Compotition One Scored tablet contains bromocriptine* mesylate 2.87 mg (corresponding to 2.5 mg bromocriptine base).

Transcription

1 Parlodel PRESCRIPTION ONLY Compotition One Scored tablet contains bromocriptine* mesylate 2.87 mg (corresponding to 2.5 mg bromocriptine base). Indications Menstrual cycle disorders, female infertility Prolactin-dependent or apparently normoprolactinaemic conditions amenorrhoea (with or without galactorrhoea), oligomenorrhoea. luteal phase deficiency drug-induced hyperprolactinaemic disorders (e.g. induced by certain psychotropic or antihypertensive agents). Prolactin-independent female infertility - polycystic ovary syndrome - anovulatory cycles (supplementary to anti-estrogens, e.g.clomiphene). Premenstrual symptoms Breast tenderness, cyclical oedema, bloating and mood disturbances. Hyperprolactinaemia in men Prolactin-related hypogonadism (oligospermia, loss of libido, impotence). Prolactinomas Conservative treatment of prolactin-secreting pituitary micro-or macro-adenomas Prior to surgery in order to reduce tumour size and to facilitate removal. After surgery if prolactin level is still elevated. Acromegaly As an adjunct or in special cases as an alternative, to surgery or radiotherapy. Inhibition of lactation Prevention or suppression of puerperal lactation for medical reasons. Prevention of lactation after abortion. Puerperal breast engorgement. Incipient puerperal mastitis. Benign breast disease Mastalgia (isolated or in association with premenstrual syndrome or with benign nodular or cystic alterations). Benign cystic and / or nodular conditions, in particular fibrocystic breast disease. Parkinson's disease All stages of idiopathic and postencephalitic Parkinson's disease, either as monotherapy or in combination with other antiparkinsonian drugs. Posology and method of administration Parlodel should always be taken with food.

2 Menstrual cycle disorders, female infertility Half a tablet 2 or 3 times daily; if this proves inadequate, gradually increase to 1 tablet 2 or 3 times daily. Continue treatment until the menstrual cycle has returned to norma, and/or ovulation is restored. If required, treatment may be continued over several cycles to prevent relapse. Premenstrual symptoms The treatment begins on the 14 th day of cycle with half a tablet daily, the dosage being increased in steps of half a tablet daily up to one tablet twice daily until menstruation sets in. Male hypogonadism Half a tablet 2 or 3 times daily, gradually increasing to 2 to 4 tablets per day. Prolactinomas Half tablet 2 or 3 times daily, gradually increasing to several tablets or capsules daily as required to keep plasma prolactin adequately suppressed. Acromegaly Initially half a tablet 2 or 3 times daily, gradually increasing to 4 to 8 tablets daily, depending on clinical response and side effects. Inhibition of lactation One tablet twice daily, with morning and evening meals for 14 days. To prevent the onset of lactation, treatment should be instituted within a few hours of parturition or abortion, but not before vital signs have stabilized. Slight milk secretion occasionally occurs 2 or 3 days after treatment has been withdrawn. This can be stopped by resuming treatment at the same dosage for a further week. Puerperal breast engorgement Single dose of 1 tablet; may be repeated after 6 to 12 hours without causing inappropriate suppression of lactation. Incipient puerperal mastitis Same dosage as for inhibition of lactation. An antibiotic should be added to the regimen, as required. Benign breast disease Half a tablet 2 or 3 times daily, gradually increasing to 2 or 3 tablets per day. Parkinson's disease In order to ensure optimal tolerability, treatment should be started with a low dose of 1.25 mg (half a tablet of Parlodel ) per day, given preferably in the evening, for the first week. Parlodel should be titrated slowly in order to provide each patients with the minimal effective dose. The increase in daily dose should be gradual, by increments of 1.25 mg a day every week. The daily dosage should be increased gradually into 2 to 3 single doses. An adequate therapeutic response may be reached within 6 to 8 weeks; otherwise, the dose may be further by increments of 2.5 mg a day every week. Should undesirable reactions occur during the titration phase, the daily dose is to be reduced and maintained constant for at least a week. If the adverse effects disappear, the dose can be increased again. For patients exhibiting motor disorders on levodopa therapy, it i s suggested that the levodopa dosage should be reduced before initiating Parlodel treatment. When a satisfactory response to Parlodel has been obtained, the dosage of levodopa may be further decreased stepwise. In certain

