SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 14 SPECIAL HANDLING INSTRUCTIONS 14 DOSAGE FORMS, COMPOSITION AND PACKAGING 14
PHARMACEUTICAL INFORMATION 15 CLINICAL TRIALS 16 DETAILED PHARMACOLOGY 17 TOXICOLOGY 19
CO
CABERGOLINE
(cabergoline)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet / 0.5 mg | Lactose For a complete listing see Dosage Forms, Composition and Packaging section. |
CO
Cabergoline (cabergoline) is indicated for:
Treatment of hyperprolactinemic disorders
, either idiopathic or due to pituitary adenomas.
Inhibition of physiological lactation. CO Cabergoline is indicated for the prevention of the onset of physiological lactation in the puerperium for clearly defined medical reasons. These medical reasons may include birth of a still born baby, neonatal death, conditions interfering with suckling (cleft lip or palate of the baby), severe acute or chronic mental illness or medical conditions, maternal disease which may be transmitted to the baby that require medications which are excreted in the milk.
CO
Cabergoline is not indicated for the purpose of suppression of already established post partum lactation.
Geriatrics (> 65 years of age):
No data is available.
Pediatrics (< 16 years of age):
No data is available.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
Patients with uncontrolled hypertension or known hypersensitivity to ergot derivatives.
General
Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia and eclampsia, unless the potential benefit is judged to outweigh the possible risk. Cabergoline should be given with caution to subjects with cardiovascular disease, Raynaud's syndrome, renal insufficiency, peptic ulcer, gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disease. Particular care should be taken when patients are taking concomitant psychoactive medication. The effects of alcohol on overall tolerability of cabergoline are currently unknown.
: Cabergoline has been associated with somnolence. Suddden sleep onset episodes that can be associated with dopamine agonists usually occur in patients with Parkinson's disease. A reduction of dosage or termination of therapy may be considered.
: Patients being treated with cabergoline should be warned of the potential for experiencing somnolence. Patients should be cautioned about engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) in case somnolence does occur.
Carcinogenesis and Mutagenesis
See TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data. See also Special Populations, Women of Childbearing Potential and Pregnant Women.
Cardiovascular
: Initial doses higher than 1.0 mg may produce orthostatic hypotension. Care should be exercised when administering cabergoline with other medications known to lower blood pressure.
: Symptomatic hypotension can occur with cabergoline administration. Care should be exercised when administering cabergoline concomitantly with other medications known to lower blood pressure.
: As with other ergot derivatives, pleural effusion/pulmonary fibrosis and valvulopathy have been reported following long-term administration of cabergoline. Some reports were in patients previously treated with ergotinic dopamine agonists. Therefore, cabergoline should be used with caution in patients with a history, or current signs and/or clinical symptoms of, respiratory or cardiac disorders linked to fibrotic tissue. Following diagnosis of pleural effusion/pulmonary fibrosis or valvulopathy, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms.
Hepatic/Biliary/Pancreatic
Since cabergoline is extensively metabolised by the liver, caution should be used, and careful monitoring exercised, when administering cabergoline to patients with hepatic impairment.
Special Populations
Before cabergoline administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month.
Carcinogenicity studies were conducted in mice and rats with cabergoline 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 cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D4 and chromosomal aberrations in human lymphocytes. Cabergoline 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 the body surface are basis using total mg/m2/week in rats and mg/m2/week for a 50 kg human.
Reproduction studies have been performed with cabergoline in mice, rats,
and rabbits administered by gavage. (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human.) There were maternotoxic effects but no teratogenic effects in mice given cabergoline 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 embryo fetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline 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, cabergoline 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.
Information for Patients:
A patient should be instructed to notify her physician if she suspects she is pregnant, becomes pregnant, or intends 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 her physician.
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 cabergoline, 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.
The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this interference with lactation, cabergoline should not be given to women postpartum who are breastfeeding or who are planning to breastfeed.
