Active ingredients: Cabergoline
DOSTINEX 0.5 mg tablets
Why is Dostinex used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Prolactin inhibitor.
THERAPEUTIC INDICATIONS
Inhibition / suppression of physiological lactation DOSTINEX is indicated for the prevention of physiological lactation soon after delivery and for the suppression of ongoing lactation:
- After delivery, when the mother chooses not to breastfeed the baby or when breastfeeding is contraindicated for medical reasons related to the mother or infant.
- After the birth of a stillbirth or abortion.
Treatment of disorders due to hyperprolactinaemia
DOSTINEX is indicated for the treatment of dysfunctions associated with hyperprolactinaemia such as amenorrhea, oligomenorrhea, anovulation and galactorrhea. DOSTINEX is indicated in patients with prolactin-secreting pituitary adenoma (micro and macroprolactinoma), idiopathic hyperprolactinemia or empty sella syndrome associated with hyperprolactinemia, fundamental pathologies in the clinical manifestations mentioned above.
Contraindications When Dostinex should not be used
The patient should not take the medicine if:
- is hypersensitive to the active substance or to any of the excipients or ergot alkaloids;
- you will undergo treatment with cabergoline for a long time and have or have had fibrotic (scar tissue) reactions affecting the heart (see section Special Warnings - Fibrosis and cardiac valvulopathy and possibly related clinical phenomena);
- have or have had a history of pulmonary, pericardial or retroperitoneal fibrosis.
Precautions for use What you need to know before taking Dostinex
See paragraph "Warnings".
Interactions Which drugs or foods may change the effect of Dostinex
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
No information is available on the interactions between cabergoline and the other ergot alkaloids; therefore concomitant use of these medicinal products during long-term cabergoline treatment is not recommended.
Since cabergoline exerts its therapeutic effect through the direct stimulation of dopamine receptors, it must not be administered concomitantly with drugs that have a dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) because this could lead to a reduction in inhibitory effects of cabergoline on prolactin secretion.
Like other ergot derivatives, cabergoline should not be used concomitantly with macrolide antibiotics (eg erythromycin) as there may be an increase in the bioavailability of cabergoline.
Warnings It is important to know that:
General:
Like other ergot derivatives, cabergoline should be administered with caution in subjects with severe cardiovascular disease, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, or with a history of severe mental disorders, especially psychotic ones.
Important information about some of the ingredients
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Liver failure:
In patients with severe hepatic insufficiency and treated for a long time with DOSTINEX, a lower dose should be considered. An increase in AUC was observed in patients with severe hepatic impairment (Child-Pugh Class C) who received a single 1 mg dose compared to healthy volunteers and those with milder forms of hepatic impairment.
Postural hypotension:
Following administration of cabergoline, postural hypotension may occur. Care should be taken when cabergoline is co-administered with other drugs known to lower blood pressure.
Fibrosis and cardiac valvulopathy and possibly related clinical phenomena:
The patient should be especially careful with cabergoline if she has or has had fibrotic (scar tissue) reactions involving the heart, lungs or abdomen.
If fibrotic reactions develop, treatment should be stopped.
As with other ergot derivatives, following long-term administration of cabergoline, fibrotic and inflammatory disorders of the serous membranes such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy with involvement of one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis. Some cases have occurred in patients previously treated with ergoline dopamine agonists. For this reason DOSTINEX should not be administered in patients with a history or signs and / or ongoing clinical symptoms of respiratory or cardiac disorders related to the presence of fibrotic tissue.
Erythrocyte sedimentation rate (ESR) is abnormally increased in association with pleural effusion / fibrosis. Chest X-ray is recommended in case of an abnormal and unexplained increase in ESR.
Valvular disease has been associated with the use of cumulative doses; therefore, patients should be treated with the lowest effective dose. At each visit, the benefit-risk balance of treatment for the patient should be reassessed to determine whether it is appropriate to continue the treatment. cabergoline treatment.
Withdrawal of cabergoline treatment following a diagnosis of pleural effusion, pulmonary fibrosis or valvulopathy has been observed to improve these signs / symptoms (see Contraindications).
