(tenofovir disoproxil fumarate + emtricitabine)
Dosage Forms and strength
Each tablet contains Tenofovir disoproxil fumarate …………………………………………………………… 300 mg (as tenofovir disoproxil …………………………………………………………………….… 245 mg) Emtricitabine ………………………………………………….…………………………….…… 200mg Additives (tar colorant) : Blue no. 2 Form
A blue, capsule-shaped, film-coated tablet Indication
The treatment of HIV-1 infection in adults in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) The benefit of antiretroviral therapy of combination regiment with emtricitabine and tenofovir disoproxil fumarate is only proved in clinical trials with treatment-naive HIV-1 infected patients. Dosage and Administration
1. Adults : One tablet once daily taken orally with or without food 2. Renal Impairment Significantly increased drug exposures occurred when emtricitabine or tenofovir were administered to subjects with moderate to severe renal impairment. Therefore, adjust the dosing interval of this drug in HIV-1 infected adult patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment
recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (See Warnings 3). No dose adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals with mild renal impairment(See Warnings 3). Table 1 Dosage Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance
a. Calculated using ideal (lean) body weight Precautions in Use
1. WARNINGS 1) Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, a component of this drug, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient or uninfected individual with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with this drug should be suspended in any patient or uninfected individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating this drug. This drug is not approved for the treatment of chronic HBV infection and the safety and efficacy of this drug have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been
reported in patients who are coinfected with HBV and HIV-1 and have discontinued this drug. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with this drug. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
3) New Onset or Worsening Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of this drug (See Adverse Reactions 3. 2)). It is recommended that creatinine clearance be calculated in all individuals prior to initiating therapy and as clinically appropriate during therapy with this drug. Dosing interval adjustment of this drug and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min(See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received this drug using these dosing guidelines, so the potential benefit of this drug therapy should be assessed against the potential risk of renal toxicity. This drug should not be administered to patients with creatinine clearance below 30 mL/min or patients requiring hemodialysis. This drug should be avoided with concurrent or recent use of a nephrotoxic agent.
This drug is a fixed-dose combination(FDC) of emtricitabine and tenofovir disoproxil fumarate. Do not coadminister this drug with FDC of
emtricitabine/ tenofovir/ efavirenz, emtricitabine or tenofovir. Due to similarities between emtricitabine and lamivudine, do not coadminister this drug with other drugs containing lamivudine, including FDC of lamivudine/zidovudine, lamivudine, abacavir sulfate/lamivudine, or abacavir sulfate/lamivudine/zidovudine. Do not coadminister this drug with adefovir dipivoxil.
Assessment of bone mineral density (BMD) should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected then appropriate consultation should be obtained. Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive subjects, decreases in BMD were seen at the lumbar spine and hip in both
arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir + lamivudine + efavirenz(-2.2%±3.9) compared with subjects receiving stavudine + lamivudine + efavirenz(-1.0%±4.6). Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through 144 weeks. 28% of tenofovir-treated subjects vs. 21% of stavudine subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir group and 6 subjects in the stavudine group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir. The effects of tenofovir-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Cases of osteomalacia associated with proximal renal tubulopathy and which may contribute to fractures have been reported in association with the use of tenofovir (See Adverse Reactions 2).
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.
2. Do not administer to the following patients 1) Patients who are hypersensitive to this drug or other ingredients
2) Since this drug contains lactase, it should not be administered to patients
with genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
3. ADVERSE REACTIONS 1) Adverse Reactions from Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 2 for the frequency of treatment-emergent adverse reactions (Grade 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group in this trial. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown. In Study 934, 511 antiretroviral naive subjects received either tenofovir + emtricitabine administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment- experienced or treatment-naive subjects receiving tenofovir and/or emtricitabine (Table 2).
Table 2 Selected Treatment-Emergent Adverse Reactionsa (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)
Emtricitabine+ tenofovir zidovudine/lamivudine
a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received efavirenz + this drug in place of emtricitabine + tenofovir + efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.
