Norprolac Tablets - Product Information
|Ingredients:||quinagolide hydrochloride, silica (colloidal anhydrous), magnesium stearate, methylhydroxy-propylcellulose, maize starch, cellulose (microcrystalline), lactose.|
Summary Product Information
|Route of Administration||Dosage Form / Strength||Clinically Relevant Nonmedicinal Ingredients|
|Oral||Tablets 0.025 mg, 0.050 mg, 0.075 mg and 0.150 mg||Silica (colloidal anhydrous), magnesium stearate, methylhydroxy-propylcellulose, maize starch, cellulose (microcrystalline), lactose.|
Indications and Clinical Use
NORPROLAC is indicated for the treatment of hyperprolactinemia (idiopathic or originating from a prolactin-secreting pituitary microadenoma or macroadenoma)
Hypersensitivity to the drug and impaired hepatic or renal function. For procedure during pregnancy, see “Use in Pregnancy and Lactation”, under PRECAUTIONS.
Warnings and Precautions
Fertility may be restored in patients receiving treatment with NORPROLAC (quinagolide hydrochloride). Women of child-bearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception.
Treatment with NORPROLAC may effectively lower prolactin levels in patients with pituitary tumours but does not obviate the necessity for radiotherapy or surgical intervention where appropriate.
Caution should be exercised when administering NORPROLAC to patients with a history of psychotic disorders due to its stimulant effect on D2 receptors. In a few isolated cases, treatment with NORPROLAC has been associated with the occurrence of acute psychosis, reversible upon discontinuation.
NORPROLAC has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Patients must be informed of this and advised not to drive or operate machines if they experience any episodes of sudden sleep onset. Furthermore, if sudden onset of sleep does develop, a reduction of dosage or termination or therapy may be necessary.
Effects on Ability to Drive and Use Machines
Patients being treated with NORPROLAC 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.
Impulse control disorders:
Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers should be made aware that behavioural symptoms of impulse control disorders including:
- pathological gambling,
- increased libido,
- compulsive spending or buying,
- binge eating and compulsive eating can occur in patients treated with dopamine agonists including Norprolac.
Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Hypotensive reactions may occur during the first few days of treatment with NORPROLAC (quinagolide hydrochloride) and patients should be cautious when driving a vehicle or operating machinery. Since, on rare occasions, orthostatic hypotension may result in syncope, it is recommended to check blood pressure during the first few days of therapy.
Use in Pregnancy and Lactation
Animal data provide no evidence that NORPROLAC has any embryotoxic or teratogenic potential, but experience in pregnant women is still limited. In patients wishing to conceive, NORPROLAC should be discontinued when pregnancy is confirmed, unless there is a medical reason for continuing therapy. So far, no increased incidence of abortion has been observed following withdrawal of the drug during pregnancy.
If pregnancy occurs in the presence of a pituitary adenoma and NORPROLAC treatment has been stopped, close supervision throughout pregnancy is essential. In patients who show symptoms of tumour enlargement, e.g. visual field deterioration or headache, NORPROLAC treatment may be re-instituted or surgery may be appropriate.
Owing to its inhibitory effect on prolactin secretion, NORPROLAC suppresses lactation. Therefore, mothers receiving the drug cannot breast-feed.
Carcinogenesis and Mutagenesis
A 2-year carcinogenicity study was conducted in rats using dietary levels of quinagolide hydrochloride equivalent to oral doses of 0.01, 0.06 and 0.2 mg/kg/day. A 90-week study in mice was conducted using dietary levels equivalent to oral doses of 0.02, 0.1 and 0.4 mg/kg/day. The highest doses tested in rats and mice were approximately 10 and 20 times the maximum human oral dose administered in controlled clinical trials (0.9 mg/day equivalent to 0.02 mg/kg/day).
A low incidence of Leydig-cell adenomas in male rats and mesenchymal uterine tumours in mice was observed. The occurrence of these neoplasms is probably attributable to the high luteinizing hormone secretion and estrogen/progesterone ratio that would occur in rodents as a result of the prolactin-inhibiting action of quinagolide. In addition, quinagolide showed no mutagenic or genotoxic potential in various assay systems investigated. The findings in rats and mice were not shown to be relevant for humans due to the fundamental difference in the regulation of the endocrine system between rodents and humans. However, even though there is no known correlation between testicular tumours and uterine malignancies occurring in quinagolide-treated rodents and human risk, there are no human data to substantiate this conclusion.
Quinagolide was not embryotoxic or teratogenic in rats and rabbits. Hypoprolactinemia was associated with reduced pregnancy rate and inhibition of lactation of rat dams and slightly retarded but otherwise normal development of rat pups.
Safety and effectiveness in children has not been established.
No specific laboratory tests are deemed essential for the management of patients on NORPROLAC (quinagolide hydrochloride). Periodic routine evaluation of all patients, however, is appropriate.
