Anagrelide

Generic Name: Anagrelide hydrochloride
Dosage Form: capsule

Anagrelide HYDROCHLORIDE CAPSULES
5241
5240
Rx only

Anagrelide Description

Anagrelide hydrochloride is an off white powder that is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and in dimethylformamide. Anagrelide hydrochloride is a platelet-reducing agent with a chemical name of 6,7-dichloro-1,5-dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate, and it has the following structural formula:

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C10H7Cl2N3O·HCl·H2O M.W. 310.56

Each Anagrelide Hydrochloride Capsule, for oral administration, contains either 0.5 mg or 1 mg of Anagrelide base (as Anagrelide hydrochloride) and has the following inactive ingredients: black iron oxide, crospovidone, D&C Yellow #10 Aluminum Lake, FD&C Blue #1/Brilliant Blue Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Red #40/Allura Red Aluminum Lake, gelatin, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, shellac glaze and titanium dioxide.

Anagrelide - 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 In blood withdrawn from normal volunteers treated with Anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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.

Effects on Heart Rate and QTc Interval

The effect of Anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential was evaluated in a double-blind, randomized, placebo-and active-controlled, cross-over study in 60 healthy adult men and women.

A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal drug concentration (0.5 to 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.

Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI (individual subject correction) from placebo after baseline-correction was 7 (9.8) ms and 13 (15.7) ms following Anagrelide doses of 0.5 mg and 2.5 mg, respectively.

Pharmacokinetics

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 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 for t1/2 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 to 14 years) and adult (age range 16 to 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 to 75 years) compared to fasting adult patients (age range 22 to 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 < 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.

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:

Platelet count ≥ 900,000/µL on two 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

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 to 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 to 2 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 (150,000 to 400,000/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:

 

 

Time on Treatment

 

 

Weeks

Years

 

Baseline

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.

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

Indications and Usage for Anagrelide

Anagrelide Hydrochloride 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).

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).

Warnings

Cardiovascular

Torsade de pointes and ventricular tachycardia have been reported with Anagrelide treatment. Obtain a pre-treatment cardiovascular examination, including an ECG in all patients. During treatment with Anagrelide, monitor patients for cardiovascular effects and evaluate as necessary.

Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers (see CLINICAL PHARMACOLOGY). Anagrelide should not be used in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia.

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Laboratory Tests).

Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure.

In patients with cardiac disease, use Anagrelide only when the benefits outweigh the risks.

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 QTc prolongation and other cardiovascular effects (see DOSAGE AND ADMINISTRATIONfor 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 postmarketing 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 and laboratory monitoring, including complete blood count (hemoglobin, white blood cell, and platelet counts), assessment of renal function (serum creatinine, BUN) and electrolytes (potassium, magnesium, and calcium). Since 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 enzymes (ALT, AST) before initiating Anagrelide treatment and during therapy.

Hypotension

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 Anagrelide 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.

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, coadministration of single-dose Anagrelide 1 mg and aspirin 900 mg or repeat-dose Anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Coadministered Anagrelide 1 mg and aspirin 900 mg 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 coadministered 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.

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 30 mg/kg/day (at least 174 times human AUC exposure after a 1 mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg 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 to 14 years of age (8 patients 7 to 11 years of age and 9 patients 11 to 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 1 mg for each of the three age groups (7 to 11 and 11 to 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 to 11 years of age, 2 mg in patients 11 to 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 q.i.d. 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 Anagrelide, 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.

Adverse Reactions

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%

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 and 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 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:

Postmarketing Reports

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

Overdosage

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.

Anagrelide Dosage and Administration

Treatment with Anagrelide Hydrochloride Capsules should be initiated under close medical supervision. The recommended starting dosage of Anagrelide Hydrochloride Capsules 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 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

How is Anagrelide Supplied

Anagrelide Hydrochloride Capsules are available as light gray cap/white body hard gelatin capsules, spin printed in black ink

“5241” on the cap and "0.5 mg" on the body containing 0.5 mg of Anagrelide base (as Anagrelide hydrochloride) packaged in bottles of 100 capsules.

Anagrelide Hydrochloride Capsules are available as white hard gelatin capsules, spin printed in black ink

“5240” on the cap and "1 mg" on the body containing 1 mg of Anagrelide base (as Anagrelide hydrochloride) packaged in bottles of 100 capsules.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In India By:

Cipla Ltd.

Goa, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. F 2/2014

Package/Label Display Panel

Anagrelide HYDROCHLORIDE Capsules 0.5 mg 100s Label Text

NDC 0172-5241-60

Anagrelide
HYDROCHLORIDE
Capsules
0.5 mg

PLATELET-REDUCING AGENT

Rx only

100 CAPSULES

TEVA

Package/Label Display Panel

Anagrelide HYDROCHLORIDE Capsules 1 mg 100s Label Text

NDC 0172-5240-60

Anagrelide
HYDROCHLORIDE
Capsules
1 mg

PLATELET-REDUCING AGENT

Rx only

100 CAPSULES

TEVA

Anagrelide HYDROCHLORIDE 
Anagrelide hydrochloride capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0172-5241
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Anagrelide HYDROCHLORIDE (Anagrelide) Anagrelide 0.5 mg
Inactive Ingredients
Ingredient Name Strength
FERROSOFERRIC OXIDE  
CROSPOVIDONE  
D&C YELLOW NO. 10  
ALUMINUM OXIDE  
FD&C BLUE NO. 1  
FD&C BLUE NO. 2  
INDIGOTINDISULFONATE SODIUM  
FD&C RED NO. 40  
GELATIN  
ANHYDROUS LACTOSE  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE K30  
PROPYLENE GLYCOL  
SHELLAC  
TITANIUM DIOXIDE  
Product Characteristics
Color GRAY (light gray) , WHITE Score no score
Shape CAPSULE Size 14mm
Flavor Imprint Code 5241;0;5;mg
Contains         
Packaging
# Item Code Package Description
1 NDC:0172-5241-60 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076468 04/18/2005
Anagrelide HYDROCHLORIDE 
Anagrelide hydrochloride capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0172-5240
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Anagrelide HYDROCHLORIDE (Anagrelide) Anagrelide 1 mg
Inactive Ingredients
Ingredient Name Strength
FERROSOFERRIC OXIDE  
CROSPOVIDONE  
D&C YELLOW NO. 10  
ALUMINUM OXIDE  
FD&C BLUE NO. 1  
FD&C BLUE NO. 2  
INDIGOTINDISULFONATE SODIUM  
FD&C RED NO. 40  
GELATIN  
ANHYDROUS LACTOSE  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONE K30  
PROPYLENE GLYCOL  
SHELLAC  
TITANIUM DIOXIDE  
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 16mm
Flavor Imprint Code 5240;1;mg
Contains         
Packaging
# Item Code Package Description
1 NDC:0172-5240-60 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076468 04/18/2005
Labeler - IVAX Pharmaceuticals, Inc. (884075235)
Revised: 04/2014
 
IVAX Pharmaceuticals, Inc.
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