DOSTINEX Tablets contain cabergoline, a dopamine receptor agonist. The chemical name for cabergoline is
1-[(6-allylergolin-8(beta)-yl)- carbonyl] -1- [3-(dimethylamino)propyl]-3-ethylurea. Its empirical formula is C 26
H 37 N 5 O 2 , and its molecular weight is 451.62. The structural formula is as follows:
Cabergoline is a white powder soluble in ethyl alcohol, chloroform, and N, N-dimethylformamide (DMF);
slightly soluble in 0.1N hydrochloric acid; very slightly soluble in n-hexane; and insoluble in water.
DOSTINEX Tablets, for oral administration, contain 0.5 mg of cabergoline. Inactive ingredients consist of
leucine, USP, and lactose, NF.
CLINICAL PHARMACOLOGY
Mechanism of Action: The secretion of prolactin by the anterior pituitary is mainly under hypothalmic
inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a
long-acting dopamine receptor agonist with a high affinity for D 2 receptors. Results of in vitro studies
demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary
lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats. Receptor-binding studies
indicate that cabergoline has low affinity for dopamine D 1 , (alpha) 1 - and (alpha) 2 -adrenergic, and 5-HT 1 -
and 5-HT 2 -serotonin receptors.
Clinical Studies: The prolactin-lowering efficacy of DOSTINEX was demonstrated in hyperprolactinemic
women in two randomized, double-blind, comparative studies, one with placebo and the other with
bromocriptine. In the placebo-controlled study (placebo n=20; cabergoline n=168), DOSTINEX produced a
dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%,
76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1.0 mg twice weekly respectively.
In the 8-week, double-blind period of the comparative trial with bromocriptine (cabergoline n=223;
bromocriptine n=236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated
with DOSTINEX at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg
twice daily. Restoration of menses occurred in 77% of the women treated with DOSTINEX, compared with
70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in
73% of those treated with DOSTINEX compared with 56% of those treated with bromocriptine.
Pharmacokinetics
Absorption: Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean
peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over
the 0.5-to-7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult
volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that
steady-state levels following a once-weekly dosing schedule are expected to be twofold to threefold higher
than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the
administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from
urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect
of cabergoline may be related to its slow elimination and long half-life.
Distribution: In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown
extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by >100-fold and was
eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting
prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal
uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the
milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed
throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a
concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its
disposition.
Metabolism: In both animals and humans, cabergoline is extensively metabolized, predominately via
hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be
minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea
or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far
do not contribute to the therapeutic effect.
Excretion: After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and
60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose
was excreted unchanged in the urine. Nonrenal and renal clearances for cabergoline are about 3.2 L/min
and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar.
Special Populations
Renal Insufficiency: The pharmacokinetics of cabergoline were not altered in 12 patients with
moderate-to-severe renal insufficiency as assessed by creatinine clearance.
Hepatic Insufficiency: In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score </=10),
no effect on mean cabergoline C max or area under the plasma concentration curve (AUC) was observed.
However, patients with severe insufficiency (Child-Pugh score >10) show a substantial increase in the mean
cabergoline C max and AUC, and thus necessitate caution.
Elderly: Effect of age on the pharmacokinetics of cabergoline has not been studied.
Food-Drug Interaction
In 12 healthy adult volunteers, food did not alter cabergoline kinetics.
Pharmacodynamics
Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been
documented following single cabergoline doses to healthy volunteers (0.05 to 1.5 mg) and
hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses >0.2 mg,
while doses >/=0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin
suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12
healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect
within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after
the 0.5 mg dose.
In hyperprolactinemic patients (N=51), the maximal prolactin decrease after a 0.6 mg single dose of
cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer
(14 days vs 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs
48 hours).
In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of
prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or
cortisol.
INDICATIONS AND USAGE
DOSTINEX Tablets are indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due
to pituitary adenomas.
CONTRAINDICATIONS
DOSTINEX Tablets are contraindicated in patients with uncontrolled hypertension or known hypersensitivity
to ergot derivatives.
WARNINGS
Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for
example, preeclampsia and eclampsia, unless the potential benefit is judged to outweigh the possible risk.
PRECAUTIONS
General: Initial doses higher than 1.0 mg may produce orthostatic hypotension. Care should be exercised
when administering DOSTINEX with other medications known to lower blood pressure.
Postpartum Lactation Inhibition or Suppression: DOSTINEX is not indicated for the inhibition or
suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this purpose, has
been associated with cases of hypertension, stroke, and seizures.
Hepatic Impairment: Since cabergoline is extensively metabolized by the liver, caution should be used,
and careful monitoring exercised, when administering DOSTINEX to patients with hepatic impairment.
Information for Patients: A patient should be instructed to notify her physician if she suspects she is
pregnant, becomes pregnant, or intends to become pregnant during therapy. A pregnancy test should be
done if there is any suspicion of pregnancy and continuation of treatment should be discussed with her
physician.
Drug Interactions: DOSTINEX should not be administered concurrently with D 2 -antagonists, such as
phenothiazines, butyrophenones, thioxanthines, or metoclopramide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in mice
and rats with cabergoline given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively.
These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface
area basis using total mg/m 2 /week in rodents and mg/m 2 /week for a 50 kg human.
