Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
Clinical Trials Experience in Pediatric Subjects
Abacavir,
Dolutegravir and Lamivudine: The safety of
TRIUMEQ PD and TRIUMEQ in pediatric subjects with HIV-1 infection weighing at
least 6 kg was evaluated in the IMPAACT 2019 trial. This was a multicenter,
open-label, non-comparative trial of pediatric subjects with HIV-1 infection,
younger than 12 years of age. Fifty-seven subjects weighing at least 6 kg to
less than 40 kg were enrolled in this trial [see Use in Specific Populations
(8.4), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Overall, the
safety data in this pediatric study was similar to that seen in adults.
The safety analysis through Week 48 included 57
subjects weighing at least 6 kg at enrollment who received the recommended dose
(determined by weight) and formulation. This analysis showed that 26% of
subjects experienced clinical adverse reactions. The most common adverse
reactions were classified as laboratory abnormalities and included decreased
glomerular filtration rate (n = 13, 23%), increased blood creatinine (n = 10, 18%),
and increased ALT (n = 3, 5%). All other adverse reactions occurred at a rate
of <2% of participants. Two subjects reported Grade 3 or 4 adverse
reactions. One subject, an 8-year-old female who weighed 22 kg at baseline,
experienced Grade 3 increased blood creatinine and Grade 3 decreased glomerular
filtration rate. By Week 48, the glomerular filtration rate was improving, and
the events did not lead to drug discontinuation. Another subject, a 7-year-old
male who weighed 20 kg at baseline, experienced drug-induced liver injury with
Grade 4 increased ALT and AST following 36 weeks of treatment with TRIUMEQ PD.
Clinical signs or symptoms of hepatitis were not reported, and ALT and AST
values normalized after TRIUMEQ PD was discontinued.
…
Dolutegravir:
The safety of dolutegravir in pediatric subjects
with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT
P1093 trial [see Use in Specific Populations (8.4), Clinical Pharmacology
(12.3)]. Overall, the safety data in this pediatric study was similar to
that seen in adults.
IMPAACT P1093 is an ongoing multicenter,
open-label, non-comparative trial of pediatric subjects with HIV-1 infection,
aged <18 years. One hundred and forty-two subjects weighing at least 6
kg were enrolled in this trial [see Use in Specific Populations (8.4),
Clinical Pharmacology (12.3), Clinical Studies (14.2)].
The safety analysis through Week 24 included 60
subjects weighing at least 6 kg at enrollment who received the
recommended dose (determined by weight and age) and formulation. This analysis
showed that 13% of subjects experienced adverse reactions. Grade 1 to
2 adverse reactions reported by more than one subject was immune reconstitution
inflammatory syndrome (n = 2). There were no Grade 3 or 4 adverse reactions
reported. No adverse reactions led to discontinuation.
The Grade 3 or 4
laboratory abnormalities reported in more than one subject weighing at
least 6 kg at
enrollment were decreased neutrophil count (n = 5), decreased blood
bicarbonate (n = 3), increased lipase (n = 2), and increased blood
potassium (n = 2). These laboratory events were not considered to be drug
related. Changes in median serum creatinine were similar
to those observed in adults.
7
Drug Interactions
7.3
Established and Other Potentially Significant Drug Interactions
Extensive
changes to table 6; please refer to label for complete information
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
The clinical data supporting use of TRIUMEQ and
TRIUMEQ PD in pediatric patients with HIV-1 infection aged at least 3 months
and weighing at least 6 kg is derived from the following previously
conducted pediatric trials using TRIUMEQ and TRIUMEQ PD or the individual
components:
The safety, pharmacokinetics, and antiviral activity (efficacy) of
TRIUMEQ and TRIUMEQ PD were established through an open-label, multicenter
clinical trial (IMPAACT 2019), in which HIV-1–infected, treatment-naive or
treatment-experienced, pediatric subjects younger than 12 years and weighing at
least 6 kg to less than 40 kg were treated with TRIUMEQ or TRIUMEQ PD [see Adverse Reactions (6.1), Clinical
Pharmacology (12.3), Clinical Studies (14.2)].
…
The
safety and effectiveness of TRIUMEQ PD have not been established in pediatric
patients aged less than 3 months or weighing less than 6 kg.
8.6 Patients with Impaired Renal Function
Additions
and/or revisions underlined:
TRIUMEQ
and TRIUMEQ PD are not recommended for patients with creatinine clearance
<30
mL/min and pediatric patients with a similar degree of renal impairment
based on age- appropriate assessment of renal function because TRIUMEQ and
TRIUMEQ PD are fixed-dose combinations and the dosage of the individual
components cannot be adjusted. If a dose reduction of lamivudine, a component
of TRIUMEQ and TRIUMEQ PD, is required for patients with creatinine clearance
<30 mL/min and in pediatric patients with a similar degree of renal
impairment based on age-appropriate assessment of renal function, then the
individual components should be used [see
Clinical Pharmacology (12.3)].
…
Patients
with a sustained creatinine clearance between 30 and 49 mL/min or pediatric
patients with a similar degree of renal impairment based on age-appropriate
assessment of renal function who receive TRIUMEQ or TRIUMEQ PD should be
monitored for hematologic toxicities.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions and/or revisions underlined:
…
Inform
patients and caregivers that TRIUMEQ PD tablets for oral suspension should be
dispersed in drinking water and should not be chewed, cut, crushed or
swallowed whole [see Dosage and
Administration (2.5)]. Inform patients and caregivers that an appropriate-sized
syringe may be used to administer the oral suspension if the patient is unable
to use the supplied cup [see Dosage
and Administration (2.5)].
MEDICATION GUIDE
Additions and/or revisions underlined:
What is TRIUMEQ
and TRIUMEQ PD?
TRIUMEQ
and TRIUMEQ PD are prescription medicines used to treat HIV-1 infection in
adults and children who are at least 3 months of age and weigh at least 13.2
pounds (6 kg).
…
It
is not known if TRIUMEQ PD is safe and effective in children who are less
than 3 months of age or weigh less than 13.2 pounds (6 kg).
…
How
should I take TRIUMEQ or TRIUMEQ PD?
…
Do
not chew, cut, or crush TRIUMEQ tablets or TRIUMEQ PD tablets for oral
suspension. Do not swallow TRIUMEQ PD tablets for oral suspension whole.
…
If
you need to take iron or calcium supplements, or multivitamin supplements
that contain iron or
calcium, by mouth during
treatment with TRIUMEQ or TRIUMEQ PD:
…
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
Data
Additions
and/or revisions underlined:
…
Based on
prospective reports to the APR of over 1,000 exposures to dolutegravir during
pregnancy resulting in live births
(including 634 exposed
in the first trimester), the prevalence of defects in live births was 3.3% (95%
CI: 2.1% to 5.0%) following first-trimester exposure to dolutegravir-containing
regimens and 5.1% (95% CI: 3.2% to 7.7%) following second-/third- trimester
exposure to dolutegravir-containing regimens. In the U.S. reference population
of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background
birth defect rate was 2.7%.