Before starting long-term treatment:
All patients should undergo a cardiovascular evaluation, including an echocardiogram, to determine the potential presence of asymptomatic valve disease. It is also helpful to perform an erythrocyte sedimentation rate (ESR) or other inflammatory marker analysis, a pulmonary function test / chest X-ray examination, and renal function tests prior to initiating therapy.
It is not known whether cabergoline treatment in patients with valve reflux will aggravate the underlying disease. If valvular fibrosis is diagnosed, the patient should not be treated with cabergoline (see section 4.3 - Contraindications).
During long-term treatment:
Fibrotic diseases can have an insidious onset and patients must be constantly monitored to avoid the risk of possible manifestations of progressive fibrosis.
During treatment it is therefore recommended to pay attention to the signs and symptoms of:
- Pleuropulmonary disorders, such as dyspnoea, shortness of breath, persistent cough and chest pain
- Renal failure or vascular obstruction of the ureter or abdomen leading to pain in the hips / low back pain and edema in the lower limbs, as well as any abdominal mass or tenderness that may indicate retroperitoneal fibrosis.
- Heart failure, as cases of valvular and pericardial fibrosis have often manifested as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out if such symptoms appear.
Appropriate clinical and diagnostic monitoring for the development of fibrotic disorders is recommended. A first echocardiogram must be performed within 3-6 months from the start of therapy, after which the frequency of echocardiographic monitoring must be determined by an appropriate individual clinical evaluation, paying particular attention to the aforementioned signs and symptoms, but always with a minimum frequency of 6 -12 months.
Cabergoline treatment should be discontinued if an echocardiogram reveals new valve reflux or aggravation of an existing reflux, valve narrowing or valve leaflet thickening (see section - Contraindications).
The need for further clinical monitoring (eg physical examination, including "careful cardiac auscultation, x-ray, CT scan) should be determined on an individual basis.
Additional tests such as erythrocyte sedimentation rate (ESR) and serum creatinine measurements should be performed as needed to support a diagnosis of fibrotic disease.
Drowsiness / Sudden sleep attacks
Cabergoline has been associated with somnolence. Dopamine agonists can be associated with episodes of sudden sleep attacks in people with Parkinson's disease. A reduction in dosage or discontinuation of therapy may be considered (see section "Effects on ability to drive and" use machines ").
Inhibition / suppression of physiological lactation
As with other ergot derivatives, cabergoline should not be given to women with pregnancy-induced hypertension, such as preeclampsia or postpartum hypertension, unless the potential benefit is deemed to outweigh the possible risk.
Cabergoline should not be administered in single doses greater than 0.25 mg to nursing women under treatment for lactation suppression to avoid the risk of postural hypotension. (see section "Dose, method and time of administration - Inhibition / suppression of physiological lactation and the section above - Postural hypotension").
Treatment of disorders due to hyperprolactinaemia
Since hyperprolactinaemia with amenorrhea / galactorrhea and infertility may be associated with pituitary tumors, a complete check of pituitary gland function should be envisaged before starting treatment with cabergoline.
Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism.
Before starting treatment with cabergoline, pregnancy must be ruled out. Since there is still limited clinical experience to date and the drug has a long half-life, as a precautionary measure, women wishing to become pregnant are advised, once regular ovulatory cycles have been achieved, to stop taking cabergoline one month before the attempt. of conception.
As pregnancy may occur before menstruation resumes, it is recommended that a pregnancy test be performed at least every 4 weeks during the amenorrhea period and thereafter whenever the menstrual period is delayed more than three days. Women who do not wish to become pregnant should be advised to adopt a method of mechanical contraception during treatment with cabergoline and after discontinuation of cabergoline until ovulatory cycles have disappeared.
If pregnancy is ascertained during treatment, as a precautionary measure, patients should be monitored for signs of increased pituitary size, as' expansion of pre-existing pituitary tumors may occur during gestation.
Psychiatric disorders
Tell your doctor if you or someone in your family / caregiver notices that urges or desires are developing to behave in ways that are unusual for you and you cannot resist the urge or temptation to perform certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviors such as gambling addiction, excessive eating or spending, an abnormal, exaggerated sexual desire, or an increase in sexual thoughts or feelings. Your doctor may find it necessary to change or discontinue your dose.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
Adequate and well-controlled studies on the use of cabergoline in pregnant women have not been conducted. Animal studies have not shown teratogenic effects, but decreased fertility and embryotoxicity were observed concurrently with pharmacodynamic activity.
