Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
5
Warnings and Precautions
Newly added subsection below:
5.7 Risks in Postpartum Patients
CYCLOSET is
contraindicated in postpartum patients. Serious and life-threatening adverse
reactions including hypertension, myocardial infarction, seizures, stroke and
psychosis have been reported postmarketing in postpartum women who were
administered bromocriptine for inhibition of lactation [see Adverse Reactions (6.2)]. These risks may be higher in postpartum patients with
cardiovascular disease. The indication for use of bromocriptine for inhibition
of postpartum lactation was withdrawn from bromocriptine-containing products
and is not approved for CYCLOSET.
6
Adverse Reactions
Newly added:
The
following clinically significant adverse reactions are described elsewhere in
the labeling:
6.1 Clinical Trials Experience
‘Events’ replaced by ‘Reactions’ throughout the section
Additions and/or revisions underlined:
Table 1: Adverse
Reactions Occurring in greater
than or equal to 5% in CYCLOSET-Treated Patients and More Frequent
than in Placebo in CYCLOSET Clinical Trials
Following Table 1, additions and/or
revisions underlined:
Hypoglycemia
In the
monotherapy trial, hypoglycemia, a blood glucose level of less than 60
mg/dL, was reported in 2 CYCLOSET- treated patients (3.7%) and 1
placebo-treated patient (1.3%) …
Newly added following Central Nervous System
Fibrotic-Related Complications
Among the
CYCLOSET–treated patients (n = 2500) in controlled clinical trials, there was
one case (0.04% event rate) of an adverse reaction of pulmonary fibrosis.
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The
following adverse reactions have been identified during post approval use of other
formulations of bromocriptine mesylate for indications for which
CYCLOSET is not approved (e.g., hyperprolactinemia, acromegaly, and
Parkinson's disease), generally at doses higher than those approved for the
treatment of type 2 diabetes …
Newly added following Psychotic and Psychiatric Disorders
Adverse Reactions in Postpartum Patients
Serious and
life-threatening adverse reactions including hypertension, myocardial infarction,
seizures, stroke and psychosis have been reported in postpartum women who were
administered bromocriptine for inhibition of lactation.
8
Use in Specific Populations
8.1 Pregnancy
PLLR Conversion; additions and/or revisions underlined:
Risk Summary
There are
no available data on CYCLOSET use in pregnant women with type 2 diabetes. However, prolonged experience with
bromocriptine use in pregnant women for other indications over several decades,
based on data from published clinical trials, case reports, and epidemiological
studies, have not established a drug-associated risk for major birth defects,
miscarriage, or adverse maternal or fetal outcomes. Furthermore, only a trace amount of
bromocriptine was shown to be transported across the placenta in vitro in a published ex vivo human placental perfusion model.
There are risks to the mother and fetus associated with poorly controlled diabetes
in pregnancy (see Clinical
Considerations). In
animal reproduction studies in which bromocriptine mesylate was
administered orally during the period of organogenesis, increased prenatal
mortality occurred in rats and rabbits at maternally toxic dosages that were
more than 24-times the human dose of 4.8 mg/day based on body surface
area. No adverse developmental outcomes were observed in monkeys administered
bromocriptine mesylate orally during various periods of gestation at doses up
to 10-times a human dose of 4.8 mg daily (see
Data).
The
estimated background risk of major birth defects is 6-10% in women with
pre-gestational diabetes with an HbA1c >7 and has been reported to be as
high as 20-25% in women with an 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, and
delivery complications. Poorly controlled diabetes increases the fetal risk for
major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
While
available studies cannot definitively establish the absence of risk, data from
published studies have not established an association with bromocriptine use
during pregnancy and major birth defects, miscarriage, or adverse maternal or
fetal outcomes. Available epidemiological studies have methodological
limitations including small sample size and inconsistent comparator groups.
Animal Data
Two strains
of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day from Gestation
Day (GD) 6-15 and with a single dose of 10 mg/kg on GD 5. Implantation was
inhibited at 10 and 30 mg/kg (24 and 72 times the human 4.8 mg daily dose,
based on mg/m2 comparison). When rats were dosed with 3, 10, and 30 mg/kg/day
from GD 8-15 there was an increase in resorptions at greater than or equal
to10 mg/kg. These effects were probably due to the dependence of
implantation and maintenance of gestation upon prolactin in the rat and are not
clinically relevant as these events in humans are dependent upon
luteinizing hormone. There were no drug-related malformations in the rat.
In two
strains of pregnant rabbits treated from GD 6-18 with oral doses of 3, 10, 30,
100, and 300 mg/kg/day, there was maternal toxicity and embryolethality
(post-implantation loss/early resorptions) at doses greater than or equal to 10
mg/kg/day (>48 times the human 4.8 mg daily dose, based on mg/m2 comparison)
and a low incidences of fetal abnormalities at maternally toxic doses > 100
mg/kg/day (>480 times the human 4.8 mg daily dose, based on mg/m2
comparison). There were no treatment- related fetal malformations at doses less
than or equal to 30 mg/kg/day (140 times the human 4.8 mg daily dose, based on
mg/m2 comparison). Implantation was not affected in rabbits treated
from GD 1-6 with oral doses of 100-300 mg/kg/day (480- 1400 times the human 4.8
mg daily dose, based on mg/m2 comparison).
In a small
study in macaque monkeys given oral doses of 2 mg/kg/day (10 times the human
4.8 mg daily dose, based on mg/m2 comparison) during organogenesis, no
embryotoxic or teratologic effects were observed.
