Anagrelide (Agrylin)
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Anagrelide (Agrylin)

AGRYLIN®
(anagrelide hydrochloride) Capsules

DRUG DESCRIPTION

Name: AGRYLIN® (anagrelide hydrochloride)
Dosage Form:
0.5 mg capsules for oral administration
Active Ingredient: AGRYLIN®
Capsules contain 0.5 mg of anagrelide base (as anagrelide hydrochloride).
Inactive Ingredients:
Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF, Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.
Pharmacological Classification:
Platelet-reducing agent.
Chemical Name:
6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate.
Molecular formula:
C10H7Cl2N3O•HCl•H2O
Molecular weight:
310.55 Structural formula:

AGRYLIN® (anagrelide hydrochloride) Structural Formula Illustration

Appearance: Off-white powder
Solubility:

Water……………………….. Very slightly soluble
Dimethyl Sulfoxide………… Sparingly soluble
Dimethylformamide………... Sparingly soluble

What are the possible side effects of anagrelide (Agrylin)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • wheezing, rapid breathing, feeling short of breath, dry cough, fever;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • swelling, rapid weight gain;
  • fast, pounding, or uneven heartbeats;
  • sudden numbness or weakness, especially on one side of the...

Read All Potential Side Effects and See Pictures of Agrylin »

What are the precautions when taking anagrelide (Agrylin)?

Before taking anagrelide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., heart attack, heart failure, irregular heartbeat), lung problems, kidney problems, liver problems.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure...

Read All Potential Precautions of Agrylin »

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

AGRYLIN® Capsules are indicated for the 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 thrombo-hemorrhagic events (see Clinical Studies, DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION

Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid (2 capsules of 0.5 mg twice a day), which should be maintained for at least one week. Starting doses in pediatric patients have ranged from 0.5 mg per day to 0.5 mg qid. As there are limited data on the appropriate starting dose for pediatric patients, an initial dose of 0.5 mg per day is recommended. In both adult and pediatric patients, dosage should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count below 600,000/μL, and ideally to the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week. Maintenance dosing is not expected to be different between adult and pediatric patients. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose (see PRECAUTIONS).

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 or moderate impairment of hepatic function should be assessed before treatment is commenced. Use of anagrelide in patients with severe hepatic impairment has not been studied. Use of anagrelide in patients with severe hepatic impairment is contraindicated (see CONTRAINDICATIONS).

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/μL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

HOW SUPPLIED

AGRYLIN® is available as:

0.5 mg, opaque, white capsules imprinted “ S 063” in black ink: NDC 54092-063-01 = bottle of 100

Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room Temperature]. Store in a light resistant container.

Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087. Rev. 11/11.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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, palpitations, 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:

Headache................................43.5%
Palpitations.............................26.1%
Diarrhea..................................25.7%
Asthenia .................................23.1%
Edema, other ..........................20.6%
Nausea....................................17.1%
Abdominal Pain .....................16.4%
Dizziness................................15.4%
Pain, other ..............................15.0%
Dyspnea..................................11.9%
Flatulence...............................10.2%
Vomiting ................................9.7%
Fever ......................................8.9%
Peripheral Edema...................8.5%
Rash, including urticaria ........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%
Pruritus...................................5.5%
Dyspepsia...............................5.2%

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 & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy. Platelet counts below 100,000/μL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/μL 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 1.5-6.0 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)

All Patients with Myeloproliferative Disease - Illustration

Postmarketing Reports

Cases of interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity have been reported (See WARNINGS, Interstitial Lung Diseases and PRECAUTIONS, Laboratory Tests).

Read the Agrylin (anagrelide) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.

In two clinical interaction studies in healthy subjects, co-administration of single-dose anagrelide 1mg and aspirin 900mg or repeat-dose anagrelide 1mg once daily and aspirin 75mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Coadministered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Analyses of an ongoing observational study in patients with ET suggest the rate of major hemorrhagic events (MHEs) in patients treated with anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily, aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is initiated.

Drug interaction studies have not been conducted with the other common medications used concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol.

Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g. theophylline.

Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.

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.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

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.

Hepatic

Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not been studied. 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. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for cardiovascular effects (see DOSAGE AND ADMINISTRATION for specific dosing recommendations).

