Norprolac Tablets - Scientific Information
|Ingredients:||quinagolide hydrochloride, silica (colloidal anhydrous), magnesium stearate, methylhydroxy-propylcellulose, maize starch, cellulose (microcrystalline), lactose.|
|Proper name:||quinagolide hydr°chloride|
|Chemical name:||(3α,4aα,10aβ)-(±)-N,N-Diethyl-N'1,2,3,4,4a,5,10,10a-°ctahydro-6-hydroxy-1-propylbenzo[g] quinolin-3-yl-sulfamide hydr°chloride|
|Empirical formula:||C20H33N3O3S • HCl|
|Molecular Weight:||432 (salt)|
|Description:||The drug substance is a white to almost-white, finely crystalline |
powder, which is hygroscopic and light sensitive.
|Solubility:||Sparingly soluble in water (0.2%) and ethanol (0.1%).|
|Melting point:||With degradation, 231-237°C. |
pH of a 1% solution in water/ethanol (1:1 (v/v)): 3.3-5.0
pKa at 20± 2°C in water: 7.65 ± 0.15
Six dose-titration and long-term therapeutic studies were conducted with orally administered quinagolide in a total of 678 patients with hyperprolactinemia of idiopathic or adenomatous origin and its clinical manifestations. Four of the studies were well-controlled double-blind, and randomized trials in hyperprolactinemic women. The other two studies were open label studies involving patients with mostly macroadenemas.
The effect of quinagolide in women with hyperprolactinemia of idiopathic or microadenoma origin was compared to placebo in two of the studies, and to bromocriptine in another two.
The primary endpoint used to evaluate the efficacy of quinagolide treatment was the plasma/serum prolactin concentration at baseline and at various intervals throughout the trials. The dopamine agonist induced decrease of plasma prolactin concentration is usually paralleled by an improvement of the clinical manifestations (Thorner, 1980). The improvement or absence of clinical manifestations of hyperprolactinemia such as amenorrhea, galactorrhea, decreased libido or impotence were used as secondary endpoints. A total of approximately 80% of patients enrolled in the clinical trials were pretreated with dopamine agonists. In these patients, a one-month washout period prior to study entry was necessary to increase plasma prolactin levels at baseline. Success of treatment was based on:
- normalization of serum/plasma prolactin (≤ 20 ng/mL)
- regulation of menstrual function
- absence of galactorrhea
Quinagolide was administered at bedtime with a snack in all clinical trials. A starting dose of 0.05 mg quinagolide was used in two of the studies during the double-blind phase. Dosage escalation by monthly increments of 0.025 mg during the open-label phase was based on normalization of prolactin levels and good tolerability.
Hyperprolactinemia of Idiopathic or Microadenoma Origins
Results from placebo-controlled double-blind parallel group studies showed that quinagolide at single oral doses of >0.05 mg daily is statistically more effective than placebo (p<0.001) in suppressing prolactin plasma levels in hyperprolactinemic women (idiopathic or microadenoma origin) after only 2 weeks of treatment. Normalization of prolactin levels occurred in approximately 70% of patients at doses between 0.05 and 0.075 mg/day.
In the two multicenter double-blind parallel group studies comparing quinagolide to bromocriptine, no clinically or statistically significant difference in efficacy parameters were found between the 2 drugs in suppressing prolactin levels, relieving galactorrhea and restoring gonadal function.
Hyperprolactinemia AAssociated with Macroadenomas
Two open-label multicenter studies were conducted in a total of 228 patients (91 men and 137 women), most of whom had a history or presence of macroadenoma. Baseline serum prolactin levels were widely distributed among patients ranging from 27 to 39,000 ng/mL. In one study, the mean baseline prolactin was 1405 ng/mL.
These studies showed that quinagolide was effective in treating at least 60% of patients with macroadenomas (including those who were previously untreated). Optimal prolactin response was achieved with 12 weeks in approximately 40% of patients while others required up to 12 months to achieve normal prolactin levels. Dose titration steps of 0.075 mg or 0.150 mg quinagolide were well tolerated.
Gross symptomatology such as tumour-related headache, subnormal libido and diminished well-being improved more rapidly than did gonadal function in both men and women.
Clinical symptoms of hyperprolactinemia were relieved or disappeared following quinagolide treatment in males and females. In one study, mild to moderate galactorrhea recorded in 7/65 men (11%) at entry was present in only 2 male patients (4%) up to Month 6 and none at Month 12. At baseline, 23 of the 73 women (32%) had mild to moderate galactorrhea. Galactorrhea was reported in 4/44 (9%) of women at Month 6 and 2/32 (6%) women at Month 12. In the second study, resolution of galactorrhea at month 6 was obtained in 54% of women and all men presenting with this symptom at baseline.