There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine
leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus
and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged
suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus
luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk
for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in
serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid
synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these
tumors to humans is not known.
The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests.
These tests included the bacterial mutation (Ames) test with Salmonella typhimurium , the gene mutation
assay with Schizosaccharomyces pombe P 1 and V79 Chinese hamster cells, DNA damage and repair in
Saccharomyces cerevisiae D 4 , and chromosomal aberrations in human lymphocytes. Cabergoline was also
negative in the bone marrow micronucleus test in the mouse.
In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period
inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose
calculated on a body surface area basis using total mg/m 2 /week in rats and mg/m 2 /week for a 50 kg
human.
Pregnancy: Teratogenic Effects: Category B. Reproduction studies have been performed with
cabergoline in mice, rats, and rabbits administered by gavage.
(Multiples of the maximum recommended human dose in this section are calculated on a body surface area
basis using total mg/m 2 /week for animals and mg/m 2 /week for a 50 kg human.)
There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8
mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of
organogenesis.
A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of
organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be
due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day
(approximately 19 times the maximum recommended human dose) during the period of organogenesis in the
rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food
consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose)
during the period of organogenesis in the rabbit caused an increased occurrence of various malformations.
However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were
observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).
In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose)
from 6 days before parturition and throughout the lactation period inhibited growth and caused death of
offspring due to decreased milk secretion.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
cabergoline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother. Use of DOSTINEX for the inhibition or suppression of
physiologic lactation is not recommended (see PRECAUTIONS section).
The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this
interference with lactation, DOSTINEX should not be given to women postpartum who are breastfeeding or
who are planning to breastfeed.
Pediatric Use: Safety and effectiveness of DOSTINEX in pediatric patients have not been established.
ADVERSE REACTIONS
The safety of DOSTINEX Tablets has been evaluated in more than 900 patients with hyperprolactinemic
disorders. Most adverse events were mild or moderate in severity.
In a 4-week, double-blind, placebo-controlled study, treatment consisted of placebo or cabergoline at fixed
doses of 0.125, 0.5, 0.75, or 1.0 mg twice weekly. Doses were halved during the first week. Since a possible
dose-related effect was observed for nausea only, the four cabergoline treatment groups have been
combined. The incidence of the most common adverse events during the placebo-controlled study is
presented in the following table.
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In the 8-week, double-blind period of the comparative trial with bromocriptine, DOSTINEX (at a dose of 0.5 mg twice weekly) was discontinued because of an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued in 14 of 231 patients (6%). The most common reasons for discontinuation from DOSTINEX were headache, nausea and vomiting (3, 2 and 2 patients respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10, 3, 3, and 3 patients respectively). The incidence of the most common adverse events during the double-blind portion of the comparative trial with bromocriptine is presented in the following table.
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Other adverse events that were reported at an incidence of <1.0% in the overall clinical studies
follow:
Body As a Whole: facial edema, influenza-like symptoms, malaise
Cardiovascular System: hypotension, syncope, palpitations
Digestive System: dry mouth, flatulence, diarrhea, anorexia
Metabolic and Nutritional System: weight loss, weight gain
Nervous System: somnolence, nervousness, paresthesia, insomnia, anxiety
Respiratory System: nasal stuffiness, epistaxis
Skin and Appendages: acne, pruritus
Special Senses: abnormal vision
Urogenital System: dysmenorrhea, increased libido
The safety of cabergoline has been evaluated in approximately 1,200 patients with Parkinson's disease in
controlled and uncontrolled studies at dosages of up to 11.5 mg/day which greatly exceeds the maximum
recommended dosage of cabergoline for hyperprolactinemic disorders. In addition to the adverse events that
occurred in the patients with hyperprolactinemic disorders, the most common adverse events in patients with
Parkinson's disease were dyskinesia, hallucinations, confusion, and peripheral edema. Heart failure, pleural
effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive
pericarditis has been reported.
OVERDOSAGE
Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to
support blood pressure should be taken if necessary.
DOSAGE AND ADMINISTRATION
The recommended dosage of DOSTINEX Tablets for initiation of therapy is 0.25 mg twice a week. Dosage
may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient's
serum prolactin level.
Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the
patient's response to each dosage level. If the patient does not respond adequately, and no additional
benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and
other therapeutic approaches considered.
After a normal serum prolactin level has been maintained for 6 months, DOSTINEX may be discontinued,
with periodic monitoring of the serum prolactin level to determine whether or when treatment with DOSTINEX
should be reinstituted. The durability of efficacy beyond 24 months of therapy with DOSTINEX has not been
established.
HOW SUPPLIED
DOSTINEX Tablets are white, scored, capsule-shaped tablets containing 0.5 mg cabergoline. Each tablet is
scored on one side and has the letter P and the letter U on either side of the breakline. The other side of the
tablet is engraved with the number 700.
DOSTINEX is available as follows:
Bottles of 8 tablets NDC 0013-7001-12
STORAGE
Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP].
Rx only
U.S. Patent No. 4,526,892.
Manufactured for:
Pharmacia & Upjohn Company
Kalamazoo, MI 49001, USA
by:
Pharmacia & Upjohn S.p.A.
Milan, Italy