ANAGRELIDE HYDROCHLORIDE capsule
For Healthcare Providers >

1. Patient Information
2. Cardiovascular Effects:
3. Risk Of Bleeding:
4. Manufactured For:

Patient Information ⮝

Dose:Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted[see Dosage and Administration (2)].

Cardiovascular Effects: ⮝

Tell the patient to contact a doctor immediately if they experience chest pain, palpitations, or feel their heartbeat is irregular[see Warnings and Precautions (5.1)].

Risk Of Bleeding: ⮝

Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise more easily than usual[see Warnings and Precautions (5.2), Drug Interactions (7.1)].

Manufactured For: ⮝

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. I 7/2015

1. Description
2. Clinical Pharmacology
3. Warnings
4. Precautions
5. Overdosage
6. Principal Display Panel
7. 16 How Supplied/storage And Handling
8. Package/label Display Panel
9. Highlights Of Prescribing Information
10. Recent Major Changes
11. Indications And Usage
12. Dosage And Administration
13. Dosage Forms And Strengths
14. Contraindications
15. Warnings And Precautions
16. Adverse Reactions
17. Drug Interactions
18. Use In Specific Populations
19. 1 Indications And Usage
20. 2 Dosage And Administration
21. 3 Dosage Forms And Strengths
22. 4 Contraindications
23. 5 Warnings And Precautions
24. 6 Adverse Reactions
25. 7 Drug Interactions
26. 8 Use In Specific Populations
27. 10 Overdosage
28. 11 Description
29. 12 Clinical Pharmacology
30. 13 Nonclinical Toxicology
31. 14 Clinical Studies
32. How Supplied
33. Anagrelide Hcl

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:

C10H7Cl2N3O HCl H2O M.W. 310.55

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.

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 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 AUC , of anagrelide were lower in the pediatric patients compared to the adult patients (Cmax 48%, AUC 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/ L 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/ L without evidence of infection
• Absolute basophil count 100/ L
• 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/ L, in absence of iron deficiency or bleeding
• B2 Leukocytosis ( 12,000/ L, 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/ L)
• 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/ L on two occasions or 650,000/ L 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/ L). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to 600,000/ L, 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:

* x103/ L ** 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.
		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

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.

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 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 ⮝

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 postmarketing 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 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).

The potential risks and benefits of concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is commenced.

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 non-delivering 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 were 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 palpitation, 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.

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.

Principal Display Panel ⮝

Anagrelide 0.5 mg Text

ANAGRELIDE

HYDROCHLORIDE

Capsules

0.5 mg

PLATELET-REDUCING AGENT

Rx only

ANAGRELIDE HYDROCHLORIDE anagrelide hydrochloride capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5443(NDC:0172-5241) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Anagrelide Hydrochloride (UNII: VNS4435G39) (Anagrelide - UNII:K9X45X0051) Anagrelide 0.5 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) ALUMINUM OXIDE (UNII: LMI26O6933) FERROSOFERRIC OXIDE (UNII: XM0M87F357) GELATIN (UNII: 2G86QN327L) ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color GRAY (light gray cap/white body) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 5241;05mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5443-2 30 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076468 07/19/2007

ANAGRELIDE HYDROCHLORIDE anagrelide hydrochloride capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5385(NDC:0172-5240) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Anagrelide Hydrochloride (UNII: VNS4435G39) (Anagrelide - UNII:K9X45X0051) Anagrelide 1 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) ALUMINUM OXIDE (UNII: LMI26O6933) FERROSOFERRIC OXIDE (UNII: XM0M87F357) GELATIN (UNII: 2G86QN327L) ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape CAPSULE Size 16mm Flavor Imprint Code 5240;1mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5385-0 30 in 1 BOTTLE 2 NDC:54868-5385-1 10 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076468 08/15/2005 06/30/2011

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel, repack

Revised: 4/2012 Document Id: e34908ed-0298-4597-812e-7108d8a56d98 34391-3 Set id: 5e6cf1e5-94e4-4124-b7bf-e74647532246 Version: 2 Effective Time: 20120427 Physicians Total Care, Inc.

16 How Supplied/storage And Handling ⮝

Anagrelide Capsules USP, 0.5 mg are available as light gray opaque cap/white opaque body hard gelatin capsules, spin printed in black ink Ivax hourglass logo 5241 on the cap and 0.5 mg on the body containing 0.5 mg of anagrelide base (as anagrelide hydrochloride, USP).

NDC 0172-5241-60 0.5 mg packaged in bottles of 100 capsules

Anagrelide Capsules USP, 1 mg are available as white opaque hard gelatin capsules, spin printed in black ink Ivax hourglass logo 5240 on the cap and 1 mg on the body containing 1 mg of anagrelide base (as anagrelide hydrochloride, USP).

NDC 0172-5240-60 1 mg 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.