Interstitial Lung Diseases

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. In most cases, the symptoms improved after discontinuation of anagrelide (See ADVERSE REACTIONS).

PRECAUTIONS

Bleeding

Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide with aspirin, particularly in patients with a high risk profile for hemorrhage.

Laboratory Tests

Anagrelide therapy requires close clinical supervision of the patient. While the platelet count is being lowered (usually during the first two weeks of treatment), blood counts (hemoglobin, white blood cells), and renal function (serum creatinine, BUN) should be monitored. Cases of clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported in post marketing surveillance. Measure liver function tests (ALT, AST) before initiating anagrelide treatment and during therapy.

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 four days.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day and above, and in females receiving 10mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1mg twice daily dose). Anagrelide hydrochloride 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 hydrochloride at oral doses up to 240 mg/kg/day (1,440 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.

Pregnancy

Pregnancy Category C - Teratogenic Effects

Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5,400 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 hydrochloride.

Nonteratogenic Effects

A fertility and reproductive performance study performed in female rats revealed that anagrelide hydrochloride 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 hydrochloride 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.

There are however, no adequate and well controlled studies with anagrelide hydrochloride in pregnant women. Because animal reproduction studies are not always predictive of human response, anagrelide hydrochloride should be used during pregnancy only if clearly needed.

Nonclinical toxicology

In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.

Five women became pregnant while on anagrelide treatment at doses of 1 to 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 hydrochloride 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 child-bearing 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.

Nursing Mothers

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 hydrochloride, 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.

Pediatric Use

Myeloproliferative disorders are uncommon in pediatric patients and limited data are available in this population. An open label safety and PK/PD study (see CLINICAL PHARMACOLOGY) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11 years of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females) with thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years, 9 males and 9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18 adult patients had received anagrelide treatment for an average of 2 years. The median starting total daily dose, determined by retrospective chart review, for pediatric and adult ET patients who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 11-14 year old patients and adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2 mg in patients 11-14 years of age, and 1.5 mg for adults.

The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide, including platelet counts (see CLINICAL PHARMACOLOGY).

The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during a 3-months treatment of anagrelide in the study. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps. Episodes of increased pulse rate and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed in some patients. Reported AEs were consistent with the known pharmacological profile of anagrelide and the underlying disease. There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients. No overall difference in dosing and safety were observed between pediatric and adult patients.

In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age range 6.8 to 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 qid up to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months with a range of 3.1 to 92 months. Three patients received treatment for greater than three years. Other adverse events reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

Geriatric Use

Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were 65 years and over, while 14.9% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Acute Toxicity and Symptoms

Single oral doses of anagrelide hydrochloride at 2,500, 1,500 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 have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. 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 and 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.

CONTRAINDICATIONS

Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not been studied (see also WARNINGS: Hepatic).

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

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. 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 of 14C-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 2.0 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).

There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and t½ for anagrelide, 3-hydroxy anagrelide, or RL603.

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 Cmax by 14%, but increased the AUC by 20%.

Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86 years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).

Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared to fasting adult patients (age range 22-50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance < 30ml/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.

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 three clinical trials. Patients with OMPD included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative disorders.

Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:

ET

CML

  • Persistent granulocyte count ≥ 50,000/μL without evidence of infection
  • Absolute basophil count ≥ 100/μL
  • Evidence for hyperplasia of the granulocytic line in the bone marrow
  • Philadelphia chromosome is present
  • Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range

PV†

  • A1 Increased red cell mass
  • A2 Normal arterial oxygen saturation
  • A3 Splenomegaly
  • B1 Platelet count ≥ 400,000/μL, in absence of iron deficiency or bleeding
  • B2 Leukocytosis ( ≥ 12,000/μL, in the absence of infection)
  • B3 Elevated leukocyte alkaline phosphatase
  • B4 Elevated serum B12
  • †Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any two of B1, B2, or B3.