Dolutegravir has been shown to cross the placenta.
In a clinical trial in Uganda and South Africa in women during the last trimester
of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median
dolutegravir concentration in fetal umbilical cord to that in maternal
peripheral plasma was 1.21 (range 0.51-2.11) (n = 15).
…
8.2 Lactation
Risk Summary
Additions
and/or revisions underlined:
The Centers for Disease
Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants
to avoid risking postnatal transmission of HIV-1 infection.
Abacavir, dolutegravir and lamivudine are present in human milk. There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production.
Because of the
potential for (1) HIV-1 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 TRIUMEQ.
Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined
WARNING: HYPERSENSITIVITY REACTIONS, AND
EXACERBATIONS OF HEPATITIS B
Hypersensitivity Reactions
Serious and sometimes fatal hypersensitivity
reactions, with multiple organ involvement, have occurred with abacavir, a
component of TRIUMEQ and TRIUMEQ PD (abacavir, dolutegravir, and
lamivudine). Patients who carry the HLA-B*5701 allele are at a higher risk of a
hypersensitivity reaction to abacavir, although hypersensitivity reactions have
occurred in patients who do not carry the HLA-B*5701 allele [see Warnings
and Precautions (5.1)].
TRIUMEQ and TRIUMEQ PD are contraindicated
in patients with a prior hypersensitivity reaction to abacavir and in
HLA-B*5701-positive patients [see C ontraindications (4), Warnings and Precautions (5.1)]. All patients
should be screened for the HLA-B*5701 allele prior to initiating therapy with
TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ
PD, unless patients have a previously documented HLA-B*5701 allele
assessment. Discontinue TRIUMEQ or TRIUMEQ PD immediately if a
hypersensitivity reaction is suspected, regardless of
HLA-B*5701
status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)].
Following
a hypersensitivity reaction to TRIUMEQ or TRIUMEQ PD, NEVER restart
TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product because
more severe symptoms, including death can occur within hours. Similar severe
reactions have also occurred rarely following the reintroduction of abacavir-containing
products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)].
![]()
Exacerbations of
Hepatitis B
All
patients with HIV-1 should be tested for the presence of hepatitis B virus
(HBV) prior to or when initiating TRIUMEQ or TRIUMEQ PD. Emergence of
lamivudine-resistant HBV variants associated with lamivudine-containing
antiretroviral regimens has been reported. If TRIUMEQ or TRIUMEQ PD is used in
patients co-infected with HIV-1 and HBV, additional treatment should be
considered for appropriate treatment of chronic HBV; otherwise, consider an
alternative regimen.
Severe
acute exacerbations of hepatitis B have been reported in patients who are
co-infected
with HBV and HIV-1 and have discontinued lamivudine, a component of TRIUMEQ and
TRIUMEQ PD. Closely monitor hepatic function in these patients and, if
appropriate, initiate anti-HBV treatment [see
Warnings and Precautions (5.2)].
4
Contraindications
Additions
underlined
TRIUMEQ and TRIUMEQ PD are contraindicated
in patients:
…
5
Warnings and Precautions
5.2 Patients Co-infected with HIV-1 and HBV: Emergence of Lamivudine-Resistant HBV and the Risk of Posttreatment Exacerbations of HBV
Additions
underlined
All patients with HIV-1 should be tested for the
presence of HBV prior to or when initiating TRIUMEQ or TRIUMEQ PD.
Emergence of Lamivudine Resistant HBV
![]()
Safety and efficacy of lamivudine have not been established for
treatment of chronic HBV in subjects dually
infected with HIV-1 and HBV. Emergence of HBV variants associated with
resistance to lamivudine has been reported in HIV-1?infected subjects who have
received lamivudine-containing antiretroviral regimens in the presence of
concurrent infection with HBV. If a decision is made to administer
TRIUMEQ or TRIUMEQ PD to patients co-infected with HIV-1 and HBV, additional
treatment should be considered for appropriate treatment of chronic HBV;
otherwise, consider an alternative regimen.
Severe Acute Exacerbations of HBV in Patients
Co-infected with HIV-1 and HBV
Severe acute exacerbations
of HBV have been reported in patients who are co-infected with HIV-1
and HBV and have discontinued products containing lamivudine, and may occur
with discontinuation of TRIUMEQ or TRIUMEQ PD. Patients who are
co-infected with HIV-1 and HBV who discontinue TRIUMEQ or TRIUMEQ PD should
be closely monitored with both clinical and laboratory follow-up for at least
several months after stopping treatment with TRIUMEQ or TRIUMEQ PD. If
appropriate, initiation of anti-HBV therapy may be warranted, especially in
patients with advanced liver disease or cirrhosis, since posttreatment
exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.3 Hepatotoxicity
Additions
underlined
…
Cases of hepatic toxicity, including elevated serum
liver biochemistries, hepatitis, and acute liver failure, have also been
reported in patients, including pediatric patients receiving a
dolutegravir-containing regimen who had no pre-existing hepatic disease or
other identifiable risk factors. Drug-induced liver injury leading to liver
transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is
recommended.
5.8 Different Formulations Are Not Interchangeable
New subsection
added
TRIUMEQ and TRIUMEQ PD are not bioequivalent and
are not interchangeable on a
milligram-per-milligram basis [see Clinical
Pharmacology (12.3)]. If a pediatric patient switches from the tablets for
oral suspension to the tablets, the dosage must be adjusted [see Dosage and
Administration (2.3, 2.5)]. Incorrect dosing of a given formulation may
result in underdosing and loss of therapeutic effect and possible development
of resistance or possible clinically significant adverse reactions from greater
exposure to the individual components.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions underlined
…
Dolutegravir: The safety of dolutegravir
in pediatric subjects with HIV-1 infection weighing at least 10 kg was
evaluated in the IMPAACT P1093 trial [see
Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. Overall,
the safety data in this pediatric study was similar to that seen in adults.
IMPAACT P1093 is an ongoing multicenter,
open-label, non-comparative trial of pediatric subjects with HIV-1
infection, aged <18 years. One hundred and five subjects weighing at
least 10 kg were enrolled in this trial [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3),
Clinical Studies (14.2)].
The safety analysis through Week 24 included 40
subjects from Cohorts I (n = 19), IIA (n = 5),
III-DT (n = 15), and IV-DT (n=1) weighing at least 10 kg at enrollment who
received the recommended dose (determined by weight and age) and formulation.
This analysis showed that 6 subjects (all from Cohort I) experienced
drug-related clinical adverse reactions. There were no Grade 3 or 4 drug-related
adverse reactions reported. No adverse reactions led to
discontinuation.