In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving emtricitabine or tenofovir with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain,
back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.
2) Postmarketing Experience The following adverse reactions have been identified during postapproval use of tenofovir. No additional adverse reactions have been identified during postapproval use of emtricitabine. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders
allergic reaction (including angioedema)
lactic acidosis, hypokalemia , hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders
pancreatitis, increased amylase, abdominal pain
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
General Disorders and Administration Site Conditions
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypo- phosphatemia. 4. General Precautions The following points should be considered when initiating therapy with this drug.
- It is not recommended that this drug be used as a component of a
- In treatment experienced patients, the use of this drug should be
guided by laboratory testing and treatment history.
5. General Precautions DRUG INTERACTIONS No drug interaction trials have been conducted using this drug tablets, however, drug interaction trials have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of this drug. This section describes clinically relevant drug interactions observed with emtricitabine and tenofovir disoproxil fumarate. 1) Didanosine
Coadministration of this drug and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine(administered as either the common tablet or enteric-coated tablet) increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily. In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with tenofovir. Data are not available to recommend a dose adjustment of didanosine for patients weighing less than 60 kg. When coadministered, tenofovir and didanosine enteric-coated tablet may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). Coadministration of didanosine common tablet formulation with tenofovir should be under fasted conditions.
Atazanavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and this drug should be monitored for this drug-associated adverse reactions. This drug should be discontinued in patients who develop this drug-associated adverse reactions. Tenofovir decreases the AUC and Cmin of atazanavir. When coadministered with this drug, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with tenofovir.
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ ritonavir and this drug should be monitored for this drug-associated adverse reactions. This drug should be discontinued in patients who develop this drug-associated adverse reactions.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of this drug with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
6. Administration in Pregnant Women and Breast-feeding Women 1) Pregnancy
Pregnancy Category B Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled trials in pregnant women. Because the studies in humans cannot rule out the possibility of harm, this drug should be used during pregnancy only if clearly needed.
In order to prevent HIV-1 transmission, it is recommended that HIV-1-infected mothers not breast-feed their infants. Studies in rats have confirmed that tenofovir is secreted in milk. It is not known whether tenofovir is secreted in human milk as well. Since there is a possibility of HIV-1 transmission and serious adverse reactions in breast-feeding infants, mothers taking this drug should be instructed not to breast-feed.
7. Pediatric Use
As the safety and efficacy of tenofovir have not been established in pediatric patients less than 18 years of age, this drug is not recommended to patients under 18 years old. 8. Geriatric Use Clinical trials of Emtricitabine or tenofovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 9. Patients with Impaired Renal Function The dosing interval for this drug should be modified in HIV-infected adult patients with creatinine clearance of 30–49 mL/min. This drug should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis.
10. Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of tenofovir and/or emtricitabine(Table 3). Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Study 934 (0–144 Weeks)
(>550 U/L) AST (M: >180 U/L)(F: >170 U/L)
(M: >215 U/L)(F: >170 U/L) Hemoglobin
(>750 mg/dL) a. From Weeks 96 to 144 of the trial, subjects received this drug with efavirenz in place of tenofovir + emtricitabine with efavirenz. In addition to the laboratory abnormalities described above for Study 934, Grade ¾ laboratory abnormalities of increased bilirubin (>2.5 x ULN), increased pancreatic amylase (>2.0 x ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 x ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir with other antiretroviral agents in clinical trials.
11. OVERDOSAGE If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacological trial, single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of 300 mg is available. In one trial, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28
days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis (with an extraction coefficient of approximately 54%). Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
12. Cautions in Storage and Handling 1) Please store out of reach of children. 2) Since removing a medicinal product from its original container and storing
it in another container may cause accident through misuse or lowering of the quality, it should be kept in the original container with the lid tightly closed.
Storage Store in a tight container at room temperature (1~30C )
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Ministry of Food and Drug Safety- ezdrug(http://ezdrug.mfds.go.kr), 『Drug Info』.
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