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(Dostinex)
Midland Therapeutic Review
& Advisory Committee
for the treatment of hyperprolactinaemia
Licensed Indication:
Cabergoline ‘is indicated for the treatment of
dysfunctions associated with hyperprolactinaemia,
including amenorrhoea, oligomenorrhoea, anovulation
1
and galactorrhoea.’
Cabergoline ‘is indicated in patients with prolactinsecreting
pituitary
adenomas
(microand
macroprolactinomas), idiopathic hyperprolactinaemia,
or empty sella syndrome with associated
hyperprolactinaemia, which represent the basic
underlying pathologies contributing to the above
1
clinical manifestations’.
The safety and efficacy of cabergoline has not been
1
established in individuals < 16 years of age.
Background information
Hyperprolactinaemia is an endocrine disorder seen in
men and women, which is associated with impaired
gonadal function. The most common symptoms in
women are secondary amenorrhoea, reduced libido,
2
menstrual disorders, and galactorrhoea.
In men,
symptoms generally include reduced libido and/or
impotence.
Hypogonadism
caused
by
hyperprolactinaemia can lead to infertility, but also to
conditions such as osteoporosis due to low oestrogen
levels.
Hyperprolactinaemia can be idiopathic, or caused by
drugs or other disease states. Drugs noted to cause
hyperprolactinaemia include those that block D 2receptors eg antipsychotics, or those that reduce
dopamine levels, eg methyldopa.
Conditions
associated
with
the
development
of
hyperprolactinaemia are described under the licensed
indication (see above).
Current treatment options
In patients with drug-induced hyperprolactinaemia, the
causative agent should be withdrawn.
In hyperprolactinaemia of other aetiologies, treatment
options include drug therapy with dopamine agonists,
surgery, or radiotherapy. Drug treatment is generally
regarded as first line management.
Dopamine
agonists, by stimulation of D 2-receptors, inhibit
prolactin secretion from the lactotroph cells of the
anterior pituitary gland. Bromocriptine is regarded as
the reference standard whereas quinagolide and
cabergoline are newer, longer-acting compounds.
The main indications for surgery are tumours resistant
to dopamine agonists, poor compliance with drug
treatment, or drug intolerance. Radiotherapy can be
used in patients who have not responded satisfactorily
3
to medical or surgical treatment.
Dosage and administration
The recommended initial dosage is 0.5mg (500
micrograms) per week.
This dose should be
increased gradually, preferably by 0.5mg/week at
monthly intervals until an optimal therapeutic response
is achieved. The therapeutic dosage is usually
1mg/week (range 0.25mg to 2mg). The weekly dose
may be administered as a single dose, or in 2 or more
divided doses according to patient tolerability,
1
preferably with food.
‘Patients should be evaluated during dose escalation
to determine the lowest dosage that produces the
therapeutic response. Monitoring of serum prolactin
1
levels at monthly intervals is advised.’
Clinical Efficacy
The efficacy of cabergoline for the treatment of
hyperprolactinaemia (of various aetiologies) has been
evaluated in numerous open-label studies, in
randomised placebo-controlled studies, and in
comparative
studies
with
bromocriptine
or
quinagolide. The outcomes evaluated were primarily
normalisation of prolactin levels.
Placebo-controlled studies
A dose-response, double-blind, placebo-controlled,
study evaluated four biweekly (twice weekly) dosages
of
cabergoline
in
188
women
with
5
hyperprolactinaemia over a 4-week period.
Normalisation of prolactin levels occurred in 30%,
74%, 74% and 95% of women from the 0.125mg,
0.5mg, 0.75mg and 1mg biweekly groups
respectively. No women receiving placebo achieved
normalisation of prolactin levels.
In an open-label follow-up study of 162 patients from
the dose-response study, normal prolactin levels were
achieved or maintained in 138 patients (85%) with
continued cabergoline treatment for up to 1 year (dose
6
0.125−4mg/week).
Open-label studies
Two open-label studies (n>100) provide further
efficacy data in patients with hyperprolactinaemia.
The first enrolled 127 patients (124 women, 3 men)
who were treated with cabergoline 0.2 −3.5mg/week
7
for 3−52 months (median 14).
Normalisation of
prolactin levels occurred in 114 (90%) patients.
The second open-label study enrolled 110 patients
(70 women, 40 men) with prolactinomas, 84 of whom
had previously been treated with quinagolide or
8
bromocriptine.
Patients were flexibly dosed with
cabergoline.
By study endpoint (3 years),
normalisation
of
prolactin
levels
occurred in 109 patients (99%). Significant reduction in
tumour size from baseline was evident in all patients after 1
year (p<0.01). In dopamine-agonist naïve patients (n=26)
the nadir prolactin level was significantly lower, and tumour
shrinkage significantly greater after 3 years than in the other
patients (p<0.01).
Comparative studies with bromocriptine
A randomised, double-blind study with open-label follow-up
compared cabergoline to bromocriptine in women with
hyperprolactinaemic amenorrhoea over 24 weeks (n =
9
459). The dosages of the drugs taken by the majority of
women were 1mg weekly of cabergoline (range 0.5 −2mg),
and 5mg daily of bromocriptine (range 2.5 −10mg).
Cabergoline or bromocriptine treatment had previously
been taken by 68% of women.
Normalisation of prolactin levels occurred in 83% treated
with cabergoline vs 58% with bromocriptine (25%
difference, 95% CI 17%−33%, p<0.001). Complete clinical
success rates (defined as the occurrence of at least 2
consecutive menses with biochemical evidence of ovulation
at least once) were 72% with cabergoline vs 52% with
bromocriptine, p<0.001, (20% difference, 95% CI
11%−28%).
