Wick Hustenlöser-Therapie may be available in the countries listed below.
Ambroxol hydrochloride (a derivative of Ambroxol) is reported as an ingredient of Wick Hustenlöser-Therapie in the following countries:
International Drug Name Search
Parlodel®
SnapTabs®
(bromocriptine mesylate) tablets, USP
(bromocriptine mesylate) capsules, USP
Rx only
Prescribing Information
Parlodel® (bromocriptine mesylate) is an ergot derivative with potent dopamine receptor agonist activity. Each Parlodel® (bromocriptine mesylate) SnapTabs® tablet for oral administration contains 2½ mg and each capsule contains 5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is chemically designated as Ergotaman-3′,6′,18-trione, 2-bromo-12′-hydroxy-2′- (1-methylethyl)-5′-(2-methylpropyl)-, (5′α)-monomethanesulfonate (salt).
The structural formula is:
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and another ingredient
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium stearate, red iron oxide, silicon dioxide, sodium lauryl sulfate, starch, titanium dioxide, yellow iron oxide, and another ingredient
Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, Parlodel significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.
Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.
Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.
Absorption
Following single dose administration of Parlodel tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively.1 Linear relationship was found between single doses of Parlodel and Cmax and AUC in the dose range of 1 to 7.5 mg.2 The pharmacokinetics of bromocriptine metabolites have not been reported.
Food did not significantly affect the systemic exposure of bromocriptine following administration of Parlodel tablets, 2.5 mg.3 It is recommended that Parlodel be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions.
Following Parlodel 5 mg administered twice daily for 14 days, the bromocriptine Cmax and AUC at steady state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.4
Distribution
In vitro experiments showed that bromocriptine was 90%-96% bound to serum albumin.
Metabolism
Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces.
In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway. 5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions section). The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM.6 Given the low therapeutic concentrations of bromocriptine in patients (Cmax=0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported.
Excretion
About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine.5
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1 Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin Pharmacol Ther; 47(6):694-7.
2 Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne, D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York, Rave Press.
3 Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81
4 Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465
5 Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56.
6 Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14.
Effect of Renal Impairment
The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated.
Since parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites (see PRECAUTIONS, general).
Effect of Hepatic Impairment
The effect of liver impairment on the PK of Parlodel and its metabolites has not been evaluated. Since Parlodel is mainly eliminated by metabolism, liver impairment may increase the plasma levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, general).
The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated.
Clinical Studies
In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.
Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8 months.
Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some patients may fail to respond even after 12 months of therapy.
In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating levels of serum growth hormone.
Parlodel® (bromocriptine mesylate) is indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Parlodel treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of Parlodel therapy may be used to reduce the tumor mass prior to surgery.
Parlodel therapy is indicated in the treatment of acromegaly. Parlodel therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels.
Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with Parlodel offers potential benefit before the effects of irradiation are manifested.
Parlodel SnapTabs® or capsules are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), Parlodel therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose failure’’ on levodopa therapy. Parlodel therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function (“on-off’’ phenomenon). Continued efficacy of Parlodel therapy during treatment of more than 2 years has not been established.
Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease with Parlodel. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in Parlodel-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for Parlodel therapy.
Hypersensitivity to bromocriptine or to any of the excipients of Parlodel® (bromocriptine mesylate), uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing Parlodel must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When Parlodel is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to be medically contraindicated.
The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period, the patient should be observed with caution.
Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with Parlodel® (bromocriptine mesylate).
If pregnancy occurs during Parlodel administration, careful observation of these patients is mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of Parlodel treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of Parlodel treatment during pregnancy to the mother and fetus has not been established.
Parlodel has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Symptomatic hypotension can occur in patients treated with Parlodel for any indication. In postpartum studies with Parlodel, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving Parlodel. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg.
Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery.
While hypotension during the start of therapy with Parlodel occurs in some patients, in rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been reported in postpartum women treated with Parlodel for the inhibition of lactation. Hypertension have been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have also been reported both with and without the prior development of hypertension; stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing seizures (including cases of status epilepticus) and/or strokes reported developing a constant and often progressively severe headache hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness). Cases of acute myocardial infarction have also been reported.
Although a causal relationship between Parlodel administration and hypertension, seizures, strokes, and myocardial infarction in postpartum women has not been established, use of the drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended. In patients being treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing Parlodel must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When Parlodel is being used to treat acromegaly or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to be medically contraindicated. Because of the possibility of an interaction between Parlodel and other ergot alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated promptly. Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the puerperium is not recommended.