Following a twelve-year observational study on the effects of cabergoline-based therapy in pregnancy, information is now available on 256 pregnancies.Of these 256 pregnancies, seventeen (6.6%) resulted in severe congenital malformations or miscarriages. . Information is available on 23 of 258 infants who had a total of 27 more or less severe neonatal anomalies. The most common neonatal anomalies were the malformations of the musculoskeletal system, followed by the anomalies of the cardio-pulmonary system. There is no information regarding perinatal disease or long-term effects on infants who have been exposed to cabergoline during intrauterine life. Based on the recently published literature, a prevalence of severe congenital malformations of 6.9% or greater has been reported in the general population. The percentage of congenital anomalies varies in different populations. It is not possible to accurately determine whether there is an increased risk as a control group has not been included.
Before administration of DOSTINEX it is necessary to exclude a state of pregnancy.
Cabergoline should only be used in pregnancy if clearly indicated and after a careful "benefit / risk assessment" (see section Special warnings).
In view of the drug's long half-life and limited intrauterine exposure data, women planning to become pregnant will need to discontinue cabergoline one month before attempting to conceive. If conception occurs during therapy, treatment should not be discontinued. as soon as you become aware of the current pregnancy to limit the exposure of the fetus to the medicine.
Feeding time
In rats, cabergoline and / or its metabolites are excreted in milk. There is no information on the excretion of the drug in breast milk; however, women should be advised not to breastfeed in case of unsuccessful inhibition / suppression of lactation with cabergoline. Cabergoline should not be given to women with hyperprolactinemic disorders who intend to breastfeed their babies because it inhibits lactation.
Effects on ability to drive and use machines
During the initial phase of treatment, patients should be careful when performing actions that require quick and accurate reactions.
DOSTINEX can cause drowsiness (excessive numbness) and episodes of sudden sleep attacks.
For this reason, the patient must refrain from driving or engaging in any activity in which impaired attention could expose himself or others to the risk of serious harm or death (eg the use of machinery) until such episodes recurrence and sleepiness has not resolved (see also section "Special Warnings - Somnolence / Sudden Sleep Attacks")
Dosage and method of use How to use Dostinex: Dosage
DOSTINEX should be administered orally and it is recommended that its intake be preferably with food.
Adults
Inhibition / suppression of physiological lactation
For inhibition of lactation DOSTINEX should be administered on the first day after delivery. The recommended posology is 1 mg (two 0.5 mg tablets) given as a single dose.
For the suppression of lactation the recommended dosage is 0.25 mg (half a 0.5 mg tablet) every 12 hours for two days (1 mg total dose).
Treatment of disorders due to hyperprolactinaemia
The initial recommended dose of DOSTINEX is 0.5 mg / week given once or twice (half a 0.5 mg tablet per week e.g. Monday and Thursday). The weekly dose should be gradually increased, preferably by adding 0.5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dose is usually 1 mg per week, but can range from 0, 25 mg to 2 mg per week DOSTINEX doses of up to 4.5 mg per week have been used in hyperprolactinemic patients.
The weekly dose can be administered in a single solution or divided into two or more times a week according to the patient's degree of tolerability.
When doses higher than 1 mg per week are indicated, splitting the weekly dose into multiple administrations is recommended as the tolerability of such doses taken in a single weekly solution has only been evaluated in a few patients.
Patients should be monitored during the dose adjustment phase to determine the lowest dose that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is recommended as normalization of serum prolactin is usually observed within 2-4 weeks once the effective regimen is reached.
Use in pediatrics
The safety and efficacy of DOSTINEX have not been established in subjects below 16 years of age.
Use in the elderly
As a consequence of the indications for which DOSTINEX is currently recommended, experience in the elderly is very limited. The available data do not indicate any particular risk.
Overdose What to do if you have taken too much Dostinex
Symptoms of overdose are likely to be those due to dopamine receptor hyperstimulation, such as nausea, vomiting, stomach discomfort, postural hypotension, confusion / psychosis or hallucinations.
