WARNING: POST
TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Odefsey is not
approved for the treatment of chronic hepatitis B virus (HBV) infection, and
the safety and efficacy of Odefsey have not been established in patients
coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute
exacerbations of hepatitis B have been reported in patients who are coinfected
with HIV-1 and HBV and have discontinued products containing emtricitabine
(FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with
discontinuation of Odefsey.
Hepatic function
should be monitored closely with both clinical and laboratory follow-up for at
least several months in patients who are coinfected with HIV-1 and HBV and
discontinue Odefsey. If appropriate, initiation of anti-hepatitis B therapy may
be warranted [see Warnings and Precautions (5.1)].
Indications and
Usage for Odefsey
Odefsey is
indicated as a complete regimen for the treatment of HIV-1 infection in
patients 12 years of age and older as initial therapy in those with no
antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000
copies per mL; or to replace a stable antiretroviral regimen in those who are
virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least
six months with no history of treatment failure and no known substitutions
associated with resistance to the individual components of Odefsey [see Microbiology
(12.4) and Clinical Studies
(14)].
Odefsey Dosage
and Administration
Testing Prior to
Initiation of Odefsey
Prior to
initiation of Odefsey, patients should be tested for hepatitis B virus
infection [see Warnings and Precautions (5.1)].
It is
recommended that serum creatinine, serum phosphorus, estimated creatinine
clearance, urine glucose, and urine protein should be assessed before
initiating Odefsey and during therapy in all patients as clinically
appropriate [see Warnings and Precautions (5.8)].
Recommended
Dosage
Odefsey is a
3-drug fixed dose combination product containing 200 mg of emtricitabine (FTC),
25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The
recommended dosage of Odefsey is one tablet taken orally once daily with a meal
in the following patient population: adults and in pediatric patients 12 years
of age and older with body weight greater than or equal to 35 kg and a
creatinine clearance greater than or equal to 30 mL per minute [see Clinical
Pharmacology (12.3)].
Testing After
Initiation of Odefsey
In
virologically-suppressed patients, additional monitoring of HIV-1 RNA and
regimen tolerability is recommended after replacing therapy to assess for
potential virologic failure or rebound [see Clinical Studies
(14)].
Not Recommended
in Patients with Severe Renal Impairment
Odefsey is not
recommended in patients with estimated creatinine clearance below 30 mL per
minute [see Warnings and Precautions (5.8) and Use in Specific
Populations (8.6)].
Dosage Forms and
Strengths
Each Odefsey
tablet contains 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV)
(equivalent to 27.5 mg of rilpivirine hydrochloride), and 25 mg of tenofovir alafenamide
(TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate).
The tablets are
gray, capsule-shaped, film-coated and debossed with "GSI" on one side
and "255" on the other side.
Contraindications
Odefsey is
contraindicated when coadministered with the following drugs; coadministration
may result in loss of virologic response and possible resistance to Odefsey or
to the class of NNRTIs [see Warnings and Precautions (5.3), Drug
Interactions (7) and Clinical
Pharmacology (12.3)]:
the
anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytointhe
antimycobacterials rifampin and rifapentineproton
pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole,
omeprazole, pantoprazole, rabeprazolethe
glucocorticoid systemic dexamethasone (more than a single dose)St.
John's wort (Hypericum perforatum)
Warnings and
Precautions
Severe Acute
Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
Patients with
HIV-1 should be tested for the presence of hepatitis B virus (HBV) before
initiating antiretroviral therapy [see Dosage and
Administration (2.1)]. Odefsey is not approved for the
treatment of chronic HBV infection, and the safety and efficacy of Odefsey have
not been established in patients coinfected with HIV-1 and HBV.
Severe acute
exacerbations of hepatitis B (e.g., liver decompensation and liver failure)
have been reported in patients who are coinfected with HIV-1 and HBV and have
discontinued products containing FTC and/or TDF, and may occur with discontinuation
of Odefsey. Patients coinfected with HIV-1 and HBV who discontinue Odefsey
should be closely monitored with both clinical and laboratory follow-up for at
least several months after stopping treatment. If appropriate, initiation of
antihepatitis B therapy may be warranted, especially in patients with advanced
liver disease or cirrhosis, since post treatment exacerbation of hepatitis may
lead to hepatic decompensation and liver failure.
Skin and
Hypersensitivity Reactions
Severe skin and
hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia
and Systemic Symptoms (DRESS), have been reported during postmarketing
experience with RPV-containing regimens. While some skin reactions were
accompanied by constitutional symptoms such as fever, other skin reactions were
associated with organ dysfunction, including elevations in hepatic serum
biochemistries. During Phase 3 clinical trials of RPV, treatment-related rashes
with at least Grade 2 severity were reported in 1% of subjects. Overall, most
rashes were Grade 1 or 2 and occurred in the first four to six weeks of
therapy [see Adverse Reactions (6.2)].
Discontinue
Odefsey immediately if signs or symptoms of severe skin or hypersensitivity
reactions develop, including but not limited to, severe rash or rash
accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial
edema, angioedema, hepatitis, or eosinophilia. Clinical status including
laboratory parameters should be monitored and appropriate therapy should be
initiated.
Loss of
Virologic Response Due to Drug Interactions
The concomitant
use of Odefsey and other drugs may result in known or potentially significant
drug interactions, some of which may lead to loss of therapeutic effect of
Odefsey and possible development of resistance due to reduced exposure of RPV.
See Table 3 for steps
to prevent or manage these possible and known significant drug interactions,
including dosing recommendations [see Contraindications
(4) and Drug
Interactions (7)]. Consider the potential for drug
interactions prior to and during Odefsey therapy; review concomitant
medications during Odefsey therapy; and monitor for the adverse reactions
associated with the concomitant drugs.
Prolongation of
QTc Interval with Higher Than Recommended Dosages
In healthy
subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg
once daily – 3 and 12 times the recommended dosages, respectively) have been
shown to prolong the QTc interval of the electrocardiogram [see Drug
Interactions (7.2) and Clinical
Pharmacology (12.2)]. Consider alternatives to Odefsey when
coadministered with a drug with a known risk of Torsade de Pointes or when
administered to patients at higher risk of Torsades de Pointes.
Depressive
Disorders
Depressive
disorders (including depressed mood, depression, dysphoria, major depression,
mood altered, negative thoughts, suicide attempt, suicidal ideation) have been
reported with RPV. Promptly evaluate patients with severe depressive symptoms
to assess whether the symptoms are related to Odefsey, and to determine whether
the risks of continued therapy outweigh the benefits.
In Phase 3
trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of
depressive disorders (regardless of causality, severity) reported among
RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in
severity. In RPV-treated subjects, the incidence of Grades 3 and 4 depressive
disorders (regardless of causality) was 1%, the incidence of discontinuation
due to depressive disorders was 1%, and suicidal ideation and suicide attempt
was reported in 4 and 2 subjects, respectively.
During the Phase
2 trial in RPV-treated pediatric subjects 12 to less than 18 years of age
(N=36), the incidence of depressive disorders (regardless of causality,
severity) was 19% (7/36) through 48 weeks. Most events were mild or moderate in
severity. The incidence of Grade 3 and 4 depressive disorders (regardless of
causality) was 6% (2/36). None of the subjects discontinued due to depressive
disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
Hepatotoxicity
Hepatic adverse
events have been reported in patients receiving an RPV-containing regimen.
Patients with underlying hepatitis B or C, or marked elevations in
liver-associated tests prior to treatment, may be at increased risk for
worsening or development of liver-associated test elevations with use of
Odefsey. A few cases of hepatic toxicity have been reported in adult patients
receiving a RPV-containing regimen who had no preexisting hepatic disease or
other identifiable risk factors. Appropriate laboratory testing prior to
initiating therapy and monitoring for hepatotoxicity during therapy with
Odefsey is recommended in patients with underlying hepatic disease such as
hepatitis B or C, or in patients with marked elevations in liver-associated
tests prior to treatment initiation. Liver-associated test monitoring should
also be considered for patients without preexisting hepatic dysfunction or
other risk factors.
Immune
Reconstitution Syndrome
Immune
reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including FTC and RPV, both components of Odefsey.
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.
New Onset or
Worsening Renal Impairment
Renal impairment,
including cases of acute renal failure and Fanconi syndrome (renal tubular
injury with severe hypophosphatemia), has been reported with the use of
tenofovir prodrugs in both animal toxicology studies and human trials. In
clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi
syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF
with EVG+COBI in treatment-naïve subjects and in virologically-suppressed
subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per
minute, renal serious adverse events or discontinuations due to renal adverse
reactions were encountered in less than 1% of participants treated with FTC+TAF
with EVG+COBI. In a study of virologically-suppressed subjects with baseline
eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a
median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued
due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR
between 30 and 50 mL per minute [see Adverse Reactions (6.1)]. Odefsey is not
recommended in patients with estimated creatinine clearance below 30 mL per
minute because data in this population are insufficient.
Patients taking
tenofovir prodrugs who have impaired renal function and those taking
nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at
increased risk of developing renal-related adverse reactions.
It is
recommended that serum creatinine, serum phosphorus, estimated creatinine
clearance, urine glucose and urine protein be assessed before initiating
Odefsey therapy and during therapy in all patients as clinically appropriate.
Discontinue Odefsey in patients who develop clinically significant decreases in
renal function or evidence of Fanconi syndrome.
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 emtricitabine, a
component of Odefsey, and tenofovir DF, another prodrug of tenofovir, alone or
in combination with other antiretrovirals. Treatment with Odefsey 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).
Adverse
Reactions
The following
adverse reactions are discussed in other sections of the labeling:
Severe
Acute Exacerbations of Hepatitis B [See Warnings
and Precautions (5.1)]Skin
and Hypersensitivity Reactions [See Warnings
and Precautions (5.2)]Depressive
Disorders [See Warnings
and Precautions (5.5)]Hepatotoxicity [See Warnings
and Precautions (5.6)]Immune
Reconstitution Syndrome [See Warnings
and Precautions (5.7)]New
Onset or Worsening Renal Impairment [see Warnings
and Precautions (5.8)]Lactic
Acidosis/Severe Hepatomegaly with Steatosis [See Warnings
and Precautions (5.9)]
Clinical Trials
Experience
Because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug (or a drug given in various
combinations with other concomitant therapy) cannot be directly compared to
rates in the clinical trials of another drug (or drug given in the same or
different combination therapy) and may not reflect the rates observed in
practice.
Adverse
Reactions in Clinical Trials of Odefsey in Virologically-Suppressed Adult
Subjects with HIV-1 Infection
The safety of
Odefsey in virologically-suppressed adults is based on Week 48 data from two
randomized, double-blinded, active-controlled clinical trials, 1160 and 1216,
that enrolled 1505 adult subjects who were virologically-suppressed for at
least 6 months. Both trials were designed to compare switching to Odefsey to
maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)
or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in
Trials 1160 and 1216, respectively. A total of 754 subjects received one tablet
of Odefsey daily [see Clinical Studies (14.1)].
The most common
adverse reactions (all Grades) reported in at least 2% of subjects in the
Odefsey group across Trials 1216 and 1160 were headache and sleep disturbances
(Table 1). Over 98% of the adverse reactions in the Odefsey group were of mild
to moderate intensity. The proportion of subjects who discontinued treatment
with Odefsey due to adverse events, regardless of severity, was 2% compared to
1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.
