Cabergolin Tablets USP 0.25mg TajPharma

1. Name of the medicinal product
a) Cabergolin Tablets USP 0.25mg TajPharma
b) Cabergolin Tablets USP 0.5mg TajPharma

2. Qualitative and quantitative composition
a) Each uncoated tablet contains:
Cabergolin USP            0.25mg
Excipients                        q.s.

b) Each uncoated tablet contains:
Cabergolin USP                0.5mg
Excipients                        q.s.

3. Pharmaceutical form
Tablet. Flat, capsule-shaped, 4 x 8 mm, scored, white tablets.

4. Clinical particulars
4.1 Therapeutic indications
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.

4.2 Posology and method of administration
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. The recommended therapeutic dose 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). 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.

Treatment of hyperprolactinaemic disorders
The recommended initial dosage of cabergoline is 0.5 mg per week given in one or two (one-half of one 0.5 mg tablet) doses (e.g. on Monday and Thursday) 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 of cabergoline up to 4.5 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.

4.3 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.

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 Cabergolin. 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 5HT_2B 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.

4.5 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.

4.6 Fertility, 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.

4.7 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).

4.8 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)

*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 Cabergolin (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.

4.9 Overdose
Symptoms of overdose 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 taken to remove any unabsorbed drug and maintain blood pressure, if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.

5. Pharmacological properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Prolactine inhibitors

Cabergoline is a dopaminergic ergoline derivative endowed with a potent and long-lasting PRL-lowering activity. It acts by direct stimulation of the D₂-dopamine receptors on pituitary lactotrophs, thus inhibiting PRL secretion. In rats the compound decreases PRL secretion at oral doses of 3-25 mcg/kg, and in-vitro at a concentration of 45 pg/ml. In addition, cabergoline exerts a central dopaminergic effect via D₂ receptor stimulation at oral doses higher than those effective in lowering serum PRL levels. The long lasting PRL-lowering effect of cabergoline is probably due to its long persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after single oral dose in rats (t_½ of approximately 60 hours).

The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, puerperal women and hyperprolactinaemic patients. After a single oral administration of cabergoline (0.3 – 1.5 mg), a significant decrease in serum PRL levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7 – 28 days in healthy volunteers and hyperprolactinaemic patients, and up to 14 – 21 days in puerperal women). The PRL-lowering effect is dose-related both in terms of degree of effect and duration of action.

With regard to the endocrine effects of cabergoline not related to the antiprolactinaemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a very selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect only relate to blood pressure decrease. The maximal hypotensive effect of cabergoline as single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.

5.2 Pharmacokinetic properties
The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes and in female hyperprolactinaemic patients.

After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours.

Ten days after administration about 18% and 72% of the radioactive dose was recovered in urine and faeces, respectively. Unchanged drug in urine accounted for 2-3% of the dose.

In urine, the main metabolite identified was 6-allyl-8β-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline in inhibiting prolactin secretion in vitro. Cabergoline biotransformation was also studied in plasma of healthy male volunteers treated with [¹⁴C]-cabergoline: a rapid and extensive biotransformation of cabergoline was shown.

The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non-radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers (using a radio-immuno assay), 79-115 hours in hyperprolactinaemic patients (using a HPLC method).

On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37 ± 8 pg/ml) and after a 4 week multiple regimen (101 ± 43 pg/ml).

In vitro experiments showed that the drug at concentrations of 0.1-10 ng/ml is 41-42% bound to plasma proteins. Food does not appear to affect absorption and disposition of cabergoline.

5.3 Preclinical safety data
There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.

A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofoetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofoetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

6. Pharmaceutical particulars

6.1 List of excipients
Lactose
Leucine

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
2 years.