3 patients, levodopa may be withdrawn completely. The usual therapeutic range for monotherapy and combined therapy is mg bromocriptine per day. In some patients, higher doses are required. Contraindications Hypersensitivity to any of the components of Parlodel or other ergot alkaloids. Uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, preeciampsla or pregnancy-induced hypertension), hypertension post partum and in the puerperium. Coronary artery disease and other severe cardiovascular conditions. Symptoms and/or a history of serious psychic disorders For procedure during pregnancy, see Pregnancy and lactation. Special Warnings and Special Precautions for use General Fertility may be restored by treatment with Parlodel. Women of childbearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception. If women with conditions not associated with hyperprolactinaemia are treated with Parlodel, the drug should be given in the lowest effective dose necessary to relieve the symptoms; this is in order to avoid the possibility of suppressing plasma prolactin below normal levels, with a consequent impairment of luteal function. In patients to be treated for mastalgia, and nodular and/or cystic breast alterations, malignancy must be excluded by appropriate diagnostic procedures. A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, Parlodel should be withdrawn. Patients with a history or evidence of peptic ulceration should be closely monitored when receiving the treatment. Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. Parlodel has been associated with somnolence, and episodes of sudden sleep onset, particularly in patiens with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely, Patients must be informed of this and advised not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered. Use in postpartum women In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with Parlodel for the inhibition of lactation, in some patients the development or seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving Parlodel for the inhibition of lactation, as well as in patients treated for any other

4 condition. If hypertension, severe, progressive or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of Parlodel should be discontinued and the patient should be evaluated promptly. Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g. vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine. Although there is no conclusive evidence of an interaction between Parlodel and these drugs, their concomitant use in the puerperium is not recommended. Use in prolactin-secreting adenoma patients Since patients with macro-adenomas of the pituitary might have accompanying hypopituitarism due to compression or destruction of pituitary tissue, one should make a complete evaluation of pituitary functions and institute appropriate substitution therapy prior to administration of Parlodel. In patients with secondary adrenal insufficiency, substitution with corticosteroids is essential. The evolution of tumour size in patients with pituitary macro-adenomas should be carefully monitored and, if evidence of tumour expansion develops, surgical procedures must be considered. If, in adenoma patients, pregnancy occurs after the administration of Parlodel careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with Parlodel often results in tumour shrinkage and rapid improvement of the visual field defects. In severe cases, compression of the optic or other cranial nerves may necessitate emergency pituitary surgery. Visual field impairment is a known complication of macroprolactinoma. Effective treatment with Parlodel leads to a reduction in hyperprolactinaemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalised prolactin levels and tumour shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumour re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage. Use in parkinsonian patients Among parkinsonian patients on long-term high-dose Parlodel treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of Parlodel therapy shouid be contemplated. In a few patients treated over years with Parlodel at daily doses higher than 30 mg retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g back pain, oedema of the lower limbs, impaired kidney function) should be watched in this category of patients. Parlodel medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected. Interaction with other medicinal product and other forms of interaction

5 T h e concomitant use of erythromycin, josamycin, other macrolide antibiotics, or octreotide may increase the plasma levels of bromocriptine. The tolerability to Parlodel may be reduced by alcohol. Pregnancy and Lactation Use during pregnancy in patients wishing to conceive, Parlodel, like all other drugs, should be discontinued when pregnancy is confirmed, unless there is a medical reason for continuing therapy. No increased incidence of abortion has been observed following withdrawal of Parlodel at this point. Extensive experience indicates that Parlodel, administered during pregnancy, does not adversely affect its course or outcome. If pregnancy occurs in the presence of a pituitary adenoma and Parlodel treatment has been stopped close supervision throughout pregnancy is essential in patient who show symptoms of a pronounced enlargement or a prolactinoma, e.g. headache or visual field deterioration, Parlodel treatment may be re-instituted or surgery may be appropriate. Use during lactation Since Parlodel inhibits lactation, it should not be administered to mothers who elect to breastfeed. Effect on ability to Drive and Use Machines Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercise when driving a vehicle or operating machinery. Patients being treated with Parlodel and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g.operating machines) until such recurrent episodes and somnolence have resolved (see "Special warnings and special precautions for use ). Undesirable effects During the first few days of treatment some patients may experience nausea and, more rarely, dizziness, fatigue or vomiting, which are not, however, sufficiently serious to require discontinuation of treatment. If necessary, initial nausea and/or vomiting may be prevented by the intake of a peripheral dopaminergic antagonist such as domperidone, for a few days, at least 1 hour prior to the administration of Parlodel. Parlodel may induce hypotension including orthostatic hypotension, which occasionally may lead to collapse; it is therefore advisable to check blood pressure particularly during the first days of treatment. Orthostatic hypotension may be troublesome but can be treated symptomatically. In addition, nasal congestion, constipation, drowsiness, headache, and, less frequently, confusion, psychomotor excitation, hallucinations, dyskinesia, n i ks c i g redryness l l a, sof mpa the r c ge mouth l, reactions, and hair loss have been reported. Usually, these side effects are dose dependent and can be controlled by a reduction in dosage. Episodes of reversible pallor of the fingers and toes induced by cold have occasionally been

6 reported to occur during prolonged treatment, particularly in patients previously exhibiting Raynaud's phenomenon. The use of Parlodel for the inhibition of physiological lactation postpartum has been associated with the rare occurrence of hypertension, myocardial infarction, seizures, stroke or psychic disorders (see "Special warnings and special precautions for use"), Pleural and pericardial effusions, pleural and pulmonary fibrosis or retroperitoneal fibrosis and constrictive pericarditis have been reported rarely in patients treated with Parlodel (see "Special warnings and special precautions for use"), Parlodel is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes (see "Special warnings and special precautions for use"). Overdose All patients who have taken an overdose of Parlodel alone have survived; the maximum single dose so far ingested is 325 mg. The observed symptoms were nausea, vomiting, dizziness, postural hypotension, drowsiness, and hallucinations. The management of acute intoxicaton is symptomatic. Metoclopramide may be indicated for the treatment of emesis or hallucinations. Pharmacological Properties Pharmacodynamic properties Pharmacotherapeutic group: Stimulator of dopamine receptors (ATC code N04B C01), inhibitor prolactin secretion (ATC code G02C BO1) Bromocriptine inhibits th e secretion o f th e anterior pituitary hormone prolactin without affecting normal levels o f other pituitary hormones. It can, however, reduce elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors. In the puerperium prolactin is necessary for the initiation and maintenance of puerperal lactation. At other times increased prolactin secretion gives rise to pathological lactation (galactorrhoea) and/or disorders of ovulation and menstruation. As a specific inhibitor of prolactin secretion, Bromocriptine can be used to prevent or suppress physiological lactation as well as to treat prolactin-induced pathological states. In amenorrhoea and/or anovulation (with or without galactorrhea), Parlodel can be used to restore menstrual cycles and ovulation. Customary measures taken during lactation suppression, such as the restriction of fluid intake, are not necessary with Bromocriptine In addition, Parlodel does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism. Bromocriptine has been shown to arrest the growth or to reduce the size of prolactin-secreting pituitary adenomas (prolactinomas). In acromegalic patients in addition to lowering the plasma levels of growth hormone and prolactin. Bromocriptine has a beneficial effect on clinical symptoms and on glucose tolerance. Bromocriptine improves the clinical symptoms of the polycystic ovary syndrome by restoring a

7 normal pattern of LH secretion. In patients with benign breast disease, Bromocriptine reduces the size and number of cysts and/or nodules in the breast and alleviates the breast pain often associated with such conditions by normalising the underlying progesterone/estrogen imbalance. At the same time it reduces prolactin secretion patients with elevated levels.. Because of its dopaminergic activity, Bromocriptine, at doses usually higher than those for endocrinological indications, is effective in the treatment of Parkinson's disease, which is characterized by a specific nigrostriatal dopamine deficiency. In this condition, the stimulation of dopamine receptors by Bromocriptine can restore the neurochemical balance within the striatum. Clinically, Bromocriptine improves tremor, rigidity, bradykinesia and other parkinsonian symptoms at all stages of the disease. Usually the therapeutic effectiveness lasts over years (so far, good results have been reported in patients treated for up to 8 years). Bromocriptine can be given either alone or - at both early and advanced stages combined with other antiparkinsonian drugs. Combination with levodopa treatment results in enhanced antiparkinsonian effect, often making possible a reduction of the levodopa dosage. Bromocriptine offer particular benefit to patients on levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreo-athetoid dyskinesia and/or painful dystonia), end-of-dose failure, and 'on-off phenomenon. Bromocriptine improves the depressive symptomatology often observed in parkinsonians. This is due to its inherent antidepressant properties as substantiated by controlled studies in nonparkinsonian patients with endogenous or psychogenic depression. Pharmacokinetic properties Absorption Bromocriptine well absorbed after oral administration. When tablets or standard capsules are administered to healthy volunteers, the absorption half-life is 0.2 to 0.5 hours, and peak plasma levels of bromocriptine are reached within 1 to 3 hours. The prolactin-lowering effect begins within 1 to 2 hours of ingestion, reaches its maximum, i.e. a reduction of prolactin in the plasma by more than 80%, within 5 to 10 hours and remains close to maximum for 8 to 12 hours. Distribution With single-dose administration the bioavailability of SRO capsules relative to the standard capsules is more than 90%, Under steady-state conditions, a slight reduction in bioavailability (to about 80%) is observed, but there is no loss of therapeutic effectiveness. Plasma protein binding is 96%. Elimination The elimination of the parent drug from plasma is biphasic, with a terminal half-life of about 15 hours (range 8 to 20 hours). Parent drug and metabolites are almost completely excreted via the liver, only 6% being eliminated via the kidney. Characteristic in patients In patients with repaired hepatic function, the speed of elimination may be retarded and plasma levels may increase requiring dose adjustment. Preclinical Safety Data

