Description
CB-Lin tablets contain Cabergoline
0.5 mg, which is a dopamine receptor agonist. The chemical name
for Cabergoline is (1 – [ (6-allylergolin – 8beta
– yl) carbonyl ] – 1 – [3- (dimenthylamino)
propyl] –3-ethylurea). Its empirical formula is C26H37N502
and its molecular weight is 451.52.
Clinical Pharmacology
The secretion of prolactin by the anterior pituitary is mainly
under hypothalamic inhibitory control, likely extended through
release of dopamine by tuberoinfundibular neurons. Cabergoline
is a long lasting dopamine receptor agonist with a high affinity
for D2 receptors. Results of in Vitro studies demonstrate that
Cabergoline exerts a direct inhibitory effect on the secretion
of prolactin by pituitary lactotrophs. Cabergoline decreased serum
prolactin levels in reserpinized rats. Comparative studies conducted
in hyperolactinemic women in comparison with placebo and bromocriptine
adequately demonstrated the prolactin-lowering efficacy of Cabergoline,
in terms of prolactin level normalization, restoration of menses
and relief from galactorrhoea.
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. 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:
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. Cabergoline in moderately bound (40 %
to 42 %) to human plasma proteins in a concentration independent
manner. Concomitant dosing of highly protein bound drugs is unlikely
to effect its disposition. Metabolism: In both animals and humans,
Cabergoline is extensively metabolized, predominately via hydrolysis
of the acylurea bond or the urea moiety. Cytchrome P-450 mediated
metabolism appears to be minimal. 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 dosage of radioactive
Cabergoline to five healthy volunteers, approximately 22 % to
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. Non-renal and renal clearances for Cabergoline are
about 32 L/min and 0.08 L/min, respectively. Urinary excretion
in hyperlactinemic patients was similar.
Special Populations: The pharmacokinetics of Cabergoline were
not altered in patients with moderate to severe renal insufficiency
and patients with mild to moderate hepatic dysfunction. However
patients with severe hepatic insufficiency (child-pugh-score>10)
show a substantial increase in the mean Cabergoline C and AUC
and thus necessitate caution.
Food-Drug interaction: Food does not alter Cabergoline kinetics.
Pharamcodynamics:
After a single oral administration of Cabergoline (0.3-1.5 mg),
a significant decrease in serum PRL levels was observed in healthy
volunteers, puerperal women and hyperprolactinaemic patients.
The effect is prompt (within 3 hours from administration) and
persistent (up to 7-28 days in healthy volunteers and hyperprolactinaemic
patients and up to 14-21 days in puerperal women). The PRL-lowering
effect is dose-related both in terms of degree of effect and duration
of action. Cabergoline has no effect on basal secretion or of
the pituitary hormones or cortisol. The pharmacodynamic actions
of Cabergoline not correlated with the therapeutic effect only
relate to blood pressure decrease. The maximal hypotensive effect
of Cabergoline as single dose usually occurs during the first
6 hours after drug intake and is dose dependent both in terms
of maximal decrease and frequency.
Indications and usage:
-
Inhibition/suppression
of physiological lactation
CB-Lin prevents/suppresses physiological lactation
by inhibiting prolactin secretion. CB-Lin is indicated for the
inhibition of physiological lactation soon after delivery and
for suppression of already established lactation: 1 after parturition,
when the mother elects not to breast-feed the infant or when
the breast feeding is contraindicated due to medicinal reasons
related to the mother or the new-born. 2.After stillbirth or
abortion
-
Treatment of hyperprolactinaemic
disorders
CB-Lin is indicated for the treatment of dysfunctions
associated with hyperprolactinaemia, including amenorrhoea,
oligomenorrhoea, anovulation and galactorrhoea. CB-Lin is indicated
in patients with prolactin-secreting pituitary adenomas (micro-
and macroprolactinomas), idiopathic hyperprolactinaemia, or
empty sella syndrome with associated hyperprolactinaemia, which
represent the basic underlying pathologies contributing to the
above clinical manifestations.
Contra-indications:
CB-Lin is contraindicated in uncontrolled hypotension,
hypersensitivity to any ergot alkaloid, hepatic insufficiency
and toxaemia of pregnancy. CB-Lin should not be co-administered
with anti-psychotic medications or administered to women with
a history of puerperal psychosis.