6.4 Special precautions for storage
Do not store above 25°C. Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature and contents of container
Class I amber glass bottles, stoppered with an aluminum tamper-evident screw cap with silica gel insert or high-density polyethylene (HDPE) bottles with child-resistant polypropylene (PP) cap with inner low-density polyethylene (LDPE) desiccant canister containing silica gel.
Each bottle contains 2, 4 or 8 tablets and is enclosed in an outer cardboard carton.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
Bottles of Cabergolin are supplied with desiccant in caps. This desiccant must not be removed.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Cabergolin Tablets USP 0.25mg TajPharma

Package leaflet: Information for the patient

a) Cabergolin Tablets USP 0.25mg TajPharma
b) Cabergolin Tablets USP 0.5mg TajPharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet
1. What Cabergolin Tablets are and what they are used for
2. What you need to know before you take Cabergolin Tablets
3. How to take Cabergolin Tablets
4. Possible side effects
5. How to store Cabergolin Tablets
6. Contents of the pack and other information

1. WHAT CABERGOLIN TABLETS ARE AND WHAT THEY ARE USED FOR
Cabergolin belongs to a group of medicines known as prolactin inhibitors. Cabergolin prevents lactation (production of milk) by decreasing levels of a hormone known as prolactin. Cabergolin can also be used to reduce abnormal quantities of the hormone prolactin in the blood

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE CABERGOLIN TABLETS
Do not take Cabergolin if you:
• are allergic to Cabergolin or other ergot alkaloids (e.g. bromocriptine), or to any of the other ingredients of this medicine
• have (or have had in the past) psychosis or you are at risk of psychosis after childbirth
• have severely impaired liver function
• have swelling of the hands, feet and a high blood pressure during pregnancy (pre-eclampsia, eclampsia)
• have uncontrolled high blood pressure or high blood pressure after childbirth
• are pregnant or breast-feeding
• have previously experienced side effects affecting lung, such as fibrosis, associated with the use of dopamine agonists (e.g. bromocriptine, pergolide)
• will be treated with Cabergolin for a long period and have or had fibrotic reactions (scar tissue) affecting your heart.

Warnings and precautions
If you have any of the following health problems you must inform your doctor before taking Cabergolin as the medicinal product may be unsuitable for you:
• cardiovascular disease
• stomach ulcer or bleeding in the gastrointestinal tract, (this condition can cause black faeces or vomiting with blood)
• impaired kidney function
• liver or kidney disease
• history of serious mental disease, particularly psychotic disorders
• Raynaud’s disease (when it is cold the fingers and toes become bluish white, with no pulse, cold, insensitive and numb)
• low blood pressure or you are taking medicines to lower blood pressure
• increased blood pressure after giving birth
• serious chest complaint (e.g. pain in the chest when breathing, fluid in the lungs, inflammation or infection of the lungs)
• if you have ever been diagnosed in the past with a problem known as fibrotic disease (scar tissue) affecting the lungs, lower back and kidneys or heart.
In case you are treated with Cabergolin for a long period, your doctor will check before starting treatment whether your heart, lungs and kidneys are in a good condition. He/she will also have an echocardiogram (an ultrasound test of the heart) taken before treatment is started and at regular intervals during treatment. If fibrotic reactions occur, treatment will have to be discontinued.
Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose.
The effect of alcohol on the tolerability of Cabergolin is unknown.
Infertility can be reversed in women taking Cabergolin, and pregnancy can occur before the menstrual cycle has normalised. Suitable means of contraception should therefore be used during treatment if necessary.
It is recommended that women on long term treatment with Cabergolin for hormonal disorders should have regular gynaecological exams including smear tests. Your doctor will continue to monitor your medical condition while you are taking Cabergolin tablets. Children and adolescents
The safety and efficacy of Cabergolin has not been established in children and adolescents less than 16 years of age.
Other medicines and Cabergolin
• Certain medicines used for reducing blood pressure and certain medicinal products (e.g. phenothiazines, butyrophenones, thioxanthene) used for the treatment of psychological illnesses (schizophrenia or psychoses), if taken at the same time as Cabergolin, can interfere with the effects of Cabergolin. The treating doctor should therefore be aware of such simultaneous medication.
• There are other medicines such as other ergot alkaloids, medicines to prevent vomiting (metoclopramide), medicines for reducing high blood pressure, and macrolide antibiotics (such as erythromycin) that may affect the activity and tolerability of Cabergolin. Tell your doctor or pharmacist if you are taking or have recently taken any other medicinal products, including those obtained without a prescription and natural medical products/natural products.
Cabergolin with food and drink
• Cabergolin should be taken by mouth, preferably with meals.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
 • There is only limited experience of the use of Cabergolin during pregnancy. You should therefore consult your doctor if you are pregnant or plan to become pregnant before the treatment is started.
• If you are being treated with Cabergolin and become pregnant during this time you should discontinue the treatment and contact your doctor as soon as possible
• Contraception should be continued for at least 4 weeks after stopping Cabergolin.
Breast-feeding
• It is not known whether Cabergolin passes into breast milk
• Cabergolin should not be taken by mothers who intend to breast-feed as it prevents lactation. Nursing mothers should note that the quantity of milk can diminish.
Fertility
• If you are planning to become pregnant the Cabergolin should be discontinued one month before intended pregnancy. You should therefore consult your doctor if you are pregnant or plan to become pregnant before the treatment is started.
 Driving and using machines
• Cabergolin can negatively affect the ability to react in some people and this should be considered in cases where a high level of alertness is required, e.g. driving a car and in precision work
• Cabergolin can cause somnolence (extreme drowsiness) and sudden sleep onset. Persons affected by this should therefore not drive or take part in activities in which reduced alertness could incur a risk of serious harm (e.g. using machines), until such recurrent episodes and somnolence have resolved.
Cabergolin contains lactose
• Cabergolin 0.5mg tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars you should contact your doctor before taking this medicine.

