Agrylin

Name: Agrylin

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Inform MD

Before taking Agrylin,

  • tell your doctor and pharmacist if you are allergic to Agrylin or any other medications.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had bleeding problems; high or low blood pressure; lactose intolerance (inability to digest dairy products) or heart, kidney, or liver disease.
  • do not take Agrylin if you are pregnant or plan to become pregnant. You should use an effective form of birth control to prevent pregnancy during your treatment with Agrylin. Talk to your doctor about types of birth control that are right for you. If you become pregnant while taking Agrylin, call your doctor immediately. Do not breast-feed while you are taking Agrylin.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking Agrylin.
  • you should know that Agrylin may make you dizzy, especially when you first start taking the medication. Do not drive a car or operate machinery until you know how this medication affects you.
  • you should know that Agrylin may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking Agrylin. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Agrylin may make your skin sensitive to sunlight.

What should I avoid while taking Agrylin (anagrelide)?

Do not take aspirin unless your doctor has told you to. Follow your doctor's instructions about how much aspirin to take, and how often to take it.

Ask a doctor or pharmacist before using any pain, cold, allergy, or sleep medication. Aspirin (sometimes abbreviated as ASA) is contained in many combination medicines. Check the label to see if a medicine contains aspirin or ASA.

Ask your doctor before using anagrelide if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with anagrelide may cause you to bruise or bleed easily.

Introduction

Platelet-reducing agent; imidazoquinazoline derivative.1 4 5 7 9 10 11 12 14 15 16 17 18 22 23 24 26 31 32

Interactions for Agrylin

Metabolized partially by CYP1A2; inhibits CYP1A2 to a limited extent.1

Inhibits phosphodiesterase (PDE) type 3.1 4 5 9 10 11 16 18 22 23

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: Potential pharmacokinetic interaction (decreased clearance of anagrelide).1 9 22

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 substrates: Potential pharmacokinetic interaction (decreased clearance of substrate).1 22

Specific Drugs or Foods

Drug or Food

Interaction

Comments

Aspirin

No clinically important interaction observed in vivo;1 however, potential for increased risk of bleeding due to additive platelet inhibition3 5 9 10 11 14 22 27

Use concomitantly with caution, considering individual risks of thrombosis and bleeding; carefully monitor for bleeding3 5 11 27

Digoxin

Pharmacokinetic interaction unlikely1 9 22

Fluvoxamine

Possible decreased clearance of anagrelide1 9 22

Grapefruit juice

Possible decreased clearance of anagrelide 9 22

Omeprazole

Possible decreased clerance of anagrelide 22

PDE type 3 inhibitors (e.g., amrinone, cilostazol, milrinone)

Possible additive pharmacologic effects1 9 22

Use with caution22

Sucralfate

Possible decreased absorption of anagrelide1

Theophylline

Possible decreased clearance of theophylline 1 9 22

Warfarin

Pharmacokinetic interaction unlikely1 9 22

Stability

Storage

Oral

Tablets

25°C in light-resistant container; may be exposed to 15–30°C.1

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of lung or breathing problems like shortness of breath or other trouble breathing, cough, or fever.
  • Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Chest pain or pressure or a fast heartbeat.
  • A heartbeat that does not feel normal.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Very bad dizziness or passing out.
  • Very bad headache.
  • Feeling very tired or weak.
  • Change in eyesight.
  • Not able to pass urine or change in how much urine is passed.
  • Low mood (depression).
  • Feeling confused.
  • Memory problems or loss.
  • A burning, numbness, or tingling feeling that is not normal.
  • Seizures.

Agrylin Dosage and Administration

Starting Dose

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

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

Titration

Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/µL, and ideally between 150,000/µL and 400,000/µL. 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 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.

Dose Modifications for Hepatic Impairment

In patients with moderate hepatic impairment (Child Pugh score 7-9) start Agrylin 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 Agrylin 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 Agrylin in patients with severe hepatic impairment.

Clinical Monitoring

Agrylin 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/µL, 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.

Agrylin - 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.

Dosing & Uses

Dosage Forms & Strengths

capsule

  • 0.5mg
  • 1mg

Thrombocythemia

Indicated for essential thrombocythemia and for thrombocythemia secondary to myeloproliferative disorders to decrease risk thrombosis and thrombo-hemorrhagic event

0.5 PO q6hr or 1 mg q12hr; increase PRN not more frequently than 0.5 mg/day/week

Not to exceed 10 mg/day or 2.5 mg/dose

Platelet count responds typically in 7-14 days; time to complete response is 4 to 12 weeks

Polycythemia Vera (Orphan)

Orphan indication sponsor

  • Roberts Pharmaceutical Corp; Meridian Center II, 4 Industrial Way West; Eatontown, NJ 07724-2274

Hepatic Impairment

Moderate: Start with 0.5 mg/day for at least 1 week; increase PRN no more frequently than 0.5 mg/day/week

Severe: Contraindicated

Monitor

Platelet count

Dosage Forms & Strengths

capsule

  • 0.5mg
  • 1mg

Thrombocythemia

0.5 mg/day to 0.5 mg PO q6hr; adjust dose PRN no more frequently than 0.5 mg/day/week

Platelet count responds typically in 7-14 days; time to complete response is 4 to 12 weeks

Warnings

Contraindications

Severe hepatic impairment

Cautions

Caution in heart disease, renal impairment, mild-moderate hepatic impairment

Torsades de pointes and ventricular tachycardia reported; obtain pretreatment cardiovascular exam, including EKG, in all patients

Hepatic impairment increases anagrelide exposure and could increase risk of QTc prolongation; monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions

Increases QTc interval and heart rate in healthy volunteers; should not be used in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia

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

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic ECG monitoring

Orthostatic hypotension reported with higher doses; minimal BP changes observed following 2 mg/dose

Coadministration with aspirin increases risk for major hemorrhagic event

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) reported to be associated with use of anagrelide in post-marketing reports; most cases presented with progressive dyspnea with lung infiltrations; time of onset ranged from 1 week to several years after initiating anagrelide; discontinue anagrelide if it occurs and evaluate; symptoms may improve after discontinuation

Monitor platelets, Hgb, WBC, LFTs, Cr, BUN for at least first 2 weeks

May induce highoutput heart failure by PDE4 inhibition (may be reversible upon discontinuation)

Pharmacology

Mechanism of Action

Phosphodiesterase 3 (PDE3) inhibitor; inhibits nucleotide PDE and the release of arachidonic acid from phospholipase A2; reduces also platelet production by disrupting the maturation phase of megakaryocytes

Pharmacokinetics

Onset of action: Within 7-14 days (initial); 4-12 weeks (complete)

Peak plasma time: 1 hr

Duration: 6-24 hr

Metabolism: Extensive; partially through CYP1A2

Half-life: 1.3 hr

Excretion: Urine (<1%)

In Summary

Common side effects of Agrylin include: abdominal pain, dizziness, headache, nausea, and palpitations. Other side effects include: back pain, fever, tachycardia, vomiting, and anorexia. See below for a comprehensive list of adverse effects.

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