Cabergoline

Inhibition/suppression of physiological lactation Cabergoline is indicated for the inhibition of physiological lactation soon after delivery and for suppression of already established lactation: 1. After parturition, when the mother elects not to breast feed the infant or when breast feeding is contraindicated due to medical reasons related to the mother or the new-born.

2. After stillbirth or abortion. Cabergoline prevents/suppresses physiological lactation by inhibiting prolactin secretion. In controlled clinical trials, cabergoline given as a single 1 mg administration during the first day post-partum, was effective in inhibiting milk secretion, as well as breast engorgement and pain in 70 - 90% of the women.

Less than 5% of women experienced rebound breast symptomatology during the third post-partum week (which was usually mild in severity). Suppression of milk secretion and relief of breast engorgement and pain are obtained in approximately 85% of nursing women treated with a total dose of 1 mg cabergoline given in four divided doses over two days.

Rebound breast symptomatology after day 10 is uncommon (approximately 2% of cases). Treatment of hyperprolactinaemic disorders Cabergoline is indicated for the treatment of dysfunctions associated with hyperprolactinaemia, including amenorrhoea, oligomenorrhoea, anovulation and galactorrhoea.

Cabergoline is indicated in patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinaemia, or empty sella syndrome with associated hyperprolactinaemia, which represent the basic underlying pathologies contributing to the above clinical manifestations.

On chronic therapy, cabergoline at doses ranging between 1 and 2 mg per week, was effective in normalising serum prolactin levels in approximately 84% of hyperprolactinaemic patients. Regular cycles were resumed in 83% of previously amennorhoeic women.

Restoration of ovulation was documented in 89% of women with progesterone levels monitored during the luteal phase. Galactorrhoea disappeared in 90% of cases showing this symptom before therapy. Reduction in tumour size was obtained in 50 - 90% of female and male patients with micro- or macroprolactinoma.

Cabergoline is to be administered by the oral route. Since in clinical studies cabergoline has been mainly administered with food and since the tolerability of this class of compounds is improved with food, it is recommended that cabergoline be preferably taken with meals for all the therapeutic indications.

Inhibition/suppression of physiological lactation For inhibition of lactation cabergoline should be administered during the first day post-partum. 5 mg tablets) given as a single dose. 5 mg tablet) every 12 hours for two days (1 mg total dose).

This dosage regimen has been demonstrated to be better tolerated than the single dose regimen in women electing to suppress lactation having a lower incidence of adverse events, in particular of hypotensive symptoms. g. on Monday and Thursday) per week.

5 mg per week at monthly intervals until an optimal therapeutic response is achieved. 25 mg to 2 mg per week. 5 mg per week have been used in hyperprolactinaemic patients. The maximum dose should not exceed 3mg per day. The weekly dose may be given as a single administration or divided into two or more doses per week according to patient tolerability.

Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given since the tolerability of doses greater than 1 mg taken as a single weekly dose has been evaluated only in a few patients.

Patients should be evaluated during dose escalation to determine the lowest dosage that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is advised since, once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within two to four weeks.

After cabergoline withdrawal, recurrence of hyperprolactinaemia is usually observed. However, persistent suppression of prolactin levels has been observed for several months in some patients. Of the group of women followed up, 23/29 had ovulatory cycles which continued for greater than 6 months after cabergoline discontinuation.

Paediatric population The safety and efficacy of cabergoline has not been established in subjects less than 16 years of age. Use in the elderly As a consequence of the indications for which cabergoline is presently proposed, the experience in elderly is very limited.

Available data do not indicate a special risk.

Adverse events are generally dose related. g. 25 mg once a week, with subsequent gradual increase until the therapeutic dosage is reached. g. 25 mg/week every two weeks, may increase tolerability. The following undesirable effects have been observed and reported during treatment with cabergoline with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data).

MedDRA System Organ Class Frequency Undesirable Effects Very Common Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion) Uncommon Palpitations Cardiac disorders Not Known Angina pectoris Uncommon Dyspnea, pleural effusion, fibrosis, (including pulmonary fibrosis), epistaxis Very rare Pleural fibrosis Respiratory, thoracic and mediastinal disorders Not Known Respiratory disorder, respiratory failure, pleuritis, chest pain Immune system disorders Uncommon Hypersensitivity reaction Very common Headache*, dizziness/vertigo* Common somnolence Uncommon Transient hemianopsia, syncope, paresthesia Nervous system disorders Not Known Sudden sleep onset, tremor Eye disorders Not Known Visual impairment Common Depression Uncommon Increased libido Psychiatric disorders Not Known Aggression, delusions, hypersexuality, pathological gambling, psychotic disorder, hallucinations Common Cabergoline generally exerts a hypotensive effect in patients on long- term treatment.

Postural hypotension, hot flushes** Vascular disorders Uncommon Digital vasospasm, fainting Very common Nausea*, dyspepsia, gastritis, abdominal pain* Common Constipation, vomiting** Gastrointestinal disorders Rare Epigastric pain Very Common Asthenia***, fatigueGeneral disorders and administration site conditions Uncommon Oedema, peripheral oedema Hepato-biliary disorders Not Known Hepatic function abnormal Skin and subcutaneous tissue disorders Uncommon Rash, alopecia Musculoskeletal and connective tissue disorders Uncommon Leg cramps Reproductive system and breast disorders Common Breast pain Common Asymptomatic decreases in blood pressure (≥ 20 mmHg systolic and ≥ 10 mmHg diastolic) Uncommon A decrease in haemoglobin values have been observed in amenhorrheic women during the first few months after menses.

Investigations Not Known Blood creatinine phosphokinase increased, liver function tests abnormal *Very common in patients treated for hyperprolactinaemin disorders; Common in patients treated for inhibition/suppression of lactation.