3. HOW TO TAKE CABERGOLIN TABLETS
Always take Cabergolin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
The dose is determined by your doctor who adjusts it individually for you. The tablets should be taken with meals to reduce certain side effects such as nausea, vomiting and stomach pains.
•To stop the production of breast milk:
The usual dose is 1 mg (as a single dose) within 24 hours after giving birth

• To reduce the concentration of prolactin in the body:
Usually the treatment is started with 0.5 mg per week, but higher doses may then be necessary. Your doctor will tell you for how long you must take your tablets.
Cabergolin 0.5mg Tablets have a score and can be divided into two equal halves. When you first start taking the tablet, it is recommended you slowly change position when trying to sit, stand or lie down, this is because Cabergolin may cause a drop in blood pressure that could make you dizzy when you move from a position. It is also recommended that you avoid alcohol and other medicines that cause drowsiness as this could increase the risk of dizziness. During treatment your doctor may need to check your blood pressure, particularly in the first few days of treatment. A gynaecological assessment may also be carried out on the cells of your cervix or womb lining.

If you take more Cabergolin than you should
It is important not to take too many tablets. Contact your nearest hospital Accident and Emergency department or a doctor for advice if you have taken too many tablets or if you think a child has swallowed any. Symptoms of overdose may include nausea, vomiting, reduced blood pressure, stomach pain, changes in behaviour, confusion or hallucinations (seeing things). Take this leaflet and any tablets that you still have to show the doctor.

If you forget to take Cabergolin
 If you forget to take a dose at the right time, you can take it as soon as you remember it. If it is almost time to take the next dose, skip the forgotten dose and take the next dose as usual.