Table 1 Adverse Reactions* (All Grades) Reported in ≥1% of HIV-1 Infected
Virologically-Suppressed Adults in Trial 1160 or Trial 1216 (Week 48
analysis)
|
|
Adverse Reaction
|
Trial 1160
|
Trial 1216
|
|
|
Odefsey
(N=438)
|
EFV/FTC/TDF
(N=437)†
|
Odefsey
(N=316)
|
FTC/RPV/TDF
(N=313)†
|
|
*
a. Frequencies of adverse reactions are based on all
adverse events attributed to study drugs by the investigator.
†
Data from Trials
1160 and 1216 do not provide an adequate basis for comparison of adverse
reaction incidences between Odefsey and the FTC/RPV/TDF and EFV/FTC/TDF
groups.
|
|
Headache
|
2%
|
1%
|
0
|
1%
|
|
Flatulence
|
1%
|
<1%
|
<1%
|
1%
|
|
Sleep Disturbances
|
2%
|
1%
|
0
|
<1%
|
|
Abnormal Dreams
|
1%
|
1%
|
0
|
2%
|
|
Diarrhea
|
1%
|
3%
|
1%
|
2%
|
|
Nausea
|
1%
|
1%
|
1%
|
1%
|
Renal Laboratory
Tests
In Trial 1216,
the median baseline eGFR was104 mL per minute for subjects who switched to
Odefsey from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by
0.02 mg per dL from baseline to Week 48.
In Trial 1160,
the median baseline eGFR was 110 mL per minute for subjects who switched to
Odefsey from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by
0.1 mg per dL from baseline to Week 48.
Bone Mineral
Density Effects
Changes in BMD
from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry
(DXA) in Trials 1216 and 1160.
In Trial 1216,
mean bone mineral density (BMD) increased in subjects who switched to Odefsey
(1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in
subjects who remained on FTC/RPV/TDF (0.08% lumbar spine, –0.25% total hip).
BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of
Odefsey subjects and 3.0% of FTC/RPV/TDF subjects. BMD declines of 7% or
greater at the femoral neck were experienced by 0% of Odefsey subjects and 1.2%
of FTC/RPV/TDF subjects.
In Trial 1160,
mean BMD increased in subjects who switched to Odefsey (1.65% lumbar spine,
1.28% total hip) and decreased slightly in subjects who remained on EFV/FTC/TDF
(–0.05% lumbar spine, –0.13% total hip). BMD declines of 5% or greater at the
lumbar spine were experienced by 2.3% of Odefsey subjects and 4.9% of
EFV/FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were
experienced by 1.4% of Odefsey subjects and 3.3% of EFV/FTC/TDF subjects. The
long-term clinical significance of these BMD changes is not known.
Serum Lipids
Changes from baseline
in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and
total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.
Table 2 Lipid Values, Mean Change from Baseline
Reported in Subjects Receiving Odefsey, FTC/RPV/TDF and EFV/FTC/TDF in
Trials 1216 and 1160 at 48 Weeks
|
|
|
Trial 1216
|
Trial 1160
|
|
|
Odefsey
N=316
[n=235]
|
FTC/RPV/TDF
N=314
[n=245]
|
Odefsey
N=438
[n=295]
|
EFV/FTC/TDF
N=437
[n=308]
|
|
|
Baseline
|
Week 48
|
Baseline
|
Week 48
|
Baseline
|
Week 48
|
Baseline
|
Week 48
|
|
|
mg/dL
|
Change*,†
|
mg/dL
|
Change*,†
|
mg/dL
|
Change*,†
|
mg/dL
|
Change*,†
|
|
*
The change from baseline is the mean of within-subject
changes from baseline for subjects with both baseline and Week 48 values.
†
Subjects who received lipid-lowering agents during the
treatment period were excluded.
‡
[n=296] for
Odefsey group in Study 1160 for LDL-Cholesterol (fasted)
|
|
Total Cholesterol (fasted)
|
176
|
+17
|
171
|
0
|
193
|
-7
|
192
|
-3
|
|
HDL-Cholesterol (fasted)
|
50
|
+3
|
48
|
0
|
56
|
-4
|
55
|
-2
|
|
LDL-Cholesterol (fasted)
|
111
|
+13
|
108
|
+1
|
118‡
|
-1‡
|
119
|
-1
|
|
Triglycerides (fasted)
|
116
|
+12
|
119
|
-9
|
139
|
-12
|
133
|
+3
|
|
Total Cholesterol to HDL Ratio
|
3.7
|
+0.2
|
3.8
|
+0.1
|
3.7
|
+0.2
|
3.8
|
0
|
Adverse
Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve
Adult Subjects with HIV-1 Infection
In pooled
96-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects,
the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550)
(incidence greater than or equal to 2%, Grades 2−4) were headache, depressive
disorders, and insomnia. The proportion of subjects who discontinued treatment
with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The
most common adverse reactions that led to discontinuation in this treatment
group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety
profile was similar in virologically-suppressed adults with HIV-1 infection who
were switched to RPV and other antiretroviral drugs, the frequency of adverse
events increased by 20% (N=317).
Adverse
Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult
Subjects with HIV-1 Infection
In pooled
48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects,
the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI
(N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%).
In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI
due to adverse event [see Clinical Studies (14)]. Antiretroviral
treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced
mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7
mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.
Renal Laboratory
Tests
In two 48-week
trials in antiretroviral treatment-naïve HIV-1 infected adults treated with
FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute,
mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In a
24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per
minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5
mg per dL at both baseline and Week 24.
Bone Mineral
Density Effects
In the pooled
analysis of two 48-week trials of antiretroviral treatment-naïve HIV-1 infected
adult subjects, bone mineral density (BMD) from baseline to Week 48 was
assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from
baseline to Week 48 by −1.30% with FTC+TAF with EVG+COBI at the lumbar spine
and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine
were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7%
or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI
subjects. The long-term clinical significance of these BMD changes is not
known.
Adverse
Reactions in Clinical Trials in Pediatric Subjects with HIV-1 Infection
In an open-label
48-week trial of 36 antiretroviral treatment-naïve HIV-1 infected pediatric
subjects 12 to less than 18 years old (weighing at least 32 kg) treated with 25
mg per day of RPV and other antiretrovirals, the most common adverse reactions
were headache (19%), depression (19%), somnolence (14%), nausea (11%),
dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%).
In a 24-week,
open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric
subjects aged 12 to less than 18 years old (weighing at least 35 kg) who
received FTC+TAF with EVG+COBI, the safety of this combination was similar to
that of adults. Among these pediatric subjects, mean BMD increased from
baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body
less head. Mean changes from baseline BMD Z-scores were -0.10 for lumbar spine
and -0.11 for total body less head at Week 24. Two subjects had significant
(greater than 4%) lumbar spine BMD loss at Week 24.
Postmarketing
Experience
The following
adverse reactions have been identified during postmarketing experience in
patients receiving RPV-containing regimens. Because these 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.
Metabolism and
Nutrition Disorders
Weight increased
Skin and
Subcutaneous Tissue Disorders
Severe skin and
hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and
Systemic Symptoms)
Renal and
Urinary Disorders
Nephrotic
syndrome
Drug
Interactions
Potential for
Other Drugs to Affect One or More Components of Odefsey
Drugs that
Induce or Inhibit CYP3A Enzymes
RPV is primarily
metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the
clearance of RPV [see Clinical Pharmacology (12.3)].
Coadministration of RPV and drugs that induce CYP3A may result in decreased
plasma concentrations of RPV and loss of virologic response and possible
resistance to RPV or to the class of NNRTIs [see Contraindications
(4), Warnings and Precautions (5.3), and Table 3]. These drugs
are contraindicated and include:
·
the anticonvulsants carbamazepine, oxcarbazepine,
phenobarbital, phenytoin
·
the antimycobacterials rifampin and rifapentine
·
the glucocorticoid systemic dexamethasone (more than a
single dose)
·
St. John's wort (Hypericum
perforatum)
Coadministration
of RPV and drugs that inhibit CYP3A may result in increased plasma
concentrations of RPV and possible adverse events.
Drugs that
Induce or Inhibit P-glycoprotein
TAF, a component
of Odefsey, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that
strongly affect P-gp and BCRP activity may lead to changes in TAF
absorption (see Table 3). Drugs that
induce P-gp activity are expected to decrease the absorption of TAF, resulting
in decreased plasma concentration of TAF, which may lead to loss of therapeutic
effect of Odefsey and development of resistance. Coadministration of Odefsey
with other drugs that inhibit P-gp and BCRP may increase the absorption and
plasma concentration of TAF.
Drugs that
Increase Gastric pH
Coadministration
of RPV with drugs that increase gastric pH may decrease plasma concentrations
of RPV and lead to loss of virologic response and possible resistance to RPV or
to the class of NNRTIs. Use of RPV with proton pump inhibitors is
contraindicated and use of RPV with H2-receptor antagonists requires staggered
administration (see see Contraindications
(4) and Table 3).
QT Prolonging
Drugs
There is limited
information available on the potential for a pharmacodynamic interaction
between RPV and drugs that prolong the QTc interval. In a study of healthy
subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg
once daily (3 times and 12 times recommended daily dose in Odefsey) prolonged
the QTc interval [see Warnings and Precautions (5.4) and Clinical
Pharmacology (12.2)]. Consider alternative medications to
Odefsey in patients taking a drug with a known risk of Torsade de Pointes.
Drugs that
Affect Renal Function
Because FTC and
tenofovir are primarily excreted by the kidneys by a combination of glomerular
filtration and active tubular secretion, coadministration of Odefsey with drugs
that reduce renal function or compete for active tubular secretion may increase
concentrations of FTC, tenofovir, and other renally eliminated drugs and this
may increase the risk of adverse reactions. Some examples of drugs that are
eliminated by active tubular secretion include, but are not limited to,
acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir,
aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and
Precautions (5.8)].
Established and
Other Potentially Significant Drug Interactions
Table 3 provides
a listing of established or potentially clinically significant drug
interactions with recommended steps to prevent or manage the drug interaction
(the table is not all inclusive). The drug interactions described are based on
studies conducted with either Odefsey, the components of Odefsey (FTC, RPV and
TAF) as individual agents, or are predicted drug interactions that may occur
with Odefsey. For pharmacokinetic data, see Tables 7–10 [see Clinical
Pharmacology (12.3)].
Table 3 Established and Other Potentially Significant* Drug Interactions
|
|
Concomitant Drug Class: Drug Name
|
Effect on Concentration†
|
Clinical Comment
|
|
*
This table is not all inclusive.
†
Increase=↑; Decrease=↓; No Effect=↔
‡
The interaction was evaluated in a clinical study. All
other drug interactions shown are predicted.
