anagrelide

Trade Name:

Agrylin®

Appearance:

capsule

Monograph Name:

anagrelide

Monograph Body:

Drug Monograph

A - Drug Name

anagrelide

COMMON TRADE NAME(S): Agrylin®

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.

** 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

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
Toxicity	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
Teratogenicity: Probable

Anagrelide is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 6 months after the last dose. (general recommendation)
Excretion into breast milk: Yes

Breastfeeding is not recommended.
Fertility effects: Yes

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

J - Supplementary Public Funding

ODB Limited Use (ODB Formulary )

anagrelide

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.

April 2024 Updated Pregnancy and Lactation section

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.

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.

Info Sheet Name:

anagrelide (patient)

Info Sheet Introduction:

• For treating a condition where there are too many platelets in the blood. Platelets help blood to clot.

Info Sheet Date: Vendredi, juillet 28, 2017 Info Sheet body:

Medication Information Sheet

anagrelide (an-AG-gre-lide)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Agrylin®

Appearance:

capsule

What is this medication for?

For treating a condition where there are too many platelets in the blood. Platelets help blood to clot.

What should I do before I have this medication?

Tell your doctor and pharmacist if you have or had significant medical condition(s) such as:
- liver problems
- kidney problems
- lung problems
- heart problems, including irregular heartbeat
- low salt levels (for example, potassium, magnesium, calcium) in your blood
- any allergies
This drug contains a small amount of lactose. If you cannot tolerate lactose, talk to your health care team.
Patients with too many platelets have a higher risk of getting blood clots or some types of cancers. Some treatments may increase this risk. Discuss this with your health care team.

How will this medication affect sex, pregnancy and breastfeeding?

The use of this medication in men or women may cause harm to the unborn baby if pregnancy occurs. Let your health care team know if you or your partner is pregnant, becomes pregnant during treatment, or if you are breastfeeding.
If there is any chance that you or your partner may become pregnant, you and your partner together must:
- ► Use 2 effective forms of birth control at the same time while taking this drug. Keep using birth control for at least 6 months after your last dose unless your health care team told you differently. Talk to your health care team to figure out the best method(s) for you and/or your partner.
Do not breastfeed while using this drug.
This medication may affect fertility (ability to get pregnant)

How is this medication given?

Swallow whole with a glass of water, with or without food.
Do not crush or open the capsules.

Anagrelide is usually taken multiple times a day.
Take it exactly as directed by your doctor. Make sure you understand the instructions.
If you miss a dose, take it as soon as you remember. If it is almost time for next dose, skip the missed dose and take your next dose as scheduled. Do not take 2 doses at the same time.

What else do I need to know while on this medication?

This medication can interact with other medications and can result in the treatment not working as well or cause severe side effects.
Make sure your health care team knows about all your medications (prescription, over-the-counter, herbals and supplements). Check with your health care team before starting or stopping any of them.
For mild aches and pain:
- You may take acetaminophen (Tylenol®) tablets. Ask your health care team about the right dose for you.
- Ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin (acetylsalicylic acid, ASA), including low dose aspirin for heart conditions, may increase your chance of bleeding.
- Talk to your health care team before you start or stop these medications.
- If you feel unwell, take your temperature before taking any of these medications. They may hide a fever.
- Talk to your health care team or go to the closest emergency room right away if you have a fever. See the Fever pamphlet for more information.
Drinking alcohol and smoking during your treatment may increase some side effects and make your medication less effective. Speak to your health care team about smoking and drinking alcohol while on treatment.

Do not eat or drink grapefruit, grapefruit juice and related products while taking this drug. They may increase the amount of drug in your blood and increase side effects.

How should I safely store this medication?

Keep this medication in the original packaging at room temperature in a dry place, away from heat and light. Keep out of sight and reach of children and pets.
Do not throw out any unused medications at home. Bring them to your pharmacy to be thrown away safely.

What are the side effects of this medication?

You may not have all of the side effects below. You may have side effects that are not listed.

Side effects and what to do	When to contact doctor?
Common Side Effects (25 to 49 out of 100 people)

Headache; mild joint, muscle pain or cramps

Take your pain medication as prescribed by your doctor.
You can take acetaminophen (Tylenol®) tablets as needed for mild aches and pains. Ask your doctor or pharmacist about the right dose for you.
Talk to your doctor or pharmacist first before taking ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin. These medication may increase bleeding risk.
Rest often and try light exercise as it may help.

