(additions
underlined)
Pioglitazone
Tumors were observed in the
urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. In addition,
during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%)
randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to
placebo were diagnosed with bladder cancer. After excluding patients in
whom exposure to study drug was less than one year at the time of diagnosis of
bladder cancer, there were 6 (0.23%) cases on pioglitazone and two
(0.08%) cases on placebo. After completion of the trial, a large subset of
patients was observed for up to 10 additional years, with little additional
exposure to pioglitazone. During the 13 years of both PROactive and
observational follow-up, the occurrence of bladder cancer did not differ
between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI:
0.59–1.72]).Findings regarding the risk of bladder cancer in patients exposed
to pioglitazone vary among observational studies; some did not find an
increased risk of bladder cancer associated with pioglitazone, while others
did.
A large prospective
10-year observational cohort study conducted in the United States found no
statistically significant increase in the risk of bladder cancer in diabetic
patients ever exposed to pioglitazone, compared to those never
exposed to pioglitazone (HR=1.06 [95% CI 0.89–1.26]).
A retrospective
cohort study conducted with data from the United Kingdom found a statistically
significant association between ever exposure to pioglitazone and bladder
cancer (HR: 1.63; [95% CI: 1.22–2.19]).
Associations
between cumulative dose or cumulative duration of exposure to pioglitazone and
bladder cancer were not detected in some studies including the 10- year
observational study in the U.S., but were in others. Inconsistent findings and
limitations inherent in these and other studies preclude conclusive
interpretations of the observational data..
Pioglitazone may be associated with an increase in
the risk of urinary bladder tumors.
There are insufficient data to determine whether pioglitazone is a tumor
promoter for urinary bladder tumors.
Consequently, DUETACT should
not be used in patients with active bladder cancer and the benefits of glycemic
control versus unknown risks for cancer recurrence with DUETACT should be
considered in patients with a prior history of bladder cancer.
(PLLR conversion)
Risk Summary
imited data with DUETACT or
pioglitazone in pregnant women are not sufficient to determine a
drug-associated risk for major birth defects or miscarriage. There are clinical
considerations related to fetal and neonatal adverse reactions and drug
discontinuation if glimepiride is used during pregnancy. There are risks to the
mother and fetus associated with poorly controlled diabetes in pregnancy.
No adverse developmental
effects were observed when pioglitazone was administered to pregnant rats and
rabbits during organogenesis at exposures up to 5- and 35- times the 45 mg
clinical dose, respectively, based on the body surface areaob. Administration
of glimepiride to pregnant rats and rabbits during organogenesis induced
maternal hypoglycemia and also increased fetal mortality at doses 50 (rats) and
0.1-times (rabbits) the 8 mg clinical dose, respectively, based on body surface
area [see Data].
The estimated background risk
of major birth defects is 6-10% in women with pre- gestational diabetes with a
HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c
>10. The estimated background risk of miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20% respectively.
Clinical
Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy
increases the maternal risk for diabetic ketoacidosis, pre-eclampsia,
spontaneous abortions, preterm delivery, still birth and delivery
complications. Poorly controlled diabetes increases the fetal risk for major
birth defects, still birth, and macrosomia related morbidity.
Fetal/Neonatal Adverse Reaction
Neonates of women with
gestational diabetes, who are treated with sulfonylureas during pregnancy, may
be at increased risk for neonatal intensive care unit admission, and
may develop respiratory distress,
hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10
days, has been reported in neonates Page 23 of 49born to mothers receiving a
sulfonylurea at the time of delivery and has been reported with the use of
agents with a prolonged half-life. Observe newborns for symptoms of
hypoglycemia and respiratory distress and manage accordingly.
Dose adjustments during pregnancy and the postpartum
period
Due to reports of prolonged
severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the
time of delivery, DUETACT should be discontinued at least two weeks before
expected delivery [see Fetal/Neonatal
Adverse Reaction].
Data
Animal Data
Pioglitazone and Glimepiride
Animal reproduction studies
were not conducted with the combined products in DUETACT. The following data
are based on studies conducted with the individual components of DUETACT.
Pioglitazone
ioglitazone administered to
pregnant rats during organogenesis did not cause adverse developmental effects
at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed
parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ?9-times
the 45 mg clinical dose, by body surface area. In pregnant rabbits administered
pioglitazone during organogenesis, no adverse developmental effects were
observed at
80 mg/kg (~35-times the 45 mg
clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times
the 45 mg clinical dose, by body surface area. When pregnant rats received
pioglitazone during late gestation and lactation, delayed postnatal
development, attributed to decreased body weight occurred in offspring at
maternal
doses of 10 mg/kg and above or
?2 times the 45 mg clinical dose, by body surface area.
Glimepiride
Fetal deaths occurred in rats
and rabbits administered glimepiride during the period of organogenesis at
doses 50-times (rats) and 0.1-times (rabbits) the 8 mg clinical dose, based on
body surface area. This fetotoxicity, observed only at doses inducing maternal
hypoglycemia, is believed to be directly related to the pharmacologic
(hypoglycemic) action of glimepiride and has been similarly noted with other
sulfonylureas.
(PLLR
conversion)
Risk Summary
here is no information
regarding the presence of pioglitazone or glimepiride in human milk, the
effects on the breastfed infant, or the effects on milk production.
Pioglitazone and glimepiride are present in rat milk; however, due to
species-specific differences in lactation physiology, animal data may not
reliably predict drug levels in human milk [see
Data].
The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for DUETACT and any potential adverse effects on the breastfed infant from
DUETACT or from the underlying maternal condition.
Data
During pre- and postnatal
studies in rats, glimepiride was present in lactational milk and in serum of
nursing rat pups. Offspring exposed to high levels of glimepiride during lactation
developed skeletal abnormalities (shortening, thickening and bending of the
humerus) during the postnatal period.
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