Dostinex 0,5 mg TABLET

u2022 Inhibition of lactation before the commencement of breastfeeding as well as inhibition of established lactation for medical reasons.

u2022 Not recommended for the routine suppression of lactation or for the relief of symptoms of postpartum pain and engorgement, which can be adequately treated with simple analgesics and breast support.

u2022 Treatment of hyperprolactinaemic disorders.

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. Once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within two to four weeks.

Posology

Adults

For inhibition of lactation

DOSTINEX should be administered during the first day post-partum. The recommended therapeutic dosage is 1 mg (two 0,5 mg tablets) given as a single dose.

For suppression of established lactation

The recommended therapeutic dosage regimen is 0,25 mg (one-half 0,5 mg tablet) every 12 hours for two days (1 mg total dose). DOSTINEX should not be administered as a single dose greater than 0,25 mg in this indication since this reduces tolerability.

For treatment of hyperprolactinaemic disorders

The recommended initial dosage is 0,5 mg given in one or two doses per week. The weekly dose should be increased gradually, preferably by adding 0,5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dosage is usually 1 mg per week and ranges from 0,25 mg to 2 mg per week. Doses up to 4,5 mg per week have been used. The dosage should preferably be adjusted according to prolactin blood levels.

Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given.

Special populations

Use in the elderly

DOSTINEX has not been formally studied in elderly patients with hyperprolactinaemic disorders.

Paediatric population

Safety and efficacy have not been established in patients younger than 16 years.

Method of administration

DOSTINEX is to be administered by the oral route, preferably taken with meals.

u2022 Hypersensitivity to cabergoline, any ergot alkaloid or to any of the excipients of DOSTINEX (listed in section 6.1)

u2022 Pregnancy and breastfeeding (see section 4.6)

u2022 By analogy with other ergot derivatives, DOSTINEX should not be used in women with pre-eclampsia or post-partum hypertension

u2022 History of pulmonary, pericardial and retroperitoneal fibrotic disorders (see section 4.4)

u2022 DOSTINEX is contraindicated in patients with hepatic insufficiency (see section 4.4)

Long-term treatment

Long term treatment is contraindicated in patients with cardiac valvulopathy as determined by pre-treatment echocardiogram showing valve leaflet thickening, valve restriction, valve mixed restriction-stenosis (see section 4.4).

General

DOSTINEX should be given with caution to patients with cardiovascular disease, Raynaud's syndrome, renal insufficiency, peptic ulcer or gastro-intestinal bleeding or with a history of serious, particularly psychotic, mental disorders.

Hepatic insufficiency

Biliary excretion represents the main route of elimination DOSTINEX, it is advisable not to administer DOSTINEX to subjects with severe liver insufficiency (see section 4.3). 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 DOSTINEX. Care should be exercised when administering DOSTINEX concomitantly with other medicines known to lower blood pressure.

Fibrosis/valvulopathy

Pleural effusion/pulmonary fibrosis and valvulopathy have been reported following long-term administration of DOSTINEX. Therefore, DOSTINEX should be not be used in patients with a history of, or current signs and/or clinical symptoms of, respiratory or cardiac disorders linked to fibrotic tissue. 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 or valvulopathy, the discontinuance of DOSTINEX has been reported to result in improvement of signs and symptoms (see section 4.3).

Long-term treatment

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 DOSTINEX treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with DOSTINEX (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. DOSTINEX 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.

Somnolence/sudden sleep onset

DOSTINEX has been associated with somnolence. Dopamine agonists can be associated with sudden sleep onset episodes in patients with Parkinsonu2019s disease. A reduction of dosage or termination of therapy may be considered (see section 4.7).

Inhibition/suppression of physiologic lactation

DOSTINEX should not be used in women with certain pregnancy-induced hypertension, namely pre-eclampsia and post-partum hypertension (see section 4.3). Serious adverse events including hypertension, myocardial infarction, seizures, stroke or psychiatric disorders have been reported in postpartum women treated with cabergoline for inhibition of lactation. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Blood pressure should be carefully monitored after the treatment. If hypertension, suggestive chest pain, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of central nervous system toxicity develop, cabergoline should be discontinued and the patient should be evaluated promptly. A single dose of 0,25 mg of DOSTINEX should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension (see Postural hypotension and section 4.3).

Treatment of hyperprolactinaemic disorders

Since hyperprolactinaemia with amenorrhoea/galactorrhoea and infertility may be associated with pituitary tumours, a complete evaluation of the pituitary is indicated before treatment with DOSTINEX is initiated.

Psychiatric

Impulse control disorders such as pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists including DOSTINEX. This has been generally reversible upon reduction of the dose or treatment discontinuation.

Special populations

The safety and efficacy of DOSTINEX have not been established in patients with renal and hepatic disease or in patients younger than 16 years.

Excipients with known effect

DOSTINEX contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No information is available about interactions between DOSTINEX and other ergot alkaloids, therefore the concomitant use of these medicines during therapy with DOSTINEX is not recommended. Since DOSTINEX exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with medicines which have dopamine antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide), since these might reduce the prolactin-lowering effect of DOSTINEX. DOSTINEX should not be used with macrolide antibiotics (e.g. erythromycin) due to the increased systemic bioavailability of DOSTINEX.

