Drug information of Anagrelide

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Anagrelide

فارسی

agrelide 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.

Mechanism of effect

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In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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

Pharmacodynamic

Anagrelide is a drug used for the treatment of essential thrombocytosis. It works by inhibiting the maturation of megakaryocytes into platelets. The exact mechanism of action is unclear, although it is known to be a potent (IC50 = 36nM) inhibitor of phosphodiesterase-III.

Pharmacokinetics

Absorption : Not Available

Protein binding : Not Available

Metabolism : Liver

Half time : At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.

Toxicity : There are no reports of overdosage with anagrelide, however thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Single oral doses of anagrelide 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.

Drug indications

thrombocytopenia

Dosage

Usual Adult Dose :
Thrombocythemia:
Initial dose: 0.5 mg orally 4 times a day, or 1 mg orally twice a day, for a minimum of 7 days.
Maintenance dose: Increase the dosage by no more than 0.5 mg/day in any 1 week period.
The dosage should not exceed 10 mg/day or 2.5 mg in any single dose.
Usual Pediatric Dose:
Chronic Myelogenous Leukemia:
Initial dose: 0.5 mg orally daily (recommended) to 0.5 mg orally 4 times daily
Maintenance: Increase the dosage by no more than 0.5 mg/day in any 1 week period.
The dosage should not exceed 10 mg/day or 2.5 mg in any single dose.
Thrombocythemia:
Initial dose: 0.5 mg orally daily (recommended) to 0.5 mg orally 4 times daily
Maintenance: Increase the dosage by no more than 0.5 mg/day in any 1 week period.
The dosage should not exceed 10 mg/day or 2.5 mg in any single dose.
Renal Dose Adjustments:
Moderate hepatic impairment: Single 1 mg dose showed an 8-fold increase in total exposure (AUC) to anagrelide
Severe renal impairment (creatinine clearance less than 30 mL/min): Single 1 mg dose showed no significant effects on the pharmacokinetics of anagrelide
Liver Dose Adjustments
Use of anagrelide in patients with severe hepatic impairment is contraindicated. Patients with moderate hepatic impairment should receive a starting dose of 0.5 mg/day and be maintained at that dose for a minimum of 1 week (careful monitoring of cardiovascular effects should be instituted during this time). Incremental increases should not exceed more than 0.5 mg/day in any 1 week.
Dose Adjustments
Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage.
Precautions:
-Anagrelide has not been studied in pediatric patients less than 7 years of age.

Alerts

  • Obtain pretreatment cardiovascular exam, including ECG, in all patients.
  • tell your doctor and pharmacist if you are allergic to anagrelide 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. Be sure to mention any of the following: atazanavir (Reyataz); cilostazol (Pletal); cimetidine (Tagamet); clozapine (Clozaril); cyclobenzaprine (Flexeril); fluoroquinolone antibiotics including ciprofloxacin (Cipro), gatifloxacin (Tequin), levofloxacin (Levaquin), norfloxacin (Noroxin), ofloxacin (Floxin), others; fluvoxamine (Luvox); imipramine (Tofranil); inamrinone; mexiletine (Mexitil); milrinone (Primacor); naproxen (Aleve, Naprosyn, in PrevacidNapraPAC); riluzole (Rilutek); sucralfate (Carafate); tacrine (Cognex);theophylline (Elixophyllin, Theo-24, Theolair, others); and ticlopidine (Ticlid). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • 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 anagrelide 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 anagrelide. Talk to your doctor about types of birth control that are right for you. If you become pregnant while taking anagrelide, call your doctor immediately. Do not breast-feed while you are taking anagrelide.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking anagrelide.
  • you should know that anagrelide 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 anagrelide 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 anagrelide. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
  • Hepatic impairment increases anagrelide exposure and could increase risk of QT prolongation; monitor patients with hepatic impairment for QT prolongation and other cardiovascular adverse reactions
  • Increases QT 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 QT prolongation, medicinal products that can prolong QT interval and hypokalemia
  • Orthostatic hypotension reported with higher doses; minimal BP changes observed following 2 mg/dose
Coadministration with aspirin increases risk for major hemorrhagic event

Points of recommendation

  • Caution in heart disease, renal impairment, mild-moderate hepatic impairment
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Anagrelide may make your skin sensitive to sunlight.
  • 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)
  • Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) reported to be associated with use of anagrelide in post-marketing reports. Discontinue anagrelide if it occurs and evaluate; symptoms may improve after discontinuation
  • In patients with cardiac disease, use only when benefits outweigh risks
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic ECG monitoring

Pregnancy level

C

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