Approved Drug Label (PDF)
7
Drug Interactions
7.2 Riociguat
New subsection
added
Coadministration
with fixed-dose abacavir/dolutegravir/lamivudine 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
Additions and/or
revisions underlind
…
Data
Human Data: 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 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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
underlined
…
Tell your
healthcare provider if you take:
…
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or revisions underlined:
5.2 Lactic Acidosis and Severe Hepatomegaly with
Steatosis
Lactic acidosis and
severe hepatomegaly with steatosis, including fatal cases, have been reported with
the use of nucleoside analogues, including ZIAGEN. 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.
5.4 Myocardial Infarction
Several prospective, observational,
epidemiological studies have reported an association with the use of abacavir
and the risk of sponsomyocardial 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 treatment and the risk of MI is inconclusive.
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or revisions underlined:
5.2 Lactic Acidosis and Severe Hepatomegaly with
Steatosis
Lactic acidosis and
severe hepatomegaly with steatosis, including fatal cases, have been reported with
the use of nucleoside analogues, including ZIAGEN. 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.
5.4 Myocardial Infarction
Several prospective, observational,
epidemiological studies have reported an association with the use of abacavir
and the risk of sponsomyocardial 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 treatment and the risk of MI is inconclusive.
Approved Drug Label (PDF)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING:
HYPERSENSITIVITY REACTIONS, and LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH
STEATOSIS
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are underlined)
Pregnancy
Exposure Registry
Healthcare
Providers are encouraged to
register patients by calling the Antiretroviral Pregnancy Registry (APR)
at 1-800-258-4263.
Risk Summary
Available data from
the APR show no difference in the overall risk of birth defects
for abacavir compared with the background rate for birth defects of 2.7% in the
Metropolitan Atlanta Congenital Defects Program (MACDP) reference
population. The APR uses the MACDP as the U.S. reference population for birth
defects in the general population. The MACDP evaluates women and infants from a
limited geographic area and does not include outcomes for births that occurred
at less than 20 weeks gestation. The rate of miscarriage is not reported in the
APR. The estimated background rate of miscarriage in clinically recognized
pregnancies in the U.S. general population is 15% to 20%. The background risk
for major birth defects and miscarriage for the indicated population is
unknown.
In animal
reproduction studies, 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 recommended clinical daily
dose. However, 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
recommended clinical dose.
Data
Human Data: Based
on prospective reports to the APR of over 2,000 exposures to abacavir
during pregnancy resulting in live births (including over 1,000 exposed in the
first 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 2.9% (95% CI: 2.0% to 4.1%)
following first trimester exposure
to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) 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.
Animal Data: Abacavir was administered orally to pregnant rats (at 100, 300, and
1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day)
during organogenesis (on gestation Days 6 through 17 and 6 through 20,
respectively). Fetal
malformations (increased incidences of fetal anasarca and skeletal
malformations) or developmental toxicity (decreased fetal body
weight and crown-rump length)
were observed in rats at doses up to 1,000 mg per kg per day, resulting in
exposures approximately 35 times the human exposure (AUC) at the
recommended daily dose. No developmental effects were observed in rats at 100
mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at
the recommended daily dose. In a fertility and early embryo-fetal development
study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic
and fetal toxicities (increased resorptions, decreased fetal body weights) or
toxicities to the offspring (increased incidence of stillbirth and lower body
weights) occurred at doses up to 500 mg per kg per day. No developmental
effects were observed in rats at 60 mg per kg per day, resulting in
exposures (AUC) approximately 4 times the human exposure at the recommended
daily dose. Studies in pregnant rats showed that abacavir is transferred to the
fetus through the placenta. In pregnant rabbits, no developmental
toxicities and no increases in fetal malformations occurred at up to the
highest dose evaluated, resulting in exposures (AUC) approximately 9
times the human exposure at the recommended dose.
8.2 Lactation
(Additions and/or revisions are underlined)
Risk Summary
Abacavir is
present in human milk. There is no information on the effects of abacavir 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 ZIAGEN.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Hypersensitivity
Reactions
Inform patients:
Lactic
Acidosis/Hepatomegaly with Steatosis
Advise patients that lactic acidosis and severe
hepatomegaly with steatosis have been reported with use of nucleoside
analogues and other antiretrovirals. Advise patients to stop taking ZIAGEN if
they develop clinical symptoms suggestive of lactic acidosis or pronounced
hepatotoxicity.
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 ZIAGEN is started.
Pregnancy Registry
Advise patients
that there is a pregnancy exposure registry that monitors pregnancy outcomes in
women exposed to ZIAGEN 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 ZIAGEN, 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 ZIAGEN…
MEDICATION GUIDE
(Additions and/or revisions are underlined)
What is the most
important information I should know about ZIAGEN? ZIAGEN can cause serious side
effects, including:
WARNING CARD
(Additions and/or revisions are underlined)
If you have an
allergic reaction, dispose of any unused ZIAGEN. Ask your pharmacist how to
properly dispose of medicines. If you take ZIAGEN or another abacavir-containing medicine again after
you have had an allergic reaction, WITHIN HOURS you may get life-threatening
symptoms that may include very low blood pressure or death…
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