It is a long-acting dopamine receptor agonist that blocks prolactin secretion from the pituitary gland .
Its common brand name is Dostinex. Cabergoline is used to treat overproduction of a natural hormone called prolactin. The excess production of this hormone is due to unknown causes or abnormal growths in the pituitary .
This medicine helps prevent infertility, sexual problems, and bone loss caused by excess prolactin production in men and women who are not breastfeeding.
It is also used as a second-line therapy in the treatment of signs and symptoms of Parkinson’s disease together with carbidopa-levodopa or as a single agent in case of failure or intolerance to a non-ergot compound.
Cabergoline differs from the other DA agonists in that it has a very long half-life and can be administered orally once or twice a week.
It is available in the form of a 0.5 mg tablet, usually given in a dose of 0.25 mg twice a week, maximum dose of 1 mg.
The long duration of action is due to its slow clearance from the pituitary gland tissue, its high affinity binding to the DA receptors of the pituitary gland, and its extensive enterohepatic recycling.
After oral administration, plasma prolactin lowering effects are initially detectable at 3 hours, then gradually increase so that there is a plateau of effect between 48 and 120 hours; with weekly doses, there is a sustained reduction in plasma prolactin.
Cabergoline appears to be superior to bromocriptine in lowering serum prolactin levels. A normalization of prolactin levels can be expected with an efficacy rate of 80-90%.
Although in pregnancy bromocriptine is often still chosen as there is less data on safety in pregnancy for cabergoline.
Take cabergoline according to all the instructions in the package leaflet or leaflet. Do not take larger amounts than recommended.
Consult your doctor if you experience any undesirable effects. Make sure the course of treatment has been completed. Do not stop using this medicine without first consulting your doctor.
Lactation suppression, hyperprolactinemia; monotherapy of Parkinson’s disease in the early stage, treatment of uterine fibroids. Supportive treatment for prolactin-producing tumors of the pituitary gland (prolactinomas).
Combination therapy, together with levodopa and a decarboxylase inhibitor such as carbidopa, in progressive-phase Parkinson’s disease.
In adjunctive therapy for acromegaly, cabergoline has low efficacy in suppressing growth hormone levels and is highly effective in suppressing hyperprolactinemia which is present in 20-30% of acromegaly cases.
Growth hormone and prolactin are structurally similar and have similar effects on many target tissues, therefore prolactin selection can help symptoms when growth hormone secretion cannot be sufficiently controlled by other methods.
Cabergoline has been suggested to play a role in the treatment of Cushing’s disease.
Analysis of pathology samples suggests that dopamine D2 receptor expression may be present in up to 80% of pituitary adenomas in Cushing’s disease.
Furthermore, in vitro and in vivo studies show that the expression of D2 receptors can help predict the response to cabergoline treatment, as measured by both cortisol and adrenocorticotropin levels.
Use outside the conditions authorized in the technical sheet
It has sometimes been used as an adjunct to selective serotonin reuptake inhibitor antidepressants, as there is some evidence that it counteracts certain side effects of these drugs, such as reduced libido and anorgasmia.
It has also been suggested that it has a possible recreational use to reduce or eliminate the male refractory period, thus allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least one scientific study supports those speculations.
Furthermore, a systematic review and meta-analysis concluded that prophylactic cabergoline treatment reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in women who undergo stimulated cycles of fertilization. in vitro (IVF).
A study in rats found that cabergoline reduced voluntary alcohol consumption, possibly by increasing the expression of Glial cell-derived neurotrophic factor (GDNF) in the ventral tegmental area.
Pregnancy and breastfeeding
Relatively little is known about the effects of this drug during pregnancy and lactation. In some cases, the related bromocriptine may be an alternative when pregnancy is expected.
Pregnancy : Preliminary data available indicate a somewhat higher rate of congenital abnormalities in patients who became pregnant while being treated with cabergoline.
However, one study concluded that “fetal exposure to cabergoline during early pregnancy does not induce any increased risk of miscarriage or fetal malformation .”
Lactation : cabergoline was found in maternal milk in rats. Because it is not known whether this effect also occurs in humans, breastfeeding is generally not recommended if / when cabergoline treatment is necessary.
Lactation Suppression : In some countries, cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancies in dogs.
Contraindications and precautions
Hypersensitivity to ergot derivatives, pediatric patients (without clinical experience). Serious impairment of liver function or cholestasis.
Co-medication with drugs primarily metabolized by CYP P450 such as erythromycin and ketoconazole, because elevated plasma levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism).
Precautions: severe cardiovascular disease, Raynaud’s disease, gastroduodenal ulcers, active gastrointestinal bleeding, and hypotension.
Side effects are mainly dose dependent. Much more severe side effects have been reported for the treatment of Parkinson’s disease and (off-label treatment) for restless leg syndrome, both of which typically require very high doses.
Side effects are considered mild when used for the treatment of hyperprolactinemia and other endocrine disorders or gynecological indications where the typical dose is one hundred to one tenth that for Parkinson’s disease.
Cabergoline requires a slow titration of the dose (2 to 4 weeks for hyperprolactinemia, often much longer for other conditions) to minimize side effects.
The extremely long bioavailability of the medication can complicate dosing regimens during titration and require particular precautions.
Cabergoline is considered the best tolerable option for the treatment of hyperprolactinemia, although the newer and less proven quinagolide may offer an equally favorable side effect profile with faster titer times.
Approximately 200 patients with newly diagnosed Parkinson’s disease participated in a cabergoline monotherapy clinical study. Seventy-nine (79) percent reported at least one side effect. These side effects were mostly mild or moderate:
Gastrointestinal tract : side effects were extremely frequent. Fifty-three percent of the patients reported side effects.
Very common : nausea (30%), constipation (22%) and dry mouth (10%).
Psychiatric and central nervous system (CNS) disorders : In total, 51 percent of patients were affected.
Very common : sleep disorders (drowsiness 18%, insomnia 11%), vertigo (27%) and depression (13%).
Cardiovascular – About 30 percent of patients experienced side effects. The most frequent were hypotension (10%), peripheral edema (14%) and nonspecific edema (2%). Arrhythmias were found in 4.8%, palpitations in 4.3% and angina pectoris in 1.4%.
In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy.
Additional side effects were rare cases of haematological side effects and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.
As with other ergot derivatives, pleurisy, exudative disease of the pleura, fibrosis of the pleura, pulmonary fibrosis, and pericarditis are seen. They require immediate termination of treatment.
Clinical improvement and normalization of x-ray results are usually seen soon after withdrawal from cabergoline. It appears that the dose typically used for the treatment of hyperprolactinemia is too low to cause these types of side effects.
Heart valve disease
In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.
As a result of this, the Food and Drug Administration recalled the pergolide from the US market on March 29, 2007.
Because cabergoline is not approved in the United States for Parkinson’s disease, but rather for hyperprolactinemia, the drug remains on the market.
The lower doses required for the treatment of hyperprolactinemia have been found not to be associated with clinically significant heart valve disease or heart valve regurgitation.
No interactions were observed with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some of the effects of cabergoline.
The use of antihypertensive drugs should be monitored intensively because the combination can result in excessive hypotension.
Interactions between diseases
Heart valve disorders
The use of cabergoline is not recommended in patients with heart valve disorders. A cardiovascular evaluation is recommended before starting therapy with this drug.
It is advised that you should inform the doctor about all your medical conditions before starting treatment with this medicine.
Caution is advised while using this medication in patients with Parkinson’s disease and patients receiving medications for high blood pressure due to the increased risk of hypotension while rising from a lying or sitting position.
Close control of blood pressure is necessary during treatment with this medicine. Patients are advised to get up slowly from a sitting or lying position to avoid these episodes.
Caution is advised while using this medication in patients with a history of psychotic episodes due to the increased risk of worsening the patient’s condition. Patients should be closely monitored for any changes in their mood or behavior.
Although cabergoline is commonly described primarily as a dopamine D2 receptor agonist, it also possesses significant affinity for D3, D4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, αB- receptors and moderate / low affinity. for D1 and 5-HT7 receptors.
Cabergoline functions as an agonist at all of these receptors except 5-HT7 and αB-, where it acts as an antagonist.
Mechanism of action
Cabergoline is a long-acting dopamine D2 receptor agonist and in vitro studies with rats show a direct inhibitory effect on prolactin secretion in lactotrophic cells of the pituitary.
Receptor binding studies indicate a low affinity for dopamine D1 receptors, α-adrenergic receptors, and α-adrenergic receptors.
Cabergoline has been studied in a person with Cushing’s disease to lower levels of adrenocorticotropic hormone and cause regression of adrenocorticotropic hormone that leads to pituitary adenomas.
The first publication was a scientific abstract at the meeting of the Society for Neuroscience in 1991.
Cabergoline was first marketed in the Netherlands as Dostinex in 1992. The drug was approved by the Food and Drug Administration on December 23, 1996. It became generic in late 2005, following the expiration of the US patent. .
Many studies reported better efficacy and tolerability of cabergoline compared to bromocriptine.
In a study of 20 patients with persistent disease after pituitary surgery, cabergoline used at doses of 1-7 mg / week resulted in a short-term response (defined as a> 25% reduction in urinary free cortisol). in 75% of patients at 3 months and in 40% of patients at 2 years.
Mild hyperprolactinemia was present in 45% of the patients and was highly predictive of their response to cabergoline treatment at 3 months, but not at 2 years.
