Agrylin

Agrylin

anagrelide

Manufacturer:

Takeda

Distributor:

Zuellig
/
Firma Chun Cheong
Full Prescribing Info
Contents
Anagrelide HCl.
Description
Agrylin capsule contains the following inactive ingredients: Povidone USP, anhydrous lactose NF, lactose monohydrate NF, microcrystalline cellulose NF, crospovidone NF and magnesium stearate NF.
Agrylin is 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate. It has a molecular formula of C10H7Cl2N3O·HCl·H2O and its molecular weight is 310.55.
Anagrelide HCl is an off-white powder which is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and dimethylformamide.
Action
Platelet-reducing agent.
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 In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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 people 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 14C-anagrelide in people, >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 and 2 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hrs. 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; <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 hrs), when compared to the 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 hrs.
Clinical Studies: A total of 942 patients with myeloproliferative disorders including 551 patients with essential thrombocythemia (ET), 117 patients with polycythemia vera (PV), 178 patients with chronic myelogenous leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD), were treated with anagrelide in 3 clinical trials. Patients with OMPD included 87 patients who had myeloid metaplasia with myelofibrosis (MMM) and 9 patients who had unknown myeloproliferative disorders.
Patients with ET, PV, CML or MMM were diagnosed based on the following criteria: ET: Platelet count ≥900,000/microliter on 2 determinations; profound megakaryocytic hyperplasia in bone marrow; absence of Philadelphia chromosome; normal red cell mass; normal serum iron and ferritin and normal marrow iron stores.
PV*: A1 increased red cell mass; A2 normal arterial oxygen saturation; A3 splenomegaly; B1 platelet count ≥400,000/microliter, in absence of iron deficiency or bleeding; B2 leucocytosis (≥12,000/microliter in the absence of infection); B3 elevated leucocyte alkaline phosphatase; B4 elevated serum B12.
*Diagnosis is positive if A1, A2 and A3 are present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any 2 of B1, B2 or B3.
CML: Persistent granulocyte count ≥50,000/microliter without evidence of infection; absolute basophil count ≥100/microliter; evidence for hyperplasia of the granulocytic line in the bone marrow; Philadelphia chromosome present; leucocyte alkaline phosphatase less than or equal to the lower limit of laboratory normal range.
MMM: Myelofibrotic (hypocellular, fibrotic) bone marrow; prominent megakaryocytic metaplasia in the bone marrow; splenomegaly; moderate to severe normochromic, normocytic anemia; white cell count may be variable (80,000-100,000/microliter); increased platelet count; variable red cell mass, teardrop poikilocytes; normal to high leucocyte alkaline phosphatase; absence of Philadelphia chromosome.
Patients were enrolled in clinical trials if their platelet count was ≥900,000/microliter on 2 occasions or ≥650,000/microliter on 2 occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML and OMPD patients was 65, 67, 40 and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with anagrelide starting at doses of 0.5-2 mg every 6 hrs. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/microliter). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤600,000/microliter or by at least 50% from baseline value. Subjects treated for <4 weeks were not considered evaluable. The results are depicted as follows: (See figure.)

Click on icon to see table/diagram/image

See table.