Pregnancy

DOSTINEX is contraindicated in confirmed or suspected pregnancy. If conception occurs during therapy with DOSTINEX, treatment should be discontinued. Before DOSTINEX is administered, pregnancy must be excluded. Pregnancy should be avoided for at least one month following discontinuation of treatment with DOSTINEX due to the long half-life of the medicine and the limited data on in utero exposure (see section 4.3). Pregnancy could occur in women treated for hyperprolactinaemic hypogonadism before restoration of the menstrual cycle; it is advisable to carry out a pregnancy test at least every four weeks during the period of amenorrhoea and afterwards every time the menstrual period is delayed by more than three days. Women who do not wish to become pregnant should use a mechanical contraceptive during the treatment and after discontinuation until the ovulatory cycles cease. When pregnancy is confirmed during the treatment, the use of DOSTINEX should be suspended, and as a precautionary measure, pituitary size should be monitored since expansion of pre-existent tumours could occur during pregnancy.

Breastfeeding

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

Patients being treated with DOSTINEX and presenting with somnolence must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) (see section 4.4, Somnolence/sudden sleep onset). During the first days of DOSTINEX administration, patients should be cautioned about re-engaging in activities requiring rapid and precise responses such as driving an automobile or operating machinery.

Summary of the safety profile

DOSTINEX generally exerts a hypotensive effect in patients. Symptoms mainly appear during the first two weeks of therapy and disappear despite continued therapy. Being an ergot derivative, DOSTINEX may also act in some patients as a vasoconstrictor. Valvulopathy and fibrosis have been reported in association with DOSTINEX (see section 4.4).

Tabulated summary of adverse reactions

The table below contains side effects categorised as follows utilising the incidence rates: very common u2265 1/10; common u2265 1/100 to < 1/10; uncommon u2265 1/1 000 to < 1/100; rare u2265 1/10 000 to < 1/1 000; very rare < 1/10 000. Adverse events have been observed in nursing women treated with 0,25 mg of DOSTINEX every 12 hours for 2 days for suppression of lactation.

Table 1 includes side effects reported when DOSTINEX was used for the inhibition of lactation.

Table 1: Inhibition of lactation

System organ class Frequency Side effect

Nervous system disorders Common Dizziness, vertigo, headache

Uncommon Transient hemianopsia

Rare Somnolence

Cardiac disorders Uncommon Palpitations

Respiratory, thoracic and mediastinal disorders Uncommon Epistaxis

Gastrointestinal disorders Common Abdominal pain, nausea

Rare Epigastric pain

Investigations Common Decreases in blood pressure ( u2265 20 mmHg systolic and u2265 10 mmHg diastolic)

Table 2 includes events reported when DOSTINEX was used for the suppression of lactation.

Table 2: Suppression of lactation

System organ class Frequency Side effect

Nervous system disorders Common Dizziness, vertigo, headache, somnolence

Uncommon Syncope

Vascular disorders Uncommon Hot flushes

Gastrointestinal disorders Common Abdominal pain, nausea

Uncommon Vomiting

General disorders and administration site conditions Uncommon Asthenia

Hyperprolactinaemic disorders

Data obtained in a controlled clinical trial of 6 months therapy, with doses ranging between 1 and 2 mg per week given in two weekly administrations, indicate a 68 % incidence of adverse events during therapy with DOSTINEX. Most disappeared with continued therapy. Severe adverse events were reported at least once during therapy by 14 % of patients. Therapy was discontinued because of adverse events in approximately 3 % of patients. Adverse events subsided upon discontinuation of DOSTINEX, usually within a few days.

Table 3 includes events reported when DOSTINEX was used for the treatment of hyperprolactinaemic disorders.

Table 3: Hyperprolactinaemic disorders

System organ class Frequency Side effect

Psychiatric disorders Common Depression

Nervous system disorders Very common Dizziness, vertigo, headache

Uncommon Paraesthesia

Vascular disorders Common Hot flushes

Gastro-intestinal disorders Very common Abdominal pain, dyspepsia, gastritis, nausea

Common Constipation, vomiting

Reproductive system and breast disorders Common Breast pain

General disorders and administration site conditions Very common Asthenia, fatigue

General

Table 4 includes general events.

Table 4: General

System organ class Frequency Side effect

Vascular disorders Common DOSTINEX generally exerts a hypotensive effect in patients on long-term treatment, postural hypotension

Uncommon Digital vasospasm, fainting

Musculoskeletal and connective tissue disorders Uncommon Leg cramps

Investigations Uncommon Decrease in haemoglobin values in amenorrhoeic women during the first few months after menses resumption

Post-marketing studies

The following events (in Table 5) have been reported in association with DOSTINEX:

Table 5

System organ class Side effect

Psychiatric disorders Aggression, delusions, impulse control disorders such as hypersexuality, increased libido and pathological gambling, psychotic disorder

Respiratory, thoracic and mediastinal disorders Dyspnoea, respiratory disorder, respiratory failure, valvulopathy

Hepatobiliary disorders Abnormal hepatic function

Skin and subcutaneous tissue disorders Alopecia, rash

General disorders and administration site conditions Oedema, fibrosis

Investigations Abnormal liver function tests, increased blood creatinine phosphokinase

The prevalence of asymptomatic valvular regurgitation is significantly greater than that of non-ergot dopamine agonists (see section 4.3 and section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Report any suspected adverse drug reactions associated with the use of the medicine directly to Pfizer via [email protected].

Symptoms of overdosage would likely be those of over-stimulation of dopamine receptors, e.g. nausea, vomiting, gastric complaints, postural hypotension confusion/psychosis or hallucinations. Supportive measures should be undertaken to remove any unabsorbed medicine and maintain blood pressure if necessary. In addition, the administration of dopamine antagonist medicines may be advisable.