Anagrelide (Atremia) inhibits phospholipase A2 resulting in the inhibition of megakaryocyte maturation. Thus, it reduces the platelet counts. It is used to treat patients with thrombocythemia secondary to myeloproliferative disorders and essential thrombocythemia to reduce the platelet counts. It also reduces the risk of thrombosis and other symptoms associated with thrombocythemia including thrombo-hemorrhagic events.

Anagrelide dose in adults:

Anagrelide dose in the treatment of Thrombocythemia:

• 0.5 mg orally four times a day initially or 1 mg two times a day.
• Most patients respond to doses ranging from 1.5 to 3 mg per day.
• The initial treatment is given for one week after which the dose is titrated to achieve platelet counts of less than 600,000/ul.
• The dose should not be increased by more than 0.5 mg per day per week.
• The maximum single dose is 2.5 mg and the maximum recommended daily dose is 10 mg per day.

Anagrelide Dose in the treatment of essential  Thrombocythemia:

• 0.5 mg orally twice a day for 1 week.
• The dose is then adjusted to maintain platelet counts at less than 450,000/mm³ or at least less than 600,000/mm³.

Anagrelide dose in Children:

Anagrelide Dose in the treatment of Essential thrombocythemia in Children older than 6 years of age:

• 0.5 mg orally twice or thrice daily.
• The dose is increased by 0.5 mg at weekly intervals until the platelet counts begin to drop.
• The usual reported maintenance dose is between 1 to 2.5 mg/day.
• The maximum daily dose is 10 mg/day.
• The maximum dose for the treatment of essential thrombocythemia is 4 mg/day.
• After the platelet counts normalize the dose may be gradually reduced and discontinued if necessary.

Anagrelide Dose in the treatment of Secondary thrombocythemia associated with myeloproliferative disorders in children older than 6 years of age:

• 0.5 mg orally once a day initially
• The usual dose ranges between 0.5 mg once to four times a day.
• The median maintenance daily dose according to the patients' age is as follows:

  • Patient age 7-11 years:

    • 1.75 mg/day in divided doses.

  • Patient age 11-14 years:

    • 2 mg per day in divided doses.
• The dose should be maintained for one week and adjusted to the lowest effective dose to maintain the platelet counts at less than 600,000/mm³.
• The dose should not be increased by more than 0.5 mg per day in any week.
• The maximum daily dose is 10 mg/day.

Pregnancy Risk Category: C

• High platelet counts can increase the risk of poor pregnancy outcomes, including stillbirths, miscarriage and preeclampsia.
• During pregnancy, however, other agents than anagrelide may be preferred.

Anagrelide use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• It is important to avoid the neonate during treatment, and for at least one week after the last dose.

Anagrelide dose in kidney disease:

• Adjustment in the dose is not required, however, the patient should be monitored closely.

Hemodialysis:

• It is not dialyzable. 

Anagrelide dose in liver disease:

• Moderate impairment, Child Class B (Child-Pugh score 7 to 9):

  • 0.5 mg once a day for seven days.
  • If the dose is tolerated, it may be increased by no more than 0.5 mg per day in a week.
  • Careful cardiovascular monitoring is recommended.

• Severe impairment, Child Class C (Child-Pugh score ≥10):

  • Avoid its use.

Side effects of anagrelide:

• Cardiovascular:

  • Palpitations
  • Edema
  • Peripheral Edema
  • Chest pain
  • Tachycardia
  • Angina Pectoris
  • Cardiac Arrhythmia
  • Cardiac failure
  • Hypertension
  • Orthostatic hypotension
  • Syncope
  • Vasodilatation
  • Atrial fibrillation
  • Cardiomegaly
  • Cardiomyopathy
  • Cerebrovascular Accident
  • Complete atrioventricular block
  • Decreased diastolic pressure
  • Increased heart rate
  • Myocardial infarction
  • Pericardial effusion
  • Systolic hypotension

• Central nervous system:

  • Headache
  • Dizziness
  • Pain
  • Malaise
  • Paresthesia
  • Amnesia
  • Chills
  • Confusion
  • Depression
  • Drowsiness
  • Insomnia
  • Migraine
  • Nervousness
  • Fatigue

• Dermatologic:

  • Skin rash
  • Pruritus
  • Alopecia

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Abdominal pain
  • Flatulence
  • Vomiting
  • Anorexia
  • Dyspepsia
  • Constipation
  • Gastritis
  • Gastrointestinal hemorrhage
  • Pancreatitis

• Hematologic & oncologic:

  • Anemia
  • Bruise
  • Hemorrhage
  • Thrombocytopenia

• Hepatic:

  • Increased liver enzymes

• Neuromuscular & skeletal:

  • Weakness
  • Back pain
  • Arthralgia
  • Myalgia
  • Muscle cramps

• Ophthalmic:

  • Diplopia
  • Visual field defect

• Otic:

  • Tinnitus

• Renal:

  • Hematuria
  • Renal failure

• Respiratory:

  • Dyspnea
  • Cough
  • Epistaxis
  • Flu-like symptoms
  • Pneumonia
  • Pleural effusion
  • Pulmonary hypertension
  • Pulmonary fibrosis
  • Pulmonary infiltrates

• Miscellaneous:

  • Fever

Contraindication to Anagrelide Include:

• There are no contraindications for its use, according to the manufacturer.