If necessary, general supportive measures should be taken to eliminate all unabsorbed drug and to support blood pressure.
Administration of dopamine antagonist drugs may also be advisable.
In case of accidental ingestion / intake of an excessive dose of DOSTINEX, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of DOSTINEX, ask your doctor or pharmacist.
Side Effects What are the side effects of Dostinex
Like all medicines, DOSTINEX can cause side effects, although not everybody gets them.
The following undesirable effects have been observed and reported during treatment with DOSTINEX with the following frequencies: very common (≥1 / 10), common (≥1 / 100,
* Very common in patients treated for hyperprolactinaemic disorders; common in patients treated for lactation inhibition / suppression
** Common in patients treated for hyperprolactinaemic disorders; uncommon in patients treated for lactation inhibition / suppression
*** Very common in patients treated for hyperprolactinaemic disorders; uncommon in patients treated for lactation inhibition / suppression
The following side effects may occur:
inability to resist the urge to perform actions that could be harmful, which may include:
- strong urge to gamble excessively, despite serious personal or family consequences
- altered or increased sexual interest and behavior that is of significant concern to you or others, for example, increased sexual desire - uncontrollable shopping or overspending
- compulsive eating (eating large amounts of food in a short period of time) or bulimia (eating more food than normal and more than is needed to satisfy your hunger).
Tell your doctor if any of these behaviors occur so he can decide what to do to manage or reduce symptoms
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of suspected adverse reactions
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep DOSTINEX out of the reach and sight of children. The bottles of DOSTINEX are supplied with desiccant in the caps. The desiccant must not be removed.
It is recommended to close the bottle carefully after use.
Expiry: see the expiry date indicated on the package.
WARNING: Do not use the medicine after the expiry date indicated on the package. The expiry date indicated refers to the product in intact packaging, correctly stored.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
COMPOSITION
Each 0.5 mg tablet contains: active ingredient: 0.5 mg cabergoline. Excipients: lactose, leucine.
PHARMACEUTICAL FORM AND CONTENT
2 tablets 0.5 mg
4 tablets 0.5 mg
8 tablets 0.5 mg
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DOSTINEX 0.5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
active principle: cabergoline 0.5 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Inhibition / suppression of physiological lactation
DOSTINEX is indicated for the prevention of physiological lactation soon after delivery and for the suppression of ongoing lactation:
1) after delivery, when the mother chooses not to breastfeed the baby or when breastfeeding is contraindicated for medical reasons related to the mother or the baby.
2) after the birth of a stillbirth or after an abortion.
DOSTINEX prevents physiological lactation by inhibiting the secretion of prolactin.
In controlled clinical trials, DOSTINEX, given as a single dose of 1 mg on the first postpartum day, has been shown to be effective in inhibiting milk secretion, as well as reducing congestion and breast pain in the 70- 90% of women Only a small number of patients presented with relapsing breast symptoms, generally mild, in the third week after delivery.
The suppression of milk secretion and the improvement of symptoms related to breast congestion and pain following the milk rise are achieved in about 85% of women who receive a total of 1 mg of cabergoline, administered in four divided doses over the period. two days.
The return of breast symptoms after 10 days is rare.
Treatment of hyperprolactinemic disorders
DOSTINEX is indicated for the treatment of dysfunctions associated with hyperprolactinaemia such as amenorrhea, oligomenorrhea, anovulation and galactorrhea. DOSTINEX is indicated in patients with prolactin-secreting pituitary adenoma (micro and macroprolactinoma), idiopathic hyperprolactinaemia, or saddle empty syndrome associated with hyperprolactinaemia, fundamental pathologies in the clinical manifestations mentioned above.
DOSTINEX administered at doses of 1 - 2 mg per week as chronic therapy was effective in normalizing serum prolactin levels in approximately 84% of hyperprolactinemic patients. Resumption of regular cycles was observed in 83% of previously amenorrhoeic women. Based on the monitoring of progesterone levels, determined during the luteal phase, ovulation was re-established in 89% of treated women, galactorrhea disappeared in 90% of treated cases. In 50-90% of both female and male patients with micro or macroprolactinoma there was a decrease in the tumor mass.
04.2 Posology and method of administration
DOSTINEX should be administered orally.