§
This interaction
study has been performed with a dose higher than the recommended dose for
RPV. The dosing recommendation is applicable to the recommended dose of RPV
25 mg once daily.
|
|
Antacids:
antacids (e.g., aluminum, magnesium hydroxide, or calcium
carbonate)
|
↔ RPV
(antacids taken at least 2 hours before or at least 4 hours after RPV)
↓ RPV (concomitant intake)
|
Administer antacids at least 2 hours before or at least
4 hours after Odefsey.
|
|
Antimycobacterials:
rifabutin
|
↓ RPV‡
↓ TAF
|
Coadministration of Odefsey with rifabutin is not
recommended.
|
|
Azole Antifungal Agents:
fluconazole
itraconazole
ketoconazole
posaconazole
voriconazole
|
↑ RPV‡,§
↑ TAF
↓ ketoconazole‡,§
|
No dosage adjustment is required when Odefsey is
coadministered with azole antifungal agents. Clinically monitor for
breakthrough fungal infections when azole antifungals are coadministered with
Odefsey.
|
|
H2-Receptor Antagonists:
cimetidine
famotidine
nizatidine
ranitidine
|
↔ RPV‡,§
(famotidine taken 12 hours before RPV or 4 hours after RPV)
↓ RPV‡,§
(famotidine taken 2 hours before RPV)
|
Administer H2-receptor
antagonists at least 12 hours before or at least 4 hours after Odefsey.
|
|
Macrolide or Ketolide
Antibiotics:
clarithromycin
erythromycin
telithromycin
|
↑ RPV
↔ clarithromycin
↔ erythromycin
↔ telithromycin
|
Where possible, alternatives such as azithromycin
should be considered.
|
|
Narcotic Analgesics:
methadone
|
↓ R(–) methadone‡
↓ S(+) methadone‡
↔ RPV‡
↔ methadone‡(when used with tenofovir)
|
No dosage adjustments are required when initiating
coadministration of methadone with Odefsey. However, clinical monitoring is
recommended, as methadone maintenance therapy may need to be adjusted in some
patients.
|
Drugs Without
Clinically Significant Interactions with Odefsey
Based on drug
interaction studies conducted with the fixed dose combination or components of
Odefsey, no clinically significant drug interactions have been either observed
or expected when Odefsey is combined with the following drugs: acetaminophen,
atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol,
ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine,
norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir,
sofosbuvir, and velpatasvir.
USE IN SPECIFIC
POPULATIONS
Pregnancy
Pregnancy
Exposure Registry
There is a
pregnancy exposure registry that monitors pregnancy outcomes in women exposed
to Odefsey during pregnancy. Healthcare providers are encouraged to register
patients by calling the Antiretroviral Pregnancy Registry (APR) at
1-800-258-4263.
Risk Summary
There are
insufficient human data on the use of Odefsey during pregnancy to inform a
drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide
(TAF) use in women during pregnancy have not been evaluated; however,
emtricitabine (FTC) and rilpivirine (RPV) use during pregnancy has been
evaluated in a limited number of women reported to the APR. Available data from
the APR show no difference in the risk of overall major birth defects for FTC
and RPV compared with the background rate for major birth defects of 2.7% in a
US reference population of the Metropolitan Atlanta Congenital Defects Program
(MACDP). The rate of miscarriage is not reported in the APR. The estimated
background rate of miscarriage in the clinically recognized pregnancies in the
U.S. general population is 15–20%. Methodological limitations of the APR
include the use of MACDP as the external comparator group. The MACDP population
is not disease-specific, evaluates women and infants from a limited geographic
area, and does not include outcomes for births that occurred at <20 weeks
gestation.
In animal
studies, no adverse developmental effects were observed when the components of
Odefsey were administered separately during the period of organogenesis at
exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and
70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats
and rabbits, respectively; TAF) the exposure at the recommended daily dose of
these components in Odefsey [see Data (8.1)]. Likewise, no
adverse developmental effects were seen when FTC was administered to mice and
RPV was administered to rats through lactation at exposures up to approximately
60 and 63 times, respectively, the exposure at the recommended daily dose of
these components in Odefsey. No adverse effects were observed in the offspring
when TDF was administered through lactation at tenofovir exposures of
approximately 14 times the exposure at the recommended daily dosage of Odefsey.
Data
Human Data
Emtricitabine: Based on
prospective reports to the APR of 3406 exposures to FTC-containing regimens
during pregnancy (including 2326 exposed in the first trimester and 1080
exposed in the second/third trimester), there was no difference between FTC and
overall birth defects compared with the background birth defect rate of 2.7% in
the U.S. reference population of the MACDP. The prevalence of birth defects in
live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to
FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with second/third
trimester exposure to FTC-containing regimens.
Rilpivirine: Based on
prospective reports to the APR of 326 live births following exposures to
RPV-containing regimens during pregnancy (including 202 exposed in the first
trimester and 124 exposed in the second/third trimester), there was no
difference in the rate of overall birth defects for RPV compared with the
background rate of 2.7% for major birth defects in the U.S. reference
population of the MACDP. The prevalence of birth defects in live births was
0.5% (95% CI: 0.0% to 2.7%) with first trimester exposure to RPV-containing
regimens and 0.8% (95% CI: 0.0% to 4.4%) with second/third trimester exposure
to RPV-containing regimens.
Animal Data
Emtricitabine: FTC was
administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits
(100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6
through 15, and 7 through 19, respectively). No significant toxicological
effects were observed in embryo-fetal toxicity studies performed with FTC in
mice at exposures (AUC) approximately 60 times higher and in rabbits at
approximately 108 times higher than human exposures at the recommended daily
dose. In a pre/postnatal development study with FTC, mice were administered
doses up to 1000 mg/kg/day; no significant adverse effects directly related to
drug were observed in the offspring exposed daily from before birth (in utero) through sexual
maturity at daily exposures (AUC) of approximately 60-fold higher than human
exposures at the recommended daily dose.
Rilpivirine: RPV was
administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits
(5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17,
and 6 through 19, respectively). No significant toxicological effects were
observed in embryo-fetal toxicity studies performed with RPV in rats and
rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure
in humans at the recommended dose of 25 mg once daily. In a pre/postnatal
development study with RPV, where rats were administered up to 400 mg/kg/day
through lactation, no significant adverse effects directly related to drug were
noted in the offspring.
Tenofovir
Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250
mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on
gestation days 6 through 17, and 7 through 20, respectively). No adverse
embryo-fetal effects were observed in rats and rabbits at TAF exposures similar
to (rats) and approximately 53 (rabbits) times higher than the exposure in
humans at the recommended daily dose of Odefsey. TAF is rapidly converted to
tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats)
and 93 (rabbits) times higher than human tenofovir exposures at the recommended
daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir
exposure in rats and mice was observed after TAF administration compared to
tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir)
administration, a pre/postnatal development study in rats was conducted only
with TDF. Doses up to 600 mg/kg/day were administered through lactation, no
adverse effects were observed in the offspring on gestation day 7 [and
lactation day 20] at tenofovir exposures of approximately 14 [21] times higher
than the exposures in humans at the recommended daily dose of Odefsey.
Lactation
Risk Summary
The Centers for
Disease Control and Prevention recommend that HIV-infected mothers not
breastfeed their infants, to avoid risking postnatal transmission of HIV.
Based on
published data, FTC has been shown to be present in human breast milk; it is
unknown if RPV and TAF are present in human breast milk. RPV is present in rat
milk and tenofovir has been shown to be present in the milk of lactating rats
and rhesus monkeys after administration of TDF [see Data]. It is
unknown if TAF is present in animal milk.
It is not known
if Odefsey affects milk production or has effects on the breastfed infant.
Because of the potential for (1) HIV transmission (in HIV-negative infants),
(2) developing viral resistance (in HIV-positive infants), and (3) adverse
reactions in a breastfed infant similar to those seen in adults, instruct
mothers not to breastfeed if they are receiving Odefsey.
Data
Animal Data
Rilpivirine: In
animals, no studies have been conducted to assess the excretion of rilpivirine
directly; however RPV was measured in rat pups which were exposed through the
milk of treated dams (dosed up to 400 mg/kg/day).
Tenofovir
Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is
secreted in milk. Tenofovir was excreted into the milk of lactating rats
following oral administration of TDF (up to 600 mg/kg/day) at up to
approximately 24% of the median plasma concentration in the highest dosed
animals at lactation day 11 [see Data (8.1)]. Tenofovir
was excreted into the milk of lactating monkeys, following a single
subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to
approximately 4% of plasma concentration resulting in exposure (AUC) of
approximately 20% of plasma exposure.
Pediatric Use
The efficacy and
safety of Odefsey as a complete regimen for the treatment of HIV-1 infection
was established in pediatric patients 12 years of age and older with body
weight greater than or equal to 35 kg [see Dosage and
Administration (2.2)]. Use of Odefsey in this age group
is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults
with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with
EVG+COBI in adults with HIV-1 infection, and by the following pediatric
studies [see Clinical Studies (14)]:
48-week
open-label trial of 36 antiretroviral treatment-naïve HIV-1 infected
pediatric subjects 12 to less than 18 years old weighing at least 32 kg
treated with 25 mg per day of RPV and other antiretrovirals. The safety
and efficacy of RPV and other antiretrovirals was similar to that of
antiretroviral treatment-naïve HIV-1 infected adults on this regimen.24-week
open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected
pediatric subjects 12 to less than 18 years old (weighing at least 35 kg)
treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF
with EVG+COBI was similar to that of antiretroviral treatment-naïve HIV-1
infected adults on this regimen.
Because it is a
fixed-dose combination tablet, the dose of Odefsey cannot be adjusted for
patients of lower age and weight. The safety and efficacy of Odefsey have not
been established in pediatric patients less than 12 years of age or weighing
less than 35 kg [see Clinical Pharmacology (12.3)].
Geriatric Use
In clinical trials,
80 of the 97 subjects enrolled aged 65 years and over received FTC+TAF with
EVG+COBI. No differences in safety or efficacy have been observed between
elderly subjects and those between 12 and less than 65 years of age. Clinical
trials of RPV did not include sufficient numbers of subjects aged 65 years and
over to determine whether they respond differently from younger subjects [see Clinical
Pharmacology (12.3)].
Renal Impairment
Odefsey is not
recommended in patients with severe renal impairment (estimated creatinine
clearance below 30 mL per minute). No dosage adjustment of Odefsey is
recommended in patients with estimated creatinine clearance greater than or
equal to 30 mL per minute [see Dosage and Administration (2.2), Clinical
Pharmacology (12.3) and Clinical Studies
(14)].
Hepatic
Impairment
No dosage
adjustment of Odefsey is recommended in patients with mild (Child-Pugh Class A)
or moderate (Child-Pugh Class B) hepatic impairment. Odefsey has not been
studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical
Pharmacology (12.3)].
Overdosage
No data are
available on overdose of Odefsey in patients. If overdose occurs, monitor the
patient for evidence of toxicity. Treatment of overdose with Odefsey consists
of general supportive measures including monitoring of vital signs and ECG (QT
interval) as well as observation of the clinical status of the patient.
Emtricitabine
(FTC): Limited
clinical experience is available at doses higher than the recommended dosage of
FTC in Odefsey. In one clinical pharmacology study, single doses of FTC 1200 mg
(6 times the dose in Odefsey) were administered to 11 subjects. No severe
adverse reactions were reported. The effects of higher doses are not known.
Hemodialysis
treatment removes approximately 30% of the FTC dose over a 3-hour dialysis
period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per
minute and a dialysate flow rate of 600 mL per minute). It is not known whether
FTC can be removed by peritoneal dialysis.
Rilpivirine
(RPV): Human
experience of overdose with RPV is limited. There is no specific antidote for
overdose with RPV. Since RPV is highly bound to plasma protein, dialysis is
unlikely to result in significant removal of RPV.
Administration
of activated charcoal may be used to aid in removal of unabsorbed active
substance.
Tenofovir
Alafenamide (TAF): Limited clinical experience is available at doses
higher than the recommended dosage of TAF in Odefsey. A single dose of 125 mg
TAF (5 times the dose of TAF in Odefsey) was administered to 48 healthy
subjects; no serious adverse reactions were reported. The effects of higher
doses are unknown. Tenofovir is efficiently removed by hemodialysis with an
extraction coefficient of approximately 54%.
