Dostinex

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Dostinex uses

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Dostinex reviews

DESCRIPTION

Dostinex Tablets USP contain Dostinex, USP, a dopamine receptor agonist. The chemical name for Dostinex, USP is 1-[(6-Allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea and has the following structural formula:

• C₂₆H₃₇N₅O₂ M.W. 451.6

Dostinex, USP is a white powder soluble in ethyl alcohol, chloroform, and N, N-dimethylformamide (DMF); slightly soluble in 0.1N hydrochloric acid; very slightly soluble in n-hexane; and insoluble in water.

Each Dostinex Tablet USP, for oral administration, contains 0.5 mg of Dostinex, USP and has the following inactive ingredients: anhydrous lactose and leucine.

Dostinex USP structural formula

CLINICAL PHARMACOLOGY

Mechanism of Action

The secretion of prolactin by the anterior pituitary is mainly under hypothalamic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Dostinex is a long-acting dopamine receptor agonist with a high affinity for D₂ receptors. Results of in vitro studies demonstrate that Dostinex exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Dostinex decreased serum prolactin levels in reserpinized rats. Receptor-binding studies indicate that Dostinex has low affinity for dopamine D₁, α₁- and α₂-adrenergic, and 5-HT₁- and 5-HT₂-serotonin receptors.

Clinical Studies

The prolactin-lowering efficacy of Dostinex was demonstrated in hyperprolactinemic women in two randomized, double-blind, comparative studies, one with placebo and the other with bromocriptine. In the placebo-controlled study, Dostinex produced a dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%, 76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1 mg twice weekly respectively.

In the 8 week, double-blind period of the comparative trial with bromocriptine (cabergoline n = 223; bromocriptine n = 236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated with Dostinex at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg twice daily. Restoration of menses occurred in 77% of the women treated with Dostinex, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with Dostinex compared with 56% of those treated with bromocriptine.

Pharmacokinetics

Absorption

Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms /mL of Dostinex were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, Dostinex plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be two-fold to three-fold higher than after a single dose. The absolute bioavailability of Dostinex is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of Dostinex estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of Dostinex may be related to its slow elimination and long half-life.

Distribution

In animals, based on total radioactivity, Dostinex (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by > 100 fold and was eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Dostinex is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition.

Metabolism

In both animals and humans, Dostinex is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Dostinex does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of Dostinex, and major metabolites identified thus far do not contribute to the therapeutic effect.

Excretion

After oral dosing of radioactive Dostinex to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. Nonrenal and renal clearances for Dostinex are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar.

Special Populations

Renal Insufficiency

The pharmacokinetics of Dostinex were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance.

Hepatic Insufficiency

In 12 patients with mild-to-moderate hepatic dysfunction, no effect on mean Dostinex C_max or area under the plasma concentration curve (AUC) was observed. However, patients with severe insufficiency (Child-Pugh score > 10) show a substantial increase in the mean Dostinex C_max and AUC, and thus necessitate caution.

Elderly

Effect of age on the pharmacokinetics of Dostinex has not been studied.

Food-Drug Interaction

In 12 healthy adult volunteers, food did not alter Dostinex kinetics.

Pharmacodynamics

Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single Dostinex doses to healthy volunteers (0.05 to 1.5 mg) and hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose.

In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of Dostinex was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than Dostinex (6 hours vs. 48 hours).

In 72 healthy volunteers, single or multiple doses (up to 2 mg) of Dostinex resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol.

INDICATIONS AND USAGE

Dostinex Tablets USP are indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.

CONTRAINDICATIONS

Dostinex tablets are contraindicated in patients with

• Uncontrolled hypertension or known hypersensitivity to ergot derivatives.
• History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis (see WARNINGS ).
• History of pulmonary, pericardial, or retroperitoneal fibrotic disorders (see WARNINGS ).

WARNINGS

Pregnancy

Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and post partum hypertension, unless the potential benefit is judged to outweigh the possible risk.

Fibrotic Complications

Cardiac Valvulopathy

All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease. If valvular disease is detected, the patient should not be treated with Dostinex. Postmarketing cases of cardiac valvulopathy have been reported in patients receiving Dostinex. These cases have generally occurred during administration of high doses of Dostinex (> 2 mg/day) for the treatment of Parkinson’s disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses of Dostinex for the treatment of hyperprolactinemic disorders.