Since DOSTINEX was mainly administered with meals during clinical trials and since the tolerability of this class of drugs is usually enhanced by food, it is recommended that DOSTINEX is preferably taken with food.
Inhibition / suppression of physiological lactation
For the inhibition of lactation
DOSTINEX should be administered on the first day after delivery. The recommended posology is 1 mg (two 0.5 mg tablets) given as a single dose.
For the suppression of lactation
The recommended dosage is 0.25 mg (half a 0.5 mg tablet) every 12 hours for two days (1 mg total dose).
Treatment of hyperprolactinemic disorders
The initial recommended dose of DOSTINEX is 0.5 mg / week given once or twice (half a 0.5 mg tablet per week e.g. Monday and Thursday). The weekly dose should be gradually increased, preferably by adding 0.5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dose is usually 1 mg per week, but can range from 0, 25 mg to 2 mg per week DOSTINEX doses of up to 4.5 mg per week have been used in hyperprolactinemic patients.
The weekly dose can be administered in a single solution or divided into two or more times a week according to the patient's degree of tolerability.
When doses higher than 1 mg per week are indicated, splitting the weekly dose into multiple administrations is recommended as the tolerability of such doses taken in a single weekly solution has only been evaluated in a few patients.
Patients should be monitored during the dose adjustment phase to determine the lowest dose that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is recommended as normalization of serum prolactin is usually observed within 2-4 weeks once the effective regimen is reached.
On discontinuation of DOSTINEX, recurrence of hyperprolactinaemia is usually observed. However, persistent suppression of prolactin levels has been observed for several months in some patients. In most women, ovulatory cycles persist for at least 6 months after stopping DOSTINEX.
The maximum dose is 3 mg / day.
Use in pediatrics
The safety and efficacy of DOSTINEX have not been established in subjects below 16 years of age.
Use in the elderly
As a consequence of the indications for which DOSTINEX is currently recommended, experience in the elderly is very limited. The available data do not indicate any particular risk.
04.3 Contraindications
For long-term treatment: evidence of cardiac valvulopathy determined on echocardiogram performed before treatment (see section 4.4 - Special warnings and precautions for use - Fibrosis and cardiac valvulopathy and possibly related clinical phenomena).
04.4 Special warnings and appropriate precautions for use
General
DOSTINEX, like other ergot derivatives, should be administered with caution in subjects with severe cardiovascular disease, Raynaud's syndrome, peptic ulcer or gastrointestinal bleeding, or with a history of severe mental disorders, especially psychotic ones.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Hepatic insufficiency
In patients with severe hepatic insufficiency and treated for a long time with DOSTINEX, a lower dose should be considered. An increase in AUC was observed in patients with severe hepatic impairment (Child-Pugh Class C) who received a single 1 mg dose compared to healthy volunteers and those with milder forms of hepatic impairment.
Postural hypotension
Following administration of DOSTINEX, postural hypotension may occur. Care should be taken when DOSTINEX is given together with other drugs known to lower blood pressure.
Fibrosis and cardiac valvulopathy and possibly related clinical phenomena
After prolonged use of ergotamine derivatives with agonist properties for 5HT2B serotonergic receptors, such as Dostinex, fibrotic and inflammatory disorders of the serous membranes have occurred such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, heart valve disease involving one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of cabergoline treatment.
Erythrocyte sedimentation rate (ESR) is abnormally increased in association with pleural effusion / fibrosis. Chest X-ray is recommended in case of an abnormal and unexplained increase in ESR.
Valvular disease has been associated with the use of cumulative doses; therefore, patients should be treated with the lowest effective dose. At each visit, the benefit-risk balance of treatment for the patient should be reassessed to determine whether it is appropriate to continue the treatment. cabergoline treatment.
Before starting long-term treatment
All patients should undergo a cardiovascular evaluation, including an echocardiogram, to determine the potential presence of asymptomatic valve disease.
It is also helpful to perform an erythrocyte sedimentation rate (ESR) or other inflammatory marker analysis, a pulmonary function test / chest X-ray examination, and renal function tests prior to initiating therapy.
It is not known whether cabergoline treatment in patients with valve reflux will aggravate the underlying disease. If valvular fibrosis is diagnosed, the patient should not be treated with cabergoline (see section 4.3 - Contraindications).
