Agrylin

Name: Agrylin

What Is Anagrelide?

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

Anagrelide is used to treat a blood cell disorder called thrombocythemia (also called thrombocytosis), which occurs when your body produces too many platelet cells.

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

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use anagrelide if you are allergic to it.

To make sure anagrelide is safe for you, tell your doctor if you have:

  • liver disease;
  • personal or family history of long QT syndrome;
  • heart disease or congestive heart failure;
  • an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);
  • bleeding or blood clotting disorder such as hemophilia;
  • kidney disease; or
  • asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether anagrelide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using anagrelide.

Why is this medication prescribed?

Anagrelide is used to decrease the number of platelets (a type of blood cell that is needed to control bleeding) in the blood of patients who have a bone marrow disorder, in which the body makes too many of one or more types of blood cells, such as essential thrombocythemia (condition in which the body makes too many platelets) or polycythemia vera (condition in which the body makes too many red blood cells and sometimes too many platelets). Anagrelide is in a class of medications called platelet-reducing agents. It works by slowing the production of platelets in the body.

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light or excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

  • unusual bleeding or bruising

How supplied

Dosage Forms And Strengths

White, opaque capsule, containing 0.5 mg anagrelide (as anagrelide hydrochloride), imprinted with “063” in black ink.

Storage And Handling

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

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

Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA. 1-800-828-2088. Revised: July 2015.

Side effects

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

  • Cardiovascular Toxicity [see WARNINGS AND PRECAUTIONS]
  • Bleeding Risk [see WARNINGS AND PRECAUTIONS]
  • Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]

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] 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], 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 AGRYLIN
(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.

Postmarketing Experience

The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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], 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.

Clinical pharmacology

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.

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 – 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 7.0 (9.8) ms and 13.0 (15.7) ms following anagrelide doses of 0.5 mg and 2.5 mg, respectively.

Pharmacokinetics

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

Absorption

Following oral administration of AGRYLIN, 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 16-20% 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 1mg and aspirin 900mg 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 7-16 years) with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19-57 years).

Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65-75 years), than in younger adults (age range 22-50 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 7-9) 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.

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.

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 AGRYLIN 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/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 OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with AGRYLIN starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/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:

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

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

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

Clinical Study in Pediatric Patients

An open label safety and PK/PD study was conducted in 18 pediatric patients 7-16 years of age (8 patients 7-11 years of age and 10 patients 12-16 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 1mg for each of the three age groups (7-11 and 12-16 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 7-11 years of age, 2.25 mg in patients 12-16 years of age, and 1.5 mg for adults.

Side Effects of Agrylin

Common side effects of Agrylin include the following:

  • headache
  • irregular heart beats
  • diarrhea
  • weakness
  • nausea
  • dizziness
  • body swelling
  • stomach pain
  • difficulty breathing
  • flatulence
  • vomiting

This is not a complete list of Agrylin side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Serious side effects have been reported with Agrylin.

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

Other Requirements

  • Keep this medication in the container it came in, tightly closed, and out of reach of children.
  • Store it at room temperature and away from light or excess heat and moisture (not in the bathroom).

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

You should not use anagrelide if you are allergic to it.

To make sure anagrelide is safe for you, tell your doctor if you have:

  • liver disease;

  • personal or family history of long QT syndrome;

  • heart disease or congestive heart failure;

  • an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);

  • bleeding or blood clotting disorder such as hemophilia;

  • kidney disease; or

  • asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether anagrelide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using anagrelide.

How should I take Agrylin (anagrelide)?

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG) before you take this medicine.

While using anagrelide, you may need frequent blood tests. Your heart, liver, and kidney function may also need to be checked.

If you need surgery, tell the surgeon ahead of time that you are using anagrelide.

You should not stop using anagrelide suddenly. Stopping suddenly may make your condition worse.