Safety and effectiveness of cabergoline in pediatric patients have not been established.
Very limited data concerning experience of treatment of hyperprolactinemia in the elderly are available. However, available data do not indicate a special risk for this population.
Monitoring and Laboratory Tests
No information is available.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Hyperprolactinemic disorders: The safety of cabergoline 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 cabergoline at fixed doses of 0.125, 0.5, 0.75, or 1.0 mg twice weekly. Doses were halved during the first week. Since a possible dose-related effect was observed for nausea only, the four cabergoline treatment groups have been combined. The incidence of the most common adverse events during the placebo- controlled study is presented in Table 1.
Table 1 - Incidence of Reported Adverse Events During the 4-Week, Double-Blind, Placebo-Controlled Trial
| Adverse Event * | Cabergoline (n=168) 0.125 to 1 mg two times a week | Placebo (n=20) |
| Number (percent) | ||
| Gastrointestinal | 45 (27) | 4 (20) |
| Nausea | ||
| Constipation | 15 (10) | 0 |
| Abdominal pain | 9 (5) | 1 (5) |
| Dyspepsia | 4 (2) | 0 |
| Vomiting | 4 (2) | 0 |
| Central and Peripheral Nervous System | 43 (26) | 5 (25) |
| Headache | ||
| Dizziness | 25 (15) | 1 (5) |
| Paresthesia | 2 (1) | 0 |
| Vertigo | 2 (1) | 0 |
| Body as a Whole | 15 (9) | 2 (10) |
| Asthenia | ||
| Fatigue | 12 (7) | 0 |
| Hot flashes | 2 (1) | 1 (5) |
| Adverse Event * | Cabergoline (n=168) 0.125 to 1 mg two times a week | Placebo (n=20) |
| Number (percent) | ||
| Psychiatric | 9 (5) | 1 (5) |
| Somnolence | ||
| Depression | 5 (3) | 1 (5) |
| Nervousness | 4 (2) | 0 |
| Autonomic Nervous System Postural hypotension | 6 (4) | 0 |
| Reproductive - Female | 2 (1) | 0 |
| Breast pain | ||
| Dysmenorrhea | 2 (1) | |
| Vision Abnormal vision | 2 (1) | 0 |
Reported at >= 1% for cabergoline
In the 8-week, double-blind period of the comparative trial with bromocriptine, cabergoline (at a dose of 0.5 mg twice weekly) was discontinued due to an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued due to an adverse event in 14 of 231 patients (6%). The most common reasons for discontinuation from cabergoline 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 Table 2.
Table 2 - Incidence of Reported Adverse Events During the 8-Week, Double-Blind, Period of the Comparative Trial with Bromocriptine
| Adverse Event * | Cabergoline (n=221) | Bromocriptine (n=231) |
| Number (percent) | ||
| Gastrointestinal | 63 (29) | 100 (43) |
| Nausea | ||
| Constipation | 15 (7) | 21 (9) |
| Abdominal pain | 12 (5) | 19 (8) |
| Dyspepsia | 11 (5) | 16 (7) |
| Vomiting | 9 (4) | 16 (7) |
| Dry mouth | 5 (2) | 2 (1) |
| Diarrhea | 4 (2) | 7 (3) |
| Flatulence | 4 (2) | 3 (1) |
| Throat irritation | 2 (1) | 0 |
| Toothache | 2 (1) | 0 |
| Central and Peripheral Nervous System | 58 (26) | 62 (27) |
| Headache | ||
| Dizziness | 38 (17) | 42 (18) |
| Vertigo | 9 (4) | 10 (4) |
| Paresthesia | 5 (2) | 6 (3) |
| Adverse Event * | Cabergoline (n=221) | Bromocriptine (n=231) |
| Number (percent) | ||
| Body as a Whole | 13 (6) | 15 (6) |
| Asthenia | ||
| Fatigue | 10 (5) | 18 (8) |
| Syncope | 3 (1) | 3 (1) |
| Influenza-like symptoms | 2 (1) | 0 |
| Malaise | 2 (1) | 0 |
| Periorbital edema | 2 (1) | 2 (1) |
| Peripheral edema | 2 (1) | 1 |
| Psychiatric | 7 (3) | 5 (2) |
| Depression | ||
| Somnolence | 5 (2) | 5 (2) |
| Anorexia | 3 (1) | 3 (1) |
| Anxiety | 3 (1) | 3 (1) |
| Insomnia | 3 (1) | 2 (1) |
| Impaired concentration | 2 (1) | 1 |