During long-term treatment
Fibrotic diseases can have an insidious onset and patients must be constantly monitored to avoid the risk of possible manifestations of progressive fibrosis.
During treatment it is therefore recommended to pay attention to the signs and symptoms of:
• pleuropulmonary disorders such as dyspnoea, shortness of breath, persistent cough and chest pain.
• renal insufficiency or vascular obstruction of the ureter or abdomen leading to pain in the hips / back pain and edema in the lower limbs, as well as any abdominal mass or tenderness that may indicate retroperitoneal fibrosis.
• heart failure, as cases of valvular and pericardial fibrosis have often manifested themselves as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out if such symptoms appear.
Appropriate clinical and diagnostic monitoring for the development of fibrotic disorders is recommended. A first echocardiogram must be performed within 3-6 months from the start of therapy, after which the frequency of echocardiographic monitoring must be determined by an appropriate individual clinical evaluation, paying particular attention to the aforementioned signs and symptoms, but always with a minimum frequency of 6 -12 months.
Treatment with DOSTINEX should be discontinued if an echocardiogram reveals new valve reflux or aggravation of an existing reflux, valve narrowing or valve leaflet thickening (see section 4.3 - Contraindications).
The need for further clinical monitoring (eg physical examination, including "careful cardiac auscultation, x-ray, CT scan) should be determined on an individual basis.
Additional tests such as erythrocyte sedimentation rate (ESR) and serum creatinine measurements should be performed as needed to support a diagnosis of fibrotic disease.
Drowsiness / Sudden sleep attacks
DOSTINEX has been associated with somnolence. Dopamine agonists may be associated with episodes of sudden sleep attacks in individuals with Parkinson's disease. A reduction in dosage or discontinuation of therapy may be considered (see section 4.7 - Effects on the ability to drive and use of machinery).
Inhibition / suppression of physiological lactation
As with other ergot derivatives, DOSTINEX should not be administered to women with pregnancy-induced hypertension, such as preeclampsia or postpartum hypertension, unless the potential benefit is deemed to outweigh the possible risk.
DOSTINEX should not be administered in single doses greater than 0.25 mg to nursing women under treatment for lactation suppression to avoid the risk of postural hypotension. (see section 4.2 - Inhibition / suppression of physiological lactation and the section above - Postural hypotension).
Treatment of disorders due to hyperprolactinaemia
Since hyperprolactinaemia with amenorrhea / galactorrhea and infertility may be associated with pituitary tumors, a complete check of pituitary gland function should be envisaged before starting treatment with DOSTINEX.
DOSTINEX restores ovulation and fertility in women with hyperprolactinemic hypogonadism.
Before starting treatment with DOSTINEX, pregnancy must be ruled out.Since there is still limited clinical experience to date and the drug has a long half-life, as a precautionary measure, women wishing to become pregnant are advised, once regular ovulatory cycles have been achieved, to stop taking DOSTINEX one month before the attempt. of conception.
As pregnancy may occur before menstruation resumes, it is recommended that a pregnancy test be performed at least every 4 weeks during the amenorrhea period and thereafter whenever the menstrual period is delayed more than three days. Women who do not wish to become pregnant should be advised to adopt a method of mechanical contraception during treatment with DOSTINEX and after stopping DOSTINEX until the ovulatory cycles have disappeared.
If pregnancy is ascertained during treatment, as a precautionary measure, patients should be monitored for signs of increased pituitary size, as' expansion of pre-existing tumors may occur during gestation.
Impulse control disorders
Patients should be monitored regularly for the development of impulse control disorders. Patients and caregivers should be aware that behavioral symptoms of impulse control disorder including pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, bulimia, and the urge to eat can occur. in patients treated with dopamine agonists, including DOSTINEX A dose reduction / gradual withdrawal until discontinuation should be considered if such symptoms develop.
04.5 Interactions with other medicinal products and other forms of interaction
Although there is no conclusive evidence of an interaction between DOSTINEX and any other ergot alkaloid, it is recommended not to use the product concomitantly with these drugs for extended periods of time.