Comparative studies with quinagolide
Three small, (n = 12, 20, 39) open-label, cross-over studies
evaluated the effects of cabergoline and quinagolide in the
10-12
treatment of hyperprolactinaemia (61 women, 10 men).
The results from these studies suggest that cabergoline is
at least as effective as quinagolide at normalising prolactin
levels.
Pregnancies
Across these studies, 51 pregnancies were reported in
women treated with cabergoline.
There were 11
terminations, 38 deliveries, and 2 women lost to follow-up.
All infants delivered were reported to be normal.
Adverse Events
Nausea and headache were reported with cabergoline
across all studies. Other adverse effects reported in at
least one study were dizziness, fatigue, asthenia,
weakness, postural hypotension, vertigo, vomiting,
constipation, and abdominal pain.
9
Compared with bromocriptine, it was noted that
significantly fewer patients treated with cabergoline
withdrew from treatment due to adverse events, (3% vs
11%, p < 0.001), or reported nausea (30% vs 49%, p <
0.001). In the cabergoline group, nausea was also less
severe and shorter in duration than with bromocriptine.
Vomiting also occurred less frequently with cabergoline
than bromocriptine (4% vs 9%).
A reduction in blood pressure was also noted in some of
the studies. In the 1 year open-label follow-up study, mean
systolic and diastolic blood pressure values fell by 5mmHg
6
and 4mmHg respectively. In the comparative study with
bromocriptine, blood pressure fell in ~50% of women
(median decrease 10mmHg), particularly diastolic
pressure.
This was symptomatic in 7 women (3
9
cabergoline, 4 bromocriptine). In one cross-over study with
quinagolide, systolic blood pressure fell by 8 or 9 mmHg
10
with both drugs.
Costs
At current prices, one year’s treatment costs:
• £98−£783 with cabergoline 0.25−2mg weekly
• £33−£771 with bromocriptine 1−30mg daily
• £693−£1,387 with quinagolide 0.075−0.15mg daily.
Given the limited data available it is not possible to reach a
conclusion on the overall cost-effectiveness of cabergoline
compared to bromocriptine or quinagolide.
Summary
Cabergoline is a dopamine agonist for the treatment of
dysfunctions associated with hyperprolactinaemia.
A dose-response was noted in a 4-week, dose-ranging
placebo-controlled study with cabergoline.
Normal
prolactin levels were achieved or maintained in ≥85%
patients in 3 open-label studies with cabergoline (3−52
months). In comparative studies with bromocriptine and
quinagolide, cabergoline was significantly more effective
than bromocriptine, and at least as effective as quinagolide
at normalising prolactin levels.
Adverse events reported with cabergoline included nausea,
headache, dizziness, fatigue, constipation, and a fall in
blood pressure values.
Cabergoline may therefore offer a useful alternative to
bromocriptine in patients with hyperprolactinaemia.
References
1.
Pharmacia & Upjohn. Dostinex. Summary of Product
Characteristics 2000.
2.
Rains CP, Bryson HM, Fitton A. Cabergoline. Drugs 1995;49:25579.
3.
Conner P, Fried G. Hyperprolactinemia; etiology, diagnosis and
treatment alternatives. Acta Obstet Gynecol Scand 1998;77:24962.
4.
Anon. New drugs for hyperprolactinaemia. DTB 1995;33:65-72.
5.
Webster J, Piscitelli G, Polli A, D'Alberton A, Falsetti L, et al.
Dose-dependent suppression of serum prolactin by cabergoline in
hyperprolactinaemia: a placebo controlled, double blind,
multicentre study. Clinical Endocrinology 1992;37:534-41.
6.
Webster J, Piscitelli G, Polli A, D'Alberton A, Falsetti L, et al. The
efficacy and tolerability of long-term cabergoline therapy in
hyperprolactinaemic disorders: an open, uncontrolled, multicentre
study. Clinical Endocrinology 1993;39:323-9.
7.
Ferrari C, Paracchi A, Mattel AM, de Vincentiis S, D'Alberton A,
et al. Cabergoline in the long-term therapy of hyperprolactinemic
disorders. Acta Endocrinologica 1992;126:489-94.
8.
Colao A, Di Sarno A, Landi ML, Scavuzzo F, Cppabianca P, et al.
Macroprolactinoma shrinkage during cabergoline treatment is
greater in naive patients than in patients pretreated with other
dopamine agonists: A prospective study in 110 patients. J Clin
Endocrinol Metab 2000;85:2247-52.
9.
Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, et al. A
comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904-9.
10. Giusti M, Porcella E, Carraro A, Cuttica M, Valenti S, et al. A
cross-over study with the two novel dopaminergic drugs
cabergoline and quinagolide in hyperprolactinemic patients. J
Endocrinol Invest 1994;17:51-7.
11. De Luis D, Becerra A, Lahera M, Botella J, Valero M, et al. A
randomized cross-over study comparing cabergoline and
quinagolide in the treatment of hyperprolactinemic patients.
Journal of Endocrinol Invest 2000;23:428-34.
12. De Sarno A, Landi ML, Marzullo P, Di Somma C, Pivonello R, et
al. The effect of quinagolide and carbergoline, two selective
dopamine receptor type 2 agonists, in the treatment of
prolactinomas. Clinical Endocrinology 2000;53:53-60.
Date: March 2001
SS01/08
© MTRAC, Department of Medicines Management, Keele University