Tenof EM

Tenof EM

tenofovir + emtricitabine

Manufacturer:

Camber

Distributor:

Camber
Full Prescribing Info
Contents
Emtricitabine, tenofovir disoproxil fumarate.
Description
TENOF EM is available as tablets. Each tablet contains 200 mg of Emtricitabine and 300 mg of Tenofovir disoproxil fumarate (which is equivalent to 245 mg of Tenofovir disoproxil).
TENOF EM is fixed dose combination tablet containing emtricitabine and tenofovir disoproxil fumarate. Emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5' -monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.
Emtricitabine: The chemical name of emtricitabine is 5- fluoro- 1- (2R,5S) - [ 2- (hydroxymethyl) - 1,3- oxathiolan-5-yl] cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24.
Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.
Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bisisopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy] propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52.
Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
TENOF EM is for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients.
Excipients/Inactive Ingredients: Pregelatinized starch, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The tablets are coated with Opadry II Blue which contains lactose monohydrate, titanium dioxide, triacetin, hypromellose and FD&C Blue # 2 Aluminum Lake.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'- triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.
Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Antiviral Activity: Emtricitabine and Tenofovir Disoproxil Fumarate: In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013 to 0.64 μM (0.0003 to 0.158 mcg/mL). In drug combination studies of emtricitabine 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), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 μM).
Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5 to 2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 4.9 μM).
Resistance: Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical study of treatment-naive subjects [Study 934], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuation. Development of efavirenz resistance-associated mutations occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2 out of 12 (17%) analyzed patients isolates in the emtricitabine + tenofovir disoproxil fumarate group and in 7 out of 22 (32%) analyzed subjects isolates in the zidovudine/lamivudine group. Through 48 weeks of Study 934, no subjects have developed a detectable K65R mutation upon prolonged exposure to this regimen.
Emtricitabine: Emtricitabine-resistant isolates of HIV have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV RT gene at codon 184, which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R mutation in RT and showed a 2 to 4 fold reduction in susceptibility to tenofovir.
In treatment-naive subjects, isolates from 8 patients developed the K65R mutation in the tenofovir disoproxil fumarate arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14 of 304 (5%) isolates from subjects failing tenofovir disoproxil fumarate through Week 96 showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.
Cross Resistance: Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
Tenofovir Disoproxil Fumarate: HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Multi-nucleoside resistant HIV- 1 with a T69S double insertion substitution in the RT showed reduced susceptibility to Tenofovir.
Pharmacokinetics: Absorption/Distribution: The pharmacokinetic properties of emtricitabine and tenofovir are summarized in the following table. (See Table 1.)

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Emtricitabine: Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02 to 200 mcg/mL.
Emtricitabine/Tenofovir: Effect of food - Emtricitabine/Tenofovir may be administered with or without food. In previous safety and efficacy studies, tenofovir was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when emtricitabine/tenofovir was administered with a high fat or light meal.
Metabolism/Excretion: Emtricitabine: Following oral administration radiolabeled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'- sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate: Following oral administration of tenofovir disoproxil fumarate, maximum tenofovir serum concentrations are achieved in 1 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours.
Indications/Uses
TENOF EM, a combination of Emtricitabine and Tenofovir disoproxil fumarate, is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.
Dosage/Direction for Use
Recommended Dose: The dose of TENOF EM is 1 tablet (containing 200 mg of Emtricitabine and 300 mg of Tenofovir disoproxil fumarate) once daily taken orally with or without food.
Dose Adjustment for Renal Impairment: No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus for these patients. (See Table 2.)

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Overdosage
Symptoms: Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study single doses of Emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of Tenofovir disoproxil fumarate 300 mg is available. In one study, 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.
Treatment: If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Emtricitabine: 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: 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.
Contraindications
Emtricitabine and Tenofovir disoproxil fumarate Tablets is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Warnings
Lactic acidosis/severe hepatomegaly with steatosis and post trearment acute exacerbation of hepatitis B.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Tenofovir, a component of Emtricitabine and Tenofovir disoproxil fumarate, in combination with other antiretrovirals (see Precautions).
Emtricitabine and Tenofovir disoproxil fumarate is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Emtricitabine and Tenofovir disoproxil fumarate have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coninfected with HBV and HIV-1 and have discontinued Emtricitabine and Tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients appropriate, initiation of anti-hepatitis B therapy may be warranted (see Precautions).
Special Precautions
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 disoproxil fumarate, a component of emtricitabine and tenofovir disoproxil fumarate, 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 with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with emtricitabine and tenofovir disoproxil fumarate should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Patients Coinfected with HIV and HBV: It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Emtricitabine and Tenofovir disoproxil fumarate is not indicated for the treatment of chronic HBV infection and the safety and efficacy of emtricitabine and tenofovir disoproxil fumarate have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued emtricitabine and tenofovir disoproxil fumarate. For at least several months, closely monitor hepatic function with clinical and laboratory follow up in patients who discontinue emtricitabine/tenofovir and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Renal Function Impairment: Renal function impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir disoproxil fumarate. The majority of these cases occurred in patients with underlying systemic or renal disease or in patients taking nephrotoxic agents; however, some cases occurred in patients without identified risk factors.
Avoid emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent.
Bone Effect: Tenofovir Disoproxil Fumarate: In a 144-week study of treatment naive subjects, decreases in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + lamivudine + efavirenz compared with patients receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the 2 treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of the comparator patients 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 patients in the tenofovir disoproxil fumarate group and 6 patients in the comparator 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 patients receiving tenofovir disoproxil fumarate. The effects of tenofovir disoproxil fumarate-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, have been reported in association with the use of tenofovir disoproxil fumarate.
Fat Redistribution: 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: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine and tenofovir disoproxil fumarate. 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.
Use in Children: Emtricitabine and Tenofovir disoproxil fumarate is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, Tenofovir disoproxil fumarate, for which safety and efficacy have not been established in this age group.
Use in Elderly: In general, use caution when selecting dosage for elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Category B.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use emtricitabine/ tenofovir disoproxil fumarate during pregnancy only if clearly needed.
Lactation: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether Tenofovir is excreted in human milk. It is not known whether Emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Emtricitabine and Tenofovir disoproxil fumarate.
Adverse Reactions
See Table 3.

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Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in other studies of Tenofovir disoproxil fumarate and/or Emtricitabine (Table 4). (See Table 4.)

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In addition to the laboratory abnormalities described previously for Study 934, Grade 3/4 elevations of bilirubin (>2.5 x ULN), pancreatic amylase (>2.0 x ULN), serum glucose (<40 or >250 mg/dL), and serum lipase (>2.0 x ULN) and urine glucose (at least 3+) occurred in up to 3% of patients treated with Emtricitabine or Tenofovir disoproxil fumarate with other antiretroviral agents in clinical trials.
Drug Interactions
See Table 5.

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Storage
Store at temperature below 30°C.
MIMS Class
ATC Classification
J05AR03 - tenofovir disoproxil and emtricitabine ; Belongs to the class of antivirals for treatment of HIV infections, combinations.
Presentation/Packing
FC tab (blue, capsule shaped, debossed with "H" on one side and "124" on other side) x 30's, 60's.
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