MMM

  • Myelofibrotic (hypocellular, fibrotic) bone marrow
  • Prominent megakaryocytic metaplasia in bone marrow
  • Splenomegaly
  • Moderate to severe normo-chromic normocytic anemia
  • White cell count may be variable; (80,000-100,000/μL)
  • Increased platelet count
  • Variable red cell mass; teardrop poikilocytes
  • Normal to high leukocyte alkaline phosphatase
  • Absence of Philadelphia chromosome

Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/μL on two occasions or ≥ 650,000/μL on two 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 0.5-2.0 mg every 6 hours. 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 (150,000400,000/μL). The criteria for defining subjects as “responders” were reduction in platelets for at least 4 weeks to ≤ 600,000/μL, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted graphically below:

Patients with Thrombocytosis Secondary to Myeloproliferative Disorders: Mean Platelet Count During Anagrelide Therapy

Mean Platelet Count During Anagrelide Therapy - illustration

  Baseline Time on Treatment
Weeks Years
4 12 24 48 2 3 4
Mean* 1131 683 575 526 484 460 437 457
N 923† 868 814 662 530 407 207 55
*x 103/μL
†Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three research studies. Of these, 923 had platelet counts over the duration of the studies.

AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 12/16/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Agrylin Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

ANAGRELIDE - ORAL

(an-AG-re-lide)

COMMON BRAND NAME(S): Agrylin

USES: Anagrelide is used to treat a certain blood disorder (thrombocythemia), which is caused by your bone marrow making too many platelets. Platelets are a blood cell that the body uses to form blood clots. Too many platelets can cause problems with your circulation, including unwanted blood clots and bleeding problems. This drug reduces the number of platelets in the bloodstream by blocking their production.

HOW TO USE: This medicine may come with a Patient Information Leaflet. Read it carefully if available. Ask your doctor, nurse, or pharmacist any questions that you may have about this medicine.

Take this medication by mouth with or without food, usually 2 or 4 times a day or as directed by your doctor. Children or people with liver problems may start out by taking only 1 dose each day. Your doctor will adjust your dose, usually once a week, to find the best dose for you that keeps your blood counts closer to normal. The dosage is based on your medical condition and response to therapy. You should not take more than 2.5 milligrams in a single dose or more than a total of 10 milligrams in a day.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. It is important to continue taking this medication even if you feel well. People with high platelets may not feel sick. Do not stop taking this medication without consulting your doctor. Stopping anagrelide will cause your platelets to go back up.

Your doctor will check your blood counts regularly to monitor your progress and adjust your dose.

Disclaimer

Agrylin Consumer (continued)

SIDE EFFECTS: Headache, diarrhea, weakness, nausea, and dizziness may occur. If any of these effects persist or worsen, contact your doctor or pharmacist promptly.

To avoid dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual bleeding/bruising, black stools, swelling of the ankles/feet, rapid/difficult breathing, fainting, stomach/abdominal pain, unusual tiredness, change in the amount of urine, pink/bloody urine, vomit that looks like coffee grounds.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest/jaw/left arm pain, confusion/mental changes, fast/irregular/pounding heartbeat, slurred speech, vision changes, weakness on one side of the body.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Agrylin (anagrelide) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking anagrelide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., heart attack, heart failure, irregular heartbeat), lung problems, kidney problems, liver problems.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

This medication is not recommended for use during pregnancy because of possible harm to the unborn baby. Discuss the risk and benefits with your doctor. If you become pregnant or think you may be pregnant, inform your doctor immediately. Consult your doctor for more details and to discuss reliable forms of birth control.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.

Disclaimer

Agrylin Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: sucralfate.

Only take aspirin if your doctor approves of it. Aspirin can increase the risk of bleeding when used with anagrelide, especially if you already have a high risk for bleeding. However, if your doctor has directed you to take low-dose aspirin to prevent blood clots, or for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day), you should continue taking it unless your doctor instructs you otherwise. Discuss the risks and benefits with your doctor or pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: unusual bleeding/bruising, fast heartbeat, vomiting.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood counts, kidney and liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information, call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised January 2012. Copyright(c) 2012 First Databank, Inc.

Agrylin Patient Information Including Side Effects

Brand Names: Agrylin

Generic Name: anagrelide (Pronunciation: an AH gre lide)

What is anagrelide (Agrylin)?

Anagrelide lowers the number of blood clotting cells (platelets) in the body, which helps prevent blood clots from forming.

