Additions and/or
revisions underlined:
5.1 Fetal Toxicity
Lotrel
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. Resulting oligohydramnios …
5.2 Angioedema
and Anaphylactoid Reactions
Head and Neck Angioedema:
Angioedema
of the face … in patients treated with benazepril. This may occur at any
time during treatment. Angioedema associated with edema of the larynx, tongue,
or glottis can compromise the airway and be fatal. If laryngeal stridor or
angioedema of the face, tongue, or glottis occurs, discontinue treatment with Lotrel
and treat immediately.
Patients
with a history of angioedema may be at increased risk for angioedema while receiving
Lotrel.
Black patients receiving ACE inhibitors have a higher incidence of angioedema compared
to nonblacks.
5.4 Hypotension
Lotrel
can cause symptomatic hypotension, sometimes complicated by oliguria, progressive
azotemia, acute renal failure, or death. Symptomatic hypotension is most likely
to occur in patients who have heart failure, severe aortic or mitral stenosis,
obstructive hypertrophic cardiomyopathy or have been volume or salt depleted
as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or
vomiting. Correct volume and salt depletion before starting therapy with
benazepril. If hypotension occurs, place the patient in the supine position
and give physiological saline intravenously if needed. Continue treatment
with benazepril once blood pressure and volume have returned to normal.
In
patients with congestive heart failure …
8.1 Pregnancy
PLLR conversion;
additions and/or revisions underlined:
Risk
Summary
Lotrel
can cause fetal harm when administered to a pregnant woman. Use of drugs that act
on the RAS 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 RAS from other antihypertensive
agents.
When
pregnancy is detected, discontinue Lotrel 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 2-4% and 15- 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.
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 Lotrel for hypotension, oliguria, and hyperkalemia. In neonates
with a history of in utero exposure to
Lotrel, 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
Benazepril and Amlodipine:
When
rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day,
dystocia was observed at an increasing dose-related incidence at all doses tested.
On a body surface area basis, the 2.5 mg/kg/day dose of amlodipine is twice the
amlodipine dose delivered when the maximum recommended dose of Lotrel is given to
a 60 kg patient.
Similarly,
the 5 mg/kg/day dose of benazepril is approximately equivalent with the benazepril
dose delivered when the maximum recommended dose of Lotrel is given to a 60 kg patient.
No teratogenic effects were seen when benazepril and amlodipine were administered
in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg
(benazepril:amlodipine)/kg/day (12 times the MRHD on a body surface area basis,
assuming a 60 kg patient). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent
to the maximum recommended dose of Lotrel given to a 60 kg patient).
8.2 Lactation
PLLR conversion;
additions and/or revisions underlined:
Risk
Summary
Minimal
amounts of unchanged benazepril and of benazeprilat are excreted into the breast
milk of lactating women treated with benazepril, so that a newborn child ingesting
nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril
and benazeprilat. Limited available data
from a published clinical lactation study reports that amlodipine is present in
human milk at an estimated median relative infant dose of 4.2%. No adverse effects
of amlodipine on the breastfed infant have been observed. There is no available
information on the effects of amlodipine or benazepril
on milk production.
8.4 Pediatric Use
Additions and/or
revisions underlined:
Safety
and effectiveness in pediatric patients have not been established.
Additions and/or
revisions underlined:
Pregnancy: Advise female patients of
childbearing age about the consequences of exposure to Lotrel during pregnancy.
Discuss treatment options with women planning to become pregnant. Ask patients
to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.5) and Use
in Specific Populations (8.1)].
Symptomatic Hypotension:
Advise
patients that lightheadedness can occur, especially during the first days of therapy,
and that it should be reported to their healthcare provider. Tell patients that
if syncope occurs to discontinue Lotrel until the physician has been consulted.
Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea,
or vomiting can lead to an excessive fall in blood pressure, with the same consequences
of lightheadedness and possible syncope [see
Warnings and Precautions (5.3)].
Hyperkalemia: Advise patients
not to use salt substitutes without consulting their healthcare provider [see Drug Interactions (7)].
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