DOSTINEX Tablets

Active ingredients: Cabergoline

Contraindications

Hypersensitivity to cabergoline, any of the excipients listed in section 6.1 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. (See section 4.4).

Special warnings and precautions for use

General

The safety and efficacy of cabergoline have not yet been established in patients with renal and hepatic disease. As with other ergot derivatives, cabergoline should be given with caution to patients with severe cardiovascular disease, Raynaud’s syndrome, renal insufficiency, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders. Particular care should be taken when patients are taking concomitant psychoactive medication.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

The effects of alcohol on overall tolerability of cabergoline are currently unknown.

Before cabergoline administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month.

Hepatic Insufficiency

Lower doses should be considered in patients with severe hepatic insufficiency who receive prolonged treatment with cabergoline. Compared to normal volunteers and those with lesser degrees of hepatic insufficiency, an increase in AUC has been seen in patients with severe hepatic insufficiency (Child-Pugh Class C) who received a single 1 mg dose.

Postural Hypotension

Postural hypotension can occur following administration of cabergoline. Care should be exercised when administering cabergoline concomitantly with other drugs known to lower blood pressure.

Somnolence/Sudden Sleep Onset

Cabergoline has been associated with somnolence. Dopamine agonists can be associated with sudden sleep onset episodes in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with cabergoline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction in dosage or termination of therapy may be considered. (See section 4.7)

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Dostinex. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

Inhibition/suppression of physiological lactation

As with other ergot derivatives, cabergoline should not be used in women with pregnancy-induced hypertension, for example, preeclampsia or post-partum hypertension, unless the potential benefit is judged to outweigh the possible risk.

In post-partum studies with cabergoline, blood pressure decreases were mostly asymptomatic and were frequently observed on a single occasion 2 to 4 days after treatment. Since decreases in blood pressure are frequently noted during the puerperium, independently of drug therapy, it is likely that many of the observed decreases in blood pressure after cabergoline administration were not drug-induced. However, periodic monitoring of blood pressure, particularly during the first few days after cabergoline administration, is advised.

A single dose of 0.25 mg of cabergoline should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension (see section 4.2). A clinical study exploring the efficacy and tolerability of 0.5 mg of cabergoline given as a single dose for suppression of lactation has shown that the risk of side effects is approximately doubled in this indication if the drug is administered as a single dose of 0.5 mg.

Treatment of hyperprolactinaemic disorders

Because hyperprolactinaemia accompanied with amenorrhoea/galactorrhoea and infertility may be associated with pituitary tumour, a complete evaluation of the pituitary is indicated before treatment with cabergoline is initiated.

Cabergoline restores ovulation and fertility in women with hyperprolactinaemic hypogonadism.

Because pregnancy might occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrhoeic period and, once menses are reinitiated, every time a menstrual period is delayed by more than three days. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with cabergoline and after discontinuation of cabergoline until recurrence of anovulation. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation.

Before administration of cabergoline, pregnancy should be excluded. Because clinical experience is still limited and the product has a long half-life, as a precautionary measure it is recommended that once regular ovulatory cycles have been achieved women seeking pregnancy discontinue cabergoline one month before intended conception. Should pregnancy occur during treatment, cabergoline is to be discontinued. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation.

Regular gynaecological assessment, including cervical and endometrial cytology, is recommended for patients taking cabergoline for extensive periods.

Fibrosis and cardiac valvulopathy and possibly related clinical phenomena

Fibrotic and serosal inflammatory disorders such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis have occurred after prolonged usage of ergot derivatives with agonist activity at the serotonin 5HT2B receptor, such as cabergoline. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of cabergoline.

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.

Valvulopathy has been associated with cumulative doses, therefore, patients should be treated with the lowest effective dose. At each visit, the risk benefit profile of cabergoline treatment for the patient should be reassessed to determine the suitability of continued treatment with cabergoline.

Before initiating long-term 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. 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 section 4.3).

During long-term 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. Following treatment initiation, the first echocardiogram must occur within 3-6 months, thereafter, the frequency of echocardiographic monitoring should be determined by appropriate individual clinical assessment with particular emphasis on the above-mentioned signs and symptoms, but must occur at least every 6 to 12 months.

Cabergoline should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening (see section 4.3).

The need for other clinical monitoring (e.g. physical examination including, cardiac auscultation, X-ray, CT scan) should be determined on an individual basis.

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.

Interaction with other medicinal products and other forms of interaction

The concomitant use of other drugs during early puerperium, particularly of ergot alkaloids, was not associated with detectable interactions modifying the efficacy and safety of cabergoline.