All laboratory
abnormalities considered to be drug-related in subjects weighing at least 10
kg at enrollment were Grade 1 or 2 in severity. Only one grade 3 laboratory
abnormality was reported in more than 1 subject (decreased blood bicarbonate,
n = 2). Changes in median serum creatinine were similar to those observed
in adults.
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
Modifications
to Table 6; please refer to label for complete information.
8
Use in Specific Populations
8.4 Pediatric Use
Additions
underlined
…
The
safety, pharmacokinetics, and antiviral activity (efficacy) of TIVICAY
and TIVICAY PD were established through an ongoing, open-label,
multicenter, dose-finding clinical trial (IMPAACT P1093), in which HIV-1–infected,
treatment-naive or treatment-experienced, INSTI-naive, pediatric and
adolescent subjects aged 4 weeks to <18 years and weighing at
least 3 kg were treated with TIVICAY or TIVICAY PD plus optimized
background therapy [see Adverse Reactions
(6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
Additional pharmacokinetics data were evaluated in 2
pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized,
non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic
parameters of TIVICAY or TIVICAY PD plus two NRTIs (mainly abacavir and
lamivudine) compared with standard of care in HIV-1–infected pediatric subjects
younger than 18 years [see Clinical
Pharmacology (12.3)].
Overall, the safety, and efficacy profile
of TRIUMEQ and TRIUMEQ PD in pediatric patients is comparable to that observed
in adults. There are no data available on the use of lamivudine in pediatric
patients with renal impairment [see
Warnings and Precautions (5.4), Adverse Reactions (6.1), Use in Specific
Populations (8.6), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
Safety and effectiveness of TRIUMEQ PD
have not been established in pediatric patients weighing <10 kg.
8.6 Patients with Impaired Renal Function
Additions underlined
…
Additionally, there are no data available on the use of lamivudine in
pediatric patients with renal impairment. In the
original lamivudine registrational trials in combination with zidovudine,
higher lamivudine exposures were associated with higher rates of hematologic
toxicities (neutropenia and anemia), although discontinuations due to
neutropenia or anemia each occurred in <1% of subjects.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
underlined
…
Severe
Acute Exacerbations of Hepatitis in Patients with HBV Co-infection
Advise
all patients with HIV-1 to be tested for the presence of HBV prior to or when
initiating TRIUMEQ or TRIUMEQ PD. Advise patients co-infected with HIV-1 and
HBV that worsening of liver disease has occurred in some cases when treatment
with lamivudine was discontinued. Advise patients to discuss any changes in
regimen with their physician [see
Warnings and Precautions (5.2)].
…
TRIUMEQ
Tablets and TRIUMEQ PD Tablets for Oral Suspension Are Not Bioequivalent
Advise
patients that TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not
interchangeable on a milligram-per-milligram basis. Advise patients or their
care provider that patients switching from the tablets for oral suspension to
the tablets must adjust the dose [see
Dosage and Administration (2.3) and Warnings and Precautions (5.8)].
…
Administration
Instructions
To
avoid a dosing error from using the wrong formulation of TRIUMEQ, strongly
advise patients and caregivers to visually inspect the tablets to verify the
correct formulation each time the prescription is filled [see Dosage and Administration (2), Warnings and Precautions (5.8), How
Supplied/Storage and Handling (16)].
Inform
patients and caregivers that TRIUMEQ PD tablets for oral suspension should be
dispersed in drinking water and should not be chewed, cut or crushed [see Dosage and Administration (2.5)].
Instruct
patients and caregivers that if a dose of TRIUMEQ or TRIUMEQ PD is
missed, to take it as soon as they remember. Advise patients and caregivers
not to double the next dose or take more than the prescribed dose [see Dosage and Administration (2)].
MEDICATION GUIDE
Extensive
additions and revisions; please refer to label for complete information.
Other
Addition
of Triumeq PD throughout the labeling.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Embryo-Fetal Toxicity
(Additions and/or revisions underlined)
An ongoing observational study showed
an
association between dolutegravir
and an increased
risk of neural tube defects when dolutegravir was administered
at the time of conception and in early pregnancy. As
there is limited understanding of the association
of reported types of
neural tube defects with
dolutegravir use, inform adolescents and adults of childbearing potential, including
those actively trying
to become pregnant, about the
potential increased risk of
neural tube defects with TRIUMEQ. Assess
the risks and benefits of TRIUMEQ and discuss with the
patient to determine if an alternative treatment should be considered at the time of conception through the first
trimester of pregnancy or if pregnancy is confirmed in the first
trimester [see Use in Specific
Populations (8.1, 8.3)].
Pregnancy testing is recommended before initiation of TRIUMEQ
in adolescents and adults
of childbearing potential
[see
Dosage and Administration (2.2)].
Adolescents and adults
of childbearing potential
should be counseled on the consistent use of effective contraception [see Use
in Specific Populations (8.1, 8.3)].
TRIUMEQ may be considered during the second and
third trimesters of pregnancy if the expected
benefit justifies the potential risk to the pregnant woman and the
fetus.
8
Use in Specific Populations
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry
that monitors pregnancy outcomes
in individuals exposed
to TRIUMEQ during pregnancy.
Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry
(APR) at 1-800-258-4263.
Risk
Summary
Data from
an ongoing birth outcome surveillance study has
identified an increased
risk of neural
tube defects when dolutegravir,
a component
of TRIUMEQ, is administered
at the time of conception.
As defects
related to closure of the neural tube occur from conception
through the first 6 weeks of gestation,
embryos exposed to dolutegravir from
the time of conception through
the first 6 weeks of
gestation are at potential
risk.
Advise adolescents and adults of childbearing potential,
including those actively trying
to become pregnant, of the potential
risk of neural tube defects with use of TRIUMEQ. Assess the risks and
benefits of TRIUMEQ and discuss with the patient to determine if an
alternative treatment should be considered at the time of conception through the first trimester
of pregnancy or if pregnancy is confirmed in the first trimester. A
benefit-risk assessment should consider factors such as
feasibility of switching to another
antiretroviral regimen, tolerability, ability
to maintain viral suppression, and risk of HIV-1 transmission to the infant against
the risk of neural tube defects associated with in utero dolutegravir
exposure during critical
periods of fetal development [see Warnings and Precautions (5.6)].
There are insufficient human data on the use of
TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background
risk for major birth defects
for the indicated population
is unknown. In the U.S. general population, the estimated
background rate for major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15%
to 20%, respectively.
In animal reproduction
studies, no evidence of adverse developmental outcomes was observed with
dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at
the recommended human dose (RHD) (see
Data). Oral administration of abacavir to pregnant
rats during organogenesis resulted
in fetal malformations and other
embryonic and fetal
toxicities at exposures 35 times the human
exposure (AUC) at
the RHD. No adverse developmental effects were
observed following oral administration of abacavir to pregnant rabbits
during organogenesis at exposures
approximately 9 times the human
exposure (AUC) at the RHD. Oral administration
of lamivudine to pregnant rabbits
during organogenesis resulted in embryolethality at a human
exposure (AUC) similar to the
RHD; however, no adverse development effects were
observed with oral administration of lamivudine to pregnant rats
during organogenesis at plasma concentrations (Cmax) 35 times the
RHD (see Data).