| Nervousness | 2 (1) | 5 (2) |
| Cardiovascular | 6 (3) | 3 (1) |
| Hot flashes | ||
| Hypotension | 3 (1) | 4 (2) |
| Dependent edema | 2 (1) | 1 |
| Palpitation | 2 (1) | 5 (2) |
| Reproductive - Female | 5 (2) | 8 (3) |
| Breast pain | ||
| Dysmenorrhea | 2 (1) | 1 |
| Skin and Appendages | 3 (1) | 1 |
| Acne | ||
| Pruritus | 2 (1) | |
| Musculoskeletal | 4 (2) | 6 (3) |
| Pain | ||
| Arthralgia | 2 (1) | 0 |
| Respiratory Rhinitis | 2 (1) | 9 (4) |
| Vision Abnormal vision | 2 (1) | 2 (1) |
Reported at >=1% for cabergoline
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Other adverse events that were reported at an incidence of <1.0% 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:
dysmenorrhea, increased libido
Inhibition/Suppression of Physiological Lactation: The frequency of adverse events in women treated with a single 1 mg dose of cabergoline for inhibition of physiologic lactation and in nursing women treated with 0.25 mg of cabergoline every 12 hours for 2 days for suppression of lactation was similar at approximately 14%. Most side effects were transient and mild to moderate in severity. In women treated for inhibition of physiologic lactation the most frequently occurring adverse events were asymptomatic decreases in blood pressure, dizziness/vertigo, headache, nausea, and abdominal pain. In addition, on rare occasions, palpitations, epigastric pain, somnolence, epistaxis, and transient hemianopia have been reported (see WARNINGS AND PRECAUTIONS). The most frequent symptoms in the treatment of suppression of lactation were dizziness/vertigo, headache, nausea, somnolence, abdominal pain. In addition, rarely, vomiting, syncope, asthenia, and hot flushes were reported (see WARNINGS AND PRECAUTIONS).
Other Conditions
The safety of cabergoline 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 cabergoline for hyperprolactinemic disorders. In addition to the adverse events that occurred in patients with hyperprolactinemic disorders, the most common adverse events in patients with Parkinson's disease were dyskinesia, hallucinations, confusion, and peripheral edema and sudden onset of sleep. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported.
Post-Market Adverse Drug Reactions
The following events have been reported in patients who have received cabergoline: alopecia, blood creatinine phosphokinase increased, delusions, dyspnea, edema, fetal urogenital abnormalities, fibrosis, hepatic function abnormal, hypersensitivity reaction, liver function tests abnormal, rash, respiratory disorder, respiratory failure, sudden sleep onset, valvulopathy (see WARNINGS AND PRECAUTIONS). It should be noted that the uncontrolled nature of post- marketing surveillance makes it difficult to determine definitively if a reported event was actually caused by cabergoline, or to reliably assess causation in individual cases.
Drug-Drug Interactions
Although there is no conclusive evidence of an interaction between cabergoline and other ergot alkaloids, the concomitant use of these medications during long-term treatment with cabergoline is not recommended. Since cabergoline exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs that have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the prolactin-lowering effect of cabergoline. By analogy with ergot derivatives, cabergoline should not be used in association with macrolide antibiotics (e.g., erythromycin) since systemic bioavailability and also adverse effects could increase.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions
No data is available.