Amenorrhea reported in 90% (56/63) of women at study entry was reported in 36%, 44% and 44% of patients following 3, 9 and 12 months of quinagolide treatment, respectively. Subnormal libido reported in 39% of women at baseline dropped to 25% and 21% at Month 3 and 12 of treatment, respectively. Similarly, 36% (21/59) patients resumed normal menstrual function during the first 6 months of quinagolide treatment in the second study.
Non-migrainous headache judged to be tumour-related was present in 58/138 (42%) of patients at baseline. As the study progressed, this complaint diminished, so that by Month 3 and 6, 17/125 (15%) and 12% of patients reported headache, respectively. 58% (32/55) of macroadenoma patients in the second study had a reduction in the size of their prolactin-secreting pituitary tumour during the course of the study and 78% (7/9) had an improvement in tumour-related visual field deficits after 6 months of quinagolide treatment.
In an in vitro model, designed to test the effect of quinagolide on prolactin secretion by dissociated rat anterior pituitary cells, the drug was shown to have a potent prolactin inhibitory action at picomolar concentrations. The effect mimicked the action of dopamine, the comparative substance.
Selectivity of quinagolide for D2 receptors was demonstrated both by receptor binding studies and by the use of selective and unselective dopamine antagonists in reversing the quinagolide-induced inhibition of prolactin secretion in vitro.
In preclinical studies quinagolide was found to be a potent suppressor of basal and stimulated serum prolactin levels in male and female rats after parenteral and oral administration. Given subcutaneously to rats, quinagolide was found to be approximately 35 times more potent than bromocriptine in preventing ovum implantation (ED50=0.02 mg/kg), a function which in the rat is dependent on prolactin secretion. Given orally to rats, the drug was shown to be approximately 300 times more potent than bromocriptine in suppression of lactation (ED50=0.03 mg/kg). The ID50 for inhibition of basal prolactin secretion in male rats was 100 times lower than bromocriptine. Quinagolide inhibited ovulation in rats at a dose 18 times higher than the dose necessary for inhibition of implantation.
Quinagolide also suppressed the reflex release of oxytocin in rats induced by suckling pups. The subcutaneous dose necessary to inhibit milk ejection was 6 times greater than the oral dose for suppression of lactation, so it is unlikely that the inhibition of lactation or nidation is related to the effect on oxytocin.
The cardiovascular actions of quinagolide were examined in anaesthetized cat and dog models. In both models the drug caused blood pressure decreases, with and without reflex tachycardia, at i.v. doses of 4 and 2.5 g/kg, respectively. In non-anaesthetized hypertensive dogs quinagolide at doses ranging from 5 to 20 g/kg i.v. prevented the reflex compensatory blood pressure adjustment to sudden postural change.
The drug produced behavioural and biochemical central effects indicating its selective dopamine D2 receptor stimulating properties. Behavioural effects such as sudden sleep onset episodes and reduced motor activity were observed in rats at doses starting at 0.0003 mg/kg s.c. Quinagolide produced an array of actions within the central nervous system (CNS), i.e., contralateral turning in rats (> 0.3 mg/kg s.c.) with unilateral lesions of the substantia nigra and inhibition of tetrabenazine induced akinesia (0.3 mg/kg s.c.).
Quinagolide is a racemic compound. Comparative studies of the (+) and (-) enantiomers of quinagolide were conducted in various animal models. The results indicate that its relevant biological activity resides exclusively in the (-) enantiomer. Two putative metabolites of quinagolide were shown to possess pharmacological activity qualitatively similar to quinagolide. The formation of dopaminomimetic metabolites of quinagolide may contribute to the prolonged duration of action seen in man.
Acute Toxicity Studies
Acute studies were conducted using mice, rats and rabbits by the oral, intraperitoneal and intravenous routes. The following approximate LD50 values (mg/kg body weight) were determined:
|Rats||> 500||> 150||13|
|Rabbits||> 150||> 50||ND*|
* ND : not determined
Single dose studies indicate the quinagolide has a low acute toxicity compared to its therapeutic dose. No species-specific toxicity occurred. There was some evidence of central depression mainly characterized by ataxia, loss of righting reflex and decreased locomotor activity following each route of administration.
Long-Term Toxicity Studies
Quinagolide mixed in food was well-tolerated when given to rats at dose levels of 0.06, 0.2, and 0.6 mg/kg for 4 and 13 weeks. With the exception of lower feed intake and reduced body weight gain of the high dose Sprague-Dawley rats used in the 13 week study, findings were limited to the Wistar rats used in the 4 week study and comprised the following: reduced cholesterol levels and increased ovarian weights, partly with increased number and size of corpora lutea, in all treated female rats, as well as lower pituitary weights in females at mid and high dose levels. No morphological changes were detected. Uterine hydrometra were slightly more frequent in treated females. The no-toxic-effect level was between 0.2 and 0.6 mg/kg for both studies.
In a 26-week study with quinagolide at doses levels of 0.05, 0.5 and 2.5-6.0 mg/kg administered twice daily by gavage, findings included: a dose-related decrease in cholesterol levels in all treated females and an increase in the number but not the size of corpora lutea, resulting in enlarged ovaries. Hydrometra and trace to mild uterine endometritis occurred at all dose levels. The no-toxic-effect level in males was 12 mg/kg/day.