Data
Human
Data: Dolutegravir: In
a birth outcome surveillance study in
Botswana, there were 7 cases of neural tube defects reported out
of 3,591 deliveries
(0.19%) to women who were exposed to dolutegravir-containing regimens
at the time of conception. In comparison,
the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in
the non-dolutegravir arm and 0.07%
(87/119,630 deliveries) in
the HIV-uninfected arm. Seven
cases reported with dolutegravir included 3 cases
of myelomeningocele, 2 cases of encephalocele, and one case each of anencephaly and iniencephaly. In
the same study, no increased risk of neural tube defects was identified
in women who started dolutegravir
during pregnancy. Two infants out of 4,448
(0.04%) deliveries to women who started
dolutegravir during pregnancy had a neural tube defect, compared with 5
infants out of 6,748 (0.07%) deliveries to women who
started non-dolutegravir- containing regimens during pregnancy. The reported
risks of neural tube defects by treatment
groups were based on interim analyses from the ongoing surveillance
study in Botswana. It
is unknown
if baseline characteristics were balanced between the study
treatment groups. The observed
trends of association could change as
data accumulate.
Data analyzed to date from other sources including the
APR, clinical trials, and postmarketing data are insufficient to definitively address
the risk of neural tube defects with dolutegravir.
Data from the birth outcome surveillance study described
above and postmarketing sources with more
than 1,000 pregnancy outcomes
from second and third trimester exposure in pregnant women
indicate no evidence of
increased risk of adverse birth outcomes.
Based on prospective reports
to the APR of 842 exposures
to dolutegravir during pregnancy resulting in live
births (including 512
exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir- containing regimens
and
4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure
to dolutegravir-containing regimens. In
the U.S. reference population of the Metropolitan
Atlanta Congenital Defects Program (MACDP),
the background birth defect
rate was 2.7%.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions underlined)
In adolescents and adults of
childbearing potential
currently on TRIUMEQ
who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester,
assess the risks and benefits
of continuing TRIUMEQ and
discuss with the patient if an alternative treatment
should be considered [see Warnings and Precautions (5.6), Use in Specific
Populations (8.1)].
Pregnancy
Testing
Pregnancy testing is recommended in adolescents and adults
of childbearing potential
before initiation of TRIUMEQ [see Dosage and
Administration (2.2)].
Contraception
Adolescents and adults of
childbearing potential
who are taking TRIUMEQ should be counseled on the consistent use of effective
contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Additions and/or revisions underlined)
o If you can become pregnant, your healthcare provider may
perform a pregnancy test before
you start treatment with TRIUMEQ.
o If you can become pregnant, you and your healthcare
provider should talk about the use of
effective birth control (contraception) during treatment
with TRIUMEQ.
Patient Couseling Information
(Additions and/or revisions underlined)
Embryo-Fetal Toxicity
Advise adolescents and adults of childbearing potential,
including those actively trying
to become pregnant, to discuss the
risks and benefits
of TRIUMEQ with their healthcare provider to determine if an alternative treatment should be considered at
the time of conception through the first trimester
of pregnancy. If pregnancy is confirmed in the first trimester,
advise patients to contact
their healthcare provider [see Warnings and Precautions (5.6), Use in Specific Populations
(8.1, 8.3)].
Adolescents and adults
of childbearing potential
taking TRIUMEQ should be
counseled on the consistent use of effective contraception [see Warnings
and Precautions (5.6), Use in Specific Populations
(8.1, 8.3)].
Approved Drug Label (PDF)
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
Newly
added information to the end of the subsection:
Riociguat
Abacavir:
Coadministration
with TRIUMEQ resulted in increased riociguat exposure, which may increase the
risk of riociguat adverse reactions [see
Clinical Pharmacology (12.3)]. The riociguat dose may need to be reduced.
See full prescribing information for ADEMPAS
(riociguat).
8
Use in Specific Populations
8.1
Pregnancy
Data
Additions
and/or revisions underlined:
… Data from the birth outcome surveillance
study described above and postmarketing sources with more than 1,000 pregnancy
outcomes from second and third trimester exposure in pregnant women indicate no
evidence of increased risk of adverse birth outcomes.
Based on prospective reports to the APR of
exposures to dolutegravir during pregnancy resulting in live births
(including over 450 exposed in the first trimester and over 280 exposed
in the second/third trimester), there was no difference between the overall
risk of birth defects for dolutegravir compared with the background
birth defect rate of 2.7% in the U.S. reference population of the Metropolitan
Atlanta Congenital Defects Program (MACDP). The prevalence of defects in live
births was 3.5% (95% CI: 2.0% to 5.6%) following first trimester
exposure to dolutegravir-containing regimens and 4.2% (95% CI: 2.2%
to 7.2%) following second/third trimester exposure to dolutegravir-containing
regimens.
Abacavir:
Based
on prospective reports to the APR of exposures to abacavir during pregnancy
resulting in live births (including over 1,300 exposed in the first trimester
and over 1,300 exposed in the second/third trimester), there was no difference
between the overall risk of birth defects for abacavir compared with the
background birth defect rate of 2.7% in the U.S. reference population of the
MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%)
following first trimester exposure to abacavir-containing regimens and 2.9%
(95% CI: 2.1% to 4.0%) following second/third trimester exposure to
abacavir-containing regimens.
Abacavir has been shown to cross the
placenta and concentrations in neonatal plasma at birth were essentially equal
to those in maternal plasma at delivery [see
Clinical Pharmacology (12.3)].
Lamivudine:
Based
on prospective reports to the APR of exposures to lamivudine during pregnancy
resulting in live births (including over 5,300 exposed in the first
trimester and over 7,400 exposed in second/third trimester), there was
no difference between the overall risk of birth defects for lamivudine compared
with the background birth defect rate of 2.7% in the U.S. reference population
of the MACDP.
8.6
Patients with Impaired Renal Function
Additions
and/or revisions underlined:
TRIUMEQ is not recommended for patients
with creatinine clearance less than 30 mL per min because TRIUMEQ is a
fixed-dose combination and the dosage of the individual components cannot be
adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ, is
required for patients with creatinine clearance less than 30 mL per min,
then the individual components should be used [see Clinical Pharmacology (12.3)].
Patients with a creatinine clearance
between 30 and 49 mL per min receiving TRIUMEQ may experience a 1.6- to
3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine
clearance greater than or equal to50 mL per min. There are no safety data from
randomized, controlled trials comparing TRIUMEQ to the individual components in
patients with a creatinine clearance between 30 and 49 mL per min who received
dose-adjusted lamivudine. In the original lamivudine registrational trials in
combination with zidovudine, higher lamivudine exposures were associated with
higher rates of hematologic toxicities (neutropenia and anemia), although
discontinuations due to neutropenia or anemia each occurred in <1% of subjects.
