposure of the recommended dose of humans, which had no effect on fertility. In the embryo-fetal toxicity test, when mice and rabbits were given approximately 60 times and 120 times the human exposure (AUC), respectively, no increase in the incidence of fetal abnormalities and deformities was observed. The offspring mice were given approximately 60 times the exposure (AUC) of human recommended dose (200 mg / day) daily from prenatal (fetal birth) to sexual maturity, and the offspring of mice were normal in fertility.
Carcinogenicity: In the long-term carcinogenicity test of emtricitabine administered orally, mice were administered at a dose of 750 mg / kg / day (equivalent to 26 times the total human exposure at a therapeutic dose of 200 mg / day) or rats No increase in the incidence of drug-related tumors was observed when administered at a dose of 600 mg / kg / day (equivalent to 31 times the systemic exposure of a human at a therapeutic dose).
Tenofovir disoproxil fumarate:
Genotoxicity: Tenofovir disoproxil fumarate was positive for mouse lymphoma test in vitro, and negative for Ames test and mouse micronucleus test.
Reproductive toxicity: Male rats started to administer 28 days before mating, female rats started to administer 15 days before mating until the 7th day of pregnancy. Tenofovir disoproxil fumarate was administered at a dose equivalent to human Using 10 times the dose (calculated as body surface area), no effect on fertility, mating ability, or early embryo development was seen, but the estrous cycle of female rats changed. In the embryo-fetal toxicity test, rats and rabbits were administered 14 times and 19 times the human dose (calculated based on body surface area), and no fertility damage or fetal toxicity caused by tenofovir was seen.
Carcinogenicity: In the long-term carcinogenicity test of tenofovir disoproxil fumarate for oral administration, the maximum exposure was about 16 times (mouse) and 5 times (rat) the therapeutic dose of human HIV-1 infection. The incidence of liver adenoma increased in female mice at 16 times the human exposure. Carcinogenicity test results were negative in rats at exposures up to 5 times the human therapeutic dose.
Other Toxicity: In toxicology tests, rats, dogs, and monkeys were given tenofovir and tenofovir difufurate fumarate at 6 times or more human exposure (based on AUC) and found to cause bone toxicity . Osteotoxicity in monkeys was diagnosed as osteomalacia. The osteomalacia observed in monkeys is reversible when the tenofovir dose is reduced or discontinued. Bone toxicity in rats and dogs manifests as a decrease in bone mineral density. The mechanism that causes bone toxicity is unclear.
Renal toxicity was observed in all four animals, and varying levels of serum creatinine, urea nitrogen, diabetes, proteinuria, phosphate urine and / or calcium urine, and decreased serum phosphate were observed in these animals . These toxicities are observed at exposures (based on AUC) that are 2 to 20 times higher than human exposures. The relationship between kidney abnormalities (especially phosphate urine) and bone toxicity is unclear.