Dosing Considerations
CO Cabergoline is to be administered by the oral route. Since the tolerability of this class of compounds is improved when administered with food, it is recommended, that cabergoline be taken with meals, for all the therapeutic indications. Food is not noted to affect the absorption of cabergoline (see Action and Clinical Pharmacology, Pharmacokinetics).
Recommended Dose and Dosage Adjustment (Adults)
The recommended initial dose of CO Cabergoline is 0.5 mg per week given in one or two (one- half of one 0.5 mg tablet) doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually, preferably by adding 0.5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dosage is usually 1 mg per week and ranges from 0.25 mg to 2.0 mg per week. The weekly dose may be given as a single administration or divided into two or more doses per week according to patient tolerability. Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given, since the tolerability of doses greater than 1 mg taken as a single weekly dose has been evaluated only in a few patients. Patients should be evaluated during dose escalation to determine the lowest dosage that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is advised since, once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within 2 to 4 weeks. After a normal serum prolactin level has been maintained for 6 months, CO Cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with CO Cabergoline should be reinstituted.
For inhibition of physiological lactation the recommended therapeutic dosage is 1 mg (two 0.5 mg tablets) given as a single dose. CO Cabergoline should be administered during the first day post-partum.
Missed Dose
Patients should be instructed that if a dose is missed, it should be taken as soon as possible unless it is time to take the next one. Then continue with the remaining doses as before. Patients should not take more than one dose at a time.
There is no experience with cabergoline in humans of overdosage when used in the proposed indications. Doses of cabergoline up to 4.5 mg per week have been used in hyperprolactinemic patients. Symptoms of overdose would likely be those of over-stimulation of dopamine receptors. These might include nausea, vomiting, gastric complaints, hypotension, or thought/perception disturbances (hallucinations), nasal congestion and syncope. General supportive measures should be undertaken to remove any unabsorbed drug and maintain blood pressure if necessary. In addition, the administration of dopamine antagonist drug may be advisable. Measures to support blood pressure should be taken if necessary.
Mechanism of Action
Cabergoline, the active ingredient in CO Cabergoline, is a dopaminergic ergoline derivative endowed with a potent and long-lasting prolactin-lowering activity. It acts by direct stimulation of the D2-dopamine receptors on pituitary lactotrophs, thus inhibiting prolactin secretion. In rats the compound decreases prolactin secretion at oral doses of 3 to 25 mg/kg, and in vitro at a concentration of 45 pg/mL. In addition, cabergoline exerts a central dopaminergic effect via D2- receptor stimulation at oral doses higher than those effective in lowering serum prolactin levels. The longer-lasting prolactin-lowering effect of cabergoline is probably due to its long persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after a single oral dose in rats (t1/2 of approximately 60 hours).
Pharmacodynamics
The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, puerperal women and hyperprolactinemic patients. After a single oral administration of cabergoline (0.3 to 1.5 mg), a significant decrease in serum prolactin levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7 to 28 days in healthy volunteers and hyperprolactinemic patients, and up to 14 to 21 days in puerperal women). The prolactin lowering effect is dose-related both in terms of degree of effect and duration of action. With regard to the endocrine effects of cabergoline not related to the antiprolactinemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.
Pharmacokinetics
The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes and in female hyperprolactinemic patients. After oral administration of the labelled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration, about 18% and 72% of the radioactive dose of 14C-cabergoline was recovered in the urine and feces, respectively. Unchanged drug in urine accounted for 2% to 3% of the dose. In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4% to 6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline in inhibiting prolactin secretion in vitro. The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non-radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63 to 68 hours in healthy volunteers and 79 to 115 hours in hyperprolactinemic patients as assessed by radioimmunoassay). The pharmacokinetics of cabergoline were found to be dose-independent in healthy volunteers at doses of 0.5 to 1.5 mg. On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37 +- 8 pg/mL) and after a 4-week multiple-dose regimen (101 +- 43 pg/mL). In vitro experiments showed that the drug at concentrations of 0.1 to 10 ng/mL is 41% to 42% bound to plasma proteins. Food does not appear to affect absorption and disposition of cabergoline. In 12 healthy adult volunteers, food did not alter cabergoline kinetics.