Patients with a sustained creatinine clearance between 30 and 49 mL per min who
receive TRIUMEQ should be monitored for hematologic toxicities. If new or
worsening neutropenia or anemia develop, dose adjustment of lamivudine, per
lamivudine prescribing information, is recommended. If lamivudine dose
adjustment is indicated, TRIUMEQ should be discontinued and the individual
components should be used to construct the treatment regimen.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What
is the most important information I should know about TRIUMEQ?
TRIUMEQ
can cause serious side effects, including:
Worsening of
Hepatitis B virus (HBV) infection.
If you stop taking
TRIUMEQ, your healthcare provider will need to check your health often and do
blood tests regularly for several months to check your liver function and
monitor your HBV infection. It may be necessary to give you a medicine to treat
hepatitis B. Tell your healthcare provider about any new or unusual symptoms
you may have after you stop taking TRIUMEQ.
For more
information about side effects, see “What are the possible side effects of TRIUMEQ?”
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Embryo-Fetal Toxicity
(additions and/or
revisions are underlined)
An
observational study showed an association between dolutegravir, a
component of TRIUMEQ, and an increased risk of neural tube defects when dolutegravir
was administered at the time of conception and in early pregnancy. As there
is limited understanding of reported types of neural tube defects associated
with dolutegravir use and because the date of conception may not be determined
with precision, an alternative treatment to TRIUMEQ should be
considered at the time of conception through the first trimester of
pregnancy.
Perform
pregnancy testing before initiation of TRIUMEQ in adolescents and adults of
childbearing potential to exclude use of TRIUMEQ during the first trimester of
pregnancy. Initiation of TRIUMEQ is
not recommended in adolescents and adults actively trying to become pregnant
unless there is no suitable alternative.
Counsel adolescents and
adults of childbearing potential to consistently use effective contraception.
In
adolescents and adults of childbearing potential currently on TRIUMEQ who are
actively trying to become pregnant, or if pregnancy is confirmed in the first
trimester, assess the risks and benefits of continuing TRIUMEQ versus switching
to another antiretroviral regimen and consider switching to an alternative
regimen.
TRIUMEQ
may be considered during the second and third trimesters of pregnancy if the
expected benefit justifies the potential risk to the pregnant woman and the
fetus.
8
Use in Specific Populations
8.1 Pregnancy
(additions and/or
revisions are underlined)
Pregnancy
Exposure Registry
There
is a pregnancy exposure registry that monitors pregnancy outcomes in
individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are
encouraged to register patients by calling the Antiretroviral Pregnancy
Registry (APR) at 1-800-258-4263.
Risk
Summary
Data
from a birth outcome surveillance study has identified an
increased risk of neural tube defects when dolutegravir, a component of
TRIUMEQ, is administered at the time of conception compared with
non-dolutegravir-containing antiretroviral regimens. As defects related to
closure of the neural tube occur from conception through the first 6 weeks of
gestation, embryos exposed to dolutegravir from the time of conception through
the first 6 weeks of gestation are at potential risk. In addition, 2 of the 5
birth defects (encephalocele and iniencephaly), which have been observed with
dolutegravir use, although often termed neural tube defects, may occur
post-neural tube closure, the time period of which may be later than 6 weeks of
gestation, but within the first trimester. Due to the limited understanding of
the types of reported neural tube defects associated with dolutegravir use and
because the date of conception may not be determined with precision, an
alternative treatment to TRIUMEQ should be considered at the time of
conception through the first trimester of pregnancy. Initiation of TRIUMEQ
is not recommended in adolescents and adults actively trying to become
pregnant unless there is no suitable alternative.
In
adolescents and adults of childbearing potential currently on TRIUMEQ who are
actively trying to become pregnant, or if pregnancy is confirmed in the
first trimester, assess the risks and benefits of continuing TRIUMEQ versus
switching to another antiretroviral regimen and consider switching to an
alternative regimen. Advise pregnant adolescents and adults of the potential
risk to the embryo exposed to TRIUMEQ from the time of conception through the
first trimester of pregnancy. A benefit-risk assessment should consider
factors such as feasibility of switching, tolerability, ability to maintain
viral suppression, and risk of transmission to the infant against the risk of
neural tube defects.
…
Data
Human Data: Dolutegravir:
In
a
birth outcome surveillance study in Botswana, there were 5 cases of
neural tube defects reported out of 1,683 deliveries (0.3%) to women
who were exposed to dolutegravir-containing regimens at the time of conception.
In comparison, the neural tube defect prevalence rates were 0.1% (15/14,792
deliveries) in the non-dolutegravir arm and 0.08% (70/89,372 deliveries)
in the HIV-uninfected arm. Five cases reported with dolutegravir
included one case each of encephalocele, anencephaly, and iniencephaly, and
2 cases of myelomeningocele. In the same study, one infant out of 3,840
(0.03%) deliveries to women who started dolutegravir during
pregnancy had a neural tube defect, compared with 3 infants out of 5,952
(0.05%) deliveries to women who started non-dolutegravir-containing regimens
during pregnancy.
Data
analyzed to date from other sources including the APR, clinical trials, and
postmarketing data are insufficient to address the risk of neural tube defects
with dolutegravir.
Data
from the birth outcome surveillance study described above and postmarketing
sources with more than 1,000 pregnancy outcomes from second and third trimester
exposure in pregnant women indicate no evidence of increased risk of adverse
birth outcomes.
…
8.3 Females and Males of Reproductive Potential
(additions and/or
revisions are underlined)
Pregnancy
Testing
Perform
pregnancy testing in adolescents and adults of childbearing potential before
initiation of TRIUMEQ.
Contraception
In adolescents and
adults of childbearing potential currently on TRIUMEQ who are
actively trying to become pregnant, or if pregnancy is confirmed in the first
trimester, assess the risks and benefits of continuing TRIUMEQ versus switching
to another antiretroviral regimen and consider switching to an alternative
regimen.
Counsel adolescents and
adults of childbearing potential who are taking TRIUMEQ to consistently use
effective contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions and/or
revisions are underlined)
…
Before you take TRIUMEQ,
tell your healthcare provider about all of your medical conditions, including if
you:
have
been tested and know whether or not you have a particular gene variation called
HLA-B*5701.
have
or have had liver problems, including hepatitis B or C virus infection.
have
kidney problems.
have
heart problems, smoke, or have diseases that increase your risk of heart disease
such as high blood pressure, high cholesterol, or diabetes.
drink
alcohol or take medicines that contain alcohol.
are
pregnant or plan to become pregnant. One of the medicines in TRIUMEQ called dolutegravir
may harm your unborn baby.
Your healthcare provider may prescribe a different medicine
than TRIUMEQ if you are planning
to become pregnant
or if pregnancy
is confirmed during the first 12 weeks of pregnancy.