Odefsey
Description
Odefsey
(emtricitabine, rilpivirine, and tenofovir alafenamide) is a fixed-dose
combination tablet containing emtricitabine (FTC), rilpivirine (RPV), and
tenofovir alafenamide (TAF) for oral administration.
FTC,
a synthetic nucleoside analog of cytidine, is an HIV-1 nucleoside analog
reverse transcriptase inhibitor (HIV-1 NRTI).RPV
is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).TAF,
an HIV-1 NRTI, is converted in vivo to tenofovir, an acyclic nucleoside
phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
Each tablet
contains 200 mg of FTC, 25 mg of RPV (equivalent to 27.5 of rilpivirine
hydrochloride) and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide
fumarate) and the following inactive ingredients: croscarmellose sodium,
lactose monohydrate, magnesium stearate, microcrystalline cellulose,
polysorbate 20, and povidone. The tablets are film-coated with a coating
material containing iron oxide black, polyethylene glycol, polyvinyl alcohol,
talc, and titanium dioxide.
Emtricitabine: The
chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one.
FTC 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.
FTC has a
molecular formula of C8H10FN3O3S and a
molecular weight of 247.24 and has the following structural formula:
FTC is a white
to off-white powder with a solubility of approximately 112 mg per mL in water
at 25 °C.
Rilpivirine: The
chemical name of rilpivirine hydrochloride drug substance is
4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
monohydrochloride. Its molecular formula is C22H18N6 ∙ HCl and
its molecular weight is 402.88. Rilpivirine hydrochloride has the following
structural formula:
Rilpivirine
hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is
practically insoluble in water over a wide pH range.
Tenofovir
Alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance
is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,
1-methylethyl ester, (2E)-2-butenedioate (2:1).
Tenofovir
alafenamide fumarate has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula
weight of 534.50 and has the following structural formula:
Tenofovir
alafenamide fumarate is a white to off-white or tan powder with a solubility of
4.7 mg per mL in water at 20 °C.
Odefsey -
Clinical Pharmacology
Mechanism of
Action
Odefsey is a
fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and
tenofovir alafenamide [see Microbiology (12.4)].
Pharmacodynamics
Cardiac
Electrophysiology
When higher than
recommended RPV doses of 75 mg (3 times the recommended dosage in Odefsey) once
daily and 300 mg (12 times the recommended dosage in Odefsey) once daily were
studied in healthy adults, the maximum mean time-matched (95% upper confidence
bound) differences in QTcF interval from placebo after baseline correction were
10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state
administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean
steady-state Cmax approximately 2.6 times and 6.7 times,
respectively, higher than the mean Cmaxobserved with the recommended 25 mg once
daily dose of RPV [see Warnings and Precautions (5.4)].
The effect of
RPV at the recommended dose of 25 mg once daily on the QTcF interval was
evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once
daily) controlled crossover study in 60 healthy adults, with 13 measurements over
24 hours at steady state. The maximum mean time-matched (95% upper confidence
bound) differences in QTcF interval from placebo after baseline correction was
2 (5) milliseconds (i.e., below the threshold of clinical concern).
In a thorough
QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose
approximately 5 times the recommended dose, did not affect the QT/QTc interval
and did not prolong the PR interval.
The effect of
FTC on the QT interval is not known.
Pharmacokinetics
Absorption,
Distribution, Metabolism, and Excretion
The
pharmacokinetic properties of the components of Odefsey are provided in Table
4. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its
metabolite tenofovir are provided in Table 5.
Table 4 Pharmacokinetic Properties of the Components
of Odefsey
|
|
|
Rilpivirine
|
Emtricitabine
|
Tenofovir Alafenamide
|
|
PBMCs = peripheral blood mononuclear cells; CES1 =
carboxylesterase 1.
|
|
*
Values refer to geometric mean ratio [fed/ fasted] in
PK parameters and (90% confidence interval). High-calorie/high-fat meal =
~800 kcal, 50% fat. Moderate-fat meal = ~600 kcal, 27% fat.
†
In vivo, TAF is hydrolyzed within cells to form
tenofovir (major metabolite), which is phosphorylated to the active
metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is
metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1
in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe
efavirenz, TAF exposure was unaffected.
‡
t1/2 values refer to median
terminal plasma half-life. Note that the pharmacologically active metabolite,
tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs.
§
Dosing in mass
balance studies: FTC (single dose administration of [14C] emtricitabine
after multiple dosing of emtricitabine for ten days); TAF (single dose
administration of [14C] tenofovir alafenamide).
|
|
Absorption
|
|
Tmax (h)
|
4
|
3
|
1
|
|
Effect of moderate fat meal (relative to fasting)*
|
AUC Ratio = 1.13 (1.03, 1.23)
|
AUC Ratio = 0.91 (0.89, 0.93)
|
AUC Ratio = 1.45 (1.33, 1.58)
|
|
Effect of high fat meal (relative to fasting)*
|
AUC Ratio = 1.72 (1.49, 1.99)
|
AUC Ratio = 0.88 (0.85, 0.90)
|
AUC Ratio = 1.53 (1.39, 1.69)
|
|
Distribution
|
|
% Bound to human plasma proteins
|
~99
|
<4
|
~80
|
|
Source of protein binding data
|
In vitro
|
In vitro
|
Ex vivo
|
|
Blood-to-plasma ratio
|
0.7
|
0.6
|
1.0
|
|
Metabolism
|
|
Metabolism
|
CYP3A
|
Not significantly metabolized
|
Cathepsin A† (PBMCs)
CES1 (hepatocytes)
CYP3A (minimal)
|
|
Elimination
|
|
Major route of elimination
|
Metabolism
|
Glomerular filtration and active tubular secretion
|
Metabolism (>80% of oral dose)
|
|
t1/2 (h)‡
|
50
|
10
|
0.51
|
|
% Of dose excreted in urine§
|
6
|
70
|
<1
|
|
% Of dose excreted in feces§
|
85
|
13.7
|
31.7
|
Table 5 Multiple Dose Pharmacokinetic Parameters of
Emtricitabine, Rilpivirine, Tenofovir Alafenamide and its Metabolite
Tenofovir Following Oral Administration with a Meal in HIV-Infected Adults
|
|
Parameter
Mean (CV%)
|
Emtricitabine*
|
Rilpivirine†
|
Tenofovir Alafenamide‡
|
Tenofovir§
|
|
CV = Coefficient of Variation; NA = Not Applicable
|
|
*
From Intensive PK analysis in a phase 2 trial in HIV
infected adults treated with FTC+TAF with EVG+COBI (n=19).
†
From Population PK analysis in a trial of
treatment-naïve adults with HIV-1 infection treated with RPV (n=679).
‡
From Population PK analysis in two trials of
treatment-naïve adults with HIV-1 infection treated within EVG+COBI+FTC+TAF
(n=539).
§
From Population
PK analysis in two trials of treatment-naïve adults with HIV-1 infection
treated with EVG+COBI+FTC+TAF (n=841).
|
|
Cmax
(microgram per mL)
|
2.1 (20.2)
|
NA
|
0.16 (51.1)
|
0.02 (26.1)
|
|
AUCtau
(microgram∙hour per mL)
|
11.7 (16.6)
|
2.2 (38.1)
|
0.21 (71.8)
|
0.29 (27.4)
|
|
Ctrough
(microgram per mL)
|
0.10 (46.7)
|
0.08 (44.3)
|
NA
|
0.01 (28.5)
|
|
|
|
|
|
|
|
Specific
Populations
Patients with
Renal Impairment
Rilpivirine: Population
pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1
infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method
relative to HIV-1 infected subjects with normal renal function. There is
limited or no information regarding the pharmacokinetics of RPV in patients
with moderate or severe renal impairment or in patients with end-stage renal
disease [see Use in Specific Populations (8.6)].
Tenofovir
Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected
subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault
method) were evaluated within a subset of virologically-suppressed subjects in
an open-label trial (Table 6).
Table 6 Pharmacokinetics of the FTC, TAF, and a
Metabolite of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment
as Compared to Subjects with Normal Renal Function
|
|
|
AUCtau (microgram-hour per mL)
Mean (CV%)
|
|
Creatinine Clearance
|
≥90 mL per minute (N=18)*
|
60–89 mL per minute (N=11)†
|
30–59 mL per minute (N=18)
|
|
*
From a phase 2 trial in HIV-infected adults with normal
renal function treated with FTC+TAF with EVG+COBI.
†
These subjects had an eGFR ranging from 60 to 69 mL per
minute.
‡
AUClast
|
|
Emtricitabine
|
11.4 (11.9)
|
17.6 (18.2)
|
23.0 (23.6)
|
|
Tenofovir Alafenamide‡
|
0.23 (47.2)
|
0.24 (45.6)
|
0.26 (58.8)
|
|
Tenofovir
|
0.32 (14.9)
|
0.46 (31.5)
|
0.61 (28.4)
|
Patients with
Hepatic Impairment
Emtricitabine: The
pharmacokinetics of FTC have not been studied in subjects with hepatic
impairment; however, FTC is not significantly metabolized by liver enzymes, so
the impact of hepatic impairment should be limited.
Rilpivirine: In a study
comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8
matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh
score B) to 8 matched controls, the multiple-dose exposure of RPV was 47%
higher in subjects with mild hepatic impairment and 5% higher in subjects with
moderate hepatic impairment [see Use in Specific Populations (8.7)].
Tenofovir
Alafenamide: Clinically relevant changes in the pharmacokinetics of tenofovir
alafenamide or its metabolite tenofovir were not observed in subjects with
mild, moderate, (Child-Pugh A and B) or severe hepatic impairment (Child-Pugh
C) [see Use in Specific Populations (8.7)].
Hepatitis B
and/or Hepatitis C Virus Coinfection
The
pharmacokinetics of FTC and TAF have not been fully evaluated in subjects
coinfected with hepatitis B and/or C virus. Population pharmacokinetic analysis
indicated that hepatitis B and/or C virus coinfection had no clinically
relevant effect on the exposure of RPV.
Pediatric
Patients
Exposures of TAF
in 24 pediatric subjects with HIV-1 infection aged 12 to less than 18 years who
received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to
exposures achieved in treatment-naïve adults following administration of
FTC+TAF with EVG+COBI. These exposure differences are not thought to be
clinically significant based on exposure-response relationships. FTC exposures
were similar in adolescents compared to treatment-naïve adults. The PK of RPV
in antiretroviral HIV-1-infected pediatric subjects 12 to less than 18 years of
age who received RPV 25 mg once daily were comparable to those in HIV-1
infected adults. As in adults, there was no impact of body weight on RPV PK in
pediatric subjects [see Use In Specific Populations (8.4)].
Geriatric
Patients
The
pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly
(65 years of age and older). Population pharmacokinetics analysis of
HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF with EVG+COBI
showed that age did not have a clinically relevant effect on exposures of TAF
up to 75 years of age.
The
pharmacokinetics of RPV have not been fully evaluated in the elderly (65 years
of age and older) [see Use in Specific Populations (8.5)].
Race
Based on
population pharmacokinetic analyses, no dosage adjustment is recommended based
on race.
Gender
Based on
population pharmacokinetic analyses, no dosage adjustment is recommended based
on gender.
Drug Interaction
Studies
Rilpivirine: RPV is
primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus
affect the clearance of RPV.
RPV at a dose of
25 mg once daily is not likely to have a clinically relevant effect on the
exposure of medicinal products metabolized by CYP enzymes.