In
developmental toxicity studies in monkeys, an
oral dose of 0.3 mg/kg administered prior to pregnancy and
through GD 30 or 80, or an oral dose of 2 mg/kg administered from
GD 20-24, resulted in no embryotoxicity (doses up to 10 times the
human 4.8 mg daily dose based on mg/m2 comparison).
8.2 Lactation
PLLR conversion; additions and/or revisions underlined:
Risk Summary
CYCLOSET is
contraindicated in lactating patients because its active ingredient,
bromocriptine, inhibits lactation. In addition, serious and life-threatening
adverse reactions including hypertension, myocardial infarction, seizures,
stroke, and psychosis have been reported postmarketing in postpartum women
who were administered bromocriptine for inhibition of lactation. The indication for use of bromocriptine for
inhibition of lactation was withdrawn from bromocriptine- containing
products and is not approved for CYCLOSET [see Warnings and Precautions (5.7), Adverse Reactions
(6.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Hypotension
Advise
patients that they may develop postural (orthostatic)
hypotension with or without symptoms such as dizziness, nausea, and
diaphoresis. Hypotension and syncope may occur more frequently during initial
therapy or with an increase in dose at any time. During early treatment with
CYCLOSET, advise patients to make slow postural changes and to avoid situations
that could predispose to serious injury if syncope was to occur [see Warnings and Precautions (5.1)].
Impulse Control/Compulsive Behaviors
Advise
patients that they may experience impulse control
and/or compulsive behaviors while taking CYCLOSET and to inform their physician
or healthcare provider if they develop new or increased gambling urges, sexual
urges, uncontrolled spending, binge or compulsive eating, or other urges while
being treated with CYCLOSET [see Warnings
and Precautions (5.3)].
Somnolence
Advise
patients that CYCLOSET may cause somnolence. Advise
patients not to operate heavy machinery if symptoms of somnolence occur [see Warnings and Precautions (5.4)].
Pregnancy and Lactation
Advise
patients not to take CYCLOSET postpartum or while lactating [see Warnings and
Precautions (5.7), Use in Specific Populations (8.2)]. Serious and life-threatening adverse reactions including
hypertension, myocardial infarction, seizures, stroke and psychosis have been
reported in postpartum women who were administered bromocriptine for inhibition
of lactation.
Missed Doses
Advise
patients to take CYCLOSET within 2 hours after waking in the morning. If the
morning dose is missed, instruct patients to take their usual dose the
following morning. Doses of CYCLOSET should not be doubled the following
morning.
PATIENT INFORMATION
Additions and/or revisions underlined:
What is
CYCLOSET?
CYCLOSET is a prescription medicine used with
diet and exercise to lower blood sugar in adults with type 2 diabetes.
CYCLOSET is not for
people with type 1 diabetes.
CYCLOSET is not for
people with diabetic ketoacidosis.
It is not known if
CYCLOSET is safe and effective in children.
Who should not take CYCLOSET?
Do not take CYCLOSET if you:
are allergic to bromocriptine or any of the
ingredients in CYCLOSET. See the end of this Patient Information leaflet for
a complete list of ingredients in CYCLOSET.
are allergic to ergot medicines. Ask your
healthcare provider for a list of these medicines, if you are not sure.
have fainting (syncopal) migraine headaches.
are a woman who has
recently given birth to a child (postpartum). CYCLOSET can cause serious and
life threatening problems including high blood pressure (hypertension), heart
attack, seizures, stroke and psychosis (losing touch with reality).
are breastfeeding.
Talk to
your healthcare provider before taking CYCLOSET if you have any of these
conditions.
What should I tell
my healthcare provider before taking CYCLOSET?
Before taking
CYCLOSET, tell your healthcare provider about all of your medical conditions,
including if you:
are pregnant or plan to become pregnant.
It is not known if CYCLOSET will harm your unborn baby. If you are pregnant,
talk with your healthcare provider about the best way to control your blood
sugar while you are pregnant.
medicines, vitamins, and herbal
supplements.
Especially tell your healthcare provider
if you take:
medicines
for mental health problems, especially anti-psychotic medicines called
dopamine receptor antagonists
medicines for migraine or other types of headaches
other medicines that work like CYCLOSET (dopamine
receptor agonists) to treat conditions such as Parkinson’s disease, high levels
of a hormone called prolactin in your blood (hyperprolactinemia), restless leg
syndrome and too much growth hormone (acromegaly)
medicines for type 2 diabetes
How should I take
CYCLOSET?
talk to your doctor about how to prevent,
recognize, and manage low blood sugar (hypoglycemia), high blood sugar
(hyperglycemia), and complications of diabetes
What are the
possible side effects of CYCLOSET?
CYCLOSET may cause
serious side effects, including:
Low blood pressure (hypotension) including low
blood pressure when you suddenly change positions (orthostatic hypotension). This can happen
more often when first starting CYCLOSET or if your dose is increased. Symptoms
of low blood pressure when you suddenly change positions can include dizziness,
nausea, sweating, fainting or light-headedness. Stand up slowly when moving
from a sitting or lying position. You should avoid activities that could cause
injury if you feel light-headed or faint.
Feeling tired and sleepy (somnolence). Tiredness and
sleepiness can happen with CYCLOSET, especially when first starting CYCLOSET.
Tiredness and sleepiness are common but can also be serious. If you feel tired
and sleepy while taking CYCLOSET, you should not drive or operate heavy
machinery.
Serious and life-threatening problems in women who
have recently given birth to a child (postpartum). See “Who
should not take CYCLOSET?”
How should I store CYCLOSET?
Store
CYCLOSET at room temperature between 68°F and 77°F (20°C and 25°C).
Store CYCLOSET in a tight, light resistant container.
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