If you can become pregnant, your healthcare provider will perform a pregnancy test before you start treatment
with TRIUMEQ.
If you can become
pregnant, you should
consistently use effective
birth control (contraception) during treatment with TRIUMEQ.
Tell your healthcare provider
right away if you are planning to become pregnant,
you become pregnant,
or think you may be pregnant during
treatment with TRIUMEQ.
…
PATIENT COUNSELING INFORMATION
(additions and/or
revisions are underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
Drug
Interactions
TRIUMEQ
may interact with many drugs; therefore, 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.
Hypersensitivity
Reaction
Inform patients:
that
a Medication Guide and Warning Card summarizing the symptoms of the abacavir
hypersensitivity reaction and other product information will be dispensed by
the pharmacist with each new prescription and refill of TRIUMEQ, and instruct
the patient to read the Medication Guide and Warning Card every time to obtain
any new information that may be present about TRIUMEQ. The complete text of the
Medication Guide is reprinted at the end of this document.
to
carry the Warning Card with them.
- how
to identify a hypersensitivity reaction.
- that
if they develop symptoms consistent with a hypersensitivity reaction they
should call their healthcare provider right away to determine if they should
stop taking TRIUMEQ.
- that
a hypersensitivity reaction can worsen and lead to hospitalization or death if
TRIUMEQ is not immediately discontinued.
- to
not restart TRIUMEQ or any other abacavir-containing product following a
hypersensitivity reaction because more severe symptoms can occur within hours
and may include life-threatening hypotension and death.
- that
if they have a hypersensitivity reaction, they should dispose of any unused
TRIUMEQ to avoid restarting abacavir.
- that
a hypersensitivity reaction is usually reversible if it is detected promptly
and TRIUMEQ is stopped right away.
- that
if they have interrupted TRIUMEQ for reasons other than symptoms of
hypersensitivity (for example, those who have an interruption in drug supply),
a serious or fatal hypersensitivity reaction may occur with reintroduction of
abacavir.
- to
not restart TRIUMEQ or any other abacavir-containing product without medical
consultation and only if medical care can be readily accessed by the patient or
others.
- to
not restart TRIUMEQ or any other dolutegravir-containing product following a
hypersensitivity reaction to TRIUMEQ.
Hepatotoxicity
Inform
patients that hepatotoxicity has been reported with dolutegravir, a component
of TRIUMEQ. Inform patients that monitoring for hepatotoxicity during therapy
with TRIUMEQ is recommended.
Posttreatment
Exacerbations of Hepatitis in Patients with Hepatitis B Co-infection
Advise
patients co-infected with HIV-1 and HBV that worsening of liver disease has
occurred in some cases when treatment with lamivudine was discontinued. Advise
patients to discuss any changes in regimen with their physician.
Lactic
Acidosis/Hepatomegaly
Inform
patients that some HIV medicines, including TRIUMEQ, can cause a rare, but
serious condition called lactic acidosis with liver enlargement (hepatomegaly).
Embryo-Fetal
Toxicity
Advise
adolescents and adults of childbearing potential to consider an alternative
treatment to TRIUMEQ at the time of conception through the first trimester
of pregnancy. Advise adolescents and adults of childbearing potential to
contact their healthcare provider if they plan to become pregnant, become
pregnant, or if pregnancy is suspected during treatment with TRIUMEQ.
Counsel adolescents and
adults of childbearing potential taking TRIUMEQ to consistently use effective
contraception.
Immune
Reconstitution Syndrome
Advise
patients to inform their healthcare provider immediately of any signs and
symptoms of infection as inflammation from previous infection may occur soon
after combination antiretroviral therapy, including when TRIUMEQ is started.
Pregnancy
Registry
Inform
patients that there is an antiretroviral pregnancy registry to monitor fetal
outcomes in those exposed to TRIUMEQ during pregnancy.
Lactation
Instruct
mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to
the baby in the breast milk.
Missed
Dose
Instruct
patients that if they miss a dose of TRIUMEQ, to take it as soon as they
remember. Advise patients not to double their next dose or take more than the
prescribed dose.
Availability
of Medication Guide
Instruct
patients to read the Medication Guide before starting TRIUMEQ and to re-read it
each time the prescription is renewed. Instruct patients to inform their
physician or pharmacist if they develop any unusual symptom, or if any known
symptom persists or worsens.
Storage
Instruct
patients to store TRIUMEQ in the original package, protect from moisture, and
keep the bottle tightly closed. Do not remove desiccant.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Embryo-Fetal Toxicity
(Newly added subsection)
Preliminary data from an observational study showed that dolutegravir, a component of TRIUMEQ,
was associated with increased
risk of neural tube defects when administered
at the time of conception and in early pregnancy. As
there is limited understanding of reported types of neural tube defects associated
with dolutegravir use and because the date of
conception may not be determined with precision, avoid
use of TRIUMEQ at the time of
conception through the first trimester
of pregnancy.
If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on TRIUMEQ,
if possible, switch to an alternative regimen.
Perform pregnancy testing
before initiation of TRIUMEQ in adolescents and adults
of childbearing potential
to exclude use of TRIUMEQ during the first trimester of pregnancy.
Advise adolescents and adults of childbearing potential to consistently use effective
contraception.
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are underlined)
There is a pregnancy exposure registry that
monitors pregnancy outcomes in individuals
exposed to TRIUMEQ during pregnancy.
Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry
(APR) at 1-800-258-4263.
Risk Summary
Preliminary data from an observational study has identified a possible
increased risk of neural
tube defects when dolutegravir,
a component
of TRIUMEQ, is administered
at the time of conception
compared with non-dolutegravir-containing antiretroviral
regimens. As defects related
to closure of the neural tube occur
from conception through the first 6 weeks of
gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of
gestation are at
potential risk. In addition, 2 of the 4 birth defects
(encephalocele and iniencephaly),
which have been observed with
dolutegravir use, although
often termed neural tube defects, may occur post-neural
tube closure, the time period of which may be later than 6 weeks of gestation,
but within the first trimester.
Due to the limited understanding of the types of reported
neural tube defects associated with dolutegravir
use and because the date of
conception may not
be determined with precision, avoid use of
TRIUMEQ at the time of
conception through the
first trimester of pregnancy. No neural tube defects have been reported
in infants born to
mothers who have
started dolutegravir after the first trimester
of pregnancy (see
Data).
If there are plans to become pregnant or if pregnancy is confirmed while on
TRIUMEQ during the
first trimester, if possible, switch to an alternative regimen. Advise pregnant adolescents and adults of
the potential risk to the embryo exposed to TRIUMEQ
from the time of conception through the first
trimester of pregnancy.
There are insufficient
human data on the use of
TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth
defects and miscarriage. The background risk for
major birth defects for the
indicated population is unknown.
In the U.S. general population, the estimated
background rate for major birth
defects and miscarriage in clinically recognized pregnancies
is 2% to 4% and
15% to 20%, respectively.
