Cabergoline

Cabergoline produces a profound and sustained reduction in serum prolactin via selective stimulation of dopamine D2 receptors on pituitary lactotrophs. Its long half-life supports once- or twice-weekly dosing.

Mechanism of Action

• D2 receptor agonism on lactotrophs: in the tuberoinfundibular pathway, dopamine tonically inhibits prolactin release from anterior pituitary lactotrophs via D2 receptors. Cabergoline mimics this action with high affinity and long receptor occupancy, durably suppressing prolactin secretion.
• Postsynaptic D2 stimulation in the nigrostriatal pathway underlies its antiparkinsonian effect when used in Parkinson’s disease, though newer non-ergot agonists are generally preferred.
• Tumour shrinkage: in prolactinomas, sustained D2 stimulation reduces lactotroph proliferation and tumour volume in the majority of patients.
• Off-target activity: agonism (in order of decreasing affinity) at 5-HT₂B, 5-HT₂A, 5-HT₁D, D3, 5-HT₁A, D4, and antagonism at α2-adrenoceptors. 5-HT₂B agonism is mechanistically linked to cardiac valve fibrosis with chronic high-dose exposure (Parkinson’s dosing).

Pharmacokinetics

• Absorption: rapidly absorbed after oral dosing; food does not meaningfully affect absorption. First-pass effect occurs; absolute bioavailability is not fully characterised.
• Protein binding: 40–42% (concentration-independent).
• Metabolism: extensively metabolised by hydrolysis of the acylurea bond; cytochrome P450-mediated metabolism is minor. Main urinary metabolite is 6-allyl-8β-carboxy-ergoline.
• Half-life: 63–69 hours — the longest among dopamine agonists; supports once- or twice-weekly dosing.
• Excretion: ~22% urinary and ~60% faecal recovery over 20 days; less than 4% as unchanged drug in urine.
• Clearance: renal clearance 0.008 L/min; non-renal clearance 3.2 L/min.

• Idiopathic hyperprolactinaemia in adults.
• Hyperprolactinaemia due to prolactin-secreting pituitary adenoma (micro- or macroprolactinoma) — generally first-line therapy for both prolactin normalisation and tumour shrinkage.
• Inhibition of physiological lactation — single-dose use to prevent puerperal lactation, or short course to suppress established lactation when medically indicated.
• Parkinson’s disease — as monotherapy in early disease or as adjunct to levodopa in advanced disease (use largely superseded by non-ergot agonists in most regions due to valvulopathy risk at higher chronic doses).

• Hypersensitivity to cabergoline, any ergot alkaloid, or any excipient.
• Uncontrolled hypertension.
• Pre-existing cardiac valvulopathy (echocardiographic evidence of valve thickening, restricted motion, or significant regurgitation) — contraindicated for long-term hyperprolactinaemia therapy.
• History of pulmonary, pericardial, or retroperitoneal fibrotic disorders.
• Pre-eclampsia or eclampsia (when used for lactation suppression).
• Severe hepatic impairment.

Very common (≥1/10): nausea, headache, dizziness, asthenia.

Common (≥1/100 to <1/10): postural hypotension, somnolence, fatigue, abdominal pain, dyspepsia, constipation, vomiting, hot flushes, breast pain, dysmenorrhoea, depression, paraesthesia, vertigo.

Uncommon (≥1/1,000 to <1/100): nasal congestion, syncope, hemianopia, transient elevation of liver enzymes, peripheral oedema, pleural effusion.

Rare (<1/1,000): cardiac valvulopathy (regurgitation of aortic, mitral, or tricuspid valves) and pericarditis — risk is dose- and duration-dependent and is principally seen with chronic high-dose use in Parkinson’s disease; pulmonary or retroperitoneal fibrosis; psychotic disorder, hallucinations; impulse control disorders (pathological gambling, hypersexuality, compulsive shopping/eating).

Very rare (<1/10,000): hepatic dysfunction, fibrotic and serosal inflammatory disorders.

• Dopamine antagonists (typical and atypical antipsychotics, metoclopramide, prochlorperazine, domperidone): antagonise the therapeutic effect — avoid combination where possible.
• Macrolide antibiotics (erythromycin, clarithromycin): potent CYP3A4 inhibition increases cabergoline exposure; avoid or use cautiously.
• Other ergot alkaloids: avoid concomitant use.
• Antihypertensives: additive hypotensive effect; monitor blood pressure.
• Alcohol: tolerance to cabergoline is not established; alcohol may worsen orthostatic symptoms.
• Grapefruit juice and St John’s wort: may alter serum levels (inhibition and induction respectively); avoid.

Cabergoline tablets are taken with or without food, with water. Taking with food may reduce gastric irritation.

Hyperprolactinaemia

• Starting dose: 0.5 mg per week, divided into two doses of 0.25 mg (e.g. Monday and Thursday).
• Titration: increase by 0.5 mg/week at monthly intervals according to serum prolactin and tolerability.
• Usual therapeutic dose: 1 mg per week; range 0.25–2 mg per week. Doses above 1 mg/week should be divided over two or more administrations.
• Maximum: typically 4.5 mg per week, though doses above 3 mg/week are rarely needed.
• Duration: continued until prolactin normalised and (for macroprolactinomas) tumour shrinkage achieved; cautious withdrawal may be attempted after at least 2 years of normal prolactin with no visible tumour.

Inhibition of Lactation

• Prevention of puerperal lactation: single dose of 1 mg on the first day post-partum.
• Suppression of established lactation: 0.25 mg every 12 hours for two days (total dose 1 mg).

Parkinson’s Disease

Initiate 1 mg daily and titrate slowly to typical maintenance 2–6 mg daily as monotherapy, or 0.5–4 mg daily as adjunct to levodopa. Annual echocardiographic monitoring is required.

Renal Impairment

No dose adjustment needed in mild to moderate impairment; limited data in severe impairment — use cautiously.

Hepatic Impairment

Reduce dose in severe hepatic impairment.

Missed Dose

Take as soon as remembered if within ~24 hours of scheduled time; otherwise skip and resume the schedule. Do not double up.

Cardiac Valve Monitoring

Echocardiography is recommended before initiating long-term therapy (particularly at Parkinson’s dosing) and periodically thereafter (e.g. at 6 months then annually). Discontinue if valvulopathy develops.

Postural Hypotension and Somnolence

Particularly common at initiation and dose increases. Caution with driving, operating machinery, and rising from supine or sitting.

Impulse Control Disorders

All dopamine agonists can trigger pathological gambling, hypersexuality, compulsive shopping, and compulsive eating. Counsel patients and families to monitor for new behaviours and report them promptly.

Pregnancy and Lactation

• Pregnancy: pregnancy should be excluded before treatment and effective contraception used. Cabergoline restores fertility — many patients conceive on therapy. Cabergoline is generally discontinued as soon as pregnancy is confirmed unless tumour size mandates continuation, with specialist guidance.
• Lactation: cabergoline suppresses lactation; not used in mothers wishing to breastfeed.

Elderly

Use cautiously due to higher risk of postural hypotension and confusional states.

Paediatric

Not generally used in patients under 16 years; safety and efficacy not established.

Effect on Driving

Somnolence and sudden onset of sleep have been reported; patients should be advised accordingly and should not drive if affected.

Store below 25°C in the original packaging to protect from moisture.

Typically 2 years. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).