Special Populations and Conditions
Pediatrics:
No data is available.
No data is available.
Hepatic insufficiency of severe degree (> 10 Child-Pugh score, maximum score 12) has been shown to be associated with an increase in AUC.
Renal insufficiency has been shown not to modify cabergoline kinetics.
Store at room temperature (15degC to 30degC).
None.
CO
Cabergoline (cabergoline) is available as white to off-white, capsule-shaped tablets with
"C|5" on one side and " " partial bisect " " on the other side.
CO
Cabergoline tablets contain 0.5 mg of cabergoline as the active medicinal ingredient. Non- medicinal ingredients include: lactose, leucine.
CO
Cabergoline tablets are available in amber glass bottles of 8 and 30 tablets.
PART II: SCIENTIFIC INFORMATION
Proper name: Cabergoline Chemical name: N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2- propenyl)-8b-ergoline-8-carboxamide (CAS) Molecular formula: C26H37N5O2 Molecular mass: 451.62 Structural formula:
H
O N CH3
CH3
O
N N
CH3
H
N
CH2 H
HN
Physicochemical properties: Physical form: A white or almost white crystalline powder. Solubility: Cabergoline is practically insoluble in water, freely soluble in alcohol, and very slightly soluble in hexane. It is very slightly soluble in 0.1M hydrochloric acid. pH: The pH of a suspension of the substance in twice distilled water (1% w/v) at room temperature is 9.2. The pH of a 0.5% w/v C2H5OH/H2O (1:1) mixture is 9.2. pKa: pKa1 = 9.3 (N-dimethylaminopropyl group) pKa2 = 6.4 (N-propenyl group) Melting Point: 100deg - 105degC
Cabergoline was evaluated in inhibition lactation in two pivotal studies involving 412 women: 252 received cabergoline (0.5-1.0 mg), 136 bromocriptine (2.5 mg twice daily for 14 days) and 20 placebo. In the placebo controlled dose ranging study at the highest dose (1 mg), 90% of women had complete absence of breast symptomatology and cabergoline was well tolerated. In the comparator study with bromocriptine, cabergoline was at least as effective as bromocriptine in inhibition of lactation. However there was a significant reduction in the rate of rebound lactation and of a reduced rate and severity of adverse events. Cabergoline was studied in two open label studies involving 164 women in the suppression of established lactation. The primary objective of these two studies was to determine the most advantageous dose schedule of cabergoline in nursing women in suppressing lactation. The results from these two studies demonstrated that 1 mg cabergoline given in 4 divided administration over 2 days, was as effective as one 0.5 mg dose, followed by a second 0.5 mg dose given after 3 or 4 days as required, in suppressing established lactation. However, the former dosing (1 mg given in 4 divided administrations over 2 days) resulted in reduced incidences of adverse events. The prolactin-lowering efficacy of cabergoline 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 (placebo n=20; cabergoline n=168), cabergoline 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 1.0 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 cabergoline 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 cabergoline, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with cabergoline compared with 56% of those treated with bromocriptine.
A blinded, randomized, 2-way cross-over comparative bioavailability study of CO Cabergoline 0.5 mg tablets and Dostinex(r) 0.5 mg tablets, administered as a 1 mg (2 x 0.5 mg) dose, has been performed in forty one (41) healthy male and female volunteers (18 - 55 years of age) under fasting conditions. The results of the study, based on the thirty six (36) subjects who completed the study, demonstrate that the two formulations are bioequivalent. A summary of the bioavailability data is presented below.