The adverse reactions reported with the use of NORPROLAC (quinagolide hydrochloride) are characteristic for dopamine receptor agonist therapy. The most commonly observed adverse events (>10%) reported during clinical trials with NORPROLAC were: nausea, vomiting, headache, dizziness and fatigue. Most of these adverse events occur predominantly during the first few days of the initial treatment or, as a mostly transient event, following dosage increase and are usually not sufficiently serious to require discontinuation of treatment and tend to disappear with continued treatment.
Nausea and Vomiting: Nausea and vomiting may be prevented by the intake of a peripheral dopaminergic antagonist, such as domperidone, for a few days, at least 1 hour before the ingestion of NORPROLAC .
Less frequent side effects (1 to 10%) include anorexia, abdominal pain, constipation or diarrhoea, insomnia, oedema, flushing, nasal congestion and hypotension. Orthostatic hypotension may result in faintness or syncope (see PRECAUTIONS).
In rare cases NORPROLAC has been associated with somnolence.
Relative to the occurrence of the above-mentioned reactions the following adverse reactions have been less frequently observed in clinical trials involving 549 patients during the first month of treatment. Incidence between 0.5 and 3.5%:
|Musculoskeletal:||painful extremities (0.6%)|
|Respiratory:||nasal congestion (2.4%)|
|Cardiovascular:||hypotension (1.3%), syncope (0.9%), palpitation (0.7%),
|Gastrointestinal:||constipation (3.4%), abdominal pain (3.3%), dyspepsia
(1.5%), abdominal discomfort (3.3%), diarrhoea (0.9%)
|Central Nervous System:||asthenia (2.9%), anorexia (2.4%), insomnia (2.0%), eye
disorders (1.5%), malaise (1.1%), reduced concentration
|Miscellaneous:||oedema (1.5%), breast pain (0.9%), mood lability (0.9%),
sedation (3.3%), weight gain (0.6%)
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 Norprolac. (see Warnings and Precautions )
Laboratory parameters may be affected during treatment with NORPROLAC, but the changes are usually not considered serious. Among the laboratory changes that were reported during clinical trials were increases in bilirubin, serum transaminases, CPK (creatine phosphokinase), potassium, triglycerides and decreases in hematocrit and hemoglobin. These changes were usually transient and rarely of clinical significance.
Only five patients (0.5 %) had to be discontinued from therapy because of laboratory adverse experiences, including one case of neutropenia.
In a few isolated cases, treatment with NORPROLAC has been associated with acute psychosis, reversible upon discontinuation.
Approximately 200 patients have been treated with NORPROLAC for longer than four years. There is no evidence that any type of adverse event occurs more frequently with prolonged treatment.
No interactions between NORPROLAC and other drugs have so far been reported. On theoretical grounds, a reduction of the prolactin-lowering effect could be expected when drugs (e.g. neuroleptic agents) with strong dopamine antagonist properties are used concomitantly.
NORPROLAC administered concomitantly with antihypertensive agents may have an additive effect on lowering blood pressure. In patients with angina or arrhythmias using antihypertensives, this additional hypotensive effect should be taken into consideration. The tolerability of NORPROLAC may be reduced by alcohol.
Dosage and Administration
NORPROLAC (quinagolide hydrochloride) tablets should be taken once a day at bedtime with a snack. The optimal dose must be titrated individually on the basis of the prolactin-lowering effect and patient tolerability.
Recommended Dose and Dosage Adjustment
With the 'starter pack', treatment begins with 0.025 mg/day for the first 3 days, followed by 0.050 mg/day for a further 3 days. From day 7 onwards, the recommended dose is 0.075 mg/day. If necessary, the daily dose may then be increased stepwise at intervals not shorter than 1 week until the optimal individual response is attained. The usual maintenance dosage is 0.075 to 0.150 mg/day. Daily doses of 0.300 mg or higher doses are required in less than one-third of patients. In such cases, the daily dosage may be increased by increments of 0.075 to 0.150 mg at intervals not shorter than 4 weeks. The maximum dose evaluated in efficacy studies was 0.900 mg.
Most adverse events occur predominantly during the first few days of treatment, are usually not sufficiently serious to require discontinuation of treatment and tend to disappear with continued treatment.
There is no evidence of reduced tolerance or altered dosage requirements in elderly patients.
No data are available in regard to over dosage in humans with NORPROLAC (quinagolide hydrochloride). However, based on the pharmacological properties of quinagolide, gastrointestinal (nausea, vomiting), CNS (headache, dizziness, drowsiness, hallucinations) and cardiovascular effects (hypotension) might possibly occur. In the event of overdosage, treatment should be symptomatic and supportive.
Action and Clinical Pharmacology
NORPROLAC (quinagolide hydrochloride) is a selective dopamine D2 receptor agonist not belonging to the chemical classes of ergot or ergoline compounds.