The major findings in a one and two-year study in rats were related to the pharmacodynamic action of quinagolide in rodents. At oral doses of 0.01 to 0.2 mg/kg, quinagolide caused a dose-dependent decrease in cholesterol levels as well as uterine metritis and hydrometra associated with squamous metaplasia of the endometrial epithelium in some mid and high dose females. A trend for estrogen dominance as shown by a reduced progesterone/estradiol ratio correlated with an increased number of corpora lutea in the ovaries. Changes observed in the female reproductive tract were linked with reduced LH and prolactin levels: A drug related decrease in palpable masses at 0.01 to 0.2 mg/kg was correlated with decreased prolactin levels. Mean serum LH was decreased in females at 0.06 and 0.2 mg/kg.
In male rats, an increase in luteinizing hormone levels was associated with increased numbers of Leydig cell tumours as was shown for other dopaminergic compounds. Hypoprolactinemia reduces receptor binding capacity of luteinizing hormone in Leydig cells. In male rats, reduced Leydig cell responsiveness is compensated for by chronically elevated luteinizing hormone secretion to maintain normal testosterone levels.
In a 90-week lifetime carcinogenicity study in mice, quinagolide (0.02-0.4 mg/kg) administered in feed caused a drug-related decrease in body weight in the high dose group. In addition, an increase in the incidence of mesodermal tumours was observed in the reproductive tract of mid and high dose females (leiomyoma and leiomyosarcoma of the vagina, uterus and cervix, uterine endometrial stromal polyps and sarcomas). A 4-week explanatory hormonal study in female mice showed that quinagolide (0.47, 1.53 mg/kg po) has a hyperestrogenic effect in mice.
The findings in mice and rats were not shown to be relevant for humans due to the fundamental difference in the regulation of the endocrine system between rodents and humans.
Quinagolide was associated with a decrease in body weight and with emesis when administered three times daily with escalation of the dose to 1.2 mg/kg in a 26 week study. A 12-month oral study in dogs was conducted at dose levels of 0.02, 0.2 and 0.4-0.8 mg/kg/day. Emetic episodes and excessive salivation occurring in the high dose group precluded further dose escalation.
With the exception of reduced body weight gain in the mid and high dose groups, no signs of toxicity occurred. Apart from the emesis observed during the first week, the no-toxic-effect level was 0.02 mg/kg.
Reproduction and Teratology Studies
Quinagolide was administered by oral gavage for 10 weeks to Sprague-Dawley male rats (0, 5, 50 or 500 μg/kg/day) and for 2 weeks to Sprague-Dawley females (0, 2.5, 5 or 10 μg/kg/day) prior to mating and continued until weaning of the F1 offspring. Two high dose females were in persistent estrus for 10 and 13 days during mating. A lower pregnancy rate was observed in high dose females. Body weights of high dose F1 pups were significantly lower and a slight developmental delay was noted. Subsequent mating of the F1 generation revealed no effects on reproductive performance or on the development of the F2 offspring. Effects in females and F1 offspring were related to the inhibition of prolactin secretion by quinagolide. Implantation inhibition by decreased prolactin levels is a rodent-specific finding.
Pregnant Wistar rats received quinagolide by oral gavage at doses of 0, 0.1, 0.3 and 1.0 mg/kg from days 8 to 15 of gestation. The delayed start of treatment on day 8 served to avoid implantation loss occurring as a result of administering a prolactin secretion inhibiting compound. No embryo- or feto-toxic effects were observed at dose levels up to 1.0 mg/kg (the limit for maternal toxicity), and no adverse effects were noted on F1 generation fertility and reproductive performance or on the viability and development of the F2 offspring.
In a further embryotoxicity study, pregnant Russian strain rabbits received quinagolide by oral gavage at doses of 0, 0.3, 1.0 and 3.0 mg/kg from days 6 to 18 of gestation. Quinagolide was well tolerated by the dams and without adverse effect on reproductive performance. Pregnant Sprague Dawley rats received oral doses of quinagolide (0, 5, 25 and 50 μg/kg by gavage) from day 15 of gestation through day 21 postpartum. Despite the low dose levels, neonatal mortality during the lactation period amounted to 66% and 100% in the mid and high dose groups, respectively, as a result of the pharmacodynamic action of quinagolide and lack of milk in the dams.
Refer to results in chronic toxicity studies.
The ability of quinagolide to induce mutations was examined in vitro with the Ames test using Salmonella typhimurium and various strains of E. coli both with and without activation system. Genotoxicity of the drug was examined in vitro with the unscheduled DNA repair synthesis assay, in Chinese hamster V79 cells, and in vivo in the mouse micronucleus test. Quinagolide showed no mutagenic or genotoxic potential in the assay systems investigated.