Since DOSTINEX exerts its therapeutic effect through the direct stimulation of dopamine receptors, it must not be administered concomitantly with drugs that have a dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) as this could lead to a reduction of the effects DOSTINEX inhibitors on prolactin secretion.
DOSTINEX, like other ergot derivatives, should not be used concomitantly with macrolide antibiotics (eg erythromycin) as there may be an increase in the bioavailability of DOSTINEX.
04.6 Pregnancy and lactation
Following a twelve-year observational study on the effects of cabergoline-based therapy in pregnancy, information is now available on 256 pregnancies.Of these 256 pregnancies, seventeen (6.6%) resulted in severe congenital malformations or miscarriages. . Information is available on 23 of 258 infants who had a total of 27 more or less severe neonatal anomalies. The most common neonatal anomalies were the malformations of the musculoskeletal system, followed by the anomalies of the cardio-pulmonary system. There is no information regarding perinatal disease or long-term effects on infants who have been exposed to cabergoline during intrauterine life. Based on the recently published literature, a prevalence of severe congenital malformations of 6.9% or greater has been reported in the general population. The percentage of congenital anomalies varies in different populations. It is not possible to accurately determine whether there is an increased risk as a control group has not been included.
Before administration of DOSTINEX it is necessary to exclude a state of pregnancy. It is also necessary to prevent pregnancy for at least one month after treatment. Since cabergoline has an elimination half-life of 79-115 hours in patients with hyperprolactinaemia, once regular ovulatory cycles have been achieved, women who desire a pregnancy will have to stop taking DOSTINEX one month before presumed conception. This will prevent possible fetal exposure to the drug and will not interfere with the possibility of conception because ovulatory cycles in some cases persist for 6 months after stopping the drug. . Should conception occur during therapy, treatment should be discontinued as soon as pregnancy is known to limit fetal exposure to the medicinal product (see section 4.4 - Treatment of disorders due to hyperprolactinaemia).
In rats, DOSTINEX and / or its metabolites are excreted in milk. There is no information on the excretion of the drug in breast milk; however, women should be advised not to breastfeed in case of unsuccessful inhibition / suppression of breastfeeding with DOSTINEX. DOSTINEX should not be administered to women with hyperprolactinemic disorders who intend breastfeed their babies because it inhibits lactation.
04.7 Effects on ability to drive and use machines
Patients treated with DOSTINEX who present with episodes of drowsiness and / or sudden sleep attacks should be advised to refrain from driving or from engaging in any activity in which impaired attention could expose themselves or others to the risk of serious harm or death. (eg using machines) until these recurrent episodes and sleepiness have resolved (see also section 4.4 - Special warnings and precautions for use - Somnolence / Sudden sleep attacks).
04.8 Undesirable effects
The following undesirable effects have been observed and reported during treatment with DOSTINEX with the following frequencies: very common (≥1 / 10), common (≥1 / 100,
General
Disorders due to hyperprolactinaemia
Inhibition / suppression of lactation
Post-marketing pharmacovigilance
Impulse control disorders
Pathological gambling, increased libido, hypersexuality, compulsive shopping or overspending, bulimia and binge eating may occur in patients treated with dopamine agonists, including DOSTINEX (see section 4.4 Special warnings and precautions for use).
04.9 Overdose
Symptoms of overdose are likely to be those due to dopamine receptor hyperstimulation, such as nausea, vomiting, stomach discomfort, postural hypotension, confusion / psychosis or hallucinations.
If necessary, general supportive measures should be taken to eliminate all unabsorbed drug and to support blood pressure.
Administration of dopamine antagonist drugs may also be advisable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: prolactin inhibitors
ATC code: G02CB03
DOSTINEX is a dopaminergic derivative of ergot with a potent and prolonged effect of inhibiting prolactin levels.
Through the direct stimulation of the dopaminergic D2 receptors present on the pituitary lactotropic cells, it inhibits the secretion of prolactin. In rats the compound decreases prolactin secretion at oral doses of 3-25 mcg / kg, and in vitro at a concentration of 45 pg / ml. In addition, DOSTINEX exerts a central dopaminergic effect through the stimulation of the D2 receptor, at oral doses higher than those effective for lowering serum prolactin levels.
