Approved Drug Label (PDF)
Boxed Warning
5
Warnings and Precautions
5.1 ‘Abrupt
Cessation of Therapy’ replaces ‘Cardiac Ischemia after Abrupt Discontinuation’
Additions and/or revisions underlined:
5.4 Bradycardia
Bradycardia, including sinus pause, heart block, and
cardiac arrest have occurred with the use of Dutoprol. Patients with
first-degree atrioventricular block, sinus node dysfunction, conduction
disorders (including Wolff-Parkinson-White) or on concomitant drugs that
cause bradycardia [see Drug Interactions
(7.1)] may be at increased
risk. Monitor heart rate in patients receiving Dutoprol. If severe bradycardia
develops, reduce or stop Dutoprol.
5.10 Pheochromocytoma
If DUTOPROL is used in the setting of pheochromocytoma,
it should be given in combination with an alpha blocker, and only after the
alpha blocker has been initiated. Administration of beta-blockers alone in the
setting of pheochromocytoma has been associated with a paradoxical increase
in blood pressure due to the attenuation of beta-mediated vasodilatation
in skeletal muscle.
Newly added subsection:
5.12 Anaphylactic Reaction
While taking beta-blockers, patients with a history of
severe anaphylactic reactions to a variety of allergens may be more reactive to
repeated challenge and may be unresponsive to the usual doses of epinephrine
used to treat an allergic reaction.
6
Adverse Reactions
Newly added information:
The following adverse reactions are
described elsewhere in labeling:
Worsening angina or myocardial infarction. [see
Warnings and Precautions (5)]
Worsening heart failure. [see Warnings and Precautions
(5)]
Worsening A V block. [see Contraindications (4)]
6.2 Post-Marketing Experience
Metoprolol
Additions and/or revisions underlined:
Cardiovascular: Shortness of
breath, bradycardia, cold extremities; arterial insufficiency (usually of the
Raynaud type), palpitations, peripheral edema, syncope, chest pain, hypotension.
Respiratory: Dyspnea, wheezing
(bronchospasm).
Miscellaneous: Musculoskeletal
pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus,
reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis,
Peyronie’s disease, sweating, photosensitivity, taste disturbance, depression.
Potential Adverse Reaction: In addition,
adverse reactions not listed above, that have been reported with other
beta-adrenoceptor blockers and should be considered potential adverse reactions
to DUTOPROL.
Hematologic:
Non-thrombocytopenic purpura, thrombocytopenic purpura, agranulocytosis.
7
Drug Interactions
7.1 Drug Interactions with Metoprolol
Additions and/or revisions underlined:
Catecholamine
Depleting Drugs:
The concomitant use of catecholamine-depleting drugs
(e.g., reserpine, monoamine oxidase (MAO) inhibitors) with beta adrenergic
blockers may have an additive affect and increase the risk of hypotension or
bradycardia
CYP2D6 Inhibitors:
Drugs that are strong inhibitors of CYP2D6 such
as quinidine, fluoxetine, paroxetine, and propafenone
were shown to double metoprolol concentrations. While there is no
information about moderate or weak inhibitors, these too are likely to
increase metoprolol concentration. Increases in plasma concentration
decrease the cardioselectivity of metoprolol [see Clinical Pharmacology (12.3, 12.5)].
Monitor patients closely, when the
combination cannot be avoided.
Digitalis,
Clonidine, and Calcium Channel
Blockers:
Digitalis glycosides, clonidine, diltiazem and
verapamil slow atrioventricular conduction and decrease heart rate.
Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol
are coadministered, withdraw the beta-blocker several days before
the gradual withdrawal of clonidine because beta-blockers may exacerbate the
rebound hypertension that can follow the withdrawal of clonidine. If
replacing clonidine by beta- blocker therapy, delay the introduction of beta-blockers
for several days after clonidine administration has stopped.
8
Use in Specific Populations
PLLR
conversion; newly added subsection:
8.3 Females and Males of Reproductive Potential
Infertility
Males
Based on
the published literature, beta blockers (including metoprolol) may cause
erectile dysfunction and inhibit sperm motility. No evidence of impaired
fertility due to metoprolol or hydrochlorothiazide was observed in rats [see
Nonclinical Toxicology (13.1)].
Newly
added subsection:
8.6 Hepatic Impairment
Metoprolol
No
studies have been performed with metoprolol succinate in patients with hepatic
impairment. Because metoprolol succinate is metabolized by the liver,
metoprolol blood levels are likely to increase substantially with poor hepatic
function. Therefore, initiate therapy at doses lower than those recommended for
a given indication; and increase doses gradually in patients with impaired
hepatic function.