A multi-country, retrospective cohort study using general practice records and record linkage systems in the UK, Italy and the Netherlands was conducted to assess the association between new use of dopamine agonists including Dostinex (n = 27,812) for Parkinson’s disease and hyperprolactinemia and cardiac valvular regurgitation (CVR), other fibroses, and other cardiopulmonary events over a maximum of 12 years of follow up. In this study, the use of Dostinex among persons with Parkinson's disease was associated with an increased risk of CVR when compared to non-ergot-derived dopamine agonists (DAs) and levodopa [Incidence Rate (IR) per 10,000 person years of 68.1 (95% confidence interval (CI): 37.2 to 115.3) for Dostinex vs. 10 (95% CI: 5.2 to 19.4) for non-ergot DAs and 11.3 (95% CI: 7.2 to 17) for levodopa]. In the study analysis confined to persons with dopamine agonist-treated hyperprolactinemia (n = 8,386), when compared to non-use (n = 15,147), persons exposed to Dostinex did not have an elevated risk of CVR. The findings with respect to the risk of CVR associated with Dostinex treatment for persons with Parkinson’s disease (increased risk) and those with hyperprolactinemia (no increased risk) are consistent with the findings in other published studies.

Physicians should use the lowest effective dose of Dostinex for the treatment of hyperprolactinemic disorders and should periodically reassess the need for continuing therapy with Dostinex. Following treatment initiation, clinical and diagnostic monitoring (for example, chest x-ray, CT scan and cardiac echocardiogram) should be conducted to assess the risk of cardiac valvulopathy. The recommended frequency of routine echocardiographic monitoring is every 6 to 12 months or as clinically indicated with the presence of signs and symptoms such as edema, new cardiac murmur, dyspnea, or congestive heart failure.

Dostinex should be discontinued if an echocardiogram reveals new valvular regurgitation, valvular restriction or valve leaflet thickening.

Dostinex should be used with caution in patients exposed to other medications associated with valvulopathy.

Extracardiac Fibrotic Reactions

Postmarketing cases of pleural, pericardial, and retroperitoneal fibrosis have been reported following administration of Dostinex. Some reports were in patients previously treated with other ergotinic dopamine agonists. Dostinex should not be used in patients with a history of cardiac or extracardiac fibrotic disorders.

Fibrotic disorders can have an insidious onset and patients should be monitored for manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of:

• Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain.
• Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis.
• Cardiac failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.

Clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with Dostinex.

Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of Dostinex was reported to result in improvement of signs and symptoms.

PRECAUTIONS

General

Initial doses higher than 1 mg may produce orthostatic hypotension. Care should be exercised when administering Dostinex with other medications known to lower blood pressure.

Postpartum Lactation Inhibition or Suppression

Dostinex tablets are not indicated for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this purpose, has been associated with cases of hypertension, stroke, and seizures.

Hepatic Impairment

Since Dostinex is extensively metabolized by the liver, caution should be used, and careful monitoring exercised, when administering Dostinex to patients with hepatic impairment.

Psychiatric

Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including Dostinex. This has been generally reversible upon reduction of the dose or treatment discontinuation.

Information for Patients

Patients should be instructed to notify their physician if they suspect they are pregnant, become pregnant, or intend to become pregnant during therapy. A pregnancy test should be done if there is any suspicion of pregnancy and continuation of treatment should be discussed with their physician.

Patients should notify their physician if they develop shortness of breath, persistent cough, difficulty with breathing when lying down, or swelling in their extremities.

Drug Interactions

Dostinex should not be administered concurrently with D₂-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats with Dostinex given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively. These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface area basis using total mg/m²/week in rodents and mg/m²/week for a 50 kg human.

There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these tumors to humans is not known.

The mutagenic potential of Dostinex was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P ₁ and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D ₄, and chromosomal aberrations in human lymphocytes. Dostinex was also negative in the bone marrow micronucleus test in the mouse.

In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose calculated on a body surface area basis using total mg/m²/week in rats and mg/m²/week for a 50 kg human.

Pregnancy

Teratogenic Effects

Category B

Reproduction studies have been performed with Dostinex in mice, rats, and rabbits administered by gavage.

There were maternotoxic effects but no teratogenic effects in mice given Dostinex at doses 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 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of Dostinex in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, Dostinex caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Dostinex, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Use of Dostinex for the inhibition or suppression of physiologic lactation is not recommended (see PRECAUTIONS section).

The prolactin-lowering action of Dostinex suggests that it will interfere with lactation. Due to this interference with lactation, Dostinex should not be given to women postpartum who are breastfeeding or who are planning to breastfeed.

Pediatric Use

Safety and effectiveness of Dostinex in pediatric patients have not been established.

Geriatric Use

Clinical studies of Dostinex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

The safety of Dostinex tablets has been evaluated in more than 900 patients with hyperprolactinemic disorders. Most adverse events were mild or moderate in severity.

