Cabergoline

Cabergoline (brand names Dostinex and Cabaser), a lysergic acid amide derivative, is a potent dopamine receptor agonist on D2 receptors. It also acts on dopamine receptors in lactophilic hypothalamus cells to suppress prolactin production in the pituitary gland. It is frequently used as a second-line agent in the management of prolactinomas when bromocriptine is ineffective.

History
Cabergoline was invented by scientists working for the Italian drug company Farmitalia-Carlo Erba SpA in Milan in 1981/82, who were experimenting with semisynthetic derivatives of the ergot alkaloids. Farmitalia-Carlo Erba was acquired by Pharmacia in 1992, which in turn was acquired by Pfizer in 2002. The drug was not FDA approved until 2002. It went generic in late 2005 following US patent expiration.

Intellectual property
Farmitalia filed for patent protection of Cabergoline in 1982, and U.S. Patent 4,526,892 was granted in July 1985.

Pharmacokinetics
Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson's disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80h.

Carcinogenity
In rodents a dose-dependent increase in malignant tumors has been found. The correlation is 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, together with levodopa and a decarboxylase inhibitor such as carbidopa, in progressive-phase Parkinson's disease.
 * Adjunctive therapy of prolactin-producing pituitary gland tumors (microprolactinomas).
 * In some countries also: ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, and 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. It is also used by bodybuilders to control gynecomastia caused by elevated prolactin levels caused by use of anabolic steroids such as Nandrolone.

Contraindications and precautions

 * Hypersensitivity to ergot derivatives
 * Pediatric patients (no clinical experience)
 * Severely impaired liver function or cholestasis
 * Co-medication with drugs metabolized mainly by CYP P450 such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism).
 * Cautions: severe cardiovascular disease, Raynaud's disease, 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 abortions and congenital abnormalities was comparable to nontreated patients. Nevertheless, women wishing to become pregnant should wait a period of four 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 also occurs in humans, breastfeeding women should not be treated.

Side effects
Approximately 200 patients with newly diagnosed Parkinson's disease participated in a clinical study of cabergoline monotherapy. Seventy-nine (79) percent reported at least one side effect. These side effects were chiefly mild or moderate:
 * GI tract: Side effects were extremely frequent. Fifty-three percent of patients reported side effects. Very frequent: Nausea (30%), obstipation (22%), and dry mouth (10%). Frequent:  Gastric irritation (7%), vomiting (5%), and dyspepsia (2%).
 * Psychiatric disturbances and central nervous system (CNS): Altogether 51 percent of patients were affected. Very frequent: Sleep disturbances (somnolence 18%, insomnia 11%), vertigo (27%), and depression (13%). Frequent: dyskinesia (4%) and hallucinations (4%).
 * Cardiovascular: Approximately 30 percent 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 combination 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, exudative 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.

Valvular heart 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. Both drugs are ergot-derived dopamine agonists, although their molecular skeletons are different. As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007. Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease.

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

 * Parkinson's disease: Monotherapy: Initial dose should be 0.5 mg daily. The usual maintenance dose is 2 to 4 mg daily. Combination therapy: Usually 2 to 6 mg daily.
 * Tumors of the pituitary gland and other hyperprolactinemic conditions: Initially 0.5 mg per week, slowly titrated to 4.5 mg per week, if necessary.
 * Ablactation: According to specific treatment scheme.