Table 3: Comparative Bioavailability Data for CO Cabergoline 0.5 mg tablets vs. Dostinex(r) 0.5 mg tablets (Uncorrected for Potency)
Analyte: Cabergoline (2 x 0.5 mg)
From measured data
Geometric Mean Arithmetic Mean (CV%)
| Parameter * | Cabergoline Tablets 0.5 mg | Dostinex (r) 0.5 mg + | % Ratio of Geometric Means | 90 % Confidence Interval |
| AU C 0-72 | 513.68 | 507.35 | 101.25 | 94.94 - 107.94 |
| (pg *h/mL) | 559.39 (40.38) | 558.12 (49.56) | ||
| C MAX | 19.26 | 17.85 | 107.95 | 98.55 - 118.25 |
| (pg/mL) | 20.82 (41.51) | 19.79 (55.77) | ||
| T SS MAX (h) | 1.95 (207.17) | 1.94 (150.38) |
+ The reference product, Dostinex(r) (Cabergoline, manufactured by Pharmacia Canada Inc.) was purchased in Canada.
SS
Expressed as the arithmetic mean (CV%) only.
* Due to the long elimination half-life of cabergoline, a truncated sampling interval was used in the study and therefore, meaningful AUCI and t1/2 parameters could not be calculated.
Clinical Pharmacology
Dose-response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline 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 produced 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 cabergoline 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 cabergoline (6 hours vs 48 hours). In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH and TSH) or cortisol.
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 (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline 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 twofold to threefold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life.
In animals, based on total radioactivity, cabergoline (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. Cabergoline 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.
In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat.
Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far do not contribute to the therapeutic effect.
After oral dosing of radioactive cabergoline 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 cabergoline are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar.
Renal Insufficiency
: The pharmacokinetics of cabergoline 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 (Child-Pugh score < 10), no effect on mean cabergoline Cmax 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 cabergoline Cmax and AUC, and thus necessitate caution.
Elderly
: Effect of age on the pharmacokinetics of cabergoline has not been studied.
In 12 healthy adult volunteers, food did not alter cabergoline kinetics.
Acute Toxicity
Cabergoline has a very low acute toxicity in rats and mice, with median lethal doses which are several thousand times the clinical dose.
Long-Term Toxicity
Subchronic and chronic toxicity studies have been performed in mice/rats and monkeys. The maximum tolerated long-term dose for cabergoline appears to be between 250 and 1250 mg/kg/day in monkeys, and between 400 and 3200 mg/kg/day in rats. Most of the changes observed were in endocrine (rat) and central nervous (rat and monkeys) systems and are considered a consequence of the compound's stimulation of D2 receptors, resulting in an inhibition of prolactin secretion and central neurological effects. The endocrine toxicity effect observed in the rat uterus (metritis), which has also been described for other anti-prolactin agents, is most likely due to the decrease of prolactin which has a leutrotrophic effect in this species, but not in humans. This morphological uterine effect was not observed in monkeys treated daily for up to 52 weeks. In monkeys, the major findings were CNS effects which were not accompanied by histological changes in the brain.
Carcinogenicity
Carcinogenicity studies were conducted in mice and rats with cabergoline 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.
Mutagenicity
The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D4, and chromosomal aberrations in human lymphocytes. Cabergoline was also negative in the bone marrow micronucleus test in the mouse. No mutagenic effect was seen in the short-term tests in vivo. In female rats, a daily dose of 3.0 mcg/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. Because there are species differences in the role of prolactin, the effect may not be predictive of effects in humans.
Reproduction and Teratology
Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human). There were maternotoxic effects but no teratogenic effects in mice given cabergoline 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 cabergoline 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, cabergoline 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 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.