In animal reproduction
studies, no evidence of adverse developmental
outcomes was observed with dolutegravir at systemic exposures
(AUC) less than (rabbits)
and approximately 50 times
(rats) the exposure
in humans at the recommended
human dose (RHD).
Oral administration of abacavir to pregnant rats during organogenesis
resulted in fetal malformations and other embryonic
and fetal toxicities at exposures 35 times the
human exposure (AUC) at the RHD. No adverse
developmental effects were
observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times
the human exposure (AUC)
at the RHD. Oral administration of lamivudine to pregnant
rabbits during organogenesis
resulted in embryolethality at a human
exposure (AUC) similar to the RHD; however,
no adverse development
effects were observed with oral
administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times
the RHD (see
Data).
Data
Human Data: Dolutegravir: As
of May 2018, in an ongoing birth outcome surveillance
study in Botswana,
there have been 4 cases of neural tube defects reported out
of 426 births (0.94%) to mothers
who were exposed to dolutegravir-containing regimens at
the time of conception. In comparison,
the neural tube defect prevalence rates
were 0.12% (14/11,300) in the non- dolutegravir arm and 0.09% (61/66,057) in the HIV-uninfected arm. Four
cases reported with dolutegravir included one case each of
encephalocele, anencephaly, myelomeningocele, and iniencephaly. No infant born to a woman who
started dolutegravir during pregnancy had a
neural tube defect (n
= 2,812).
Data analyzed to date from
other sources including the
APR, clinical trials, and postmarketing data are insufficient to address the risk of neural tube defects with dolutegravir.
…
8.2 Lactation
(Additions and/or revisions are
underlined)
Risk Summary
The Centers for Disease
Control and Prevention
recommends that HIV-1-infected
mothers in the United States
not breastfeed their infants to avoid risking postnatal
transmission of HIV-1 infection.
Abacavir and
lamivudine are present in human milk. When administered to lactating
rats, dolutegravir was present in
milk. There is
no information on the effects of TRIUMEQ or its components
on the breastfed infant or the effects of the drug on milk
production.
Because of the
potential for (1) HIV-1
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 TRIUMEQ.
Data
Animal Data: Dolutegravir
was the primary drug-related component excreted into the milk of lactating rats
following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3
times that of maternal plasma
concentrations observed 8 hours
postdose.
8.3 Females and Males of Reproductive Potential
(Newly added subsection)
Pregnancy Testing
Perform pregnancy testing
in adolescents and adults of
childbearing potential before initiation of TRIUMEQ.
Contraception
Adolescents
and
adults of childbearing potential should avoid use
of TRIUMEQ at the time of conception
through the first trimester of pregnancy because of the potential risk of neural tube defects.
Advise adolescents and adults of childbearing potential who are taking TRIUMEQ to consistently use effective contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
…
Embryo-Fetal
Toxicity
Advise adolescents and adults of childbearing potential to avoid use of TRIUMEQ at the time of conception
through the first trimester of pregnancy. Advise adolescents
and adults of childbearing potential
to contact
their healthcare provider if they plan
to become pregnant, become
pregnant, or if pregnancy is suspected during treatment
with TRIUMEQ.
Advise adolescents and adults of childbearing potential taking TRIUMEQ
to consistently use effective
contraception.
…
Pregnancy Registry
Inform patients that there is an antiretroviral
pregnancy registry to monitor fetal outcomes in those exposed to TRIUMEQ
during pregnancy.
Lactation
Instruct mothers with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in the breast milk.
….
MEDICATION GUIDE TRIUMEQ (TRI-u-meck)
(Additions and/or revisions are underlined)
Before you take TRIUMEQ,
tell your healthcare provider about all of your medical conditions, including
if you:
have been tested and know whether or not
you have a particular gene variation
called HLA-B*5701.
have or have had liver problems, including hepatitis B or C virus infection.
have kidney problems.
have heart problems, smoke, or
have diseases that increase your risk of heart disease such as high blood
pressure, high cholesterol, or diabetes.
drink alcohol or take medicines
that contain alcohol.
are pregnant or plan to become
pregnant. One of the medicines in TRIUMEQ called dolutegravir may
harm your unborn baby.
- You
should not take TRIUMEQ at the time of becoming pregnant or during the first 12
weeks of pregnancy. Your
healthcare provider may change your medicine during this time in your
pregnancy.
If
you can become pregnant, your healthcare provider will perform a pregnancy test
before you start treatment with TRIUMEQ.
If
you can become pregnant, you should consistently use effective birth control
(contraception) during treatment with TRIUMEQ.
- Tell
your healthcare provider right away if you are planning to become pregnant, you
become pregnant, or think you may be pregnant during treatment with TRIUMEQ.
Pregnancy Registry.
There is a pregnancy registry
for individuals who take antiretroviral medicines, including TRIUMEQ,
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.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or
revisions underlined:
5.2 Posttreatment Exacerbations of Hepatitis in
Patients with Hepatitis B Co-Infection
5.3 Emergence of Lamivudine-Resistant HBV
5.5 Lactic Acidosis and Severe Hepatomegaly with
Steatosis
Additions and/or revisions underlined:
Lactic acidosis
and severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues, including abacavir and lamivudine
(components of TRIUMEQ). A majority of these cases have been in women.
Female sex and obesity may be risk factors for the development of lactic
acidosis and severe hepatomegaly with steatosis in patients treated with
antiretroviral nucleoside analogues. See full prescribing information … suggestive
of lactic acidosis or pronounced hepatotoxicity, which may include
hepatomegaly and steatosis even in the absence of marked transaminase
elevations.
5.9 Myocardial Infarction
Additions and/or revisions underlined:
Several prospective,
observational, epidemiological studies have reported an association with
the use of abacavir and the risk of myocardial infarction (MI).
Meta-analyses of randomized, controlled clinical trials have observed
no excess risk of MI in abacavir-treated subjects as compared with control
subjects. To date, there is no established biological mechanism to explain a
potential increase in risk. In totality, the available data from the
observational studies and from controlled clinical trials show
inconsistency; therefore, evidence for a causal relationship between
abacavir and the risk of MI is inconclusive …
6
Adverse Reactions
Addition of the following:
7
Drug Interactions
Additions and/or revisions underlined:
7.3 Established and Other Potentially Significant Drug
Interactions
… Information regarding potential drug interactions
with the individual
components of TRIUMEQ
are
provided below
…
Table 5. Established and Other Potentially Significant
Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended
Based on Drug Interaction Newly added
information in table; please see label for complete information.
Addition of the following:
Sorbitol
Lamivudine: Coadministration of single doses of
lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in
lamivudine exposures. When possible, avoid use of sorbitol- containing
medicines with lamivudine-containing medicines.