Among patients on Parlodel, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of Parlodel therapy should be considered. In those instances in which Parlodel treatment was terminated, the changes slowly reverted towards normal.
In a few patients on Parlodel, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs, impaired kidney function) should be watched in this category of patients. Parlodel medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.
Safety and efficacy of Parlodel® (bromocriptine mesylate) have not been established in patients with renal or hepatic disease. Care should be exercised when administering Parlodel therapy concomitantly with other medications known to lower blood pressure.
The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with Parlodel during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease.
Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with Parlodel leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage.
The relative efficacy of Parlodel versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy.
Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with Parlodel. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with Parlodel SnapTabs® or capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of Parlodel treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.
Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with Parlodel.
Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with Parlodel. The response, should it occur, can be reversed by reducing the dose of Parlodel and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that Parlodel increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with Parlodel.
Possible tumor expansion while receiving Parlodel therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered.
Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established.
As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs.
High doses of Parlodel may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients.
Parlodel administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of Parlodel is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of Parlodel.
Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including Parlodel. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Parlodel. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Parlodel.
As with levodopa, caution should be exercised when administering Parlodel to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.
Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2-10 years) with Parlodel in doses ranging from 30-140 mg daily.
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2-approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Parlodel for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).
Discontinuation of Parlodel should be undertaken gradually whenever possible, even if the patient is to remain on l-dopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of Parlodel therapy. In postmarketing reports, Parlodel has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving Parlodel should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with Parlodel and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines).
Patients receiving Parlodel for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery, should be told to report any persistent watery nasal discharge to their physician. Patients receiving Parlodel for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms.
Patients and their caregivers should be alerted to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking Mirapex. [See Precautions].
Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery .
The risk of using Parlodel in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of Parlodel. Parlodel may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of Parlodel: phenothiazines, haloperidol, metoclopramide, pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and Cmax values increased 3.7-fold and 4.6-fold, respectively).1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%).4 Concomitant use of Parlodel with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication).
A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.
Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice.
No mutagenic effects were obtained in any of these tests.
Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg).
Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6-15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period.
Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced.
No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg.
Information concerning 1276 pregnancies in women taking Parlodel has been collected. In the majority of cases, Parlodel was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg).
Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin.
Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%.
The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.
There is no suggestion that Parlodel contributed to the type or incidence of birth defects in this group of infants.
Parlodel should not be used during lactation in postpartum women.
The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.
The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation.
Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section.
Clinical studies for Parlodel did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking Parlodel has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population.
Hyperprolactinemic Indications
The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%).
A slight hypotensive effect may accompany Parlodel® (bromocriptine mesylate) treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ SnapTabs® tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving Parlodel for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving Parlodel for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus.
Acromegaly
The most frequent adverse reactions encountered in acromegalic patients treated with Parlodel were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%).
Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported.
Parkinson’s Disease
In clinical trials in which Parlodel was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo.
Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome.
Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.
The following adverse reactions have been reported during postapproval use of Parlodel (All Indications Combined). Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Psychiatric disorders : Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality.
Nervous system disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep.
Eye disorders : Visual disturbance, vision blurred.
Ear and labyrinth disorders : Tinnitus.
Cardiac disorders : Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis.
Vascular disorders : Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon)
Respiratory, thoracic and mediastinal disorders : Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.
Gastrointestinal disorders : Nausea, constipation, vomiting, dry mouth, diarrhoea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal haemorrhage.
Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss.
Musculoskeletal and connective tissue disorders: Leg cramps.
General disorders and administration site conditions: Fatigue, peripheral oedema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of Parlodel (See Precautions).
In postpartum studies with Parlodel, 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of patients. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%). Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were usually of a transient nature. Reports of fainting in the puerperium may possibly be related to this effect. In postmarketing experience in the U.S., serious adverse reactions reported include 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum patients. Seizure cases were not necessarily accompanied by the development of hypertension. An unremitting and often progressively severe headache, sometimes accompanied by visual disturbance, often preceded by hours to days many cases of seizure and/or stroke. Most patients had shown no evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or pregnancy-induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to Parlodel administration has not been established.
In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with Parlodel. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving Parlodel. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of Parlodel should be discontinued and the patient should be evaluated promptly.
Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g. vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended.
The most commonly reported signs and symptoms associated with acute Parlodel® (bromocriptine mesylate) overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established and the drug has a very wide margin of safety. However, one death occurred in a patient who committed suicide with an unknown quantity of Parlodel and chloroquine.
Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.
There have been isolated reports of children who accidentally ingested Parlodel. Vomiting, somnolence and fever were reported as adverse events. Patients recovered either spontaneously within a few hours or after appropriate management.
It is recommended that Parlodel® (bromocriptine mesylate) be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.
The initial dosage of Parlodel SnapTabs® in adults is ½ to one 2½ mg scored tablet daily. An additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2-7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically.
Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is ½ to one 2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas.
In order to reduce the likelihood of prolonged exposure to Parlodel should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with Parlodel therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy.
Thereafter, if menstruation does not occur within 3 days of the expected date, Parlodel therapy should be discontinued and a pregnancy test performed.
Virtually all acromegalic patients receiving therapeutic benefit from Parlodel also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of Parlodel. If, after a brief trial with Parlodel therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered.
The initial recommended dosage is ½ to one 2½ mg Parlodel SnapTabs tablet on retiring (with food) for 3 days. An additional ½ to 1 SnapTabs tablet should be added to the treatment regimen as tolerated every 3-7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of Parlodel varies from 20-30 mg/day in most patients. The
Micosin may be available in the countries listed below.
Ketoconazole is reported as an ingredient of Micosin in the following countries:
International Drug Name Search
Rx only
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES
Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg provides an oral contraceptive regimen consisting of 24 active film-coated tablets each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol and 4 inert film-coated tablets. Other ingredients are anhydrous lactose, corn starch, crospovidone, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch and titanium dioxide. The inert tablets contain anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose.
Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11, 12,13,14,15,15a,16 - hexadecahydro - 10,13 - dimethylspiro - [17H - dicyclopropa - [6,7:15,16]cyclopenta[a]phenanthrene - 17,2’(5H) - furan] - 3,5’(2H) - dione) is a synthetic progestational compound. Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound. The structural formulas are as follows:
Drospirenone
C24H30O3 Molecular Weight: 366.5
Ethinyl Estradiol
C20H24O2 Molecular Weight: 296.4
Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).
Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.
Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of ethinyl estradiol and drospirenone increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of drospirenone on acne is not known.
The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of drospirenone and ethinyl estradiol tablets, which is a combination tablet of drospirenone and ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1 to 2 hours after administration of drospirenone and ethinyl estradiol tablets.
The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol tablets, steady-state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol tablets (see Table I).
For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol tablets serum Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table I).
| |||||
| Drospirenone | |||||
Cycle / Day | No. of Subjects | Cmax * (ng/mL) | Tmax† (h) | AUC (0-24h)* (ng•h/mL) | t1/2* (h) |
| 1/1 | 23 | 38.4 (25) | 1.5 (1 to 2) | 268 (19) | NA |
| 1/21 | 23 | 70.3 (15) | 1.5 (1 to 2) | 763 (17) | 30.8 (22) |
| Ethinyl Estradiol | |||||
Cycle / Day | No. of Subjects | Cmax* (pg/mL) | Tmax† (h) | AUC (0-24h)* (pg•h/mL) | t1/2* (h) |
| 1/1 | 23 | 32.8 (45) | 1.5 (1 to 2) | 108 (52) | NA |
| 1/21 | 23 | 45.1 (35) | 1.5 (1 to 2) | 220 (57) | NA |
| NA = Not available | |||||
The rate of absorption of DRSP and EE following single administration of a formulation similar to drospirenone and ethinyl estradiol tablets was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.
DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg.
DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.
The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4).
EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.
DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20% of the metabolites were excreted as glucuronides and sulfates.
For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 20 to 35) when drospirenone and ethinyl estradiol tablets were administered daily for 21 days. Other ethnic groups have not been studied.
Drospirenone and ethinyl estradiol tablets are contraindicated in patients with hepatic dysfunction (see CONTRAINDICATIONS and BOLDED WARNING). The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Drospirenone and ethinyl estradiol tablets have not been studied in women with severe hepatic impairment.
Drospirenone and ethinyl estradiol tablets are contraindicated in patients with renal insufficiency (see CONTRAINDICATIONS and BOLDED WARNING).
The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 to 65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50 to 80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30 to 50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.
Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.