No information is available about the interaction between cabergoline and other ergot alkaloids; therefore, the concomitant use of these medications during long-term treatment with cabergoline is not recommended.

Since cabergoline exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs which have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the prolactin-lowering effect of cabergoline.

As with other ergot derivatives, cabergoline should not be used with macrolide antibiotics (e.g. erythromycin) due to increased systemic bioavailability of cabergoline.

Pregnancy and lactation

There are no adequate and well-controlled studies from the use of cabergoline in pregnant women. Animal studies have not demonstrated teratogenic effects, but reduced fertility and embryo-toxicity were observed in association with pharmacodynamic activity (see section 5.3).

In a twelve year observational study on pregnancy outcomes following cabergoline therapy, information is available on 256 pregnancies. Seventeen of these 256 pregnancies (6.6%) eventuated in major congenital malformations or abortion. Information is available on 23/258 infants who had a total of 27 neonatal abnormalities, both major and minor. Musculoskeletal malformations were the most common neonatal abnormality (10), followed by cardio-pulmonary abnormalities (5). There is no information on perinatal disorders or long-term development of infants exposed to intra-uterine cabergoline. Based on recent published literature, the prevalence of major congenital malformations in the general population has been reported to be 6.9% or greater. Rates of congenital abnormality vary between different populations. It is not possible to accurately determine if there is an increased risk as no control group was included.

Cabergoline should only be used during pregnancy if clearly indicated and after an accurate benefit/risk evaluation. (See section 4.4).

Due to the long half-life of the drug and limited data on in utero exposure, women planning to become pregnant should discontinue cabergoline one month before intended conception. If conception occurs during therapy, treatment should be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug.

In rats, cabergoline and/or its metabolites are excreted in milk. No information is available on the excretion in breast milk in humans; however, mothers should be advised not to breast-feed in case of failed lactation inhibition/suppression by cabergoline. Since it prevents lactation, cabergoline should not be administered to mothers with hyperprolactinemic disorders who wish to breast-feed their infants.

Effects on ability to drive and use machines

Patients should be careful when performing actions which require fast and accurate reaction during treatment initiation.

During the first days of cabergoline administration, patients should be cautioned about re-engaging in activities requiring rapid and precise responses such as driving an automobile or operating machinery.

Patients being treated with cabergoline and presenting with somnolence must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves and others at risk of serious injury or death (e.g. operating machines) until such episodes and somnolence have resolved. (See section 4.4).

Undesirable effects

Adverse events are generally dose-related. In patients known to be intolerant to dopaminergic drugs, the likelihood of adverse events may be lessened by starting therapy with cabergoline at reduced doses, e.g. 0.25 mg once a week, with subsequent gradual increase until the therapeutic dosage is reached. If persistent or severe adverse events occur, temporary reduction of dosage followed by a more gradual increase, e.g. increments of 0.25 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).

Cardiac disorders

Very Common: Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion)

Uncommon: Palpitations

Not Known: Angina pectoris

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnea, pleural effusion, fibrosis, (including pulmonary fibrosis), epistaxis

Very rare: Pleural fibrosis

Not Known: Respiratory disorder, respiratory failure, pleuritis, chest pain

Immune system disorders

Uncommon: Hypersensitivity reaction

Nervous system disorders

Very Common: Headache*, dizziness/vertigo*

Common: somnolence

Uncommon: Transient hemianopsia, syncope, paresthesia

Not Known: Sudden sleep onset, tremor

Eye disorders

Not Known: Visual impairment

Psychiatric disorders

Common: Depression

Uncommon: Increased libido

Not Known: Aggression, delusions, hypersexuality, pathological gambling, psychotic disorder, hallucinations

Vascular disorders

Common: Cabergoline generally exerts a hypotensive effect in patients on long-term treatment; Postural hypotension, hot flushes**

Uncommon: Digital vasospasm, fainting

Gastrointestinal disorders

Very Common: Nausea*, dyspepsia, gastritis, abdominal pain*

Common: Constipation, vomiting**

Rare: Epigastric pain

General disorders and administration site conditions

Very Common: Asthenia***, fatigue

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

Investigations

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.

Not Known: Blood creatinine phosphokinase increased, liver function tests abnormal

* Very common in patients treated for hyperprolactinaemin disorders; Common in patients treated for inhibition/supression of lactation
** Common in patients treated for hyperprolactinaemin disorders; Uncommon in patients treated for inhibition/supression of lactation
*** Very common in patients treated for hyperprolactinaemin disorders; Uncommon in patients treated for inhibition/supression of lactation

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Dostinex (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Incompatibilities

Not applicable.