NORPROLAC exerts a strong and specific inhibitory effect on prolactin release by acting directly on the prolactin-secreting cells of the anterior pituitary without reducing the levels of other pituitary hormones. In some patients the reduction of prolactin secretion may be accompanied by short-lasting, small increases in plasma growth hormone levels, the clinical significance of which is unknown.
As a specific inhibitor of prolactin secretion with a prolonged duration of action (greater than 24 hours), NORPROLAC has been shown to be effective for once-a-day oral treatment of patients presenting with hyperprolactinemia and its clinical manifestations. This includes patients in whom treatment with other dopamine agonists was found ineffective or has been associated with unacceptable adverse effects.
Long-term treatment with NORPROLAC was found to reduce the size or limit the growth of prolactin-secreting pituitary macroadenomas.
Quinagolide is rapidly absorbed following oral administration of radiolabelled drug. Quinagolide has an apparent volume of distribution of 100 L. The terminal half-life for parent drug was 11.5 hours following single dose and 17 hours at steady state.
Quinagolide undergoes extensive first pass metabolism. Studies performed with 3H-labelled quinagolide revealed that more than 95% of the drug is excreted as metabolites. Almost equal amounts of total radioactivity were found in faeces (40%) and urine (50%).
In blood, quinagolide and its N-desethyl analogue are the biologically active but minor components. Their sulfate or glucuronide conjugates represent the major circulating metabolites. In urine, the main metabolites are the glucuronide and sulfate conjugates of quinagolide and the N-desethyl, N,N,-didesethyl analogues. In faeces the unconjugated forms of the three compounds were found. The major metabolites in the blood are the N-desethyl and N, N-bidesethyl analogues.
Quinagolide is approximately 90% bound to plasma proteins.
Pharmacodynamic studies using plasma prolactin levels as a reliable marker of drug activity showed that the prolactin-lowering effect of quinagolide at recommended therapeutic doses occurs within 2 hours after ingestion reaches a maximum within 4 to 6 hours and is maintained for at least 24 hours.
In healthy volunteers, the duration of the prolactin-lowering effect is proportional to the dose of quinagolide.
Quinagolide is rapidly and almost completely absorbed in animals. Almost dose-proportional blood or plasma levels of parent compound and metabolites were observed after single and multiple oral dosing, indicating linear pharmacokinetics. The pharmacokinetics are species-dependent with a terminal half-life varying between 8 hours (rabbit) and 59 hours (dog).
In rats and mice, quinagolide and/or its metabolites were extensively distributed in the extravascular compartment. Target organs were liver, kidneys, salivary glands and pituitary. In pregnant animals the fetal exposure was low due to a limited placental transfer. Elimination of radioactivity from the tissues was rapid and no retention of drug derived material was observed. Quinagolide-derived material was rapidly excreted in all species after single and multiple oral doses. Recovery of drug-derived material is almost complete within 4 days post single dose.
In healthy volunteers, single oral doses of radiolabelled quinagolide (0.025 and 0.05 mg) were rapidly (t1/2 absorption 0.1 h) and almost completely absorbed (> 95 % of dose). The absolute bioavailability was low (4 %) due to presystemic metabolism. Peak levels of radioactivity and parent drug were achieved at 0.5-1 hour post-dose. The elimination was biphasic with a terminal half-life of 12 h for parent drug and 24 h for radioactivity. Elimination occurred almost equally via the urine (50 %) and bile (40%). The pharmacokinetics of quinagolide were not altered after repeated administration of 0.075 mg/day for 5 days and an accumulation factor of less than 2 was calculated for parent drug and radioactivity.
Storage and Stability
Store between 15o to 30oC. Protect from light and humidity.
Dosage Forms, Composition and Packaging
Tablets of 0.025 and 0.050 mg are provided in a package intended for initiating therapy (`Starter Pack'). This package is a blister pack containing a total of 6 tablets: 3 X 0.025 mg tablets, 3 X 0.050 mg tablets.
Tablets of 0.075 or 0.150 mg are provided in package intended for maintenance therapy. Tablets of 0.075 mg and 0.150 mg are each supplied in blister packs of 30.
0.025 mg : Each light pink with pigment spots, circular, flat, bevelled edge tablet engraved "25" on one side and "NORPROLAC" on the other, contains 0.025 mg quinagolide (as the hydrochloride salt).
0.050 mg : Each pale blue with pigment spots, circular, flat bevelled edge tablet engraved "50" on one side and "NORPROLAC" on the other, contains 0.050 mg quinagolide (as the hydrochloride salt).
0.075 mg : Each whitish, circular, flat bevelled edge tablet engraved "75" on one side and "NORPROLAC" on the other, contains 0.075 mg quinagolide (as the hydrochloride salt).
0.150 mg : Each whitish, circular, flat bevelled edge tablet engraved "150" on one side and "NORPROLAC" on the other, contains 0.150 mg quinagolide (as the hydrochloride salt).