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topicId=teratogenicityEffectsInPregnancyBreastfeedingSection
A) Teratogenicity/Effects in Pregnancy
1) U.S. Food and Drug Administration's Pregnancy Category: Category B (All
Trimesters)
a) Either animal-reproduction studies have not demonstrated a fetal risk but there
are no controlled studies in pregnant women or animal-reproduction studies have
shown adverse effect (other than a decrease in fertility) that was not confirmed in
controlled studies in women in the first trimester (and there is no evidence of a risk
in later trimesters).
2) Australian Drug Evaluation Committee's (ADEC) Category: C
a) Drugs which, owing to their pharmacological effects, have caused or may be
suspected of causing harmful effects on the human fetus or neonate without causing
malformations. These effects may be reversible. Accompanying texts should be
consulted for further details.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
3) Crosses Placenta: Unknown
4) Clinical Management
a) Although oral hypoglycemic drugs are not always recommended during
pregnancy, abnormal blood glucose levels during pregnancy may be associated with
a higher incidence of congenital abnormalities [306]. Insulin is useful during
pregnancy for both pregestational (IDDM and NIDDM) and gestational forms of
diabetes because of the need for precise control of maternal glucose levels and the
limited information regarding fetal effects of some of the oral hypoglycemics
[307][308]. Glyburide may be a clinically effective alternative to insulin in women
with gestational diabetes [309]. However, other oral hypoglycemic agents may differ
with regard to transplacental effects and their safety in pregnancy remains to be
established.
5) Literature Reports
a) There are no reported cases of congenital malformations associated with
metformin. A retrospective study of 20 women with NIDDM who became pregnant
while using oral hypoglycemic agents were compared with 40 matched controls
(NIDDM patients who did not use oral hypoglycemics during early pregnancy) [301].
Overall, ten (50%) of the infants exposed to oral hypoglycemic agents had
congenital malformations, which was significantly higher than the rate in controls
(15%). Five (25%) of the chlorpropamide-exposed infants had ear malformations,
however, the same type of ear malformation has been reported in the infant of an
insulin-dependent mother [302]. Although this retrospective study suggests an
increase in congenital malformations due to the oral hypoglycemics above the
expected rate in NIDDM patients, the issue of glucose control over the first eight
weeks of gestation was not effectively addressed [303].
b) Diabetes mellitus in pregnant women is associated with a 3-fold increase in
congenital anomalies that include cardiac malformations, lumbosacral agenesis,
hyperbilirubinemia, polycythemia, and renal vein thrombosis. Offspring of diabetic
mothers have a mortality rate that is 5 times greater than that of nondiabetic
mothers; the mortality rate is higher at all gestational ages [304].
c) Based upon results achieved over a 5-year period which evaluated the
administration of oral hypoglycemic agents during the first trimester of pregnancy,
sulfonylurea agents and biguanides can be used safely in early pregnancy provided
that excellent control of hyperglycemia is maintained [305]. Agents evaluated were
chlorpropamide, tolbutamide, glyburide, phenformin, metformin, and buformin.
B) Breastfeeding
1) World Health Organization Rating: WHO documentation states insufficient data.
2) Thomson Lactation Rating: Infant risk is minimal.
a) The weight of an adequate body of evidence and/or expert consensus suggests
this drug poses minimal risk to the infant when used during breastfeeding.
3) Clinical Management
a) According to published reports, maternal administration of metformin appears to
be safe for the nursing infant. Metformin is transferred into human milk in very low
concentrations; adverse effects were not reported in any of the infants exposed to
metformin in breastmilk.
4) Literature Reports
a) Metformin is excreted in breast milk, but no adverse effects were seen in the 3
infants exposed to the drug through breastfeeding. In a prospective study of 5
women with non-insulin-dependent diabetes mellitus who were prescribed
metformin 500 mg twice a day, peak and trough milk and serum drug levels, as well
as the infants' blood glucose concentrations, were measured to determine the extent
of excretion of metformin and any adverse effects on the infant. Mean milk to serum
ratio was 0.63, there was minimal variation between milk concentrations over a 12hour period, and the mean infant dose was 0.65% of the mother's weight-adjusted
dose. Infant blood glucose concentrations were within normal range and the
mothers reported no adverse effects [311].
b) The transfer of metformin into human milk was described in a study involving
seven breastfeeding women and their infants. The median dose for the women was
1500 mg/day, administered orally. Both plasma and breastmilk samples were drawn
over several time points, with the mean milk:plasma ratio calculated at 0.35 and the
mean absolute infant dose estimated to be 0.04mg/kg/day [312]. No health
problems in the infants were reported.
c) Metformin therapy was concluded to be compatible with breastfeeding, based on
a study in 3 nursing mothers taking metformin for diabetes and 2 suckling infants,
plus a single-dose (500-mg) study in 5 healthy lactating female volunteers. The
amount of metformin distributed into breastmilk resulted in an median infant dose of
0.20% (range 0.11% to 0.25%) of the weight-adjusted maternal dose. The milk to
plasma concentration ratio was median 0.47, with a range of 0.27 to 0.71. In the 2
nursing infants breastfeeding from mothers taking metformin (500 mg twice daily),
metformin was undetectable in the infants' plasma. The 2 infants exhibited no
adverse effects, such as gastrointestinal distress, diarrhea, or failure to thrive. In 3
of the nursing mothers, peak plasma concentrations of metformin were 0.5 to 0.7
mg/L at 2 to 4 hours after dose ingestion. Concentrations of metformin in breast
milk ranged from 0.13 to 0.27 mg/L, and showed a generally flat, level concentration
curve [313].