European multicenter study group for cabergoline in lactation inhibition. Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: Randomized, double- blind, multicenter study. Br Med J 302(6789):1367-71, 1991. (EM 0126)
Ferrari C, Barbieri C, Caldara R, Mucci M, Codecasa F, Paracchi A, Romano C, Boghen M, Dubini A. Long-lasting prolactin-lowering effect of cabergoline, a new dopamine agonist, in hyperprolactinemic patients. J Clin Endocrinol Metab 63(4):941-5, 1986. (EM 0021)
Ferrari C, Paracchi A, Romano C, Gerevini G, Boghen M, Barreca A, Fortini P, Dubini A. Long-lasting lowering of serum growth hormone and prolactin levels by single and repetitive cabergoline administration in dopamine-responsive acromegalic patients. Clin Endocrinol 29(5): 467-76, 1988 (EM 0071)
Mattei AM, Ferrari C, Baroldi P, Cavioni V, Paracchi A, Galparoli C, et al. Prolactin- lowering effect of acute and once weekly repetitive oral administration of cabergoline at two dose levels in hyperprolactinemic patients. J Clin Endocrinol Metab 66(1): 193-8, 1998. (EM 0048)
Motta T, Maggi G, D'Alberton A, Ferrari C, Paracchi A. Twice weekly cabergoline treatment of macroprolactinoma. J Obstet Gynaecol 9(4):334-41, 1989. (EM0074)
Page SR, Nussey SS. Cabergoline therapy of a large prolactinoma in a bromocriptine- intolerant patient. J Obstet Gynaecol 10(2):156-8, 1989. (EM 0084)
Persiani S, Rocchetti M, Pacciarini MA, Holt B, Toon S, Strolin Benedetti M. The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers. Biopharm Drug Dispos (Manuscript submitted for publication). (EM 5003)
Persiani S, Sassolas G, Piscitelli G, Bizollon A, Poggesi I, Pianezzola E, Edwards DMF, Strolin Benedetti M. Pharmacodynamics and relative bioavailability of cabergoline tablets vs solution in healthy volunteers. J Pharma Sci 83(10):1421-4; 1994. (EM 0187)
Pontiroli AE, Cammelli L, Baroldi P, Pozza G. Inhibition of basal and metoclopramide- induced prolactin release by cabergoline, an extremely long-acting dopaminergic drug. J Clin Endocrinol Metab 65:1057-9, 1987. (EM 0047)
Verhelst J, Abs R, Nobels F, van Acker K, Verbessem G, Lobelle J, Mahler C. Treatment of acromegaly with cabergoline in 21 patients. J Endocrinol 1995; 144 (supple):106. (EM 0197).
Product Monograph for Dostinex(r) Tablets. Pfizer Canada Inc., Kirkland, Quebec, Canada.
Control No. 114303, Date of Revision: August 21, 2007.
PART III: CONSUMER INFORMATION
CO
CABERGOLINE
(cabergoline)
This leaflet is part III of a three-part "Product Monograph" published when CO Cabergoline was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about CO Cabergoline. Contact your doctor or pharmacist if you have any questions about the drug.
REMEMBER: This medication is for YOU. Never give it to others. It may harm them even if their symptoms are the same as yours.
ABOUT THIS MEDICATION
What the medication is used for:
CO Cabergoline may be prescribed by your doctor to lower your body's level of a hormone known as prolactin. CO Cabergoline may be needed if your levels of prolactin are
abnormally high (hyperprolactinemia).
CO
Cabergoline can also be prescribed to prevent the production of milk in women after child birth, if it is not medically advisable to breast-feed.
When it should not be used: Do not take CO Cabergoline if:
You are allergic to cabergoline or any of the nonmedicinal ingredients (see "What the important nonmedicinal ingredients are").
You are allergic to ergot alkaloids
You have uncontrolled high blood pressure
You are pregnant
What the medicinal ingredient is: Cabergoline
What the important nonmedicinal ingredients are: Lactose, leucine.
What dosage forms it comes in:
CO
Cabergoline is available as 0.5 mg tablets.
WARNINGS AND PRECAUTIONS
BEFORE you use CO Cabergoline talk to your doctor or pharmacist if:
You are pregnant, or trying to become pregnant.
