Article: Cabergoline

Cabergoline (brand names Dostinex® and Cabaser®), an lysergic acid amide-derivative, is a potent dopamine receptor agonist on D2-Receptors. It also acts on dopamine-receptors in lactophilic hypothalamus cells and causes thereby a suppression of the prolactin-production in pituitary gland.

Pharmacokinetics

Following an oral single dose the drug is resorbed within 0.5 to 4 hours from the GI-Tract with considerable interindividual differences. Meals do not alter the absorption characteristic. Human bioavailibility was not determined, because the drug is intended for oral use only. In mice and rats the absolute bioavailability was 30 and 63%, respectively. Cabergoline is rapidly and to a great extent metabolized in the liver and excreted in bile and far less in urine. All metabolites are less active than the parental drug or inactive. The human elimination halflife is estimated to be 63 to 68 hours in patients with M. Parkinson and 79 to 115 hours in patients with pituitary tumors.

Carcinogenity

In rodents a dose dependent increase in malignant tumors has been found. They are thought to be species-specific. No clinical data exists on carcinogenity in humans.

Uses

• Monotherapy of Parkinson's disease in the early phase.
• Combination therapy of Parkinson's disease in the progressive phase together with levodopa and a decarboxylase-inhibitor like carbidopa.
• Adjunctive therapy of prolactin-producing tumors of the pituitary gland (microprolactinomes).
• In some countries also : ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, und galactorrhea).

Off-Label/Recreational Uses

It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs such as reduced libido and anorgasmia. It also has been suggested online that it has a possible recreational use in reducing or eliminating the male refractory period.

Contraindications and Precautions

• Hypersensitivity to ergot-derivatives
• Pediatric Patients (no clinical experience)
• Severely impaired liver function or cholestasis
• Comedication with drugs metabolized mainly by CYP P450 such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result.
• Cautions : severe cardiovascular disease, Raynaud's Syndrome, gastroduodenal ulcers, active gastrointestinal bleeding, hypotension.

Pregnancy and Lactation

• Pregnancy : Approximately 100 female patients became pregnant under therapy with cabergoline for hyperprolactinemic conditions. The incidence of spontaneous aborts and congenital abnormalities was comparable to nontreated patients. Nonetheless women wishing to become pregnant should wait a safety period of 4 weeks after discontinuation of cabergoline. Patients becoming pregnant under therapy should terminate cabergoline immediately, if possible.
• Lactation : In rats cabergoline was found in the maternal milk. Since it is not known if this effect is also seen in humans, lactating women should not be treated.

Side effects

Approximately 200 patients with newly diagnostizised M. Parkinson participated in a clinical study regarding the monotherapy with cabergoline. Seventynine (79) % reported at least one side effect. These side effects were chiefly mild or moderate:

• GI-Tract: Side effects were extremely frequent. Fiftythree Per Cent of patients reported side effects. Nausea (30%), obstipation (22%), and dry mouth (10%) were very frequent. Frequent were gastric irritation (7%), vomiting (5%), and dyspepsia (2%).
• Psychiatric Disturbances and CNS : Altogether 51% of patients were affected. Very frequent were disturbances of sleep (somnolence 18%, insomnia 11%), vertigo (27%), and depression (13%). Frequent were dyskinesia (4%) and hallucinations (4%).
• Cardiovascular : Approximately 30% of patients experienced side effects. Most frequent were hypotension (10%), peripheral edema (14%) and non-specific edema (2%). Arrhythmias were encountered in 4.8%, palpitations in 4.3%, and angina pectoris in 1.4%.

In a combinatiion study with 2,000 patients also treated with levodopa the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.

As with other ergot-derivatives pleuritis, exsudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-Ray findings are normally seen soon after cabergoline withdrawal.

The reported incidence and severity of side effects in hyperprolactinemic patients was comparable.

Interactions

No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot-derivatives. Dopamine Antagonists such as antipsychotics and metoclopramide inhibit the clinical action of cabergoline and should therefore not be used concomitantly. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.

Dosage

• Morbus Parkinson : monotherapy : The therapy should be started with 0.5mg daily. The usual maintenance dose is 2 to 4mg daily. In combination therapy usually 2 to 6mg daily are needed.
• Tumors of the pituitary gland and other hyperprolactinemic conditions: Initially 0.5mg per week(!), slowly increasing to 4.5mg per week, if necessary.
• Ablactation : According to specific treatment scheme.