If you stop using Cabergolin
If you stop using Cabergolin the symptoms of your illness may become more severe and you should discuss with your doctor before you discontinue therapy. Cabergolin takes many days to be cleared from the bloodstream and effects may worsen over a 2 week period resulting in increased lactation.
If you have any other questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everyone gets them.
When used for stopping the production of breast milk approximately 14 in 100 patients have some form of side effects. The most common are low blood pressure, dizziness and headache. In treatment of increased prolactin levels side effects are more common as the tablets are taken for a longer period of time. Approximately 70 in 100 patients then experience side effects, but the side effects mostly disappear or decrease after approx. 2 weeks.
Tell your doctor immediately if you experience any of the following symptoms after taking this medicine. These symptoms can be severe:
• abnormal or unusual thoughts
• heart valve and related disorders e.g. inflammation (pericarditis) or leaking of fluid in the pericardium (pericardial effusion). This is a very common side effect (may affect more than 1 in 10 patients). The early symptoms may be one or more of the following: difficulty breathing, shortness of breath, pounding heart, feeling faint, chest pain, back pain, pelvic pain or swollen legs. These may be the first signs of a condition called pulmonary fibrosis, which can affect the lungs, heart/heart valves or lower back.
• development of a widespread itchy rash, difficulty breathing with or without wheezing, feeling faint, unexplained swelling of the body or tongue or any other symptoms which appear to come on rapidly after taking this medication and make you feel unwell. These may be indicative of an allergic reaction. This is an uncommon side effect (may affect 1 to 10 users in 1000).
You may experience the following side effects: Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include:
• Strong impulse to gamble excessively despite serious personal or family consequences
• Altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive
• Uncontrollable excessive shopping or spending • Binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger).
Tell your doctor if you experience any of these behaviours; they will discuss ways of managing or reducing the symptoms.
During treatment you may also notice the following side effects:

Very common side effects (may affect more than 1 user in 10):
• Dizziness or spinning feeling (vertigo), headache, feeling sick (nausea), stomach pain, upset stomach, inflammation of the stomach lining (gastritis), feeling weak, tired or fatigued. Common side effects (may affect 1 to 10 users in 100):
• low blood pressure upon standing (which can result in dizziness), depression, excessive daytime sleepiness, blurred vision, being sick (vomiting), constipation, breast pain, hot flushes, redness of the face, low blood pressure after childbirth which may not have any symptoms, low blood pressure (long term treatment).

Uncommon side effects (may affect 1 to 10 users in 1000):
• nosebleeds, leg cramps, fainting, your fingers or toes turn white or blue with a feeling of numbness after exposure to cold (digital vasospasm), crawling/prickling sensations in the body, loss of half of the vision in one or both eyes, pounding of the heart (palpitations), rash, hair loss, increased sex drive, swelling due to accumulation of fluid in the tissue (oedema), low haemoglobin values in blood, lung scar tissue, fluid in the space around the lung (pleural effusion).

Rare side effects (may affect 1 to 10 users in 10,000):
• pain in the upper central abdomen
• cramps in fingers.

Not known (cannot be estimated from the available data):
• sudden sleep attacks, seeing and hearing things that are not real (hallucinations), delusions, psychotic disorder, unintentional trembling or shaking movements (tremor), chest pain (angina), abnormal liver and abnormal blood tests of liver function, breathing problems with inadequate intake of oxygen, inflammation of the lining of the lung (pleuritis), an increase in the level of some enzymes in the blood, loss of vision and aggression.
Development of excess fibrous connective tissue (fibrosis) e.g. in the heart, lungs and kidneys has been reported. You should become aware of this as difficulty breathing, chest pain, back pain and swelling of the legs. Cabergolin has been linked with somnolence and sudden sleep attacks.

Reporting of side effects:
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE CABERGOLIN TABLETS
• Keep all medicines out of the sight and reach of children.
• Do not use Cabergolin after the expiry date which is printed on the carton or the bottle label after EXP: The expiry date refers to the last day of that month.
• Do not store above 25°C. Store in the original package in order to protect from moisture. The drying bag with silica gel must not be removed from the bottle.
• If the tablets become discoloured or show any other signs of deterioration, you should seek the advice of your pharmacist who will tell you what to do.
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment

6. Further Information

What Cabergolin Soluble Tablets contain
• The active substance is Cabergolin.
a) Each uncoated tablet contains: Cabergolin USP      0.25mg
b) Each uncoated tablet contains: Cabergolin USP            0.5mg
The other ingredients are anhydrous lactose, L-leucine and magnesium stearate.

What Cabergolin Tablets look like and contents of the pack
White, oval, flat tablets with bevelled edges. One side is smooth and the other side has a dividing score line. Each amber glass bottle contains 8 tablets with a tamper evident, child-resistant screw cap which contain silica gel desiccant.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com