TAF is not an
inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is
a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A
in vivo.
The drug
interaction studies described in Tables 7–10 were conducted with Odefsey
(FTC/RPV/TAF) or the components of Odefsey (FTC, RPV, or TAF) administered
individually.
The effects of
coadministered drugs on the exposures of RPV and TAF are shown in Tables 7 and
8, respectively. The effects of RPV and TAF on the exposure of coadministered
drugs are shown in Tables 9 and 10, respectively. For information regarding
clinical recommendations, see Drug Interactions (7).
Table 7 Changes in Pharmacokinetic Parameters for RPV
in the Presence of Coadministered Drugs in Healthy Subjects
|
|
|
Coadministered Drug
|
Dose/Schedule
|
N
|
Mean Ratio of RPV
Pharmacokinetic Parameters With/Without Coadministered Drug (90% CI);
No Effect = 1.00
|
|
|
Coadministered Drug (mg)
|
RPV (mg)
|
Cmax
|
AUC
|
Cmin
|
|
|
CI=Confidence Interval; N=maximum number of subjects
with data; NA=Not Available; ↔=no change
|
|
|
*
25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times
the recommended dose of RPV in Odefsey, respectively.
†
Comparison based on historic controls.
‡
Study conducted with Odefsey (FTC/RPV/TAF).
§
Study conducted
with FTC/RPV/TDF.
|
|
|
Acetaminophen
|
500 single dose
|
150 once daily*
|
16
|
1.09
(1.01, 1.18)
|
1.16
(1.10, 1.22)
|
1.26
(1.16, 1.38)
|
|
|
Atorvastatin
|
40 once daily
|
150 once daily*
|
16
|
0.91
(0.79, 1.06)
|
0.90
(0.81, 0.99)
|
0.90
(0.84, 0.96)
|
|
|
Chlorzoxazone
|
500 single dose taken 2 hours after RPV
|
150 once daily*
|
16
|
1.17
(1.08, 1.27)
|
1.25
(1.16, 1.35)
|
1.18
(1.09, 1.28)
|
|
|
Ethinylestradiol/Norethindrone
|
0.035 once daily /1 mg once daily
|
25 once daily
|
15
|
↔†
|
↔†
|
↔†
|
|
|
Famotidine
|
40 single dose
taken 12 hours before RPV
|
150 single dose*
|
24
|
0.99
(0.84, 1.16)
|
0.91
(0.78, 1.07)
|
NA
|
|
|
Famotidine
|
40 single dose
taken 2 hours before RPV
|
150 single dose*
|
23
|
0.15
(0.12, 0.19)
|
0.24
(0.20, 0.28)
|
NA
|
|
|
Famotidine
|
40 single dose
taken 4 hours after RPV
|
150 single dose*
|
24
|
1.21
(1.06, 1.39)
|
1.13
(1.01, 1.27)
|
NA
|
|
|
Ketoconazole
|
400 once daily
|
150 once daily*
|
15
|
1.30
(1.13, 1.48)
|
1.49
(1.31, 1.70)
|
1.76
(1.57,
1.97)
|
|
|
Methadone
|
60–100 once daily,
individualized dose
|
25 once daily
|
12
|
↔†
|
↔†
|
↔†
|
|
|
Ledipasvir/Sofosbuvir‡
|
90/400 once daily
|
25 once daily
|
42
|
0.97
(0.92, 1.02)
|
0.95
(0.91, 0.98)
|
0.93
(0.89, 0.97)
|
|
|
Omeprazole
|
20 once daily
|
25 single dose
|
15
|
0.30
(0.24, 0.38)
|
0.35
(0.28, 0.44)
|
NA
|
|
|
Rifabutin
|
300 once daily
|
25 once daily
|
18
|
0.69
(0.62, 0.76)
|
0.58
(0.52, 0.65)
|
0.52
(0.46, 0.59)
|
|
|
Rifampin
|
600 once daily
|
150 once daily*
|
16
|
0.31
(0.27, 0.36)
|
0.20
(0.18, 0.23)
|
0.11
(0.10, 0.13)
|
|
|
Simeprevir
|
25 once daily
|
150 once daily
|
23
|
1.04
(0.95, 1.30)
|
1.12
(1.05, 1.19)
|
1.25
(1.16, 1.35)
|
|
|
Sildenafil
|
50 single dose
|
75 once daily*
|
16
|
0.92
(0.85, 0.99)
|
0.98
(0.92, 1.05)
|
1.04
(0.98, 1.09)
|
|
|
Sofosbuvir/ velpatasvir
|
400/100 once daily
|
10 once daily§
|
24
|
0.93
(0.88,0.98)
|
0.95
(0.90, 1.00)
|
0.96
(0.90,1.03)
|
|
Table 8 Changes in Pharmacokinetic Parameters for TAF
in the Presence of the Coadministered Drug* in Healthy Subjects
|
|
|
Coadministered Drug
|
Dose of Coadministered Drug
(mg)
|
TAF (mg)
|
N
|
Mean Ratio of Tenofovir
Alafenamide Pharmacokinetic
Parameters (90% CI);
No Effect = 1.00
|
|
|
Cmax
|
AUC
|
Cmin
|
|
|
CI=Confidence Interval; N=maximum number of subjects
with data; NC=Not Calculated
|
|
|
*
All interaction studies conducted in healthy
volunteers.
†
Increases TAF exposure via inhibition of intestinal
P-glycoprotein.
‡
Study conducted
with Odefsey (FTC/RPV/TAF).
|
|
|
Cobicistat†
|
150 once daily
|
8 once daily
|
12
|
2.83
(2.20, 3.65)
|
2.65
(2.29, 3.07)
|
NC
|
|
|
Ledipasvir/Sofosbuvir‡
|
90/400 once daily
|
25 once daily
|
42
|
1.03
(0.94, 1.14)
|
1.32
(1.25, 1.40)
|
NC
|
|
|
|
|
|
|
|
|
|
|
|
|
Table 9 Changes in Pharmacokinetic Parameters for
Coadministered Drugs in the Presence of RPV in Healthy Subjects
|
|
|
Coadministered Drug
|
Dose/Schedule
|
N
|
Mean Ratio of Coadministered
Drug
Pharmacokinetic Parameters With/Without RPV (90% CI);
No Effect = 1.00
|
|
|
Coadministered Drug (mg)
|
RPV (mg)
|
Cmax
|
AUC
|
Cmin
|
|
|
CI=Confidence Interval; N=maximum number of subjects
with data; NA=Not Available
|
|
|
*
25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times
the recommended dose of RPV in Odefsey, respectively.
†
AUC(0–last)
‡
Study conducted with Odefsey (FTC/RPV/TAF).
§
The predominant circulating nucleoside metabolite of
sofosbuvir.
¶
N (maximum number of subjects with data for AUC(0–∞)=15)
#
Study conducted
with FTC/RPV/TDF.
|
|
|
Acetaminophen
|
500 single dose
|
150 once daily*
|
16
|
0.97
(0.86, 1.10)
|
0.92
(0.85, 0.99)
|
NA
|
|
|
Atorvastatin
|
40 once daily
|
150 once daily *
|
16
|
1.35
(1.08, 1.68)
|
1.04
(0.97, 1.12)
|
0.85
(0.69, 1.03)
|
|
|
2-hydroxy-atorvastatin
|
1.58
(1.33, 1.87)
|
1.39
(1.29, 1.50)
|
1.32
(1.10, 1.58)
|
|
|
4-hydroxy-atorvastatin
|
1.28
(1.15, 1.43)
|
1.23
(1.13, 1.33)
|
NA
|
|
|
Chlorzoxazone
|
500 single dose
taken 2 hours after RPV
|
150 once daily*
|
16
|
0.98
(0.85, 1.13)
|
1.03
(0.95, 1.13)
|
NA
|
|
|
Digoxin
|
0.5 single dose
|
25 once daily
|
22
|
1.06
(0.97, 1.17)
|
0.98
(0.93, 1.04)†
|
NA
|
|
|
Ethinylestradiol
|
0.035 once daily
|
25 once daily
|
17
|
1.17
(1.06, 1.30)
|
1.14
(1.10, 1.19)
|
1.09
(1.03, 1.16)
|
|
|
Norethindrone
|
1 mg once daily
|
0.94
(0.83, 1.06)
|
0.89
(0.84, 0.94)
|
0.99
(0.90, 1.08)
|
|
|
Ketoconazole
|
400 once daily
|
150 once daily*
|
14
|
0.85
(0.80, 0.90)
|
0.76
(0.70, 0.82)
|
0.34
(0.25, 0.46)
|
|
|
Ledipasvir
|
90 once daily
|
25 once daily‡
|
41
|
1.01
(0.97, 1.05)
|
1.02
(0.97, 1.06)
|
1.02
(0.98, 1.07)
|
|
|
Sofosbuvir
|
400 once daily
|
25 once daily‡
|
41
|
0.96
(0.89, 1.04)
|
1.05
(1.01, 1.09)
|
NA
|
|
|
GS-331007§
|
1.08
(1.05, 1.11)
|
1.08
(1.06, 1.10)
|
1.10
(1.07, 1.12)
|
|
|
R(-) methadone
|
60–100 once daily, individualized dose
|
25 once daily
|
13
|
0.86
(0.78, 0.95)
|
0.84
(0.74, 0.95)
|
0.78
(0.67, 0.91)
|
|
|
S(+) methadone
|
0.87
(0.78, 0.97)
|
0.84
(0.74, 0.96)
|
0.79
(0.67, 0.92)
|
|
|
Metformin
|
850 single dose
|
25 once daily
|
20
|
1.02
(0.95, 1.10)
|
0.97
(0.90,1.06)¶
|
NA
|
|
|
Rifampin
|
600 once daily
|
150 once daily*
|
16
|
1.02
(0.93, 1.12)
|
0.99
(0.92, 1.07)
|
NA
|
|
|
25-desacetylrifampin
|
1.00
(0.87, 1.15)
|
0.91
(0.77, 1.07)
|
NA
|
|
|
Simeprevir
|
150 once daily
|
25 once daily
|
21
|
1.10
(0.97, 1.26)
|
1.06
(0.94, 1.19)
|
0.96
(0.83, 1.11)
|
|
|
Sildenafil
|
50 single dose
|
75 once daily*
|
16
|
0.93
(0.80, 1.08)
|
0.97
(0.87, 1.08)
|
NA
|
|
|
N-desmethyl-sildenafil
|
0.90
(0.80, 1.02)
|
0.92
(0.85, 0.99)†
|
NA
|
|
|
Sofosbuvir
|
400 once daily
|
25 once daily#
|
24
|
1.09
(0.95, 1.25)
|
1.16
(1.10, 1.24)
|
NA
|
|
|
GS-331007§
|
0.96
(0.90, 1.01)
|
1.04
(1.00, 1.07)
|
1.12
(1.07, 1.17)
|
|
|
Velpatasvir
|
100 once daily
|
25 once daily#
|
24
|
0.96
(0.85, 1.10)
|
0.99
(0.88, 1.11)
|
1.02
(0.91, 1.15)
|
|
Table 10 Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of TAF in Healthy Subjects
|
|
|
Coadministered Drug
|
Dose of Coadministered Drug
(mg)
|
TAF (mg)
|
N
|
Mean Ratio of Coadministered
Drug Pharmacokinetic Parameters (90% CI);
No Effect = 1.00
|
|
|
Cmax
|
AUC
|
Cmin
|
|
|
CI=Confidence Interval; N=maximum number of subjects
with data; NC=Not Calculated
|
|
|
*
A sensitive CYP3A4 substrate.