8.1 Pregnancy
PLLR conversion; additions and/or
revisions underlined:
Risk Summary
Untreated hypertension during pregnancy can lead to
adverse outcomes for the mother and the fetus (see Clinical Considerations). Available data from published
observational studies have not demonstrated a drug-associated risk of major
birth defects, miscarriage, or adverse maternal or fetal outcomes with
metoprolol use during pregnancy. However, there are inconsistent reports of
intrauterine growth restriction, preterm birth, and perinatal mortality with
maternal use of beta blockers, including metoprolol, during pregnancy (see Data). There have been rare reports
of jaundice, thrombocytopenia, and electrolyte imbalances in infants exposed to
thiazide medications during pregnancy.
In animal reproduction studies, metoprolol has been
shown to increase post-implantation loss and decrease neonatal survival in rats
at oral dosages up to 24 times, on a mg/m2 basis, the daily dose of 200 mg in a
60-kg patient. The combination of metoprolol tartrate/hydrochlorothiazide
administered to rats from mid-late gestation through lactation also produced
increased post-implantation loss and decreased neonatal survival (see Data).
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 malformations 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
Metoprolol
Neonates born to mothers
who are receiving metoprolol during pregnancy may be at risk for hypotension,
hypoglycemia, bradycardia, and respiratory depression. Observe neonates for
symptoms of hypotension, hypoglycemia, bradycardia, and respiratory depression
and manage accordingly.
Data
Human Data
Data from published
observational studies did not demonstrate an association of major congenital
malformations and the use of either metoprolol or hydrochlorothiazide in
pregnancy. The published literature has reported inconsistent findings of
intrauterine growth retardation, preterm birth and perinatal mortality with
maternal use of metoprolol during pregnancy; however, these studies have
methodological limitations hindering interpretation. Methodological limitations
include retrospective design, concomitant use of other medications, and other
unadjusted confounders that may account for the study findings including the
underlying disease in the mother. These observational studies cannot definitely
establish or exclude any drug-associated risk during pregnancy.
Animal Data
Oral
administration of metoprolol tartrate/hydrochlorothiazide combinations to
pregnant rats during organogenesis at doses up to 200/50 mg/kg/day (10 and 20
times the MRHD on a mg/m2 basis for metoprolol and hydrochlorothiazide,
respectively) or to pregnant rabbits at doses up to 25/6.25 mg/kg/day (about
2.5 and 5 times the MRHD on a mg/m2 basis for metoprolol and
hydrochlorothiazide, respectively)
produced no teratogenic effects.
Metropolol
Metoprolol tartrate has been shown to increase post-implantation
loss and decrease neonatal survival in rats at doses up to 24 times, on
a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient.
Hydrochlorothiazide
Hydrochlorothiazide
administered to pregnant mice and rats during organogenesis at doses up to 3000
and 1000 mg/kg/day (600 and 400 times the MRHD on a mg/m2 basis),
respectively, produced no harm to the fetus. Thiazides cross the placental
barrier and appear in the cord blood.
8.2 Lactation
PLLR conversion;
additions and/or revisions underlined:
Risk Summary
There are no data on the presence of DUTOPROL in human milk, the
effects on the breastfed infant, or the effects on milk production. However,
data are available on the individual components of DUTOPROL. Available
data from published literature on metoprolol and hydrochlorothiazide report
that each drug is present in human milk (see Data). There are no reports
of adverse effects on breastfed infants exposed to metoprolol or
hydrochlorothiazide during lactation. Doses of hydrochlorothiazide associated
with clinically significant diuresis have been associated with impaired milk
production. There is no information regarding the effects of metoprolol on milk
production.
Monitor infants exposed to DUTROPROL though breastmilk for drowsiness
or poor feeding (see Clinical Considerations).
The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for DUTOPROL and any potential
adverse effects on the breastfed child from DUTOPROL or from the underlying
maternal condition.
Clinical Considerations
Monitoring for
adverse reactions
Monitor the breastfed infant for bradycardia and other symptoms of beta
blockade such as listlessness (hypoglycemia).
Data
Metoprolol
Based on published case reports, the estimated daily infant dose of
metoprolol received from breastmilk ranged from 0.05 mg to less than 1 mg. The
estimated relative infant dosage was 0.5% to 2% of the mother’s weight-adjusted
dosage In two women who were taking unspecified amount of metoprolol, milk
samples were taken after one dose of metoprolol. The estimated amount of
metoprolol and alpha-hydroxymetoprolol in breast milk
is reported to be less than 2% of the mother's weight-adjusted dosage.
In a small study, breast milk was collected
every 2 to 3 hours over one dosage interval, in three mothers (at least 3
months postpartum) who took metoprolol of unspecified amount. The average
amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to
158.7). The average relative infant dosage was 0.5% of the mother's
weight-adjusted dosage.
Hydrochlorothiazide
A single study involving one woman and
her infant showed a peak concentration of 275 mcg/L at 3 hours following 50 mg
dose. No drug was detected (< 20 mcg/L) in the infant’s plasma at 2 and 11
hours following mother’s dose.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Newly
added information:
Lactation
Advise
patients who are breastfeeding to monitor their infants for signs of
bradycardia and other symptoms of beta blockade such as listlessness
(hypoglycemia). [see Use in Specific Populations (8.2)].
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