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A - Drug Name

anagrelide

COMMON TRADE NAME(S):   Agrylin® (Shire Pharma)

 
B - Mechanism of Action and Pharmacokinetics

Anagrelide is a cyclic AMP phosphodiesterase (PDE) III inhibitor.  It may decrease megakaryocyte hypermaturation, which results in dose-related reduction in platelet production.  There is no clinically significant effect on red cell, white cell or coagulation parameters.  It is 50 times more potent than ASA as an anticoagulant; however, platelet aggregation is inhibited at higher doses than those used to reduce platelet count.  



Absorption

Longer time lag before absorption, slower absorption rate and later Tmax were observed with food administration.  Food increased anagrelide exposure by 20% but did not affect the exposure of its active metabolite.


Metabolism

Extensively metabolized by the liver, partly by CYP1A2. 

Active metabolites

Yes

Inactive metabolites

Yes

Elimination
Urine

> 70%

Half-life

1-2 hours (anagrelide); 3 hours (active metabolite)

 
C - Indications and Status
Health Canada Approvals:

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



 
D - Adverse Effects

The following adverse effects were observed in clinical trials, which occurred in ≥5% of patients (or life-threatening) with myelo-proliferative neoplasms of varying etiology [Essential Thrombocythemia (ET),  Polycythemia Vera (PV), other myeloproliferative neoplasms (OMPN)].

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arrhythmia (<5%) E
Arterial thromboembolism (rare) E  D
Cardiotoxicity (<5%) E  D
Palpitations (26%) ; tachycardia E
QT interval prolonged (rare) E
Venous thromboembolism (<5%) E  D
Dermatological Rash, pruritus (8%) E
Gastrointestinal Abdominal pain (17%) E
Anorexia (8%) E
Diarrhea (26%) E
Dyspepsia (5%) E
Flatulence (10%) E
GI hemorrhage (<5%) E
Nausea, vomiting (17%) I  E
General Edema (21%) E
Fatigue (23%) E
Fever (9%) I
Pain (15%) E
Hepatobiliary ↑ LFTs (<5%) (may be severe - hepatitis) E  D
Nervous System Dizziness (15%) E
Headache (44%) E
Paresthesia (6%) E
Renal Creatinine increased (<5%) (renal failure 1%; nephritis) E  D
Respiratory Cough, dyspnea (12%) E  D
Interstitial lung disease (e.g. allergic alveolitis, eosinophilic pneumonia) E  D  L


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for anagrelide include headache, diarrhea, palpitations, fatigue, edema, abdominal pain, nausea/vomiting, dizziness, pain, cough/dyspnea.

Interstitial lung disease has been reported, presenting with progressive dyspnea associated with lung infiltrations.  Onset ranges from 1 week to several years after starting anagrelide.  Symptoms improved after anagrelide discontinuation in most cases.

Mechanistic inotropic and chronotropic effects may result in tachycardia and cardiac effects.

 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:

Starting dose:


Oral: 0.5 mg QID

or


Oral: 1 mg BID

maintained for at least one week

Then, adjust to the lowest effective dose needed to reduce and maintain platelets to < 600 x 109/L, and ideally to the normal range.

  • Do not increase more than 0.5 mg/day in any one week
  • Maximum dose: 10 mg/day or 2.5 mg in a single dose
  • Most patients have adequate responses at 1.5 to 3 mg/day
  • Response starts within 7-14 days at the proper dosage, but may take 4-12 weeks for complete response to occur

Dosage with Toxicity:

Toxicity Action
Hold when suspected; discontinue if confirmed.
Interstitial lung disease
CHF, MI
Severe ↑ LFTs
Hepatitis

 

 



Dosage with Hepatic Impairment:

Anagrelide exposure is increased 8-fold in patients with moderate hepatic impairment. Use in mild and moderate hepatic impairment only if benefits outweigh risks. Anagrelide has not been studied in and is CONTRAINDICATED in severe hepatic impairment.

Hepatic Impairment Starting Dose
Mild No change; regular hepatic and cardiovascular monitoring
Moderate 0.5 mg/day for at least one week, titration with no more than a 0.5mg/day increase in any one week; regular hepatic and cardiovascular monitoring
Severe CONTRAINDICATED


Dosage with Renal Impairment:

Serum Creatinine (micromol/L)  Dose
< 177 No dose adjustment required
≥ 177 Give only if benefits outweigh risks. Monitor closely for nephrotoxicity.