†
Study conducted with Odefsey (FTC/RPV/TAF).
‡
The predominant circulating nucleoside metabolite of
sofosbuvir.
§
Study conducted
with FTC/TAF.
|
|
|
Midazolam*
|
2.5 single dose, orally
|
25 once daily
|
18
|
1.02
(0.92, 1.13)
|
1.13
(1.04, 1.23)
|
NC
|
|
|
1 single dose, IV
|
0.99
(0.89, 1.11)
|
1.08
(1.04, 1.13)
|
NC
|
|
|
Ledipasvir†
|
90/400 once daily
|
25 once daily
|
41
|
1.01
(0.97, 1.05)
|
1.02
(0.97, 1.06)
|
1.02
(0.98,1.07)
|
|
|
Sofosbuvir†
|
0.96
(0.89, 1.04)
|
1.05
(1.01, 1.09)
|
NC
|
|
|
GS-331007†,‡
|
1.08
(1.05, 1.11)
|
1.08
(1.06, 1.10)
|
1.10 (1.07, 1.12)
|
|
|
Norelgestromin
|
norgestimate 0.180/0.215/0.250 once daily/ethinyl
estradiol 0.025 once daily
|
25 once daily§
|
29
|
1.17
(1.07,1.26)
|
1.12
(1.07, 1.17)
|
1.16
(1.08,1.24)
|
|
|
Norgestrel
|
1.10
(1.02, 1.18)
|
1.09
(1.01, 1.18)
|
1.11
(1.03,1.20)
|
|
|
Ethinyl estradiol
|
1.22
(1.15, 1.29)
|
1.11
(1.07, 1.16)
|
1.02 (0.93,1.12)
|
|
|
|
|
|
|
|
|
|
|
|
|
Microbiology
Mechanism of
Action
Emtricitabine: FTC, 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 polymerases α, β, Ɛ, and mitochondrial DNA
polymerase γ.
Rilpivirine: RPV is a
diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and
inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does
not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA
polymerase γ.
Tenofovir
Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine
monophosphate analog). Plasma exposure to TAF allows for permeation into cells
and then TAF is intracellularly converted to tenofovir through hydrolysis by
cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to
the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1
replication through incorporation into viral DNA by the HIV reverse
transcriptase, which results in DNA chain termination.
Tenofovir has
activity against human immunodeficiency virus (HIV-1). Cell culture studies
have shown that both tenofovir and FTC can be fully phosphorylated when
combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA
polymerases that include mitochondrial DNA polymerase γ and there is no
evidence of toxicity to mitochondria cell culture.
Antiviral
Activity in Cell Culture
Emtricitabine,
Rilpivirine, and Tenofovir Alafenamide: The combinations of FTC, RPV, and
TAF were not antagonistic with each other in cell culture combination antiviral
activity assays. In addition, FTC, RPV, and TAF were not antagonistic with a
panel of representatives from the major classes of approved anti-HIV agents
(NNRTIs, NRTIs, INSTIs, and PIs).
Emtricitabine: The
antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was
assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary
peripheral blood mononuclear cells (PBMCs). The EC50 values for
FTC were in the range of 0.0013–0.64 microM. FTC displayed antiviral activity
in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values
ranged from 0.007–0.075 microM) and showed strain-specific activity against
HIV-2 (EC50 values ranged from 0.007–1.5 microM).
Rilpivirine: RPV
exhibited activity against laboratory strains of wild-type HIV-1 in an acutely
infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73
nM. RPV demonstrated limited activity in cell culture against HIV-2 with a
median EC50 value of 5220 nM (range 2510–10,830 nM). RPV
demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype
A, B, C, D, F, G, H) primary isolates with EC50 values
ranging from 0.07–1.01 nM and was less active against group O primary isolates
with EC50 values ranging from 2.88–8.45 nM.
Tenofovir
Alafenamide: The antiviral activity of TAF against laboratory and clinical
isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs,
primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for
TAF ranged from 2.0–14.7 nM.
TAF displayed
antiviral activity in cell culture against all HIV-1 groups (M, N, O),
including sub-types A, B, C, D, E, F, and G (EC50 values
ranged from 0.10–12.0 nM) and strain specific activity against HIV-2 (EC50 values
ranged from 0.91–2.63 nM).
Resistance
In Cell Culture
Emtricitabine: HIV-1
isolates with reduced susceptibility to FTC were selected in cell culture.
Reduced susceptibility to FTC was associated with M184V or I substitutions in
HIV-1 RT.
Rilpivirine: RPV-resistant
strains were selected in cell culture starting from wild-type HIV-1 of
different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently
observed amino acid substitutions that emerged and conferred decreased
phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I,
E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and
M230I and L.
Tenofovir
Alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in
cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in
HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in
addition, a K70E substitution in HIV-1 RT was observed.
In Clinical
Trials
In
HIV-1-Infected Subjects With No Antiretroviral Treatment History
Emtricitabine
and Tenofovir Alafenamide: The resistance profile of Odefsey for the treatment
of HIV-1 infection is based on studies of FTC+TAF with EVG+COBI in the
treatment of HIV-1 infection. In a pooled analysis of
antiretroviral-naïve subjects, genotyping was performed on plasma HIV-1
isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at
confirmed virologic failure, at Week 48, or at time of early study drug
discontinuation. Genotypic resistance developed in 7 of 14 evaluable subjects.
The resistance–associated substitutions that emerged were M184V/I (N=7) and
K65R (N=1). Three subjects had virus with emergent R, H, or E at the
polymorphic Q207 residue in reverse transcriptase.
Rilpivirine: In the
Week 96 pooled resistance analysis for adult subjects receiving RPV or
efavirenz in combination with FTC/TDF, the emergence of resistance was greater
among subjects' viruses in the RPV+FTC/TDF arm compared to the efavirenz +
FTC/TDF arm and was dependent on baseline viral load. In the Week 96 resistance
analysis, 14% (77/550) of the subjects in the RPV+FTC/TDF arm and 8% (43/546)
of the subjects in the efavirenz + FTC/TDF arm qualified for resistance
analysis; 61% (47/77) of the subjects who qualified for resistance analysis
(resistance-analysis subjects) in the RPV+FTC/TDF arm had virus with genotypic
and/or phenotypic resistance to RPV compared to 42% (18/43) of the
resistance-analysis subjects in the efavirenz + FTC/TDF arm who had genotypic
and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or
phenotypic resistance to emtricitabine or tenofovir emerged in viruses from 57%
(44/77) of the resistance-analysis subjects in the RPV arm compared to 26%
(11/43) in the efavirenz arm.
Emerging NNRTI
substitutions in the RPV resistance analysis of subjects' viruses included
V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and
M230L, which were associated with an RPV phenotypic fold change range of
2.6–621. The E138K substitution emerged most frequently during RPV treatment,
commonly in combination with the M184I substitution. The emtricitabine and
lamivudine resistance-associated substitutions M184I or V and NRTI
resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F,
K219E/R) emerged more frequently in the RPV resistance-analysis subjects than
in efavirenz resistance-analysis subjects.
NNRTI- and
NRTI-resistance substitutions emerged less frequently in the resistance
analysis of viruses from subjects with baseline viral loads of less than or
equal to 100,000 copies/mL compared to viruses from subjects with baseline
viral loads of greater than 100,000 copies/mL: 23% (10/44) compared to 77%
(34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80%
(35/44) of NRTI-resistance substitutions. This difference was also observed for
the individual emtricitabine/lamivudine and tenofovir resistance substitutions:
22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100%
(8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions
emerged less frequently in the resistance analysis of the viruses from subjects
with baseline CD4+ cell counts greater than or equal to 200 cells/mm3 compared
to the viruses from subjects with baseline CD4+ cell counts less than 200
cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance
substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance
substitutions.
In
Virologically-Suppressed Subjects
Emtricitabine
and Tenofovir Alafenamide: One subject was identified with emergent resistance
to FTC or TAF (M184M/I) out of 4 virologic failure subjects in a clinical study
of virologically-suppressed subjects who switched from a regimen containing
FTC+TDF to FTC+TAF with EVG+COBI (N=799).
Rilpivirine: Through
Week 48, 4 subjects who switched their protease inhibitor-based regimen to FTC/RPV/TDF
(4 of 469 subjects, 0.9%) and 1 subject who maintained their regimen (1 of 159
subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study
drug. All 4 of the subjects who had resistance emergence on FTC/RPV/TDF had
evidence of FTC resistance and 3 of the subjects had evidence of RPV
resistance.
Odefsey: Through
Week 48, in subjects who switched to Odefsey from FTC/RPV/TDF or EFV/FTC/TDF
(Trials 1216 (N=316) and 1160 (N=438), respectively), of seven subjects who
developed virologic failure, three subjects had detectable NNRTI and/or NRTI
resistance substitutions at virologic failure that were pre-existing in the
baseline sample by proviral DNA sequencing; one of these subjects resuppressed
while maintaining Odefsey.
Cross-Resistance
Emtricitabine: FTC-resistant
viruses with the M184V/I substitution were cross-resistant to lamivudine, but
retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.
Viruses
harboring substitutions conferring reduced susceptibility to stavudine and
zidovudine—thymidine analog substitutions (M41L, D67N, K70R, L210W, T215Y/F,
K219Q/E), or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the
K103N substitution or other substitutions associated with resistance to NNRTIs
was susceptible to FTC.
Rilpivirine: Considering
all of the available cell culture and clinical data, any of the following amino
acid substitutions, when present at baseline, are likely to decrease the
antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q,
V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the
combination of L100I+K103N.
Cross-resistance
in site-directed mutant virus has been observed among NNRTIs. The single NNRTI
substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12
times decreased susceptibility to RPV, respectively. The combination of E138K
and M184I showed 6.7 times reduced susceptibility to RPV compared to 2.8 times
for E138K alone. The K103N substitution did not show reduced susceptibility to
RPV by itself. However, the combination of K103N and L100I resulted in a 7
times reduced susceptibility to RPV. In another study, the Y188L substitution
resulted in a reduced susceptibility to RPV of 9 times for clinical isolates
and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI
resistance-associated substitutions gave decreased susceptibility to RPV (fold
change range of 3.7–554) in 38% and 66% of mutants, respectively.
Cross-resistance
to efavirenz, etravirine, and/or nevirapine is likely after virologic failure
and development of RPV resistance.
Tenofovir
Alafenamide: Tenofovir resistance substitutions K65R and K70E result in reduced
susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and
tenofovir.
HIV-1 with
multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y,
K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion
mutation or with a Q151M substitution complex including K65R showed reduced
susceptibility to TAF in cell culture.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Emtricitabine: In
long-term carcinogenicity studies of FTC, no drug-related increases in tumor
incidence were found in mice at doses up to 750 mg per kg per day (23 times the
human systemic exposure at the recommended dose of 200 mg per day in Odefsey)
or in rats at doses up to 600 mg per kg per day (28 times the human systemic
exposure at the recommended dose in Odefsey).
FTC was not
genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or
mouse micronucleus assays.
FTC did not
affect fertility in male rats at approximately 140 times or in male and female
mice at approximately 60 times higher exposures (AUC) than in humans given the
recommended 200 mg daily dose in Odefsey. Fertility was normal in the offspring
of mice exposed daily from before birth (in utero) through sexual maturity at
daily exposures (AUC) of approximately 60 times higher than human exposures at
the recommended 200 mg daily dose in Odefsey.