Clinical improvements were also observed at 2 years, including a 25% decrease in the prevalence rates of overweight or obesity, a 50% decrease in the prevalence of hypertension, and a 17.5% decrease in the prevalence of impaired blood pressure. fasting glucose or diabetes.
A tumor shrinkage of more than 25% was observed in four (50%) of the responding patients.
In another study of 30 patients with Cushing’s disease (27 postoperative and 3 naive), a short-term response with cabergoline doses of 1-6 mg / week was observed in only 50% of patients at 3 months, with 36.6% showing normalization of urinary free cortisol.
However, 30% demonstrated sustained responses at an average of 36 months. In this study, there was no correlation between hyperprolactinemia and response to treatment. In fact, the three patients with initial hyperprolactinemia had no response to cabergoline treatment.
In general, cabergoline was well tolerated in the studies listed above. Hypotension and severe asthenia, which led to withdrawal from the study, were observed in 2 of 20 patients in the first study and were not observed in the second study.
In particular, none of the studies demonstrated significant effects on heart valves, and only one patient demonstrated mild worsening of mild mitral regurgitation.
In a study with 37 new patients, cabergoline normalized plasma prolactin levels in 88% of 26 microprolactinomas and in 100% of 11 macroprolactinomas.
Regular menses were restored in 7 out of 10 macroprolactinomas and in all oligomenorrheic patients with microadenoma; serum testosterone levels normalized in 2 of 3 hypogonadal men.
Side effects developed in only three cases.182 Another study with cabergoline (0.5 to 3 mg / week) administered once a week was carried out in 15 patients (8 women) with macroprolactinomas.
Normal plasma prolactin levels were reached in 73% of cases. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea.
The side effects were minimal. A study addressing long-term cabergoline treatment in men showed that after 24 months of therapy, plasma prolactin levels normalized in 31 patients with macroprolactinoma (75.6%) and in 8 with microprolactinoma (80%).
Galactorrhea disappeared in all patients, and sperm volume and count normalized in all patients who normalized testosterone levels, while motility normalized by more than 80%.
One study compared the degree of tumor shrinkage among 26 drug-naïve patients, 19 who were intolerant of other dopamine agonists, 47 who were resistant to other dopamine agonists.
And 28 who responded to other dopamine agonists, but were no longer using them due to poor compliance or unavailability of the drug.
The prevalence of macroprolactinoma contraction was higher among subjects without drug treatment (92.3%).
However, significant tumor shrinkage (> 50%) still occurred in a substantial proportion of patients who had prior exposure to other dopamine agonists (38.4%) or who experienced drug intolerance (42.1%) .
The group of individuals whose tumors previously exhibited resistance to other dopamine agonists had the lowest prevalence of significant tumor shrinkage in response to cabergoline (30.3%).
In the first controlled study, 85 patients were randomly assigned to one of four treatment conditions: placebo and 0.5, 1.0, and 2.0 mg of cabergoline taken once daily.
The dose was titrated for the first 2 weeks of the study and then held constant until week 5, at which time efficacy was assessed using the validated International Restless Legs Severity Scale.
The patients then entered a longer-term open-label trial (48 weeks) with six weeks of titration to efficacy and then maintained for 42 weeks.
In the double-blind phase, mean decreases in International Restless Legs Severity Scale score from baseline were 3.3 for placebo and 13.1, 13.5, and 15.7 for 0.5 doses. , 1.0, and 2.0 mg (approximately 43% to 55% decreases).
Both the 1 mg and 2 mg doses produced a statistically significant improvement compared to placebo (p <0.05) but not the lower dose (p> 0.05).
The number of adverse effects was low and only nausea occurred more frequently than with placebo. The increase occurred in approximately 9% of those who continued in the long-term open-label study.
In the second controlled trial conducted in 51 European centers, cabergoline at fixed doses of 2 or 3 mg / day was compared with levodopa at doses of 200 or 300 mg / day over a period of 30 weeks.
The primary outcome measure was the International Restless Legs Severity Scale, which decreased by 16.1 points in the cabergoline group (n = 178) and by 9.5 points in the levodopa group. (n = 183).
More patients in the levodopa group than in the cabergoline group dropped out due to loss of efficacy (14.2% versus 7.9%) or increase (9.8% versus 4.0%), the latter primary end point.
More side effects occurred in the cabergoline group, such as gastrointestinal symptoms (55.6% versus 30.0%), and the authors concluded that cabergoline was not as well tolerated.
In summary, cabergoline provides another dopamine agonist in the treatment of restless legs syndrome. Of special interest is its long half-life, which can result in a lower incidence of increase. However, the side effects of ergot limit its use.
However, cabergoline remains the dopamine agonist that has been shown to be the most effective in establishing resistance to dopamine agonists.