Contact your health care team if no improvement or if severe

Diarrhea

May happen days to weeks after you get your treatment.

If you have diarrhea :

Take anti-diarrhea medication if your health care team prescribed it.
Avoid foods or drinks with artificial sweetener (e.g. chewing gum, “diet” drinks), coffee and alcohol.
Eat many small meals and snacks instead of 2 or 3 large meals.
Drink at least 6 to 8 cups of liquids each day. Talk to your health care team if you can’t drink 6-8 cups of liquids each day when you have diarrhea. You may need special liquids with salt and sugar, called Oral Rehydration Therapy.

See the Diarrhea pamphlet for more information.

Contact your health care team if no improvement or if severe

Pounding or irregular heartbeat

• Talk to your health care team right away or get emergency medical help if your heartbeat is irregular, unusually fast or you have chest discomfort/pain, severe shortness of breath, feel faint (pass out) or very dizzy

Side effects and what to do	When to contact doctor?
Less Common Side Effects (10 to 24 out of 100 people)

Fatigue (tiredness)

Be active and aim to get 30 minutes of moderate exercise (you are able to talk comfortably while exercising) on most days. Check with your health care team before starting any new exercise.
Pace yourself, do not rush. Put off less important activities. Rest when you need to.
Eat well and stay hydrated by drinking at least 6 to 8 glasses of water or other liquids every day (unless your doctor told you to drink more or less).
Avoid driving or using machinery if you are feeling tired

See our Fatigue pamphlet for more information.

Contact your health care team if no improvement or if severe

Mild swelling in arms and legs; puffiness

To help prevent swelling :

Eat a low-salt diet.
Avoid tight fitting clothing.

If you have swelling in your legs, keep your feet up when sitting.

Contact your health care team if no improvement or if severe

Pains or cramps in the belly

If you have constipation or diarrhea it may be causing the pain in your belly.
If the pain is severe, gets worse or doesn’t go away, talk to your health care team about other possible causes.

Contact your health care team if no improvement or if severe

Nausea and vomiting (generally mild)
May occur in hours to days after your treatment.

If you have nausea or vomiting:

Take anti-nausea medication(s) as prescribed to you by your doctor.
Drink clear liquids and have small meals. Get fresh air and rest.
Do not eat spicy, fried foods or foods with a strong smell.
Limit caffeine (e.g. coffee, tea) and alcohol.
Contact your health care team if the prescribed anti-nausea medications are not helping to control your nausea and vomiting.

Also see Nausea & Vomiting pamphlet for more information.

Contact your health care team if no improvement or if severe

Dizziness

You may feel light headed.
Lay down if this happens.
Get up and move slowly once you feel better.
Do not drive a motor vehicle or use machinery if you feel dizzy.

Contact your health care team if no improvement or if severe

Cough; feeling short of breath

You may have cough and feel short of breath without any signs of infection, such as a sore throat or a stuffed nose.

Rarely this may be severe with chest pain, trouble breathing or coughing up blood. If this happens get medical help right away.

Contact your health care team if no improvement or if severe

Passing gas

You may have bloating, pain in your belly and pass gas.

Contact your health care team if no improvement or if severe

Other rare, but serious side effects are possible.
If you experience ANY of the following, speak to your cancer health care provider or get emergency medical help right away:

yellowish skin or eyes, unusually dark pee or pain on the right side of your belly
swelling in your legs, ankles and belly, chest pain that may spread to your arm
pain, swelling and hardening of a vein in your arm or leg
passing very little or no pee, gaining weight that is new or unusual
confusion, sudden loss of vision, trouble speaking or using your arms or legs
vomiting blood or what looks like coffee-grounds
having black stools (poo) or stools with bright-red blood

For more links on how to manage your symptoms go to https://www.cancercareontario.ca/en/symptom-management.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace 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.

Info Sheet (English):

anagrelide patient.pdf Info Sheet (French):

anagrelide pour le patient.pdf Monograph:

anagrelide.pdf Funding Program: ODB Limited Use Funding Instance:

anagrelide

Phonetic Spelling:

an-AG-gre-lide

Cancer Type: Hematologic Myeloproliferative Neoplasms (MPNs) Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Lundi, avril 29, 2024 Universal Date: 2024-04-29 00:00:00 AddThis: Title URL: anagrelide Drug Display Status: Active Revision Summary:
Drug Monograph: Updated Pregnancy and Lactation section