In a 4 week, double-blind, placebo-controlled study, treatment consisted of placebo or Dostinex at fixed doses of 0.125, 0.5, 0.75, or 1 mg twice weekly. Doses were halved during the first week. Since a possible dose-related effect was observed for nausea only, the four Dostinex treatment groups have been combined. The incidence of the most common adverse events during the placebo-controlled study is presented in the following table.

In the 8 week, double-blind period of the comparative trial with bromocriptine, Dostinex (at a dose of 0.5 mg twice weekly) was discontinued because of an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued in 14 of 231 patients (6%). The most common reasons for discontinuation from Dostinex were headache, nausea and vomiting (3, 2 and 2 patients respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10, 3, 3, and 3 patients respectively). The incidence of the most common adverse events during the double-blind portion of the comparative trial with bromocriptine is presented in the following table.

Other adverse events that were reported at an incidence of < 1% in the overall clinical studies follow.

Body as a Whole

Facial edema, influenza-like symptoms, malaise

Cardiovascular System

Hypotension, syncope, palpitations

Digestive System

Dry mouth, flatulence, diarrhea, anorexia

Metabolic and Nutritional System

Weight loss, weight gain

Nervous System

Somnolence, nervousness, paresthesia, insomnia, anxiety

Respiratory System

Nasal stuffiness, epistaxis

Skin and Appendages

Acne, pruritus

Special Senses

Abnormal vision

Urogenital System

Dysmenorrhea, increased libido

The safety of Dostinex has been evaluated in approximately 1,200 patients with Parkinson’s disease in controlled and uncontrolled studies at dosages of up to 11.5 mg/day which greatly exceeds the maximum recommended dosage of Dostinex for hyperprolactinemic disorders. In addition to the adverse events that occurred in the patients with hyperprolactinemic disorders, the most common adverse events in patients with Parkinson’s disease were dyskinesia, hallucinations, confusion, and peripheral edema. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported.

Postmarketing Surveillance Data

The following events have been reported in association with Dostinex: cardiac valvulopathy and extracardiac fibrotic reactions (see WARNINGS, Cardiac Valvulopathy and Extracardiac Fibrotic Reactions ).

Other events have been reported in association with Dostinex: hypersexuality, increased libido and pathological gambling (see PRECAUTIONS, Psychiatric ). In addition, cases of alopecia, aggression and psychotic disorder have been reported in patients taking Dostinex. Some of these reports have been in patients who have had prior adverse reactions to dopamine agonist products.

OVERDOSAGE

Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary.

DOSAGE AND ADMINISTRATION

The recommended dosage of Dostinex tablets for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease.

Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient’s response to each dosage level. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long-term treatment with Dostinex should undergo periodic assessment of their cardiac status and echocardiography should be considered.

After a normal serum prolactin level has been maintained for 6 months, Dostinex may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with Dostinex should be reinstituted. The durability of efficacy beyond 24 months of therapy with Dostinex has not been established.

HOW SUPPLIED

Dostinex Tablets USP, 0.5 mg are available as white, oval-shaped, scored tablets, debossed “Ivax hourglass logo”, “0.5” with a score on one side and “5420” on the other side containing 0.5 mg Dostinex, packaged in unit-of-use bottles of 8 tablets.

Store at 20° to 25°C (68° to 77°F).

Dispense in original container.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In Czech Republic By:

TEVA CZECH INDUSTRIES s.r.o.

Opava-Komarov, Czech Republic

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. D 4/2015

Dostinex Tablets USP 0.5 mg 8s Carton, Part 1 of 2

Dostinex Tablets USP 0.5 mg 8s Carton Text

NDC 0093-5420-88

Dostinex

Tablets USP

0.5 mg

Each tablet contains:

Dostinex, USP 0.5 mg

Dispense in original container

Rx only

8 TABLETS UNIT-OF-USE

TEVA

Dostinex Tablets USP 0.5 mg 8s Carton, Part 2 of 2

Dostinex pharmaceutical active ingredients containing related brand and generic drugs:

• Cabergoline

Dostinex available forms, composition, doses:

• DOSTINEX 0.5MG TABLET
• Tablets; Oral; Cabergoline 0.5 mg

Dostinex destination | category:

• Human:
• Antiparkinsonian drugs
• Drugs affecting hormonal regulation

Dostinex Anatomical Therapeutic Chemical codes:

• G02CB03 - Cabergoline

Dostinex pharmaceutical companies:

• Kenfarma
• Paladin Laboratories
• Perrigo
• Pfizer
• Primal Chemical
• Zuellig Pharma

References

1. Dailymed."CABERGOLINE TABLET [TEVA PHARMACEUTICALS USA INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."CABERGOLINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "cabergoline". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Dostinex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Dostinex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology