PRESCRIPTION ONLY
Composition
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).
- 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 post encephalitic Parkinson's disease. either as mono therapy or in combination with other anti parkinsonian drugs.
Posology and method of administration
Parlodel® should always be taken with food.
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 normal and/or ovulation is restored. If required, treatment may be continued over several cycles to prevent relapse.
Premenstrual symptoms
The treatment begins on the 14th day of the 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 a 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 is 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 step wise. In certain patients, levodopa may be withdrawn completely. The usual therapeutic range for mono therapy and combined therapy is 10-40 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, pre-eclampsia 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 patients 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 of 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 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 normalized 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 should 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
The 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 Partodel®
. 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 supervsion throughout pregnancy is essential. In patients who show symptoms of a pronounced enlargement of 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 breast, feed.
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. contusion, psychomotor excitation, hallucinations. dyskinesia, dryness of the mouth, leg cramps, allergic skin 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 reported to occur during prolonged treatment, particularly in patients previously exhibiting Raynaud's phenomenon.
The use of Parlodel® for the inhibition of physiological lactation post partum 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 intoxication 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 of prolactin secretion (ATC code G02C B01)
Parlodel® inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of 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, Parlodel® 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 Parlodel®. In addition, Parlodel® does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.
Parlodel® 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. Parlodel® has a beneficial effect on clinical symptoms and on glucose tolerance.
Parlodel® Improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion.
In patients with benign breast disease, Parlodel® reduces the size and number of cysts and/or nodules In the breast and alleviates the breast pain often associated with such conditions by normalizing the underlying progesterone/estrogen imbalance. At the same time it reduces prolactin secretion in patients with elevated levels
Because of its dopaminergic activity, Parlodel®, 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 Parlodel® can restore the neurochemical balance within the striatum.
Clinically, Parlodel® 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). Parlodel® can be given either alone or, at both early and advanced stages combined with other anti parkinsonian drugs. Combination with levodopa treatment results in enhanced anti parkinsonian effects, often making possible a reduction of the levodopa dosage. Parlodel® offers 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.
Parlodel® 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
Parlodel® is well absorbed after oral administration. When tablets or standard capsules are administered to healthy volunteers, the absorption halt-lite 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 halt-lite 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.
Characteristics in patients
In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may Increase requiring dose adjustment.
Preclinical Safety Data
Acute toxicity
Acute toxicity studies using micronized bromocriptine revealed oral LD50 values of 2620 mg/kg in mice, higher than 1000 mg/kg in rabbits, and higher than 2000 mg/kg in rats. The LD50 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 44.5 mg/kg bodyweight per day, representing 25-100 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 decrease in the incidence of mammary tumours in females and of adrenal tumours in males. Both effects were probably related to the prolactin-inhibitory action of bromocriptine. Conversely, bromocriptine treatment increased the incidence of uterine 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 waning 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 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 prolactin inhibition by bromocriptine. However, postnatal development of the F1-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 strips @ 10 tablets
Parlodel® tablet 25 mg
Reg. No. DKL8630403210Al
| HARUS DENGAN RESEP DOKTER |
Manufactured by PT Novartis Indonesia, Citeureup, Bogor, Indonesia
under license of Novartis Pharma AG, Basel, Switzerland
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