Package/label Display Panel ⮝

Anagrelide Capsules USP 1 mg 100s Label Text

NDC 0172-5240-60

Anagrelide

Capsules USP

1 mg

PLATELET-REDUCING AGENT

Rx only

100 CAPSULES

TEVA

ANAGRELIDE HYDROCHLORIDE anagrelide hydrochloride capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0172-5241 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANAGRELIDE HYDROCHLORIDE (UNII: VNS4435G39) (ANAGRELIDE - UNII:K9X45X0051) ANAGRELIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength FERROSOFERRIC OXIDE (UNII: XM0M87F357) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) INDIGOTINDISULFONATE SODIUM (UNII: D3741U8K7L) FD&C RED NO. 40 (UNII: WZB9127XOA) GELATIN (UNII: 2G86QN327L) ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POVIDONE K30 (UNII: U725QWY32X) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

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 Marketing Start Date Marketing End Date 1 NDC:0172-5241-60 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/18/2005

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 Item Code (Source) NDC:0172-5240 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANAGRELIDE HYDROCHLORIDE (UNII: VNS4435G39) (ANAGRELIDE - UNII:K9X45X0051) ANAGRELIDE 1 mg

Inactive Ingredients Ingredient Name Strength FERROSOFERRIC OXIDE (UNII: XM0M87F357) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) INDIGOTINDISULFONATE SODIUM (UNII: D3741U8K7L) FD&C RED NO. 40 (UNII: WZB9127XOA) GELATIN (UNII: 2G86QN327L) ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POVIDONE K30 (UNII: U725QWY32X) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color WHITE Score no score Shape CAPSULE Size 16mm Flavor Imprint Code 5240;1;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0172-5240-60 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/18/2005

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076468 04/18/2005

Labeler - Teva Pharmaceuticals USA, Inc. (001627975)

Revised: 7/2018 Document Id: 46a7c296-b4f0-45ad-9839-56d9189bb47a 34391-3 Set id: 6727d5d4-e8ec-4a85-bc82-ec70b641eecf Version: 18 Effective Time: 20180709 Teva Pharmaceuticals USA, Inc.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ANAGRELIDE CAPSULES USP safely and effectively. See full prescribing information for ANAGRELIDE CAPSULES USP.
ANAGRELIDE capsules, for oral use
Initial U.S. Approval: 1997

Recent Major Changes ⮝

Dosage and Administration (2) 10/2014

Contraindications (4) 10/2014

Warnings and Precautions (5) 10/2014

Indications And Usage ⮝

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).

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 q.i.d. or 1 mg b.i.d (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 q.i.d. 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/ L, 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/ L, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

Dosage Forms And Strengths ⮝

Capsules: 0.5 mg, 1 mg (3)

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 And Precautions ⮝

Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. Monitor patients for cardiovascular effects. (5.1)

Bleeding Risk: Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (5.2)

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, palpitation, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were:

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/ L occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/ L occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide.

Hepatic System

Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide therapy.

Musculoskeletal System

Arthralgia, myalgia, leg cramps

Nervous System

Depression, somnolence, confusion, insomnia, nervousness, amnesia

Nutritional Disorders

Dehydration

Respiratory System

Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma

Skin and Appendages System

Skin disease, alopecia

Special Senses

Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia

Urogenital System

Dysuria, hematuria

Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were found to have pre-existing renal impairment. Doses ranged from 1.5 to 6 mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.

The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:

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).

Drug Interactions ⮝

Other PDE 3 inhibitors: Exacerbation of inotropic effects (7.2)

Aspirin and Drugs that Increase Bleeding Risk: Increased risk of bleeding with concomitant use (7.3)

Use In Specific Populations ⮝

Nursing Mothers: Discontinue nursing or discontinue the drug (8.3).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2016

1 Indications And Usage ⮝

Anagrelide capsules USP are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events [see Clinical Studies (14), Dosage and Administration (2)].

2 Dosage And Administration ⮝

2.1 Starting Dose

Adults: The recommended starting dosage of anagrelide capsules is 0.5 mg four times daily or 1 mg twice daily.

Pediatric Patients: The recommended starting dosage of anagrelide capsules is 0.5 mg daily.

2.2 Titration

Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/ L, and ideally between 150,000/ L and 400,000/ L. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose [see Warnings and Precautions (5)]. Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.

2.3 Dose Modifications for Hepatic Impairment

In patients with moderate hepatic impairment (Child Pugh score 7 to 9) start anagrelide capsules therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Patients with moderate hepatic impairment who have tolerated anagrelide capsules therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of anagrelide capsules in patients with severe hepatic impairment.

2.4 Clinical Monitoring

Anagrelide capsules therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes.

To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count 600,000/ L, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.

3 Dosage Forms And Strengths ⮝

Anagrelide Capsules, 0.5 mg are available as light gray opaque cap/white opaque body hard gelatin capsules, spin printed in black ink Ivax hourglass logo 5241 on the cap and 0.5 mg on the body containing 0.5 mg of anagrelide base (as anagrelide hydrochloride).

Anagrelide Capsules, 1 mg are available as white opaque hard gelatin capsules, spin printed in black ink Ivax hourglass logo 5240 on the cap and 1 mg on the body containing 1 mg of anagrelide base (as anagrelide hydrochloride).

4 Contraindications ⮝

None.

5 Warnings And Precautions ⮝

5.1 Cardiovascular Toxicity

Torsades de pointes and ventricular tachycardia have been reported with anagrelide. 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 (12.2)].

Do not use anagrelide 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 [see Drug Interactions (7.1)].

Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce anagrelide dose in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)].

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms [see Clinical Pharmacology (12.2)].

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 [see Drug Interactions (7.2)].

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

5.2 Bleeding Risk

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, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

5.3 Pulmonary Toxicity

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. If suspected, discontinue anagrelide and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions (6)].

6 Adverse Reactions ⮝

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Cardiovascular Toxicity [see Warnings and Precautions (5.1)]

Bleeding Risk [see Warnings and Precautions (5.2)]

Pulmonary Toxicity [see Warnings and Precautions (5.3)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Studies in Adult Patients

In three single-arm clinical studies, 942 patients [see Clinical Trials (14)] diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion [see Warnings and Precautions (5.1)], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.

Table 1: Adverse Reactions Reported in Clinical Studies in at least 5% of Patients

Adverse reactions	Anagrelide (N=942) (%)
Cardiac disorders
Palpitations	26%
Tachycardia	8%
Chest pain	8%
General disorders and administration site conditions
Asthenia	23%
Edema	21%
Pain	15%
Fever	9%
Peripheral edema	9%
Malaise	6%
Gastrointestinal disorders
Diarrhea	26%
Nausea	17%
Abdominal pain	16%
Vomiting	10%
Flatulence	10%
Anorexia	8%
Dyspepsia	5%
Respiratory, thoracic and mediastinal disorders
Dyspnea	12%
Cough	6%
Skin and subcutaneous tissue disorders
Rash	8%
Pruritus	6%
Musculoskeletal and connective tissue disorders
Back pain	6%
Nervous system disorders
Headache	44%
Dizziness	15%
Paresthesia	6%

Adverse Reactions (frequency 1% to < 5%) included:

General disorders and administration site conditions: Flu symptoms, chills.

Cardiac disorders: Arrhythmia, angina pectoris, heart failure, syncope.

Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.

Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.

Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.

Hepatobiliary disorders: Elevated liver enzymes.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Psychiatric disorders: Depression, confusion, nervousness.

Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.

Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.

Skin and subcutaneous tissue disorders: Alopecia.

Eye disorders: Abnormal vision, diplopia.

Ear and labyrinth disorders: Tinnitus

Renal and urinary disorders: Hematuria, renal failure.

Other less frequent adverse reactions (<1%) were:

Cardiac disorders: Ventricular tachycardia, supraventricular tachycardia.

Nervous system disorders: Hypoesthesia.

Clinical Study in Pediatric Patients

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 the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-marketing use of anagrelide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of torsades de pointes, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see Warnings and Precautions (5)], tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.

Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

7 Drug Interactions ⮝

7.1 Drugs that Prolong QT

Do not use anagrelide in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

7.2 PDE3 Inhibitors

Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

7.3 Aspirin and Drugs that Increase Bleeding Risk

Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone [see Clinical Pharmacology (12.3)]. Results from an observational study in patients with essential thrombocythemia 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 [see Warnings and Precautions (5.2)].

Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

7.4 CYP450 Interactions

CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.

CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.

CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).

8 Use In Specific Populations ⮝

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with anagrelide in pregnant women. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10 mg/day. Anagrelide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of 100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area. No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal clinical dose based on body surface area).

In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.

In a placental transfer study, a single oral dose of [14C]-anagrelide hydrochloride was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.

8.3 Nursing Mothers

Risk Summary

It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reaction in nursing infants from anagrelide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Data

In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.

8.4 Pediatric Use

Experience with anagrelide in pediatric patients was based on an open label safety and PK/PD study conducted in 18 pediatric patients aged 7 to 16 years with thrombocythemia secondary to ET [see Dosage and Administration (2.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

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 [see Adverse Reactions (6.1)].

8.5 Geriatric Use

Of the 942 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.

8.6 Hepatic Impairment

Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and Administration (2.3)]. 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 hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions (5.1)].

10 Overdosage ⮝

At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.

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 stopped, as appropriate, until the platelet count returns to within the normal range.

11 Description ⮝

Anagrelide hydrochloride, USP is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5-dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate and it has the following structural formula:

C10H7Cl2N3O HCl H2O M.W. 310.56

Anagrelide hydrochloride, USP is an off white powder that is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and in dimethylformamide.

Each Anagrelide Capsule USP, for oral administration, contains either 0.5 mg or 1 mg of anagrelide base (as anagrelide hydrochloride, USP) 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.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.

12.2 Pharmacodynamics

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. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide (IC50s = 0.9 and 36nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects including vasodilation, positive inotropy and chronotropy.

Cardiac Electrophysiology

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.

12.3 Pharmacokinetics

Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.

Absorption

Following oral administration of anagrelide, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, anagrelide peak plasma concentrations occur within about 1 hour after administration.

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%. Food decreased the Cmax of the active metabolite 3-hydroxy-anagrelide by 29%, although it had no effect on the AUC.

Metabolism

Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the urine as anagrelide, and approximately 3% and 16 to 20% of the administered dose is recovered as 3-hydroxy-anagrelide and RL603, respectively.

Elimination

Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours, respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are administered.

Drug Interactions

Aspirin: In two pharmacodynamic interaction studies in healthy subjects, co-administration 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. Co-administered anagrelide 1 mg and aspirin 900 mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of anagrelide.

Specific Populations

Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7 to 16 years) with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19 to 57 years).

Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65 to 75 years), than in younger adults (age range 22 to 50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower, respectively, in the elderly patients.

Renal Impairment: 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.

Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment (Child Pugh score 7 to 9) showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment showed 24% lower mean 3-hydroxy-anagrelide Cmax and 77% higher mean 3-hydroxy-anagrelide AUC compared to healthy subjects.

13 Nonclinical Toxicology ⮝

13.1 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 mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell (L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or the in vivo mouse micronucleus test.

Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies in female rats, oral doses of 30 mg/kg/day (29 times the recommended maximum human dose based on body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.

13.2 Animal Toxicology and/or Pharmacology

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.

14 Clinical Studies ⮝

Clinical Studies in Adult Patients:

A total of 942 patients with myeloproliferative neoplasms 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 neoplasms (OMPN), were treated with anagrelide in three clinical trials. Patients with OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unclassified myeloproliferative neoplasms.

Patients were enrolled in clinical trials if their platelet count was 900,000/ L on two occasions or 650,000/ L on two occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPN 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/ L). The criteria for defining subjects as responders were reduction in platelets for at least 4 weeks to 600,000/ L, 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:

*x 103/ L

Nine hundred and forty-two subjects with myeloproliferative neoplasms were enrolled in three research studies. Of these, 923 had platelet counts measured 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.

Clinical Study in Pediatric Patients:

An open label safety and PK/PD study was conducted in 18 pediatric patients 7 to 16 years of age (8 patients 7 to 11 years of age and 10 patients 12 to 16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females). Prior to entry on to the study, 17 of 18 pediatric patients and 12 of 17 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 patients with ET who had received anagrelide prior to study entry was 1 mg for each of the three age groups (7 to 11 and 12 to 16 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, 2.25 mg in patients 12 to 16 years of age, and 1.5 mg for adults.

How 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 30 capsules.

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

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

Manufactured In India By:

Cipla Ltd.

Goa, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. C 2/2011

ANAGRELIDE HYDROCHLORIDE CAPSULES

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma 74146

Anagrelide Hcl ⮝

ANAGRELIDE HYDROCHLORIDE anagrelide hydrochloride capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68151-2959(NDC:0172-5241) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANAGRELIDE HYDROCHLORIDE (UNII: VNS4435G39) (ANAGRELIDE - UNII:K9X45X0051) ANAGRELIDE 0.5 mg

Inactive Ingredients Ingredient Name Strength FERROSOFERRIC OXIDE (UNII: XM0M87F357) CROSPOVIDONE (UNII: 68401960MK) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) ALUMINUM OXIDE (UNII: LMI26O6933) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) INDIGOTINDISULFONATE SODIUM (UNII: D3741U8K7L) FD&C RED NO. 40 (UNII: WZB9127XOA) GELATIN (UNII: 2G86QN327L) ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POVIDONE K30 (UNII: U725QWY32X) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

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 Marketing Start Date Marketing End Date 1 NDC:68151-2959-6 1 in 1 PACKAGE; Type 0: Not a Combination Product 04/18/2005

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076468 04/18/2005

Labeler - Carilion Materials Management (079239644)

Establishment
Name	Address	ID/FEI	Business Operations
Carilion Materials Management		079239644	REPACK(68151-2959)

Revised: 8/2016 Document Id: 691914ba-6279-4b7c-9908-e258330fdb5b 34391-3 Set id: 614b45a3-7f2e-4348-9e20-ecf8dc440314 Version: 3 Effective Time: 20160804 Carilion Materials Management