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A - Regimen Name

ANGR Regimen
Anagrelide


Disease Site
Hematologic - Myeloproliferative Neoplasms (MPNs)

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

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.


Supplementary Public Funding

anagrelide
ODB - General Benefit (anagrelide)

 
B - Drug Regimen

anagrelide
0.5 to 1 mg PO BID

OR

anagrelide
0.5 mg PO QID

Titrated to lowest effective dosage

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Not applicable

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs.

  • Initial dose should be 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



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

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.

 

Dosage in 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 - Adverse Effects

Refer to anagrelide drug monograph(s) for additional details of adverse effects


Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Headache
  • Diarrhea
  • Palpitations
  • Fatigue
  • Edema
  • Abdominal pain
  • Nausea, vomiting
  • Dizziness
  • Pain
  • Cough, dyspnea
  • Flatulence
  • ↑ LFTs
  • Arrhythmia, QT interval prolonged
  • Cardiotoxicity
  • Nephritis
  • Arterial thromboembolism
  • Venous thromboembolism
  • Interstitial lung disease
  • GI bleeding
 
G - Interactions

Refer to anagrelide drug monograph(s) for additional details


  • Avoid concurrent use with QT prolonging drugs and other PDE III inhibitors
  • Caution with CYP1A2 inhibitors and inducers. Monitor for toxicity/response and adjust anagrelide dose accordingly.
  • Caution with CYP1A2 substrates, especially those with a narrow therapeutic range.  Anagrelide may inhibit metabolism of these substrates.
  • Caution with aspirin and monitor for bleeding closely. Use extreme caution in patients with high risk for hemorrhage and/or with platelets > 1000 x 109/L before treatment
  • Caution and monitor with other drugs known to cause bleeding (e.g., anticoagulants, NSAIDs, antiplatelet agents)
  • Separate administration of anagrelide and sucralfate by at least 2 hours to facilitate absorption, and monitor anagrelide response if used together.
 
H - Drug Administration and Special Precautions

Refer to anagrelide drug monograph(s) for additional details


Administration:

  • 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.

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

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
  • 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).  Breastfeeding is not recommended.
 
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

  • 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; monitor closely in patients with known or suspected heart disease
  • Clinical toxicity assessment for palpitations, blood pressure, headache, GI, fatigue, edema, bleeding, dizziness, pulmonary effects; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia. N Engl J Med 2005;353:33-45.

Gisslinger H, Gotic M, Holowiecki J, et al.  Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121(10):1720-8.

May 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. 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, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.