Warnings and precautions
- General
Dopamine agonists in general should not be used in patients with
pregnancy-induced hypertension, for example, preeclampsla and
eclampsia, unless the potential benefit outweighs the possible
risk. The safety and efficacy of Cabergoline have not yet been
established in patients with renal and hepatic disease. CB-Lin
should be given with caution to subjects with cardiovascular disease,
Raynaud’s syndrome, renal insufficiency, peptic ulcer, gastrointestinal
bleeding, or a history of serious, particularly psychotic, mental
disease. Particular acre should be taken when patients are taking
concomitant psychoactive medication. Symptomatic hypotension can
occur with CB-Lin administration for any indication. Care should
be exercised when administering CB-Lin concomitantly with other
drugs known to lower blood pressure. Before CB-Lin administration,
pregnancy should be excluded and after treatment pregnancy should
be prevented for at least one month. Cabergoline has been associated
with somnolence and episodes of sudden sleep onset. Patients must
be informed of this and advised to exercise caution while driving
or operating machines during treatment with Cabergoline. Furthermore
a reduction of dosage termination of therapy may be considered.
- Inhibition/suppression of physiological
lactation
Like other ergot alkaloids, CB-Lin should not be
used in women with pre-eclampsia and should be used with caution
in patients with post-partum hypertension. Periodic monitoring
of blood pressure, particularly during the first few days after
CB-Lin administration, is advised. CB-Lin should not be administered
as a single dose greater than 0.25 mg in nursing women treated
for suppression of established lactation.
- Treatment of hyperprolactinaemic
disorders
Since hyperprolactinaemia with amerrhoea/galactorrhoea
and infertility may be associated with pituitary tumors, a complete
evaluation of the pituitary is indicated before treatment with
CB-Lin is initiated. CB-Lin restores ovulation and fertility in
women with hyperprolactinaemic hypoganadism; since pregnancy might
occur prior to reinitiation of menses are reinitiated, every time
a menstrual period is delayed by more than three days. Women not
seeking pregnancy should be advised to use mechanical contraception
during treatment and after CB-Lin withdrawal until recurrence
of ovulatory cycles persist in some patients for 6 months after
drug withdrawal. If pregnancy occurs during treatment, CB-Lin
is to be discontinued. As a precautionary measure, women who become
pregnant should be monitored to detect signs of pituitary enlargement
since expansion of pre-existing pituitary tumors may occur during
gestation. Regular gynecological assessment, including cervical
and endometrial cytology, is recommended for patients taking CB-Lin
for extensive periods.
Drug Interactions:
Since CB-Lin exerts therapeutic effect by direct stimulation of
dopamine receptors, it should not be concurrently administered with
drugs-which have dopamine antagonist activity (such as phenothaizines,
butyophenones, thioxanthenes, metoclopramide) since these might
reduce the prolactin-lowering effect of CB-Lin. Although there is
no conclusive evidence of an interaction between CB-Lin and other
ergot alkaloids the concomitant use of these medications during
long-term treatment with CB-Lin is not recommended. Like other ergot
derivatives, CB-Lin should not be used with macrolide antibodies
(e.g. eythromycin) since the systematic bioavailability and also
adverse effects could increase.
Pregnancy & lactation
Cabergoline crosses the placenta in rats: it is unknown
whether this occurs in humans. Studies in animal models have not
demonstrated any teratogenic effect or effects on overall reproductive
performance. However, there are no adequate and well-controlled
studies in pregnant women. CB-Lin should be used during pregnancy
only if clearly needed. The use of CB-Lin does not appear to be
associated with an increased risk of abortion, premature delivery,
multiple pregnancy, or congenital abnormalities. Because clinical
experience is still limited and the drug has a long half-life, as
a precautionary measure it is recommended that once regular ovulatory
cycles have been achieved women seeking pregnancy discontinue CB-Lin
one month before intended conception. This will prevent possible
foetal exposure to the drug and will not interfere with the possibility
of conception since ovulatory cycle persists in some cases for 6
months after drug withdrawal. If conception occurs during therapy,
treatment is said to be discontinued as soon as pregnancy is confirmed
to limit foetal exposure to the drug. Before CB-Lin administration,
pregnancy should be excluded and after treatment pregnancy should
be prevented for at least one month.