Oral contraceptives are highly effective. Table II lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization and contraceptive implants and IUDs, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
Gianvi™ (drospirenone and ethinyl estradiol tablets) is indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Gianvi™ (drospirenone and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
| |||
| % of Women Experiencing an Unintended Pregnancy Within the First Year of Use | % of Women Continuing Use at One Year* | |
| Method (1) | Typical Use† (2) | Perfect Use‡ (3) | (4) |
| Chance§ | 85 | 85 | 40 |
| Spermicides¶ | 26 | 6 | 63 |
| Periodic abstinence | 25 | ||
| Calendar | 9 | ||
| Ovulation method | 3 | ||
| Sympto-thermal# | 2 | ||
| Post-ovulation | 1 | ||
| Withdrawal | 19 | 4 | |
| CapÞ | |||
| Parous women | 40 | 26 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| Sponge | |||
| Parous women | 40 | 20 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| DiaphragmÞ | 20 | 6 | 56 |
| Condomß | |||
| Female (Reality) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| progestin only | 0.5 | ||
| combined | 0.1 | ||
| IUD | |||
| Progesterone T | 2 | 1.5 | 81 |
| Copper T 380A | 0.8 | 0.6 | 78 |
| Lng 20 | 0.1 | 0.1 | 81 |
| Depo Provera | 0.3 | 0.3 | 70 |
| Norplant and Norplant-2 | 0.05 | 0.05 | 88 |
| Female sterilization | 0.5 | 0.5 | 100 |
| Male sterilization | 0.15 | 0.1 | 100 |
| Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.à | |||
| Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.è | |||
| Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. | |||
In the primary contraceptive efficacy study of drospirenone and ethinyl estradiol tablets (3 mg DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 28-day cycles of use. The age range was 17 to 36 years. The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other. Women with a BMI greater than 35 were excluded from the trial. The pregnancy rate (Pearl Index) was 1.41 per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of drospirenone and ethinyl estradiol tablets in women 35 years of age or younger during cycles in which no other form of contraception was used.
In two multicenter, double blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received drospirenone and ethinyl estradiol tablets or placebo for six 28 day cycles. The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a “clear” or “almost clear” rating on the Investigator’s Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented in Table III:
| * Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population | ||||
| Study 1 | Study 2 | |||
| Drospirenone and Ethinyl Estradiol Tablets N=228 | Placebo N=230 | Drospirenone and Ethinyl Estradiol Tablets N=218 | Placebo N=213 | |
| ISGA Success Rate | 35 (15%) | 10 (4%) | 46 (21%) | 19 (9%) |
Inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction | 33 15 (48%) | 33 11 (32%) | 32 16 (51%) | 32 11 (34%) |
Non-inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction | 47 18 (39%) | 47 10 (18%) | 44 17 (42%) | 44 11 (26%) |
Total lesions Mean Baseline Count Mean Absolute (%) reduction | 80 33 (42%) | 80 21 (25%) | 76 33 (46%) | 76 22 (31%) |
Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in women who have the following:
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Gianvi™ (drospirenone and ethinyl estradiol tablets) contains 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in patients with conditions that predispose to hyperkalemia (i.e., renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Medications that may increase serum potassium include ACE inhibitors, angiotensin – II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke), hepatic neoplasia, gallbladder disease, and hypertension. The risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiologic methods.
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table IV) among women who use oral contraceptives.
| (Adapted from P.M. Layde and V. Beral) | ||||
| AGE | EVER-USERS NON-SMOKERS | EVER-USERS SMOKERS | CONTROLS NON-SMOKERS | CONTROL SMOKERS |
| 15 to 24 | 0 | 10.5 | 0 | 0 |
| 25 to 34 | 4.4 | 14.2 | 2.7 | 4.2 |
| 35 to 44 | 21.5 | 63.4 | 6.4 | 15.2 |
| 45+ | 52.4 | 206.7 | 11.4 | 27.9 |
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in the relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued from at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, combined oral contraceptives should be started no earlier than four to six weeks after delivery and at that time only in women who elect not to breast feed.
Several studies have investigated the relative risks of thromboembolism in women using a different drospirenone-containing COC (Yasmin, which contains 0.030 mg of ethinyl estradiol and 3 mg of drospirenone) compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of Yasmin approval.1, 2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in Yasmin users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC). The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in Yasmin users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed Yasmin.
Two additional epidemiological studies, one case-control study (van Hylckama Vlieg et al.3) and one retrospective cohort study (Lidegaard et al.4) suggested that the risk of venous thromboembolism occurring in Yasmin users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so-called third generation COCs). In the case-control study, however, the number of Yasmin cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for Yasmin users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the product for 1 to 4 years, the relative risk was similar for users of Yasmin to that for users of other COC products.
Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor, for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content that is judged appropriate for the individual patient.
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women aged 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table V). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is below that associated with childbirth.