8 Acute toxicity Acute toxicity studies using micronized bromocriptine revealed oral LD 50 values of 2620 mg/kg in mice, higher than 1000 mg/kg in rabbits, and higher than 2000 mg/kg in rats. The LD 50 values obtained after i.v. injection were: mouse 190 mg/kg, rat 72 mg/kg and rabbit 12.5 mg/kg. Signs of toxicity consisted of motor excitation, eventually cramps, dyspnoea, and coma. The high sensitivity of rabbits is typical of ergot compounds in general. Mutagenicity Bromocriptine was devoid of genotoxic potential when investigated for mutagenic effects in Salmonella typhimurium with and without metabolic activation, and of clastogenic potential in the bone marrow in vitro (micronucleus test in mice, metaphase chromosomes in Chinese hamsters). Carcinogenicity In a 100-week study in rats, bromocriptine was administered in the feed at dose levels of 1.8, 9.9, or mg/kg bodyweight per day, representing times the prolactin-inhibiting human therapeutic dose. Treatment caused a dose-dependent decrease in the overall incidence of tumours in all treated groups. This reflected a general decreased in the incidence of mammary tumours in females and of adrenal tumours in males. Both effects were probably related to the prolactininhibitory action of bromocriptine. Conversely, bromocriptine treatment increased the incidence of tumours at the mid- and high-dose levels. It had been shown in the one-year rat study that uterine effects resulted from prolonged oestrogen dominance caused by the prolactin-inhibitory effect of bromocriptine, superimposed on the warning endocrine system of the ageing female rat. In the 100- week rat study, bromocriptine was in fact demonstrated to have inhibited the rise in plasma progesterone levels associated with the state of pseudopregnancy normally seen in old female rats, but oestradiol levels were unaffected. Therefore, it was not old unexpected hat the hyperplastic and metaplastic lesions seen in the uteri at 53 weeks should progress to neoplasia when the duration of treatment was extended to 100 weeks. This finding is not relevant to women because of the fundamental differences in the ageing process of reproductive functions. In ageing rats, in contrast to women, responsive ovaries remain to support either pseudopregnancy upon continued prolactin stimulation, if hyperprolactinaemia is suppressed by bromocriptine, to support oestrogen dominance resulting in squamous metaplasia of the genital tract. There is no evidence that these rat-specific pharmacodynamic effects are of any clinical significance in humans. The lack of a direct uterine-stimulating effect of bromocriptine was further evidenced in a 104-week study in ovariectomized rats. A dose of 10 mg/kg per day given in the feed failed to induce uterine tumours or pre-neoplastic changes. The absence of carcinogenic potential was confirmed in mice which received bromocriptine in the feed at dose levels of up to 50 mg/kg body weight per day. There was no difference in tumour incidence of any site between treated animals and controls. Reproductive toxicity No embryotoxic or teratogenic potential of bromocriptine was revealed in rats, rabbits or monkeys. In the male animals, bromocriptine had no effect on germ cells, fertility and development of the offspring. In the female animals fertility and prenatal development of the offspring were not adversely affected by oral treatment with bromocriptine. A high dose of 30 mg/kg body weight given to rats during the last third of pregnancy until delivery reduced survival and weight gain of the pups. This is attributed to reduced lactation as a result of

9 prolactin inhibition by bromocriptin. However, postnatal development of the Fl-animals was not impaired, regardless of whether treatment was given during early or late phases of pregnancy. When given to female stumptailed monkeys for one or more cycles and for subsequent pregnancy, twice-daily doses of 0.15 mg/kg bromocriptine had no effect on fertility, nor on fetal development of the offspring. Pharmaceutical Particulars Incompatibilities Not applicable Storage Do not store above 25 C. Protect from light Parlodel should be kept out of the reach and sight of children. Package Boxes of 3 10 tablets Parlodel tablet 2.5mg Reg No. DKL A1 HARUS DENGAN RESEP DOKTER Manufactured by PT Novartis Indonesia, dakarta, Indonesia under license of Novartis Pharma AG, Basel, Switzerland