CB-Lin should not be administered to mothers who elect to breast-feed
their infants since it prevents lactation and no information is
available on excretion of the drug in maternal milk
Adverse reactions
Most adverse events were mild or moderate in severity. The most
common adverse events are Nausea, constipation, abdominal pain,
Dysepsia, Vomiting, Headache, Dizziness, Paresthesia, Vertigo, Asthenia,
Fatigue, Hot flashes, Somnolence, Depression, Nervousness, Postural
Hypotension, Breast pain, Dry mouth, Diarrhea, Flatulence, Rarely
palpitations, epistaxis, transient hemianopia, epigastric pain,
Throat irritation, Toothache, Syncope, Influenza like symptoms,
Malaise, Perlorbital edema, Peripheral edema, Anorexia, Anxiety,
Insomnia, Impaired concentration, dependent edema, Palpitation,
Dysmenorrhea, Acne, Pruritis, Arthralgia, Rhinitis, Abnormal vision,
Weight gain, Weight loss, increased libido, digital vasospasm and
leg cramps have been reported.
Overdosage
There is no experience in humans for overdosage with CB-Lin in the
proposed indications: It is likely to lead to symptoms due to over
stimulation of dopamine receptors. These might include nausea, vomiting,
gastric complaints, hypotension, confusion/psychosis or hallucinations.
General supportive measures should be undertaken to remove any unabsorbed
drug and maintain blood pressure if necessary. In addition, the
administration of dopamine entagonist drugs may be available.
Dosage and administration
CB-Lin is to administered by the oral route. It is recommended that
CB-Lin be preferably taken with meals for all the therapeutic indications.
- Inhibition of lactation:
CB-Lin should be administered during the first
day post-partum. The recommended therapeutic dose is 1 mg (two
0.5 mg tablets) given as a single dose.
- Suppression of established lactation:
The recommended therapeutic dosage regimen is 0.25 mg
(one-half 0.5 mg tablet) every 12 hours for two days (1 mg total
dose). This dosage regimen has been demonstrated to be better
tolerated than the single dose regimen in women electing to suppress
lactation having a lower incidence of adverse events, in particular
of hypotensive symptoms.
- Hyperolactinaemic disorders:
The recommended initial dosage of CB-Lin 0.5 mg per week given
in one or two (one-half of one 0.5 mg tablet) doses (e.g. on Monday
and Thursday) per week. The weekly dosage should be increased
gradually, preferably by adding 0.5 mg per week at monthly intervals
until an optimal therapeutic response is achieved. The therapeutic
dosage usually 1 mg per week and ranges from 0.25 mg to 2 mg per
week. Doses of CB-Lin up to 4.5 mg per week have been used in
hyperolactinaemic patients. The weekly dose may be given as a
single administrator or divided into two or more doses per week
according to patient tolerability. Division of the weekly dose
into multiple administrations is advised when doses higher than
1 mg per week are to be given since the tolerability of doses
greater than 1 mg taken as a single weekly dose has been evaluated
only in a few patients. Patients should be evaluated during dose
escalation to determine the lowest dosage that produces the therapeutic
response. Monitoring of serum prolactin levels at monthly intervals
is advised since, once the effective therapeutic dosage regimen
has been reached, serum prolactin normalization is usually observed
within two to four weeks. After CB-Lin withdrawal, recurrence
of Hyperolactinaemia is usually observed. However, persistent
suppression of prolactin levels has been observed for several
months in some patients. Of the group of women followed up, 23/29
had ovulatory cycles, which continued for greater than 6 months
after CB-Lin discontinuation.
Use in children
The safety and efficiency of CB-Lin has not been established in
subjects less than 16 years of age
Use in the elderly
As a consequence of the indications for which CB-Lin is presently
proposed, the experience in elderly is very limited. Available data
do not indicate special risk.
Presentation: CB-Lin is available in strips of
4 tablets.
Storage: Store in a cool dry place, protected from
light.
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