Click on icon to see table/diagram/image

Agrylin was effective in phlebotomized patients as well as in patients with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus and alkylating agents.
Indications/Uses
Treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombohemorrhagic events (see Pharmacology: Clinical Studies under Actions and Dosage & Administration).
Dosage/Direction for Use
Treatment with Agrylin should be initiated under close medical supervision. The recommended starting dosage of Agrylin is 0.5 mg 4 times a day or 1 mg 2 times a day, 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 <600,000/microliter 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). The decision to treat asymptomatic young adults with thrombocythemia secondary to myoproliferative disorders should be individualized.
To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every 2 days during the 1st week of treatment and at least weekly thereafter until the maintenance dosage is reached.
Typically, platelet count begins to respond within to 7-14 days at the proper dosage. The time to complete response, defined as platelet count ≤600,000/microliter, ranged from 4-12 weeks. Most patients will experience an adequate response at a dose of 1.5-3 mg/day. Patients with known or suspected heart disease, renal insufficiency or hepatic dysfunction should be monitored closely.
Overdosage
Symptoms: Acute Toxicity: Single oral doses of anagrelide HCl at 2500, 1500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: Decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
There are no reports of overdosage with anagrelide HCl. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Should overdosage occur, cardiac and central nervous system toxicity can also be expected.
Management: In case of overdosage, close clinical supervision of 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 within the normal range.
Warnings
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 Reactions: Urogenital System).
Hepatic: It is recommended that patients with evidence of hepatic dysfunction (bilirubin, SGOT or measures of liver function >1.5 times the upper limit of normal) receive anagrelide when, in the physician's judgment, the potential benefits outweigh the potential risks. These patients should be monitored closely for signs of hepatic toxicity while receiving anagrelide (see Adverse Reactions: Hepatic System).
Special Precautions
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While the platelet count is being lowered (usually during the first 2 weeks of treatment), blood counts (hemoglobin, white blood cells), liver function (SGOT, SGPT) and renal function (serum creatinine, BUN) should be monitored.
In 9 subjects receiving a single 5-mg dose of anagrelide, standing blood pressure fell an average of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2 mg.
Cessation of Agrylin Treatment: In general, interruption of anagrelide treatment is followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count can be observed within 4 days.
Carcinogenicity, Mutagenicity & Impairment of Fertility: No long-term studies in animals have been performed to evaluate carcinogenic potential of anagrelide HCl. Anagrelide HCl was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK±) forward mutation test, the human lymphocyte chromosome aberration test or the mouse micronucleus test. Anagrelide HCl at oral doses up to 240 mg/kg/day (1440 mg/m2/day, 195 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher, it disrupted implantation when administered in early pregnancy and retarded or blocked parturition when administered in late pregnancy.
Use in pregnancy: Teratogenic Effects: Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5400 mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to anagrelide HCl.
Nonteratogenic Effects: A fertility and reproductive performance study performed in female rats revealed that anagrelide HCl at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide HCl at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering pregnant dams and their fully developed fetuses and increased mortality in the pups born. Five women became pregnant while on anagrelide treatment at doses of 1-4 mg/day. Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There are no adequate and well-controlled studies in pregnant women. Anagrelide HCl should be used during pregnancy only it 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.
Use in lactation: It is not known whether Agrylin 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 HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: The safety and efficacy of anagrelide in patients <16 years have not been established. Myeloproliferative disorders are uncommon in pediatric patients. Anagrelide has been used successfully in 12 pediatric patients (age range 6.8-17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with CML, 1 patient with PV and 1 patient with OMPD. Patients were started on therapy with 0.5 mg 4 times daily to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months with a range of 3.1-92 months. Three patients received treatment for >3 years.
Use In Pregnancy & Lactation
Use in pregnancy: Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5400 mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to anagrelide HCl.
Nonteratogenic Effects: A fertility and reproductive performance study performed in female rats revealed that anagrelide HCl at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide HCl at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering pregnant dams and their fully developed fetuses and increased mortality in the pups born. Five women became pregnant while on anagrelide treatment at doses of 1-4 mg/day. Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There are no adequate and well-controlled studies in pregnant women. Anagrelide HCl should be used during pregnancy only it 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.
Use in lactation: It is not known whether Agrylin 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 HCl, 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.
Adverse Reactions
Analysis of the adverse events in a population consisting of 942 patients 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, 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 17.9/1000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.
The most frequently reported adverse reactions to anagrelide (in ≥5% of 942 patients with myeloproliferative disease) in clinical trials were: Headache 43.5%, palpitations 26.1%, diarrhea 25.7%, asthenia 23.1%, edema 20.6%, nausea 17.1%, abdominal pain 16.4%, dizziness 15.4%, pain 15%, dyspnea 11.9%, flatulence 10.2%, vomiting 9.7%, fever 8.9%, peripheral edema 8.5%, rash including urticarcia 8.3%, chest pain 7.8%, anorexia 7.7%, tachycardia 7.5%, pharyngitis 6.8%, malaise 6.4%, cough 6.3%, paresthesia 5.9%, back pain 5.9%, pruritis 5.5% and dyspepsia 5.2%.
Adverse events with an incidence of 1% to <5% included:
Body as a Whole: Flu symptoms, chills, photosensitivity.
Cardiovascular System: Arrhythmia, hemorrhage, 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 & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy. Platelet count <100,000/microliter occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction <50,000/microliter 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, hypertension, nervousness, amnesia.
Nutritional Disorders: Dehydration.
Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.
Skin and Appendages: 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 preexisting renal impairment. Doses ranged from 1.5-6 mg/day, with exposure periods of 2-12 months. No dose adjustment was required because of renal insufficiency.
The adverse event profile for patients in clinical trials on anagrelide therapy (in ≥5% of 942 patients with myeloproliferative diseases) is shown in the following bar graph: (See diagram.)

Click on icon to see table/diagram/image
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 aspirin, 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.
Storage
Store from 15-25°C (59-77°F), in a light-resistant container.
ATC Classification
L01XX35 - anagrelide ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Cap 0.5 mg (opaque, white, imprinted "ROBERTS 063" in black ink) x 100's.
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