8
Use in Specific Populations
8.1 Pregnancy
Recommended daily dose replaces RHD in the Lamivudine
section.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Other revisions and reformatting has occurred in this
section; please refer to label for complete information.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Hepatotoxicity
(Additions
and/or revisions are underlined)
Hepatic
adverse events have been reported in patients receiving a
dolutegravir-containing regimen. Patients with underlying hepatitis B or
C may be at increased risk for worsening or development of transaminase
elevations with use of TRIUMEQ. In some cases, the elevations in transaminases
were consistent with immune reconstitution syndrome or hepatitis B reactivation
particularly in the setting where anti-hepatitis therapy was withdrawn. Cases
of hepatic toxicity including elevated serum liver biochemistries, hepatitis,
and acute liver failure have also been reported in patients receiving a
dolutegravir-containing regimen who had no pre-existing hepatic disease or
other identifiable risk factors. Drug-induced liver injury leading to liver
transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is
recommended.
5.4 Posttreatment Exacerbations of Hepatitis in Patients with Hepatitis B Co-infection
(Newly titled
subsection)
5.6 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
(Newly added subsection)
The
concomitant use of TRIUMEQ and other drugs may result in known or potentially
significant drug interactions, some of which may lead to:
- Possible
clinically significant adverse reactions from greater exposures of concomitant
drugs.
See
Table 5 for steps to prevent or manage these possible and known significant
drug interactions, including dosing recommendations. Consider the potential for
drug interactions prior to and during therapy with TRIUMEQ; review concomitant
medications during therapy with TRIUMEQ; and monitor for the adverse reactions
associated with the concomitant drugs.
6
Adverse Reactions
(Additions
and/or revisions are underlined)
The following adverse reactions are
discussed in other sections of the labeling:
6.1 Clinical Trials Experience
(Additions
and/or revisions are underlined)
Clinical
Trials Experience in Pediatric Subjects
Abacavir and
Lamivudine:
The safety of once-daily compared with twice-daily dosing of abacavir and
lamivudine, administered as either single products or as EPZICOM, was assessed
in the ARROW trial (n = 336). Primary safety assessment in the ARROW
(COL105677) trial was based on Grade 3 and Grade 4 adverse events. One event of
Grade 4 hepatitis in the once-daily cohort was considered as uncertain
causality by the investigator and all other Grade 3 or 4 adverse events were
considered not related by the investigator. No additional safety issues were
identified in pediatric subjects compared with historical data in adults.
Dolutegravir: IMPAACT P1093
is a 48-week multicenter, open-label, non-comparative trial of approximately
160 HIV-1-infected pediatric subjects aged 4 weeks to less than 18 years, of
which, 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18
years were enrolled.
The
ADR profile was similar to that for adults. Grade 2 ADRs reported by more than
one subject were decreased neutrophil count (n = 2). No Grade 3 or 4 ADRs were
reported. No ADRs led to discontinuation. The Grade 3 laboratory abnormalities
reported in 1 subject each were elevated total bilirubin, elevated lipase, and
decreased white blood cell count. There was one Grade 4 decreased neutrophil
count. The changes in mean serum creatinine were similar to those observed in adults.
6.2 Postmarketing Experience
(Additions and/or
revisions are underlined)
Hepatobiliary
Disorders
Acute
liver failure, liver transplant.
Psychiatric
Anxiety.
7
Drug Interactions
7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents
(Additions
and/or revisions are underlined)
In
vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the
following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1,
UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile
salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1,
OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4….
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy
and Lactation Labeling Rule (PLLR) conversion; please refer to label)
8.2 Lactation
(Newly
added subsection)
The
Centers for Disease Control and Prevention recommend that HIV-1-infected
mothers in the United States not breastfeed their infants to avoid risking
postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present
in human milk. When administered to lactating rats, dolutegravir was present in
milk (see Data). There is no
information on the effects of TRIUMEQ or its components on the breastfed infant
or the effects of the drug on milk production. Because of the potential for (1)
HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance
(in HIV-positive infants), and (3) serious adverse reactions in a breastfed
infant, instruct mothers not to breastfeed if they are receiving TRIUMEQ.
Data
Animal Data: Dolutegravir was
the primary drug-related component excreted into the milk of lactating rats
following a single oral dose of 50 mg per kg on lactation Day 10, with milk
concentrations of up to approximately 1.3 times that of maternal plasma
concentrations observed 8 hours’ post-dose.
8.4 Pediatric Use
(Additions
and/or revisions are underlined)
The
clinical data supporting use of TRIUMEQ in HIV-1 infected pediatric
patients weighing at least 40 kg is derived from the following previously
conducted pediatric trials using the individual components of TRIUMEQ:
- The safety and
efficacy of once-daily abacavir and lamivudine were established with
a randomized, multicenter trial (ARROW [COL105677]) in HIV-1–infected,
treatment-naïve subjects aged 3 months to 17 years with a first-line regimen
containing abacavir and lamivudine, using either the combination of EPIVIR and
ZIAGEN or EPZICOM.
The
safety and antiviral activity (efficacy) of dolutegravir was established
through a 48-week, open-label, multicenter, dose-finding clinical trial
(IMPAACT P1093), in which treatment-experienced, INSTI-naïve, HIV-1–infected
subjects aged 6 to less than 18 years were treated with dolutegravir (TIVICAY)
plus optimized background therapy.TRIUMEQ is a
fixed-dose combination tablet which cannot be adjusted for patients weighing
less than 40 kg.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
Drug
Interactions
TRIUMEQ
may interact with many drugs; therefore, 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.
Hepatotoxicity
Inform
patients that hepatotoxicity has been reported with dolutegravir, a component of TRIUMEQ.
Inform patients that monitoring for hepatotoxicity during therapy with TRIUMEQ
is recommended.
Posttreatment
Exacerbations of Hepatitis in Patients with Hepatitis B Co-infection
Advise
patients co-infected with HIV-1 and HBV that worsening of liver disease has
occurred in some cases when treatment with lamivudine was discontinued. Advise
patients to discuss any changes in regimen with their physician .
Use
with Interferon- and Ribavirin-Based Regimens in Patients with Hepatitis C
Co-infection
Immune
Reconstitution Syndrome
Advise
patients to inform their healthcare provider immediately of any signs and symptoms
of infection as inflammation from previous infection may occur soon
after combination antiretroviral therapy, including when TRIUMEQ is started.
Pregnancy
Registry
Advise
patients that there is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to TRIUMEQ during pregnancy.
Lactation
Instruct
women with HIV-1 infection not to breastfeed because HIV-1 can be passed
to the baby in the breast milk.
Missed
Dose
Instruct
patients that if they miss a dose of TRIUMEQ, to take it as soon as they
remember. Advise patients not to double their next dose or take more than the
prescribed dose
Availability
of Medication Guide
MEDICATION GUIDE TRIUMEQ (TRI-u-meck) (abacavir, dolutegravir, and lamivudine) tablets
(Extensive
changes; please refer to label)
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