6.2
Postmarketing Experience
Additions
and/or revisions underlined:
The
following additional adverse reactions have been reported in postmarketing use
of valsartan. 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.
Hypersensitivity: Angioedema has been reported. Some of these
patients previously experienced angioedema with other drugs, including ACE
inhibitors. Valsartan should not be re-administered to patients who have had
angioedema.
Digestive: Elevated liver enzymes and very rare reports of
hepatitis
Musculoskeletal: Rhabdomyolysis
Renal: Impaired renal function, renal failure
Dermatologic: Alopecia, bullous dermatitis
Blood and Lymphatic: Thrombocytopenia.
Vascular: Vasculitis
7.1 Agents Increasing
Serum Potassium
Additions
and/or revisions underlined:
Concomitant
use of valsartan with other agents that block the renin-angiotensin system,
potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride),
potassium supplements, salt substitutes containing potassium or other drugs
that may increase potassium levels (e.g., heparin) may lead to increases in
serum potassium and in heart failure patients to increases in serum creatinine.
If co-medication is considered necessary, monitoring of serum potassium is
advisable.
8.1
Pregnancy
Additions
and/or revisions underlined:
Risk
Summary
PREXXARTAN™
can cause fetal harm when administered to a pregnant woman. Use of drugs that
act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal
morbidity and death. Most epidemiologic studies examining fetal abnormalities
after exposure to antihypertensive use in the first trimester have not
distinguished drugs affecting the renin-angiotensin system from other
antihypertensive agents. Published reports include cases of anhydramnios and
oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations). Studies in rats and rabbits with
valsartan showed fetotoxicity only at maternally toxic doses (see Data).
When
pregnancy is detected, consider alternative drug treatment and
discontinue PREXXARTAN™ as soon as possible.
The
estimated background risk of major birth defects and miscarriage for the
indicated population is unknown. All pregnancies have a background risk of
birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2 to 4%, and 15 to 20%, respectively.
Clinical
Considerations
Disease-associated
maternal and/or embryo/fetal risk
Hypertension
in pregnancy increases the maternal risk for pre-eclampsia, gestational
diabetes, premature delivery, and delivery complications (e.g., need for
cesarean section, and post-partum hemorrhage). Hypertension increases the fetal
risk for intrauterine growth restriction and intrauterine death. Pregnant women
with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal
Adverse Reactions
Oligohydramnios
in pregnant women who use drugs affecting the renin-angiotensin system in the
second and third trimesters of pregnancy can result in the following: reduced
fetal renal function leading to anuria and renal failure, fetal lung
hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and
death. In the unusual case that there is no appropriate alternative to therapy
with drugs affecting the renin-angiotensin system for a particular patient,
apprise the mother of the potential risk to the fetus.
In
patients taking PREXXARTAN™ during pregnancy, perform serial ultrasound
examinations to assess the intra-amniotic environment. Fetal testing may be
appropriate, based on the week of gestation. Patients and physicians should be
aware, however, that oligohydramnios may not appear until after the fetus has
sustained irreversible injury. If oligohydramnios is observed, consider
alternative drug treatment. Closely observe neonates with histories
of in utero exposure to PREXXARTAN™
for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to PREXXARTAN™, if
oliguria or hypotension occurs, support blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing
hypotension and replacing renal function.
Data
Animal Data
No
teratogenic effects were observed when valsartan was administered to pregnant
mice and rats at oral doses of up to 600 mg/kg/day (9 and 18 times
the maximum recommended human dose (MRHD) on a mg/m2 basis)
and to pregnant rabbits at oral doses of up to 10 mg/kg/day.
In
rats, oral valsartan administered at maternally toxic doses (600
mg/kg/day) during organogenesis or late gestation and lactation, resulted
in decreased fetal and pup weight, pup survival and delayed
developmental milestones. In rabbits administered maternally toxic doses
of 5 and 10 mg/kg/day, fetotoxicity was observed.
8.2
Lactation
Additions
and/or revisions underlined:
.
. .
Data
Valsartan
was detected in the milk of lactating rats 15 minutes after oral
administration of a 3 mg/kg dose.
8.5 Geriatric Use
Additions
and/or revisions underlined:
.
. .
Exposure
[measured by area under the curve (AUC)] to valsartan is higher by 70% in the
elderly than in the young, however no dosage adjustment is necessary [see Clinical Pharmacology (12.3)].
.
. .
8.6
Renal Impairment
Additions
and/or revisions underlined:
Safety
and effectiveness of valsartan in patients with severe renal impairment (glomerular
filtration rate less than 30 mL/min/1.73m2) have not been
established. No dose adjustment is required in patients with mild (glomerular
filtration rate 60 to 90 mL/min/1.73m2) or moderate (glomerular
filtration rate 30 to 60 mL/min/1.73m2) renal impairment.
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