Warnings and precautions

• Bleeding risk:
  • It may be associated with an increased risk of bleeding diathesis when used with aspirin.
  • Patients on anticoagulants (warfarin and rivaroxaban) and antiplatelet agents like aspirin, clopidogrel and prasugrel should be closely monitored for bleeding.
• Cardiovascular adverse events:
  • It is associated with a higher risk of developing cardiac arrhythmias.
  • Patients can develop ventricular tachycardia or torsades-de-pointes.
  • Anagrelide, like other PDE3 inhibitors can cause vasodilation and tachycardia.
  • PDE3 inhibitors have a lower survival rate in class III and IV heart disease than placebo.
  • It can also cause QTc prolongation. QTc prolongation can be caused by dose.
  • Patients with hypokalemia, congenital QT syndrome, congenital long QT syndrome, and patients with a history of QTc prolongation or concomitant medication that can prolong the QTc interval should avoid it.
  • Higher doses of medication can cause hypotension in patients.
  • Patients with heart disease, bradyarrhythmias and electrolyte abnormalities, especially hypokalemia, should have periodic ECGs.
• Hypertension in the lungs:
  • Patients should be evaluated before starting treatment and every other day for any cardiorespiratory symptoms.
  • Long-term use of the drug could lead to pulmonary hypertension.
• Toxicity in the lungs:
  • Interstitial lung disease can occur in patients with eosinophilic or interstitial pneumonia.
  • ILD can present as soon as the disease has begun or after several years of drug abuse.
  • Patients will most likely present with progressive dyspnea and dry cough.
• Renal abnormalities
  • Patients suffering from renal disease should be cautious about taking the drug.
  • Acute renal shutdown can occur in those with pre-existing kidney disease.
  • An adjustment to the dose is not necessary.
• Hepatic impairment
  • It should be avoided in cases of severe hepatic impairment.
  • Mild to moderate hepatic impairment may require a reduction in dose and close monitoring of the heart.
  • QTc prolongation may be possible when drug exposure is increased in liver disease.
  • Before and during treatment, it is important to monitor the liver functions.

Anagrelide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• The platelet counts should be monitored every two days during the first week, weekly thereafter till the maintenance dose is reached, and periodically till the drug is continued.
• Monitor CBC with differential during the first two weeks of treatment
• Liver function tests including ALT and AST prior to treatment initiation and during the treatment.
• Renal function tests (BUN, and serum creatinine) during the first few weeks of treatment
• Monitor serum electrolytes
• Vital signs including the blood pressure and heart rate
• Cardiovascular exam, including ECG before treatment initiation and periodically as needed.
• Monitor for thrombosis and bleeding
• Observe for the clinical features of interstitial lung disease (Shortness of breath and dry cough)

How to take Anagrelide?

• It may be administered with or without food as food does not affect its bioavailability.

Mechanism of action of Anagrelide:

• Anagrelide inhibits PhospholipaseA2 which results in the inhibition cyclic nucletide phosphodiesterase as well as the release arachidonic acid by phospholipase.
• It also interrupts the postmitotic stage of megakaryocyte maturation, resulting in a dose-related decrease in platelet production.

It has beenThe beginning of actionThe platelets will be reduced to 600,000./ul within seven to fourteen days. It may take up to 12 weeks to receive a complete response.

TheDuration of the actionThe drug works for approximately 6 to 24 hours. After discontinuing treatment, platelet counts start to rise after approximately 96 hours. It isMetabolizedThrough CYP1A2 (liver), two major metabolites are formed: an active metabolite 3-hydroxyanagrelide, and an inactive one RL603. ThebioavailabilityThe drug's effect on the body is not significantly affected if taken with food. 

Thehalf-life eliminationThe half-life of the drug is approximately 1.5 hours, while the active metabolite takes about 2.5 hours. It takes time to get there peak serum concentration It takes approximately one hour. excreted In the urine.

Anagrelide Brand Names (International):

• Agry-Gen
• Agrylin
• DOM-Anagrelide
• MYLAN-Anagrelide [DSC]
• PMS-Anagrelide
• SANDOZ Anagrelide
• Agrelid
• Agrylin
• Anagrid
• Atremia
• Embodot
• Grenalvon
• Magicrelide
• Replcount
• Thrombonorm
• Thromboreductin
• Xagrid

Anagrelide Brand Names in Pakistan: