| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Capsule 200 mg | None. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section |
EMTRIVA is indicated, in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts from controlled studies of 48 weeks duration in antiretroviral-naive patients and antiretroviral- treatment-experienced patients who were virologically suppressed on an HIV treatment regimen. In antiretroviral-treatment-experienced patients, the use of EMTRIVA may be considered for adults with HIV strains that are expected to be susceptible to EMTRIVA as assessed by genotypic or phenotypic testing.
Geriatrics (>65 years of age):
Clinical studies of EMTRIVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects (see WARNINGS AND PRECAUTIONS, Geriatrics and DOSAGE AND ADMINISTRATION).
Pediatrics:
EMTRIVA is not approved for use in patients < 18 years of age.
EMTRIVA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
EMTRIVA is a component of TRUVADA (a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate) and ATRIPLA (a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate). EMTRIVA should not be coadministered with TRUVADA or ATRIPLA. Due to similarities between emtricitabine and lamviudine, EMTRIVA should not be coadministered with other drugs containing lamivudine such as COMBIVIR(r), 3TC(r), HEPTOVIR(r), KIVEXA(r) or TRIZIVIR(r).
In long-term oral carcinogenicity studies of emtricitabine, no drug-related increase in tumor incidence was found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
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 unknown. A causal relationship has not been established.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or 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 EMTRIVA 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).
: During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB) which may necessitate further evaluation and treatment.
Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions and DOSAGE AND ADMINISTRATION).
It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. EMTRIVA is not approved for the treatment of chronic HBV infection and the safety and efficacy of EMTRIVA have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of EMTRIVA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be closely monitored with both clinical and laboratory follow up for at least several months in patients who are co-infected with HIV and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
There are no adequate and well-controlled studies in pregnant women. 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. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.
To monitor fetal outcomes of pregnant women exposed to
emtricitabine, an antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
. It is not known whether emtricitabine is secreted into human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants,
Clinical studies of EMTRIVA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION).
Adverse Drug Reaction Overview
The most common adverse events that occurred in patients receiving EMTRIVA with other antiretroviral agents in clinical trials included headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in EMTRIVA and control treatment groups with the exception of skin discoloration which was reported with higher frequency in the EMTRIVA treated group. Skin discoloration, mainly manifested by hyperpigmentation on the palms and/or soles, was generally mild, asymptomatic and of little clinical significance. The mechanism is unknown. In Study FTC-203, an open-label, uncontrolled study of 116 pediatric patients, anemia was observed with an incidence rate of 10% and hyperpigmentation was observed with an incidence of >10%.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. More than 2000 adult patients with HIV infection have been treated with EMTRIVA alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in Phase 1-3 clinical trials. Assessment of adverse reactions is based on data from studies 301A and 303 in which 571 treatment naive (301A) and 440 treatment experienced (303) patients received EMTRIVA 200 mg (N=580) or comparator drug (N=431) for 48 weeks. A summary of EMTRIVA treatment emergent clinical adverse events in studies 301A and 303 is provided in Table 1.
Table 1 Selected Treatment-Emergent Adverse Events (All Grades, Regardless of Causality) Reported in >=3% of EMTRIVA-Treated Patients in Either Study
A or 303 (0-48 weeks)
| Adverse E vent | 303 | 301A | ||
| EMTRIVA + ZDV/d4T + NNRTI/PI (N=294) | Lamivudine + ZDV/d4T + NNRTI/PI (N=146) | EMTRIVA + didanosine + efavirenz (N=286) | Stavudine + didanosine + efavirenz (N=285) | |
| Body as a Whole | ||||
| Abdominal pain | 8% | 11% | 14% | 17% |
| Asthenia | 16% | 10% | 12% | 17% |
| Headache | 13% | 6% | 22% | 24% |
| Digestive System | ||||
| Diarrhea | 22% | 19% | 23% | 32% |
| Dyspepsia | 4% | 5% | 8% | 12% |
| Nausea | 18% | 12% | 13% | 23% |
| Vomiting | 9% | 7% | 9% | 12% |
| Musculoskeletal | ||||
| Arthralgia | 3% | 4% | 5% | 6% |
| Myalgia | 4% | 3% | 6% | 3% |
| Nervous System | ||||
| Abnormal dreams | 2% | <1% | 11% | 19% |
| Depressive disorders | 6% | 10% | 9% | 13% |
| Dizziness | 4% | 5% | 25% | 25% |
| Insomnia | 7% | 3% | 16% | 21% |
| Neuropathy/peripheral neuritis | 4% | 3% | 4% | 13% |
| Paresthesia | 5% | 6% | 6% | 12% |
| Respiratory | ||||
| Increased cough | 14% | 11% | 14% | 8% |
| Rhinitis | 17% | 12% | 12% | 10% |
| Skin | ||||
| Rash event 1 | 16% | 10% | 32% | 36% |
1. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Abnormal Hematologic and Clinical Chemistry Findings
Laboratory abnormalities in these studies occurred with similar frequency in the EMTRIVA and comparator groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 2.
Table 2 Treatment-Emergent Grade 3/4 Laboratory Abnormalities Reported in >=1%
of EMTRIVA-Treated Patients in Either Study 301A or 303
| Number of Patients Treated | 303 | 301A | ||
| EMTRIVA + ZDV/d4T + NNRTI/PI (N=294) | Lamivudine + ZDV/d4T + NNRTI/PI (N=146) | EMTRIVA + didanosine + efavirenz (N=286) | Stavudine + didanosine + efavirenz (N=285) | |
| Percentage with grade 3/4 laboratory abnormality | 30% | 27% | 31% | 37% |
| ALT (>5.0 x ULN 1 ) | 2% | 1% | 4% | 5% |
| AST (>5.0 x ULN) | 3% | 1% | 5% | 8% |
| Bilirubin (>2.5 x ULN) | 1% | 2% | <1% | <1% |
| Creatine kinase (>4.0 x ULN) | 11% | 13% | 10% | 9% |
| Neutrophils (<750 mm 3 ) | 5% | 3% | 5% | 7% |
| Pancreatic amylase (>2.0 x ULN) | 2% | 2% | <1% | 1% |
| Serum amylase (>2.0 x ULN) | 2% | 2% | 4% | 9% |
| Serum glucose (<40 or >250 mg/dL) | 2% | 2% | 3% | 3% |
| Serum lipase (>2.0 x ULN) | 1% | 1% | 1% | 2% |
1. ULN = Upper limit of normal
Cases of spontaneously resolving grade 2, 3, or 4 neutropenia events occurred in 12/286 patients (4%) on FTC-containing antiretroviral regimen in FTC-301A and 2/294 patients (<1%) in FTC-303 where a relationship to emtricitabine could not be ruled out.
Post-Market Adverse Drug Reactions
The following adverse experiences have been reported in post-marketing experience without regard to causality. Because these events are voluntarily reported from a population of unknown size, estimates of frequency cannot be made.
Blood and lymphatic system disorders:
Thrombocytopenia
Gastrointestinal disorders:
Pancreatitis
General disorders and administration site conditions:
Pyrexia
Metabolism and nutrition disorders:
Lactic acidosis
In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy an inflammatory reaction to infectious pathogens (active or inactive) may arise (see WARNINGS and PRECAUTIONS).
At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. Emtricitabine has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. Tables 3 and 4 summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.
| Coadministered Drug | Dose of Coadministered Drug (mg) | Emtricitabine Dose (mg) | N | % Change of Emtricitabine Pharmacokinetic Parameters 2 (90% CI) | ||
| C max | AUC | C min | ||||
| Tenofovir DF | 300 once daily x 7 days | 200 once daily x 7 days | 17 | = | = | | 20 ( | 12 to | 29) |
| Zidovudine | 300 twice daily x 7 days | 200 once daily x 7 days | 27 | = | = | = |
| Indinavir | 800 x 1 | 200 x 1 | 12 | = | = | NA |
| Famciclovir | 500 x 1 | 200 x 1 | 12 | = | = | NA |
| Stavudine | 40 x 1 | 200 x 1 | 6 | = | = | NA |
All interaction studies conducted in healthy volunteers.
|= Increase; | = Decrease; = = No Effect; NA = Not Applicable
| Coadministered Drug | Dose of Coadministered Drug (mg) | Emtricitabine Dose (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters 2 (90% CI) | ||
| C max | AUC | C min | ||||
| Tenofovir DF | 300 once daily x 7 days | 200 once daily x 7 days | 17 | = | = | = |
| Zidovudine | 300 twice daily x 7 days | 200 once daily x 7 days | 27 | | 17 ( | 0 to | 38) | | 13 ( | 5 to | 20) | = |
| Indinavir | 800 x 1 | 200 x 1 | 12 | = | = | NA |
| Famciclovir | 500 x 1 | 200 x 1 | 12 | = | = | NA |
| Stavudine | 40 x 1 | 200 x 1 | 6 | = | = | NA |
All interaction studies conducted in healthy volunteers.
|= Increase; | = Decrease; = = No Effect; NA = Not Applicable
For adults 18 years of age and older, the dose of EMTRIVA is 200 mg once daily taken orally with or without food.
Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment, (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Therefore, the dosing interval of EMTRIVA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following guidelines (see Table 5). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
| Creatinine Clearance (mL/min) | ||||
| >=50 | 30-49 | 15-29 | <15 (including patients requiring hemodialysis) 1 | |
| Recommended Dose and Dosing Interval | 200 mg every 24 hours | 200 mg every 48 hours | 200 mg every 72 hours | 200 mg every 96 hours |
1. Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.
There is no known antidote for EMTRIVA. Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known. If overdose occurs the patient should be monitored for signs of toxicity, and standard supportive treatment applied as necessary. 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), however, a single treatment does not significantly affect emtricitabine Cmax or AUC. It is not known whether emtricitabine can be removed by peritoneal dialysis.
Emtricitabine, a synthetic nucleoside analog of cytosine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase 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 a, b, e and mitochondrial DNA polymerase g. Emtricitabine displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, and G (IC50 values ranged from 0.007 to 0.075 mM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 mM).
The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25 to 400 mg a day of EMTRIVA as monotherapy for 10 to 14 days. A dose- related antiviral effect was observed, with a median decrease from baseline in plasma HIV-1 RNA of 1.3 log10 at a dose of 25 mg QD and 1.7 log10 to 1.9 log10 at a dose of 200 mg QD or BID.
The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-infected individuals. Emtricitabine pharmacokinetics are similar between these populations. Figure 1 shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV- infected subjects receiving EMTRIVA.
10.00
Emtricitabine Concentration (mg/mL)
1.00
0.10
0 4 8 12 16 20 24
Time (hours)
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration of EMTRIVA to 20 HIV-infected subjects, the (mean +- SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 +- 0.7 mg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 +- 3.1 mg *hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 mg/mL. The mean absolute bioavailability of EMTRIVA was 93%. The multiple dose pharmacokinetics of emtricitabine are dose proportional over a dose range of 25 to 200 mg.
EMTRIVA may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA was administered with food (an approximately 1000 kcal high-fat meal).
In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02-200 mg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable.
The plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
The pharmacokinetics of emtricitabine were similar in male and female patients and no pharmacokinetic differences due to race have been identified.
EMTRIVA is not approved for use in patients < 18 years of age.
Pharmacokinetic data are not available in the elderly.
The pharmacokinetics of emtricitabine are altered in patients with renal impairment (see WARNINGS AND PRECAUTIONS). In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to a reduction in renal clearance (Table 6). It is recommended that the dosing interval for EMTRIVA be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (see DOSAGE AND ADMINISTRATION).
| Creatinine Clearance (mL/min) | >80 (N=6) | 50-80 (N=6) | 30-49 (N=6) | <30 (N=5) | ESRD 1 <30 (N=5) |
| Baseline creatinine clearance (mL/min) | 107 +- 21 | 59.8 +- 6.5 | 40.9 +- 5.1 | 22.9 +- 5.3 | 8.8 +- 1.4 |
| C max ( m g/mL) | 2.2 +- 0.6 | 3.8 +- 0.9 | 3.2 +- 0.6 | 2.8 +- 0.7 | 2.8 +- 0.5 |
| AUC ( m g *hr/mL) | 11.8 +- 2.9 | 19.9 +- 1.1 | 25.1 +- 5.7 | 33.7 +- 2.1 | 53.2 +- 9.9 |
| CL/F (mL/min) | 302 +- 94 | 168 +- 10 | 138 +- 28 | 99 +- 6 | 64 +- 12 |
| CLr (mL/min) | 213 +- 89 | 121 +- 39 | 69 +- 32 | 30 +- 11 | NA 2 |
ESRD patients requiring dialysis.
NA = Not Applicable
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), but a single treatment does not significantly affect emtricitabine Cmax or AUC. It is not known whether emtricitabine can be removed by peritoneal dialysis.
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment, however, emtricitabine has not been shown to be metabolized by liver enzymes, so the impact of liver impairment is likely to be limited.
Store EMTRIVA (emtricitabine) capsules at 15-30 degC (59-86 degF).
EMTRIVA is available as capsules each containing 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone. EMTRIVA 200 mg capsules are size 1 hard gelatin capsules with a blue cap and white body, printed with "200 mg" in black on the cap and "GILEAD" and the corporate logo in black on the body. EMTRIVA capsules are packaged in bottles of 30 capsules with induction sealed child- resistant closures.