Action And Clinical Pharmacology: 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 In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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. Platelet aggregation is inhibited in humans at doses higher than those required to reduce platelet count. Anagrelide inhibits cyclic AMP phosphodiesterase, as well as ADP- and collagen-induced platelet aggregation.
Following oral administration of 4-anagrelide in humans, more than 70% of the radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 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. The drug is extensively metabolized; less than 1% is recovered in the urine as anagrelide.
When a 0.5 mg dose of anagrelide was taken after food, its bioavailability (based on AUC values) was modestly reduced by an average of 13.8% and its plasma half-life slightly increased (to 1.8 hours), when compared with drug administered to the same subjects in the fasted state. The peak plasma level was lowered by an average of 45% and delayed by 2 hours.
Indications And Clinical Uses: For the treatment of patients with essential thrombocythemia (ET) to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms.
Anagrelide is intended for chronic usage and has not been evaluated for treatment of the acute life-threatening complications of thrombocytosis.
Manufacturers’ Warnings In Clinical States: Cardiovascular: Anagrelide should be used with caution in patients with known or suspected heart disease, and only if the potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects and side effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Renal: It is recommended that patients with renal insufficiency (creatinine 2 mg/dL) receive anagrelide when, in the physician’s judgment, the potential benefits of therapy outweigh the potential risks. These patients should be monitored closely for signs of renal toxicity while receiving anagrelide (see Adverse Effects, Urogenital).
Hepatic: It is recommended that patients with evidence of hepatic dysfunction (bilirubin, AST, or measures of liver function >1.5 times the upper limit of normal) receive anagrelide when, in the physician’s judgment, the potential benefits of therapy outweigh the potential risks. These patients should be monitored closely for signs of hepatic toxicity while receiving anagrelide (see Adverse Effects, Hepatic).
Children: The safety and efficacy of anagrelide in patients under the age of 16 years have not been established.
Pregnancy: There are no adequate and well-controlled studies in pregnant women. Anagrelide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be instructed that they must not be pregnant and that they should use contraception while taking anagrelide. Anagrelide may cause fetal harm when administered to a pregnant woman.
Lactation: 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 reaction in nursing infants from anagrelide, 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.
Precautions: The decision to treat asymptomatic young adults with essential thrombocythemia should be individualized.
Sudden discontinuation or interruption of anagrelide treatment is followed by an increase in platelet count. Following discontinuation, an increase in platelet count can be observed within 4 days.
Drug Interactions: Bioavailability studies evaluating possible interactions between anagrelide and other drugs have not been conducted. The most common medications used concomitantly with anagrelide have been ASA, acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. The most frequently used concomitant cardiac medication has been digoxin. Although drug-to-drug interaction studies have not been conducted, there is no clinical evidence to suggest that anagrelide interacts with any of these compounds.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Monitoring: Anagrelide therapy requires close clinical supervision of the patient. To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every 2 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. Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day. In case of overdose, close clinical supervision of the patient is required, including monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped as appropriate, until platelet count returns to within the normal range. However, in patients with hepatic insufficiency or renal insufficiency, liver function and kidney function tests should be performed at least once/month or when deemed necessary in the physician’s judgment.
Adverse Reactions: While most reported adverse events during anagrelide therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events reported in patients with ET and/or in patients with thrombocythemias of other etiologies include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure. Of the 551 ET patients treated with anagrelide for a mean duration of 65 weeks, 82 (15%) 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 551 patients with essential thrombocythemia in clinical trials were: headache 44.5%; palpitations 27.2%; diarrhea 24.3%; asthenia 22.1%; edema, other 19.8%; abdominal pain 17.4%; nausea 15.1%; pain, other 14.7%; dizziness 14.5%; dyspnea 10.5%; flatulence 10.5%; chest pain 7.8%; rash, including urticaria 7.8%; vomiting 7.4%; paresthesia 7.3%; tachycardia 7.3%; peripheral edema 7.1%; dyspepsia 6.4%; back pain 6.4%; anorexia 5.8% and malaise 5.8%.
Body as a Whole: fever, flu symptoms, chills, neck pain, photosensitivity.
Cardiovascular: arrhythmia, hemorrhage, cardiovascular disease, angina pectoris, heart failure, postural hypotension, vasodilation, migraine, syncope.
Digestive: constipation, gastrointestinal distress, gastrointestinal hemorrhage, gastritis, melena, aphthous stomatitis, eructation, nausea and vomiting.
Hemic and Lymphatic: anemia, thrombocytopenia, ecchymosis, lymphadenoma.
Platelet counts below 100 000/L occurred in 35 patients and reduction below 50 000/L occurred in 7 of the 551 ET patients while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide.
Hepatic: Elevated liver enzymes were observed in 2 of 551 patients during anagrelide therapy.
Musculoskeletal: arthralgia, myalgia, leg cramps.
Nervous System: depression, somnolence, confusion, insomnia, hypertension, nervousness, amnesia.
Nutritional Disorders: dehydration.
Respiratory: rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.
Skin and Appendages: pruritus, skin disease, alopecia.
Special Senses: amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.
Urogenital: dysuria, hematuria.
Of the 551 ET patients, 10 were found to have renal abnormalities. Six of the 10 experienced renal failure (approximately 1%) while on anagrelide treatment; in 2, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 4 were found to have pre-existing renal impairment and were successfully treated with anagrelide. Doses ranged from 1.5 to 6 mg/day, with exposure periods of 2 to 12 months. Serum creatinines remained within normal limits, and no dose adjustment was required because of renal insufficiency.
The adverse event profile for patients in clinical trials on anagrelide therapy is shown in Table I which compares the percentage of each adverse event reported in patients with essential thrombocythemia (ET) to those found in patients with thrombocytosis of other etiologies.
Symptoms And Treatment Of Overdose: Symptoms: There are no reports of overdosage with anagrelide. Platelet reduction from anagrelide therapy is dose related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Should overdosage occur, cardiac and CNS toxicity can also be expected.
Treatment: In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as appropriate, until the platelet count returns to within the normal range.
Dosage And Administration: Treatment should be initiated under close medical supervision. The decision to treat asymptomatic young adults with essential thrombocythemia should be individualized. The recommended starting dose is 0.5 mg q.i.d. or 1 mg b.i.d., which should be maintained for at least 1 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 1 week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose (see Precautions).
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every 2 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. 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.
Availability And Storage: Each white, opaque capsule, imprinted with “ROBERTS 063” in black ink, contains: anagrelide base 0.5 mg (as anagrelide HCl). Nonmedicinal ingredients: black iron oxide, crospovidone, gelatin, lactose, magnesium stearate, microcrystalline cellulose, povidone, silicon dioxide, sodium lauryl sulfate and titanium oxide. Bottles of 100. Store from 15 to 25\°C in a light-resistant container.
AGRYLIN Roberts Anagrelide HCl Platelet-reducing Agent