Emtricitabine Tenofovir Tablets Pharmacokinetics

Emtricitabine tenofovir: Take one piece of emtricitabine tenofovir on an empty stomach with one emtricitabine capsule (200 mg) plus one tablet of tenofovir dipivofurate fumarate (300 mg) Bioequivalence was demonstrated in healthy subjects (N = 39).
Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 10. After emtricitabine was taken orally, emtricitabine was quickly absorbed, and peak plasma concentrations were reached 1 to 2 hours after taking the drug. In vitro experiments show that emtricitabine binds to human plasma protein in a concentration range of less than 4% in a concentration range of 0.02 to 200 ng / mL and is independent of concentration. After taking radiolabeled emtricitabine, approximately 86% of the dose was excreted through the urine, and 13% was excreted as a metabolite. Emtricitabine's metabolites include 3'-sulfoxide diastereomers and glucuronic acid conjugates. Emtricitabine is eliminated through a combination of glomerular filtration and active tubule absorption. After a single oral administration of emtricitabine, the plasma half-life of emtricitabine was approximately 10 hours.
Tenofovir disoproxil fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 10. After the oral administration of tenofovir disoproxil fumarate, the peak time of tenofovir was 1.0 ± 0.4 hours. In vitro experiments show that tenofovir is within the concentration range of 0.01 to 25 ug / mL, and has a protein binding rate of less than 0.7% to human plasma and is independent of concentration. Approximately 70 to 80% of the dose of tenofovir is excreted in the urine as a prototype drug. Tenofovir is eliminated by a combination of glomerular filtration and active tubule absorption. After a single dose of tenofovir disoproxil fumarate, the final elimination half-life of tenofovir is approximately 17 hours.
Table 10 Single-dose pharmacokinetic parameters of emtricitabine and tenofovir in adults1
http://x1.webres.medlive.cn/drugref/ChemPreparationDetail/201608221353200455.png
a.NC = Not calculated b. Median value (range)
c. Mean (± standard deviation)
d. The data is obtained under steady state conditions.
Effects of food on oral absorption Emtricitabine tenofovir can be taken with food or alone. Taking emtricitabine tenofovir after a high-fat diet (784 kcal; 49 g fat) or a light diet (373 kcal; 8 g fat) will increase the peak time of tenofovir by about 0.75 hours. Compared to fasting, the AUC and Cmax of tenofovir increased by an average of about 35% and 15% after taking a high-fat or light diet. In previous safety and efficacy studies, tenofovir was taken while eating. Regardless of whether emtricitabine tenofovir was taken with a high fat or light diet, emtricitabine's systemic exposures (AUC and Cmax) were not affected.
Special population of panentratabine: After taking emtricitabine, no pharmacokinetic differences related to race were found.
Tenofovir disoproxil fumarate: Except for Caucasians, there is insufficient racial and ethnic data to adequately determine the pharmacokinetics that may exist after taking tenofovir disoproxil fumarate between these groups Learn the difference.
Gender The pharmacokinetics of emtricitabine and tenofovir were similar in male and female subjects.
Pediatric Patients For children under 12 years of age or weighing less than 35 kg (less than 77 lb), emtricitabine and tenofovir should not be used.
Emtricitabine: Steady-state in 27 HIV-1 infected child subjects aged 13-17 years who received oral doses of 6 mg / kg up to 240 mg daily or a 200 mg capsule The pharmacokinetics of emtricitabine was measured; in this age group, 26 of the 27 subjects received 200 mg emtricitabine capsules. The mean (standard deviation) and AUC were 2.7 ± 0.9% / 11 ^ and 12.6 ± 5.4 Hg * hr / mL, respectively. Child subjects aged 12 (inclusive) to 18 (exclusive) achieved similar exposures as adults receiving 200 mg once daily.
Tenofovir disoproxil fumarate: steady-state tenofovir pharmacokinetics in 8 HIV-1 infected child subjects (12 years old or older, under 18 years old) Evaluation. The average (± standard deviation) C_ and AUC _tau were 0.38 ± 0.13 Hg / mL and 3.39 ± 1.22 ug · hr / mL, respectively. Tenofovir exposure to pediatric patients receiving 300 mg orally of tenofovir disoproxil fumarate daily and to adults receiving 300 mg of tenofovir disoproxil fumarate daily The exposures were similar.
Elderly patients have not adequately evaluated the pharmacokinetics of emtricitabine and tenofovir in elderly patients (65 years and older).
Patients with impaired renal function In patients with impaired renal function, the pharmacokinetics of emtricitabine and tenofovir were altered (see [Warning]). In adult subjects with creatinine clearance less than 50 mL / min, both Cmax and AUC _{0- of} emtricitabine and tenofovir _were increased. For adult patients with a creatinine clearance of 30 to 49 mL / min, it is recommended to adjust the dosing interval of emtricitabine tenofovir. For children with impaired renal function, no data are available on recommended doses. Emtricitabine and tenofovir are contraindicated in patients with creatinine clearance of less than 30 mL / min and patients with advanced renal disease who need dialysis (see [Dosage and Administration]).
Patients with impaired liver function In a non-HIV-infected subject with moderate to severe liver impairment, tenofovir disoproxil fumarate 300 mg was given as a single dose of tenofovir The kinetics were studied. Compared with subjects without impaired liver function, there was no substantial change in the pharmacokinetics of tenofovir in subjects with impaired liver function. Pharmacokinetic studies of emtricitabine tenofovir or emtricitabine have not been performed in subjects with impaired liver function. However, since emtricitabine is not metabolized primarily by liver enzymes, the effects of impaired liver function on it are limited.

Emtricitabine Tenofovir Tablets Storage

Store below 30 ° C.

Emtricitabine Tenofovir Tablets Packaging

This product is packed in a high-density polyethylene bottle with a child-resistant bottle cap. Each bottle contains 30 film-coated tablets and a bag of silica gel desiccant.
Do not take if the seal on the bottle cap is damaged or missing.