Anagrelide Hydrochloride (Capsule)

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Treatment with anagrelide hydrochloride capsules should be initiated under close medical supervision. The recommended starting dosage of anagrelide hydrochloride capsules is 0.5 mg q.i.d. or 1 mg b.i.d., which should be maintained for at least one week. Dosage should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count below 600,000/��L, and ideally to the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose . Dosing information for pediatric patients is approved for Shire Pharmaceutical Development Incorporated's anagrelide capsules. However, due to Shire's marketing exclusivity rights, this drug product is not labeled with that pediatric dosing information. There are no special requirements for dosing the geriatric population. It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a dose of 0.5 mg/day and be maintained for a minimum of one week with careful monitoring of cardiovascular effects. The dosage increment must not exceed more than 0.5 mg/day in any one-week. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate impairment of hepatic function should be assessed before treatment is commenced. Use of anagrelide in patients with severe hepaticimpairment has not been studied. Use of anagrelide in patients with severe hepatic impairment is contraindicated . To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to complete response, defined as platelet count���600,000/��L, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count. Following oral administration ofC-anagrelide in people, more than 70% of radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 mg and 2 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. The available plasma concentration time data at steady state in patients showed that anagrelide does not accumulate in plasma after repeated administration. Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide). Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cby 14%, but increased the AUC by 20%. Pharmacokinetic information for pediatric patients is approved for Shire Pharmaceutical Development Incorporated's anagrelide capsules. However, due to Shire's marketing exclusivity rights, this drug product is not labeled with that pediatric pharmacokinetic information. A Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance<30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide. A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.

Anagrelide Hydrochloride Capsules are available containing 0.5 mg or 1 mg of anagrelide base (as anagrelide hydrochloride). The 0.5 mg capsule is a hard-shell gelatin capsule with a light gray opaque cap and a coral opaque body axially printed with MYLAN over 6868 in black ink on both the cap and the body. The capsule is filled with white to off-white powder. They are available as follows: NDC 0378-6868-01bottles of 100 capsules NDC 0378-6868-05bottles of 500 capsules The 1 mg capsule is a hard-shell gelatin capsule with a light gray opaque cap and an aqua blue opaque body axially printed with MYLAN over 6869 in black ink on both the cap and the body. The capsule is filled with white to off-white powder. They are available as follows: NDC 0378-6869-01bottles of 100 capsules NDC 0378-6869-05bottles of 500 capsules Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.]Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

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Anagrelide Hydrochloride

Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease groups have the same adverse event profile. While most reported adverse events during anagrelide therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events were reported in these patients. These include the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure. Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%) were discontinued from the study because of adverse events or abnormal laboratory test results. The most common adverse events for treatment discontinuation were headache, diarrhea, edema, palpitation, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide. The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were: Adverse events with an incidence of 1% to<5% included: Body as a Whole System: Flu symptoms, chills, photosensitivity. Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope. Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis, eructation. Hemic and Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy. Platelet counts below 100,000/��L occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/��L occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide. Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide therapy. Musculoskeletal System: Arthralgia, myalgia, leg cramps. Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia. Nutritional Disorders: Dehydration. Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma. Skin and Appendages System: Skin disease, alopecia. Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia. Urogenital System: Dysuria, hematuria. Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were found to have pre-existing renal impairment. Doses ranged from 1.5 to 6 mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency. The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph: All Patients with Myeloproliferative Disease (N=942)

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Anagrelide Hydrochloride