You are breast-feeding or intend to breast-feed. This medicine prevents the flow of breast milk.
You have or have had any other health problems
especially:
Kidney, heart, and liver problems
Raynaud's syndrome (associated with extreme
numbness, tingling and colour changes in the fingers due to cold)
Ulcer or bleeding in the stomach or intestines
High blood pressure after childbirth
History of severe mental illness
Past or current disorders of the lung or heart where tissues are hardened due to scarring
You are taking any other medicines, including medicines you buy without a prescription from a pharmacy,
supermarket, or health food shop.
INTERACTIONS WITH THIS MEDICATION
Some medicines and CO Cabergoline may interfere with each other. These include:
Medicines used to treat mental illness
Medicines used to treat high blood pressure
Medicines used to treat migraine
Macrolide antibiotics (i.e. erythromycin)
These medicines may be affected by cabergoline or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking CO Cabergoline.
PROPER USE OF THIS MEDICATION
Usual dose (Adults):
Follow your doctor's instructions carefully about how much CO
Cabergoline to take and when to take it.
To treat hyperprolactinaemia, the recommended initial dose is one tablet given in one or two (one-half of one 0.5 mg tablet) doses per week. The weekly dose should be increased gradually, preferably by adding one tablet per week at monthly intervals until an optimal therapeutic response is achieved.
To prevent the production of milk, the recommended dose is two tablets taken once, on the first day after delivery of the child.
CO Cabergoline should be swallowed, preferably with food. Continue taking CO Cabergoline until your doctor tells you to
stop.
While taking CO Cabergoline:
Follow your doctor's instructions carefully, and have regular check-ups while taking CO Cabergoline. Regular blood tests may be required.
CO Cabergoline may cause dizziness or affect your ability to respond quickly. Therefore, until you are reasonably certain that CO Cabergoline does not adversely affect your performance, you should refrain from driving or operating machinery.
Stop taking CO Cabergoline immediately if you become pregnant and consult your doctor.
Tell your doctor and pharmacist that you are taking cabergoline if you are about to start taking any new medicines.
Do not stop taking your medicine until your doctor tells you to, even if you are feeling better.
Do not use CO Cabergoline to treat any other medical complaints unless your doctor tells you to.
Overdose:
Do not take more tablets than your doctor has told you to. If you take too many tablets by accident, call your doctor or pharmacist immediately.
Missed Dose:
If you should forget to take your tablet at the usual time, take it as soon as your remember unless it is time to take the next one. Continue with the remaining doses as before. Do not take more
than one dose at a time.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Like many medicines, cabergoline may cause side effects. If they occur, they are likely to be minor and temporary. However, some may be serious and need medical attention.
Tell your doctor or pharmacist right away if you suffer from any of the following side effects while taking this medication:
Dizziness
Headache
Nausea or vomiting
Constipation
Abdominal pain, or heartburn, or pain in the stomach
Weakness or tiredness
Breast pain
Hot flashes
Depression
Shortness of breath
Check with your doctor or pharmacist right away if you have any problems while taking CO Cabergoline, even if you do not think the problems are connected with the medicine or are listed in this leaflet.
effects while taking CO Cabergoline, contact your doctor or pharmacist.
HOW TO STORE IT
Store at room temperature (15degC to 30degC).
You should not use your medication after the expiration date printed on the carton and label.
Keep all medications out of the reach of children. This medication could harm them.
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca
By regular mail: National AR Centre
Marketed Health Products Safety and Effectiveness Information Division
Marketed Health Products Directorate Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.
MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Cobalt Pharmaceuticals Inc., at: 1-866-254-6111
This leaflet was prepared by Cobalt Pharmaceuticals Inc. Last revised: October 30, 2007.
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | ||||
| Symptom / effect | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist | ||
| Only if severe | In all cases | |||
| Common | Flu-like symptoms | T | ||
| Uncommon | Heart palpitations | T | ||
This is not a complete list of side effects. For any unexpected