Rilpivirine: RPV was
evaluated for carcinogenic potential by oral gavage administration to mice and
rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were
administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were
administered to rats. In rats, there were no drug-related neoplasms. In mice,
RPV was positive for hepatocellular neoplasms in both males and females. The
observed hepatocellular findings in mice may be rodent-specific. At the lowest
tested doses in the carcinogenicity studies, the systemic exposures (based on
AUC) to RPV were 21 times (mice) and 3 times (rats) relative to those observed
in humans at the recommended dose (25 mg once daily) in Odefsey.
RPV has tested
negative in the absence and presence of a metabolic activation system, in the
in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma
assay. RPV did not induce chromosomal damage in the in vivo micronucleus test
in mice.
In a study
conducted in rats, there were no effects on mating or fertility with RPV up to
400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose
is associated with an exposure that is approximately 40 times higher than the
exposure in humans at the recommended dose of 25 mg once daily in Odefsey.
Tenofovir
Alafenamide: Since TAF is rapidly converted to tenofovir and a lower tenofovir
exposure in rats and mice was observed after TAF administration compared to TDF
administration, carcinogenicity studies were conducted only with TDF. Long-term
oral carcinogenicity studies of TDF in mice and rats were carried out at exposures
up to approximately 10 times (mice) and 4 times (rats) those observed in humans
at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir
exposure in these studies was approximately 167 times (mice) and 55 times (rat)
those observed in humans after administration of the daily recommended dose of
Odefsey. At the high dose in female mice, liver adenomas were increased at
tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (Odefsey)
the exposure observed in humans. In rats, the study was negative for
carcinogenic findings.
TAF was not
genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or
rat micronucleus assays.
There were no
effects on fertility, mating performance or early embryonic development when
TAF was administered to male rats at a dose equivalent to 62 times the human
dose based on body surface area comparisons for 28 days prior to mating and to
female rats for 14 days prior to mating through Day 7 of gestation.
Animal
Toxicology and/or Pharmacology
Minimal to
slight infiltration of mononuclear cells in the posterior uvea was observed in
dogs with similar severity after three- and nine-month administration of TAF;
reversibility was seen after a three-month recovery period. No eye toxicity was
observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times
the exposure seen in humans at the recommended daily TAF dose in Odefsey.
Clinical Studies
Clinical Trial
Results in HIV-1 Virologically-Suppressed Subjects Who Switched to Odefsey
In Trial 1216,
the efficacy and safety of switching from emtricitabine/rilpivirine/tenofovir
disoproxil fumarate (FTC/RPV/TDF) to Odefsey were evaluated in a randomized,
double-blind study of virologically-suppressed HIV-1 infected adults. Subjects
were suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of
FTC/RPV/TDF for at least 6 months and have no documented resistance mutations
to FTC, TAF, or RPV prior to study entry. Subjects were randomized in a 1:1
ratio to either switch to Odefsey (N=316) once daily or stay on FTC/RPV/TDF
(N=314) once daily. Subjects had a mean age of 45 years (range: 23–72), 90%
were male, 75% were White, and 19% were Black. The mean baseline CD4+ cell
count was 709 cells/mm3 (range: 104–2527).
In Trial 1160,
the efficacy and safety of switching from efavirenz/emtricitabine/tenofovir
disoproxil fumarate (EFV/FTC/TDF) to Odefsey were evaluated in a randomized,
double-blind study of virologically-suppressed HIV-1 infected adults. Subjects
must have been stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline
regimen of EFV/FTC/TDF for at least 6 months and have no documented resistance
mutations to FTC, TAF, or RPV prior to study entry. Subjects were randomized in
a 1:1 ratio to either switch to Odefsey (N=438) once daily or stay on
EFV/FTC/TDF (N=437) once daily. Subjects had a mean age of 48 years (range:
19–76), 87% were male, 67% were White, and 27% were Black. The mean baseline
CD4+ cell count was 700 cells/mm3 (range: 140–1862).
Treatment
outcomes of Trials 1216 and 1160 are presented in Table 11.
Table 11 Virologic Outcomes of Trials 1216 and 1160 at
Week 48* in Virologically-Suppressed Subjects who
Switched to Odefsey
|
|
|
Study 1216
|
Study 1160
|
|
|
Odefsey
(N=316)
|
FTC/RPV/TDF
(N=313)†
|
Odefsey
(N=438)
|
EFV/FTC/TDF
(N=437)
|
|
*
Week 48 window was between Day 295 and 378 (inclusive).
†
One subject who was not on FTC/RPV/TDF prior to
screening was excluded from the efficacy analysis.
‡
Included subjects who had HIV-1 RNA ≥50 copies/mL in
the Week 48 window; subjects who discontinued early due to lack or loss of
efficacy; subjects who discontinued for reasons other than lack or loss of
efficacy and at the time of discontinuation had a viral value of ≥50
copies/mL.
§
Includes
subjects who discontinued for reasons other than an AE, death, or lack or
loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
|
|
HIV-1 RNA <50 copies/mL
|
94%
|
94%
|
90%
|
92%
|
|
HIV-1 RNA ≥50 copies/mL‡
|
1%
|
0%
|
1%
|
1%
|
|
No Virologic Data at Week 48
Window
|
6%
|
6%
|
9%
|
7%
|
|
Discontinued Study Drug Due to AE or Death and Last
Available HIV-1 RNA <50 copies/mL
|
2%
|
1%
|
3%
|
1%
|
|
Discontinued Study Drug Due to Other Reasons and Last
Available HIV-1 RNA <50 copies/mL §
|
4%
|
4%
|
5%
|
5%
|
|
Missing Data During Window but on Study Drug
|
<1%
|
1%
|
1%
|
1%
|
Clinical Trial
Results for Subjects with no Antiretroviral Treatment History for Components of
Odefsey
The efficacy of
RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial
therapy in those with no antiretroviral treatment history [see Indications and
Usage (1)] was established in trials of:
RPV+FTC/TDF
in HIV-1 infected adults as initial therapy in those with no
antiretroviral treatment history (n=550). The virologic response rate
(i.e., HIV-1 RNA less than 50 copies per mL) was 77% at Week 96. The
virologic response rate at 96 weeks was 83% in subjects with baseline
HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in subjects
with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the
virologic response rate at 96 weeks among subjects with baseline CD4+ cell
counts less than 200 and greater than or equal to 200 cells/mm3 were 68% and 82%,
respectively.FTC+TAF
with EVG+COBI in HIV-1 infected adults as initial therapy in those with no
antiretroviral treatment history (n=866). The virologic response rate
(i.e., HIV-1 RNA less than 50 copies per mL) was 92% at Week 48.
The efficacy of
RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients
aged 12 to less than 18 years old and greater than 32–35 kg as initial therapy
in those with no antiretroviral treatment history and to replace a stable
antiretroviral regimen in those who are virologically-suppressed [see Indications and
Usage (1)] was established in trials of
antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less
than 18 years old with:
RPV
in combination with other antiretroviral agents in 36 treatment-naïve
HIV-1 infected adolescents weighing at least 32 kg. The majority of
subjects (24/36) received RPV in combination with FTC and TDF. Of these 24
subjects, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies
per mL. The virologic response rate in these 20 subjects (i.e., HIV-1 RNA
less than 50 copies per mL) was 80% (16/20) at 48 weeks.FTC+TAF
with EVG+COBI in 23 adolescents weighing at least 35 kg. The virologic
response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24
weeks.
In the clinical
trial of 248 HIV-1 infected adult patients with estimated creatinine clearance
greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of
the combined populations of treatment-naïve (N=6) begun on FTC+TAF with
EVG+COBI and those previously virologically-suppressed on other regimens
(N=242) and switched to FTC+TAF with EVG +COBI had HIV-RNA levels less than 50
copies per mL at Week 24.
How
Supplied/Storage and Handling
Odefsey tablets
are gray, capsule-shaped, and film coated with "GSI" debossed on one
side and "255" on the other side. Each bottle contains 30 tablets
(NDC 61958-2101-1), a silica gel desiccant, and a polyester coil, and is closed
with a child-resistant closure.
Store below 30
°C (86 °F).
Keep
container tightly closed.Dispense
only in original container.
Patient
Counseling Information
Advise the
patient to read the FDA-approved patient labeling (Patient Information).
Post-treatment
Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection
Severe acute
exacerbations of hepatitis B have been reported in patients who are coinfected
with HBV and HIV-1 and have discontinued products containing FTC and/or TDF,
and may likewise occur with discontinuation of Odefsey [see Warnings and
Precautions (5.1)]. Advise the patient to not discontinue
Odefsey without first informing their healthcare provider.
Severe Skin
Reactions and Hypersensitivity
Inform patients
that skin reactions ranging from mild to severe, including Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), have been reported with
RPV-containing products. Instruct patients to immediately stop taking Odefsey
and seek medical attention if they develop a rash associated with any of the
following symptoms: fever, blisters, mucosal involvement, eye inflammation
(conjunctivitis), severe allergic reaction causing swelling of the face, eyes,
lips, mouth, tongue or throat which may lead to difficulty swallowing or
breathing, and any signs and symptoms of liver problems, as they may be a sign
of a more serious reaction. Patients should understand that if severe rash
occurs, they will be closely monitored, laboratory tests will be performed and
appropriate therapy will be initiated [see Warnings and
Precautions (5.2)].
Drug
Interactions
Odefsey may
interact with many drugs and is not recommended to be coadministered with numerous
drugs. Advise patients to report to their healthcare provider the use of any
other prescription or nonprescription medication or herbal products, including
St. John's wort [see Contraindications (4), Warnings and
Precautions (5.3) and Drug
Interactions (7)].
Depressive
Disorders
Inform patients
that depressive disorders (depressed mood, depression, dysphoria, major
depression, mood altered, negative thoughts, suicide attempt, suicidal
ideation) have been reported with RPV. Inform patients to seek immediate
medical evaluation if they experience depressive symptoms [see Warnings and
Precautions (5.5)].
Hepatotoxicity
Inform patients
that hepatotoxicity has been reported with RPV, therefore, it is important to
inform the healthcare professional if patients have underlying hepatitis B or C
or elevations in liver-associated tests prior to treatment [see Dosage and
Administration (2.1) and Warnings and
Precautions (5.6)].
Immune
Reconstitution Syndrome
Advise patients
to inform their healthcare provider immediately of any symptoms of infection,
as in some patients with advanced HIV infection (AIDS), signs and symptoms of
inflammation from previous infections may occur soon after anti-HIV treatment
is started [see Warnings and Precautions (5.7)].
New Onset or
Worsening Renal Impairment
Advise patients
to avoid taking Odefsey with concurrent or recent use of nephrotoxic agents.
Renal impairment, including cases of acute renal failure, has been reported in
association with the use of tenofovir prodrugs [see Warnings and
Precautions (5.8)].
Lactic Acidosis
and Severe Hepatomegaly
Lactic acidosis
and severe hepatomegaly with steatosis, including fatal cases, have been
reported with use of drugs similar to Odefsey. Advise patients to stop taking
Odefsey if they develop clinical symptoms suggestive of lactic acidosis or
pronounced hepatotoxicity [see Warnings and Precautions (5.9)].
Missed Dosage
Inform patients
that it is important to take Odefsey on a regular dosing schedule with a meal
and to avoid missing doses, as it can result in development of resistance [see Dosage and
Administration (2.2)].