** Common in patients treated for hyperprolactinaemin disorders; Uncommon in patients treated for inhibition/suppression of lactation. 4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1 or any ergot alkaloid. History of pulmonary, pericardial and retroperitoneal fibrotic disorders. Cabergoline is contraindicated in patients with hepatic insufficiency and with toxaemia of pregnancy. Cabergoline should not be co-administered with anti- psychotic medications or administered to women with a history of puerperal psychosis.

For long-term treatment:

Evidence of cardiac valvulopathy as determined by pre- treatment echocardiography. 4).

5 mg Leucine USP and Lactose anhydrous For a complete listing see Dosage Forms, Composition and Packaging section.

INDICATIONS AND CLINICAL USE DOSTINEX* is indicated for:

Treatment of hyperprolactinemic disorders: DOSTINEX (cabergoline) is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.

Inhibition of physiological lactation:

DOSTINEX (cabergoline) is indicated for the prevention of the onset of physiological lactation in the puerperium for clearly defined medical reasons. These medical reasons may include birth of a still born baby, neonatal death, conditions interfering with suckling (cleft lip or palate of the baby), severe acute or chronic mental illness or medical conditions, maternal disease which may be transmitted to the baby that require medications which are excreted in the milk.

Dostinex is not indicated for the purpose of suppression of already established post partum lactation.

Pediatrics (<16 years of age):

Safety and effectiveness of DOSTINEX in pediatric patients have not been established.

Geriatrics (>65 years of age):

Very limited data concerning experience of treatment of hyperprolactinemia in the elderly are available. However, available data do not indicate a special risk for this population. DOSTINEX* (cabergoline) Product Monograph Page 4 of

DOSTINEX (cabergoline) is contraindicated in patients with: uncontrolled hypertension, a history of pulmonary, pericardial and retroperitoneal fibrotic disorders. (See WARNINGS AND PRECAUTIONS), anatomical evidence of cardiac valvulopathy of any valve (eg, echocardiogram showing valve leaflet thickening, valve restriction, valve mixed restriction-stenosis) Echocardiogram is required at pretreatment in patients being treated for hyperprolactinemic disorders (see WARNINGS AND PRECAUTIONS), a known hypersensitivity to this drug or any ergot derivatives and to any ingredient in the formulation.

For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING. WARNINGS AND PRECAUTIONS General Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia and eclampsia, unless the potential benefit is judged to outweigh the possible risk.

0 mg may produce orthostatic hypotension. Care should be exercised when administering DOSTINEX (cabergoline) with other medications known to lower blood pressure. The effects of alcohol on overall tolerability of DOSTINEX are currently unknown.

Before DOSTINEX administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month. Carcinogenesis and Mutagenesis Please see also TOXICOLOGY. Cardiovascular DOSTINEX should be given with caution to subjects with cardiovascular disease and Raynaud’s syndrome.

Symptomatic hypotension can occur with DOSTINEX administration. Care should be exercised when administering DOSTINEX concomitantly with other drugs known to lower blood pressure.

DOSTINEX* (cabergoline) Product Monograph Page 5 of 28 Fibrosis:

As with other ergot derivatives, pleural effusion/pulmonary fibrosis has been reported following long-term administration of cabergoline. Therefore, DOSTINEX should not be used in patients with a history of, or current signs and /or symptoms of respiratory or cardiac disorders linked to fibrotic tissue (see CONTRAINDICATIONS).

Erythrocyte sedimentation rate (ESR) has been found to be abnormally increased in association with pleural effusion/fibrosis. Chest x-ray examination is recommended in cases of unexplained ESR increases to abnormal values. Serum creatinine measurements can also be used to help in the diagnosis of fibrotic disorder.

Following diagnosis of pleural effusion/pulmonary fibrosis, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms.

Treatement for Hyperprolactinemia:

Before initiating treatment: All patients must undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of asymptomatic valvular disease. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy.

During treatment:

Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of: Pleuro-pulmonary disease such as dyspnoea, shortness of breath, persistent cough or chest pain Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb oedema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.

Cardiac failure: cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. Clinical diagnostic monitoring for development of fibrotic disorders, as appropriate, is essential.

Additional appropriate investigations such as erythrocyte sedimentation rate, and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. , physical examination including cardiac auscultation, X-ray, CT scan) should be determined on an individual basis.

DOSTINEX* (cabergoline) Product Monograph Page 6 of 28 Cardiac Valvulopathy:

There have been post-marketing reports of cardiac valvulopathy involving one or more valves in patients taking DOSTINEX. The incidence of treatment emergent cardiac valvulopathy has not yet been determined, although some studies have suggested that the risk is cumulative, and asymptomatic cases of valvulopathy have been identified using echocardiography.

Valvulopathy has been reported with substantially greater frequency during treatment with ergot derivatives with 5-HT2B agonist activity, including cabergoline, compared to non-ergot dopamine agonists. DOSTINEX is contraindicated in patients with a history of cardiac valvulopathy (see CONTRAINDICATIONS).

Physicians should inform patients/caregivers of the risk of cardiac valvulopathy.

Treatment of Hyperprolactinemia:

Before initiating treatment: All patients must undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of asymptomatic valvular disease. In patients with valvular regurgitation, it is not known whether cabergoline treatment might worsen the underlying disease.

If fibrotic valvular disease is detected, the patient should not be treated with cabergoline (See CONTRAINDICATIONS).

During treatment:

Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of: Cardiac failure: cases of valvular and pericardial fibrosis have often manifested as cardiac failure.

Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. Following treatment initiation, the first echocardiogram must occur within 3-6 months; […]