Dosage in the elderly:

No specific studies have been conducted in patients ≥ 65 years, but older patients were observed to have lower presystemic anagrelide metabolism to its active metabolite; however, no dose adjustment is needed.



Children:

Safety and efficacy of anagrelide in patients < 16 years of age have not been established.  Use with caution as lower exposure has been observed in children/adolescents compared to adults (± 50% lower Cmax and AUC).



 
F - Administration Guidelines
  • May be given with or without food
  • Grapefruit, grapefruit juice and related products should be avoided (see Drug Interactions section)
  • Store at 15°C to 25°C in a light-resistant container.
 
G - Special Precautions
Contraindications:

  • patients with hypersensitivity to this drug or to any components in the formulation or container
  • patients with severe hepatic impairment
  • not recommended in women who are or may become pregnant

Other Warnings/Precautions:

  • intended for chronic usage; not been evaluated for treatment of the acute life-threatening complications of thrombocytosis
  • patients with mild or moderate hepatic impairment
  • patients with renal impairment (Cr ≥ 177 micromol/L)
  • sudden anagrelide discontinuation or interruption results in an increase in platelet count, within 4 days
  • patients with known or suspected cardiac disease, due to anagrelide's positive inotropic and chronotropic effects
  • patients with known risk factors for QT prolongation, such as congenital long QT syndrome, known history of acquired QTc prolongation, medications that can prolong QT, hypokalemia


Other Drug Properties:

  • Carcinogenicity: Probable

    Uterine adenocarcinoma, benign and malignant pheochromocytomas were observed in animal studies.

Pregnancy and Lactation:
  • Embryotoxicity: Yes
  • Fetotoxicity: Yes

    Anagrelide is not recommended for use in pregnancy. Females of child-bearing potential must not be pregnant before starting and during treatment.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).

  • Teratogenicity: Probable
  • Fertility effects: Yes
  • Excretion into breast milk: Yes

    Breastfeeding is not recommended.

 
H - Interactions

Digoxin and warfarin do not affect pharmacokinetics (PK) of anagrelide, nor does anagrelide affect the PK of these drugs.  
 

AGENT EFFECT MECHANISM MANAGEMENT
Other PDE3 inhibitors (e.g. milrinone, cilostazol) ↑ inotropic and chronotropic effects Additive Avoid
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) ↑ risk of QT prolongation Additive Avoid
CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, grapefruit juice) ↑ anagrelide exposure anagrelide is metabolized partly by CYP1A2 Caution; monitor for anagrelide toxicity and adjust dose accordingly
CYP1A2 inducers (e.g. omeprazole, carbamazepine) ↓ anagrelide exposure ↑ metabolism of anagrelide Caution; monitor platelet response and titrate dose accordingly
CYP1A2 substrates (e.g. amitriptyline, haloperidol, theophylline) ↑ exposure of these substrates anagrelide may inhibit CYP1A2 Caution, especially for substrates with narrow therapeutic range
Aspirin ↑ risk of hemorrhage; major bleeding events have been reported Additive antiplatelet effects Caution and monitor closely; extreme caution in patients with high risk for hemorrhage and/or with platelets > 1000 x 10^9/L before treatment
Other drugs known to cause bleeding (e.g., anticoagulants, NSAIDs, antiplatelet agents) ↑ risk of bleeding Additive (has synergistic effect on platelet aggregation inhibition when given with heparin) Caution; monitor closely
Sucralfate Unknown may interfere with anagrelide absorption Separate sucralfate and anagrelide administration at least 2 hours apart
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
 

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline, then every 2 days during the first week, and at least weekly thereafter until maintenance dosage is reached

Liver function tests

Baseline, and as clinically indicated; at least monthly in patients with hepatic impairment

Renal function tests

Baseline, and as clinically indicated; at least monthly in patients with renal impairment

Electrolytes

Baseline and regular

Cardiovascular (including ECG)

Baseline, then as indicated during treatment, closely in patients with known or suspected heart disease

Clinical toxicity assessment for headache, palpitations, blood pressure, GI, fatigue, edema, bleeding, dizziness, pulmonary effects

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

Product Monograph:  Agrylin® (anagrelide).  Shire Pharma Canada, March 13, 2017.

Prescribing Information:  Agrylin® (anagrelide).Shire US Inc., July 2015.

Anagrelide monograph. British Columbia Cancer Agency, November 1, 2015.

 


 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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