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

Uses for Agrylin

Thrombocythemia

Reduction of elevated platelet counts and associated risk of thromboembolic and hemorrhagic events in patients with thrombocythemia secondary to essential thrombocythemia (ET) and other myeloproliferative disorders.1 3 7 13 14 15 17 18 23 Has been designated an orphan drug by FDA for the treatment of ET.2

Management of ET generally based on a risk-stratification approach.3 7 11 14 16 19 20 22 25 27 31 32 Treatment with a cytoreductive agent (e.g., anagrelide, hydroxyurea) usually reserved for patients at high risk (i.e., age >60 years, previous history of thrombosis, and/or platelet count ≥1,500,000/mm3) of developing thromboembolic and/or hemorrhagic complications.3 7 9 11 12 13 14 16 20 25 31 32 Some clinicians also recommend cytoreductive therapy in intermediate-risk ET patients (e.g., 40–60 years of age, platelet count >1,000,000/mm3, and cardiovascular risk factor [smoking, arterial hypertension, hypercholesterolemia, or diabetes mellitus] or familial thrombophilia).27 31 32

Hydroxyurea (often combined with low-dose aspirin) generally considered drug of choice in high-risk patients with ET because of proven efficacy and infrequent acute toxicity.3 6 7 11 14 17 20 21 22 25 27 30 32 However, because of potential leukemogenic effects with hydroxyurea when used long term or sequentially with other cytotoxic drugs,3 5 7 anagrelide or interferon alfa suggested as alternative therapy in high-risk patients, particularly younger patients (<40–60 years of age), and in those who do not respond to or cannot tolerate hydroxyurea.3 5 7 9 17 22 24 25 27 31 32 Consider cautious use of low-dose aspirin concomitantly with anagrelide based on relative risks of thrombosis and arterial hemorrhage in individual patients.3 5 6 11 27 31 32 (See Specific Drugs or Foods under Interactions.)

Agrylin Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration. 9

Following oral administration, peak plasma concentrations attained within 1–2 hours.5 9 22 23 24

No evidence of drug accumulation following multiple dosing.1 9 29

Onset

Platelet counts usually begin to decrease within 7–14 days.1 5 9 10 17 22 Complete response (e.g., platelet count ≤600,000/mm3) generally achieved within 4–12 weeks.1

Food

Food decreases peak plasma concentrations by 14% and increases AUC by 20%; not clinically important.1 5 9

Special Populations

In children and adolescents 7–14 years of age, AUC and peak plasma anagrelide concentrations lower than those in adults 16–86 years of age.1

Distribution

Extent

Distributes extensively into large peripheral compartment.24

Crosses placenta.5

Elimination

Metabolism

Extensively metabolized in liver to at least 4 metabolites, including an active hydroxylated derivative (3-hydroxyanagrelide).1 4 5 9 16 17 22 23 24

Undergoes first-pass metabolism by CYP1A2 to 3-hydroxyanagrelide.9

Elimination Route

Excreted principally in urine as metabolites (>70%) and unchanged drug (<1%).5 9 16 17 22 23 24 Approximately 10% excreted in feces through bile.5 24

Half-life

Anagrelide: Approximately 1.3 hours after a single 0.5-mg dose under fasting conditions.1 17 29

3-Hydroxyanagrelide: Approximately 3 hours.29

Special Populations

Systemic exposure increased eightfold in patients with moderate hepatic impairment compared with that in healthy individuals.1 9

Severe renal impairment (Clcr <30 mL/minute) does not appear to affect pharmacokinetics of anagrelide.1 9

Possible decreased clearance and prolonged half-life in geriatric patients.5

Warnings and Precautions

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 Agrylin 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 Agrylin 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 Agrylin dose in patients with moderate hepatic impairment. Use of Agrylin 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 Agrylin only when the benefits outweigh the risks.

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)].

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 Agrylin and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions (6)].

Drug Interactions

Drugs that Prolong QT

Do not use Agrylin 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)].

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)].

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).

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).

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of anagrelide in the elderly.

Anagrelide Pregnancy Warnings

Use is not recommended. AU TGA pregnancy category: B3 US FDA pregnancy category: C Comments: -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. -Use of adequate methods of contraception should be encouraged.

A study in female rats revealed that anagrelide hydrochloride at oral doses equivalent to 49 times the recommended maximum human dose or higher disrupted implantation and exerted adverse effect on embryo/fetal survival, produced delay or blockage of parturition, deaths of nondelivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Anagrelide Breastfeeding Warnings

Breastfeeding is not recommended during use of this drug. Excreted into human milk: Unknown Excreted into animal milk: Yes The effects in the nursing infant are unknown.

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