Anagrelide is used to treat a condition called thrombocythemia (also called thrombocytosis). Thrombocythemia is a blood cell disorder in which too many platelet cells are produced, causing bleeding or blood-clotting problems.

Anagrelide may also be used for other purposes not listed in this medication guide.

Anagrelide 0.5 mg-BAR

white, imprinted with barr 0.5 mg, 101

Anagrelide 0.5 mg-IVA

gray/white, imprinted with LOGO 5241, 0.5 mg

Anagrelide 0.5 mg-MYL

gray/pink, imprinted with MYLAN 6868

Anagrelide 1 mg-BAR

gray, imprinted with barr 1 mg, 102

Anagrelide 1 mg-IVA

white, imprinted with LOGO 5240, 1 mg

Anagrelide 1 mg-MYL

blue/gray, imprinted with MYLAN 6869

What are the possible side effects of anagrelide (Agrylin)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • wheezing, rapid breathing, feeling short of breath, dry cough, fever;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • swelling, rapid weight gain;
  • fast, pounding, or uneven heartbeats;
  • sudden numbness or weakness, especially on one side of the body;
  • sudden headache, confusion, problems with vision, speech, or balance;
  • severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
  • seizure (convulsions);
  • feeling like you might pass out;
  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
  • pale skin, easy bruising or bleeding, unusual weakness; or
  • blood in your urine, painful or difficult urination.

Less serious side effects may include:

  • dizziness, mild headache;
  • mild rash or itching;
  • constipation, diarrhea, gas;
  • loss of appetite, mild nausea or stomach pain;
  • numbness or tingly feeling in your hands or feet;
  • sore throat, runny or stuffy nose, nosebleed;
  • muscle or joint pain;
  • sleep problems (insomnia); or
  • blurred vision, ringing in your ears.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Agrylin (anagrelide) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about anagrelide (Agrylin)?

You should not use anagrelide if you are allergic to it, or if you have moderate to severe liver or kidney disease.

Before you take anagrelide, tell your doctor if you have heart disease, kidney disease, or liver disease.

To be sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your kidney and liver function may also need to be tested. Visit your doctor regularly. Tell any doctor or dentist who treats you that you are taking anagrelide, especially if you need to have any type of surgery.

Do not stop taking this medication without first talking to your doctor. Stopping suddenly can make your condition worse very quickly.

Call your doctor at once if you have a serious side effect such as dry cough, trouble breathing, swelling, fast or pounding heartbeats, chest pain, sudden numbness or weakness, confusion, problems with speech or balance, severe stomach pain, seizure, fainting, blood in your urine or stools, easy bruising or bleeding, or unusual weakness.

Side Effects Centers

Agrylin Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking anagrelide (Agrylin)?

You should not use anagrelide if you are allergic to it, or if you have moderate to severe liver or kidney disease.

If you have any of these other conditions, you may need a dose adjustment or special tests:

  • heart disease or congestive heart failure;
  • kidney disease; or
  • liver disease.

FDA pregnancy category C. It is not known whether anagrelide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether anagrelide passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take anagrelide (Agrylin)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

To be sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your kidney and liver function may also need to be tested. Visit your doctor regularly.

Do not stop taking this medication without first talking to your doctor. Stopping suddenly can make your condition worse very quickly.

If you need to surgery, tell the surgeon ahead of time that you are using anagrelide. Tell any doctor or dentist who treats you that you are taking anagrelide.

Store at room temperature away from moisture, heat, and light.

Side Effects Centers

Agrylin Patient Information including If I Miss a Dose

What happens if I miss a dose (Agrylin)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Agrylin)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause vomiting, or fast heart rate.

What should I avoid while taking anagrelide (Agrylin)?

Grapefruit and grapefruit juice may interact with anagrelide and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

What other drugs will affect anagrelide (Agrylin)?

Tell your doctor if you also use:

  • fluvoxamine (Luvox);
  • theophylline (Elixophyllin, Theo-24, Uniphyl); or
  • medication to treat congestive heart failure, such as amrinone (inamrinone, Inocor), enoximone (Perfan), or milrinone (Primacor).

This list is not complete and other drugs may interact with anagrelide. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about anagrelide.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 3.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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