Pregnancy
Registry
Inform patients
that there is an antiretroviral pregnancy registry to monitor fetal outcomes of
pregnant women exposed to Odefsey [see Use in Specific
Populations (8.1)].
Lactation
Instruct women
with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby
in breast milk [see Use in Specific Populations (8.2)].
Odefsey is a trademark
of Gilead Sciences, Inc., or its related companies. All other trademarks
referenced herein are the property of their respective owners.
|
Patient Information
Odefsey® (oh-DEF-see)
(emtricitabine, rilpivirine and tenofovir alafenamide)
tablets
|
|
This Patient Information has been approved by the U.S.
Food and Drug Administration
|
Revised: 08/2017
|
|
Important: Ask your
healthcare provider or pharmacist about medicines that should not be taken
with Odefsey. For more information,
see "What should I tell my healthcare
provider before taking Odefsey?"
|
|
What is the most important
information I should know about Odefsey?
|
|
Odefsey can cause serious
side effects, including:
|
|
Worsening of Hepatitis B
virus infection. Odefsey is
not for use to treat chronic hepatitis B virus (HBV) infection. If you have
hepatitis B virus (HBV) infection and take Odefsey, your HBV may get worse
(flare-up) if you stop taking Odefsey. A "flare-up" is when your
HBV infection suddenly returns in a worse way than before.
· Do not run out
of Odefsey. Refill your prescription or talk to your healthcare provider
before your Odefsey is all gone.
· Do not stop
taking Odefsey without first talking to your healthcare provider.
· If you stop
taking Odefsey, your healthcare provider will need to check your health often
and do blood tests regularly for several months to check your HBV infection.
Tell your healthcare provider about any new or unusual symptoms you may have
after you stop taking Odefsey.
|
|
For more information about side effects, see "What are the possible side effects of
Odefsey?"
|
|
What is Odefsey?
|
|
Odefsey is a prescription medicine that is used to
treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and
older:
|
|
· who have not
received anti-HIV-1 medicines in the past and who have an amount of HIV-1 in
their blood (this is called "viral load") that is no more than
100,000 copies/mL, or
· to replace their
current anti-HIV-1 medicines for people whose healthcare provider determines
that they meet certain requirements.
|
|
HIV-1 is the virus that causes AIDS (Acquired Immune
Deficiency Syndrome).
|
|
Odefsey contains the prescription medicines
emtricitabine, rilpivirine and tenofovir alafenamide.
|
|
It is not known if Odefsey is safe and effective in
children under 12 years of age or who weigh less than 77 lb (35 kg).
|
|
Who should not take Odefsey?
|
|
Do not take Odefsey if you
also take a medicine that contains:
carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®, TEGRETOL-XR®, TERIL®)dexamethasone (OZURDEX®, MAXIDEX®, DECADRON®, BAYCADRON™)dexlansoprazole (DEXILANT®)esomeprazole (NEXIUM®, VIMOVO®)lansoprazole (PREVACID®)omeprazole (PRILOSEC®, ZEGERID®)oxcarbazepine (TRILEPTAL®)pantoprazole sodium (PROTONIX®)phenobarbital (LUMINAL®)phenytoin (DILANTIN®, DILANTIN-125®, PHENYTEK®)rabeprazole (ACIPHEX®)rifampin (RIFADIN®, RIFAMATE®, RIFATER®, RIMACTANE®)rifapentine (PRIFTIN®)St. John's wort (Hypericum perforatum) or a product that contains St. John's wort
|
|
What should I tell my
healthcare provider before taking Odefsey?
|
|
Before taking Odefsey, tell
your healthcare provider about all your medical conditions, including if you:
|
|
· have liver
problems, including hepatitis B or C virus infection
· have kidney
problems
· have a history
of depression or suicidal thoughts
· are pregnant or
plan to become pregnant. It is not known if Odefsey can harm your unborn
baby. Tell your healthcare provider if you become pregnant during treatment
with Odefsey.
Pregnancy
Registry: There is a pregnancy
registry for women who take Odefsey during pregnancy. The purpose of this
registry is to collect information about the health of you and your baby.
Talk with your healthcare provider about how you can take part in this
registry.
· are
breastfeeding or plan to breastfeed. Do not breastfeed if you take Odefsey.
o You should not breastfeed if you have HIV-1 because of
the risk of passing HIV-1 to your baby.
o At least one of the medicines in Odefsey can pass to
your baby in your breast milk. It is not known if the other medicines in
Odefsey can pass into your breast milk.
Talk with your healthcare provider about the best way
to feed your baby during treatment with Odefsey.
|
|
Tell your healthcare
provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and
herbal supplements.
|
|
Some medicines may interact with Odefsey. Keep a list
of your medicines and show it to your healthcare provider and pharmacist when
you get a new medicine.
|
|
· You can ask your
healthcare provider or pharmacist for a list of medicines that interact with
Odefsey.
· Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is
safe to take Odefsey with other medicines.
|
|
How should I take Odefsey?
|
|
· Take Odefsey
exactly as your healthcare provider tells you to take it. Odefsey is taken by
itself (not with other HIV-1 medicines) to treat HIV-1 infection.
· Take Odefsey 1
time each day with a meal.
· Do not change
your dose or stop taking Odefsey without first talking with your healthcare
provider. Stay under a healthcare provider's care during treatment with
Odefsey.
· Do not miss a
dose of Odefsey.
· If you take too
much Odefsey, call your healthcare provider or go to the nearest hospital
emergency room right away.
· When your
Odefsey supply starts to run low, get more from your healthcare provider or
pharmacy. This is very important because the amount of virus in your blood
may increase if the medicine is stopped for even a short time. The virus may
develop resistance to Odefsey and become harder to treat.
|
|
What are the possible side
effects of Odefsey?
|
|
Odefsey may cause serious
side effects, including:
|
|
· See "What is the most important information I
should know about Odefsey?"
· Severe skin rash and allergic reactions. Skin rash is a common side effect of Odefsey. Rash can be serious.
Call your healthcare provider right away if you get a rash. In some cases,
rash and allergic reaction may need to be treated in a hospital.
If you get a
rash with any of the following symptoms, stop taking Odefsey and call your
healthcare provider or get medical help right away:
|
|
|
o fever
o skin blisters
o mouth sores
o redness or swelling of the eyes (conjunctivitis)
|
o swelling of the face, lips, mouth, or throat
o trouble breathing or swallowing
o pain on the right side of the stomach (abdominal) area
o dark "tea colored" urine
|
|
· Depression or mood changes. Tell your healthcare provider right away if
you have any of the following symptoms:
feel sad or hopelessfeel anxious or restlesshave thoughts of hurting yourself (suicide) or
have tried to hurt yourself
· Change in liver enzymes. People
with a history of hepatitis B or C virus infection or who have certain liver
enzyme changes may have an increased risk of developing new or worsening
liver problems during treatment with Odefsey. Liver problems can also happen
during treatment with Odefsey in people without a history of liver disease.
Your healthcare provider may need to do tests to check your liver enzymes
before and during treatment with Odefsey.
· Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines.
Your immune system may get stronger and begin to fight infections that have
been hidden in your body for a long time. Tell your healthcare provider right
away if you start having any new symptoms after starting your HIV-1 medicine.
· New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and
urine tests to check your kidneys before you start and during treatment with
Odefsey. Your healthcare provider may tell you to stop taking Odefsey if you
develop new or worse kidney problems.
· Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical
emergency that can lead to death. Tell your healthcare provider right away if you get
these symptoms: weakness or being more
tired than usual, unusual muscle pain, being short of breath or fast
breathing, stomach pain with nausea and vomiting, cold or blue hands and
feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
· Severe liver problems. In rare cases,
severe liver problems can happen that can lead to death. Tell your healthcare
provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark
"tea-colored" urine, light-colored stools, loss of appetite for
several days or longer, nausea, or stomach-area pain.
|
|
The most common side effects
of Odefsey are headache and problems
sleeping.
|
|
These are not all the possible side effects of Odefsey.
|
|
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
|
|
How should I store Odefsey?
|
|
· Store Odefsey
below 86°F (30°C).
· Keep Odefsey in
its original container.
· Keep the
container tightly closed.
|
|
Keep Odefsey and all
medicines out of reach of children.
|
|
General information about
the safe and effective use of Odefsey.
|
|
Medicines are sometimes prescribed for purposes other
than those listed in a Patient Information leaflet. Do not use Odefsey for a
condition for which it was not prescribed. Do not give Odefsey to other
people, even if they have the same symptoms you have. It may harm them.
|
|
You can ask your healthcare provider or pharmacist for
information about Odefsey that is written for health professionals.
|
|
For more information, call 1-800-445-3235 or go to
www.Odefsey.com.
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What are the ingredients in
Odefsey?
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Active ingredients: emtricitabine, rilpivirine, and tenofovir
alafenamide
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Inactive ingredients: croscarmellose sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, polysorbate 20, and povidone.
The tablet film coating contains iron oxide black, polyethylene glycol,
polyvinyl alcohol, talc, and titanium dioxide
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Manufactured and distributed by: Gilead Sciences, Inc.
Foster City, CA 94404
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Odefsey is a trademark of Gilead Sciences, Inc., or its
related companies. All other trademarks referenced herein are the property of
their respective owners.
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© 2017 Gilead Sciences, Inc. All rights reserved.
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208351-GS-002
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PRINCIPAL
DISPLAY PANEL - 30 Tablet Bottle Label
NDC 61958-2101-1
30 tablets
Odefsey®
(emtricitabine, rilpivirine, and
tenofovir alafenamide) Tablets
200 mg/25 mg/25 mg
Note to
pharmacist:
Do not cover ALERT box with pharmacy label.
ALERT: Find out
about medicines that
should NOT be taken with Odefsey®
|
Odefsey emtricitabine,
rilpivirine hydrochloride, and tenofovir alafenamide tablet
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Product Information
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Product Type
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HUMAN PRESCRIPTION DRUG LABEL
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Item Code (Source)
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NDC:61958-2101
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Route of Administration
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ORAL
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DEA Schedule
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|
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Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
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emtricitabine (emtricitabine)
|
emtricitabine
|
200 mg
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rilpivirine hydrochloride (rilpivirine)
|
rilpivirine
|
25 mg
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tenofovir alafenamide
fumarate (tenofovir
anhydrous)
|
tenofovir alafenamide
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25 mg
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Inactive Ingredients
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Ingredient Name
|
Strength
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LACTOSE MONOHYDRATE
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MICROCRYSTALLINE CELLULOSE
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POVIDONE, UNSPECIFIED
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POLYSORBATE 20
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CROSCARMELLOSE SODIUM
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MAGNESIUM STEARATE
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WATER
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POLYVINYL ALCOHOL,
UNSPECIFIED
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TITANIUM DIOXIDE
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POLYETHYLENE GLYCOL,
UNSPECIFIED
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TALC
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FERROSOFERRIC OXIDE
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Product Characteristics
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Color
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GRAY
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Score
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no score
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Shape
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OVAL (capsule-shaped)
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Size
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15mm
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Flavor
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Imprint Code
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GSI;255
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Contains
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|
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|
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Packaging
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#
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Item Code
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Package Description
|
|
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1
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NDC:61958-2101-1
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30 TABLET in 1 BOTTLE, PLASTIC
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Marketing Information
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|
Marketing Category
|
Application Number or Monograph Citation
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Marketing Start Date
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Marketing End Date
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|
NDA
|
NDA208351
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03/01/2016
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Labeler - Gilead Sciences, Inc. (185049848)
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Revised: 08/2017
Gilead Sciences,
Inc.