The prolonged effect of the drug on the decrease in prolactin levels 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 administration of the labeled product in rats (t1 / 2 of about 60 hours).
The pharmacodynamic effects of DOSTINEX have been studied in healthy volunteers, in new mothers and in hyperprolactinemic patients. After a single oral dose of DOSTINEX (0.3-1.5 mg), a significant decrease in serum prolactin levels is observed in all populations studied. The effect is rapid (within 3 hours after administration) and persistent (up to 7-28 days in healthy volunteers and hyperprolactinemic patients and up to 14-21 days in puerperal women). The prolactin-lowering effect is dose-related. as regards both the extent and the duration of the effect.
As for any endocrine effects not related to the antiprolactinemic action, the available data on humans confirm the experimental results which indicate that DOSTINEX is characterized by a very selective action, with no effect on the basal secretion of other pituitary hormones or cortisol. The only pharmacodynamic effect of DOSTINEX, unrelated to the therapeutic effect, refers to the decrease in blood pressure. The maximum hypotensive effect of DOSTINEX in a single dose occurs during the first 6 hours after taking the drug and is dose-dependent in both magnitude and incidence.
05.2 Pharmacokinetic properties
The pharmacokinetic and metabolic profiles of DOSTINEX were studied in healthy volunteers of both sexes and in hyperprolactinemic patients.
Following oral administration, the radiolabelled product was rapidly absorbed from the gastrointestinal tract as evidenced by peak radioactivity in plasma (between 0.5 and 4 hours post administration).
Ten days after administration, 18% and 72% of the radioactivity was found in urine and faeces, respectively. In the urine, 2-3% of the dose was found to be unchanged.
The major metabolite identified in urine is 6-allyl-8β-carboxy-ergoline, accounting for 4-6% of the dose. Three other metabolites were identified and determined in urine for 3%. The metabolites were noted to be less potent than DOSTINEX in inhibiting prolactin secretion. in vitro. The biotransformation of DOSTINEX has also been studied in the plasma of healthy male volunteers treated with labeled cabergoline: a rapid and massive biotransformation was evidenced.
The low urinary excretion of the unchanged product was also confirmed in studies with the non-radioactive product. The half-life of DOSTINEX, calculated on the percentages of urinary excretion, is very long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).
Based on the elimination half-life, steady-state conditions are reached after 4 weeks, as confirmed by the mean peak plasma levels of DOSTINEX obtained after single administration (37 ± 8 pg / ml) and after 4 weeks of repeated administration ( 101 ± 43 pg / ml).
The experiments in vitro have shown that the drug, at concentrations of 0.1-10 ng / ml binds 41-42% to plasma proteins.
Food does not appear to affect the absorption and availability of DOSTINEX.
05.3 Preclinical safety data
Maternotoxic but non-teratogenic effects were shown in mice with cabergoline dosages 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 of the maximum recommended human dose) during the period of organogenesis caused increased post-implantation embryofoetal losses in rats. cabergoline prolactin secretion in rats. Cabergoline, at daily doses of 0.5 mg / kg / day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in rabbits, caused characterized maternotoxicity weight loss and reduced food intake. Doses of 4 mg / kg / day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in rabbits caused an increase in the incidence of However, in another study in rabbits, neither treatment-related malformations nor embryotoxicity were observed at doses up to 8 mg / kg / day (approximately 300 times the maximum recommended dose. The "man).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose
Leucine
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years
06.4 Special precautions for storage
None.
06.5 Nature of the immediate packaging and contents of the package
Type I amber glass bottles with a safety screw cap containing silica gel.
Bottle of 2 tablets
Bottle of 4 tablets
Bottle of 8 tablets
06.6 Instructions for use and handling
The bottles of DOSTINEX are supplied with desiccant in the caps. This desiccant must not be removed.
It is recommended to close the bottle carefully after use.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l.
Via Isonzo 71
04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
DOSTINEX 0.5 mg tablets - 2 tablets - AIC n. 028988018
DOSTINEX 0.5 mg tablets - 4 tablets - AIC n. 028988020
DOSTINEX 0.5 mg tablets - 8 tablets - AIC n. 028988032
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
July 27, 1994
10.0 DATE OF REVISION OF THE TEXT
February 2013