Consumer medicine information

Agrylin

Anagrelide

BRAND INFORMATION

Brand name

Agrylin

Active ingredient

Anagrelide

Schedule

SUMMARY CMI

AGRYLIN^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using AGRYLIN?

AGRYLIN contains the active ingredient anagrelide hydrochloride. AGRYLIN is used to treat essential thrombocythaemia.

For more information, see Section 1. Why am I using AGRYLIN? in the full CMI.

2. What should I know before I use AGRYLIN?

Do not use if you have ever had an allergic reaction to AGRYLIN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use AGRYLIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with AGRYLIN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use AGRYLIN?

The recommended adult starting dose is 1 mg/day, which can be taken orally in two divided doses.
Take the tablet the same time each day.

More instructions can be found in Section 4. How do I use AGRYLIN? in the full CMI.

5. What should I know while using AGRYLIN?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using AGRYLIN. If you become pregnant while using this medicine, tell your doctor immediately.
Things you should not do	Do not stop using AGRYLIN or change the dosage without checking with your doctor.
Driving or using machines	AGRYLIN may cause dizziness. Be careful driving or operating machinery until you know how AGRYLIN affects you.
Looking after your medicine	Store AGRYLIN in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using AGRYLIN? in the full CMI.

6. Are there any side effects?

Serious side effects include heart problems, lung problems, yellowing of the skin and eyes caused by inflammation of the liver (hepatitis), and severe abdominal or back pain (pancreatitis).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI

FULL CMI

AGRYLIN^®

Active ingredient(s): anagrelide hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using AGRYLIN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using AGRYLIN.

The information in this leaflet was last updated in September 2022. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine.

Where to find information in this leaflet:

1. Why am I using AGRYLIN?
2. What should I know before I use AGRYLIN?
3. What if I am taking other medicines?
4. How do I use AGRYLIN?
5. What should I know while using AGRYLIN?
6. Are there any side effects?
7. Product details
8. Instructions for preparing and injecting AGRYLIN

1. Why am I using AGRYLIN?

AGRYLIN contains the active ingredient anagrelide hydrochloride. AGRYLIN acts upon the bone marrow and prevents it from producing too many of the blood cells known as "platelets".

In a disease such as "thrombocythaemia", the bone marrow produces too many of these cells, and the very large numbers of platelets in the blood can cause serious problems with blood circulation. By preventing too many platelets from being made, AGRYLIN can help prevent these problems.

Your doctor may have prescribed AGRYLIN for another reason. Ask your doctor if you have any questions about why AGRYLIN have been prescribed for you.

AGRYLIN capsules are not addictive. AGRYLIN is only available on a doctor's prescription.

2. What should I know before I use AGRYLIN?

Warnings

Do not take AGRYLIN if:

you are allergic to anagrelide, or any of the ingredients listed at the end of this leaflet
AGRYLIN contains lactose and microcrystalline cellulose. There may cause a problem in a small number of people who are sensitive to them.
you have severe liver problems.
you are pregnant or breast feeding.
the expiry date (EXP) printed on the bottle has passed. If you take AGRYLIN after the expiry date has passed, it may not work as well.
the packaging is torn or shows signs of tampering.

Tell your doctor if you:

have any allergies
have had or now have any liver or kidney disease
have heart disease, heart failure or are high risk of vascular events (thrombosis or bleeding)
an intolerance to some sugars, as AGRYLIN contains sugars as lactose.

Pregnancy and breastfeeding

If you become pregnant whilst taking AGRYLIN, you should stop taking the capsules and see your doctor immediately. Women taking AGRYLIN and who are at risk of becoming pregnant should make sure that they are using adequate contraception.

AGRYLIN should not be taken by anyone under 16 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and AGRYLIN may interfere with each other. These include:

aspirin or a medicine containing aspirin
medicines used to treat depression such as fluvoxamine
medicines used to treat gastrointestinal problems such as omeprazole
medicines used to treat severe asthma and breathing problems such as theophylline
medicines used to treat heart disorders such as milrinone
other medicines used to treat conditions affecting the platelets in your blood
medicines containing sucralfate.

Your doctor may have to change your dose of other medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

4. How do I use AGRYLIN?

How much to take

The recommended adult starting dose of anagrelide is 1 mg/day, which can be taken orally in two divided doses. This dosage will then be adjusted until your doctor has decided which dosage is best for you.
Any single dose taken during the day should not exceed 2.5 mg. Your total daily dose should not exceed four times this, i.e., 10 mg (20 of the 0.5 mg capsules).
If you are elderly, you should take the normal adult dose.
If you are not sure, ask your doctor or pharmacist for advice.
Follow all the directions given to you by your doctor or pharmacist carefully. They may differ from the information in this leaflet.

When to take AGRYLIN

Take AGRYLIN at the same time each day. This will help you remember when to take the capsules.
Food reduces the absorption of AGRYLIN slightly, but this does not have any effect on the ability to reduce your platelet count.

How long to take AGRYLIN

You should not normally stop taking AGRYLIN unless your doctor tells you to. If AGRYLIN have been successfully reducing the excess of platelets in your blood, stopping AGRYLIN will cause the number of platelets in your blood to rise again within three or four days, so that the risk of problems with blood circulation may return.
Abrupt treatment discontinuation or substantial reduction in AGRYLIN's dosage should be avoided, due to potentially severe clotting complications.
If you feel unwell during your course of treatment, tell your doctor.

If you forget to take AGRYLIN

If you forget to take a dose of AGRYLIN, leave out that dose completely. Take your next dose at the normal time it is due.
Do not take a double dose to make up for the dose you missed.
If you are not sure what to do, ask your doctor or pharmacist.
If you have trouble remembering to take AGRYLIN, ask your pharmacist for some hints.

If you take too much AGRYLIN

You should immediately:

phone the National Poisons Information Centre
(in Australia: telephone 13 11 26; in New Zealand: telephone 0800 POISON or 0800 764 766), or
contact your doctor, or
go to Accident and Emergency at the nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include fast heartbeat, vomiting and bleeding.

5. What should I know while using AGRYLIN?

Things you must do

Make sure that all your doctors and pharmacists know about your use of AGRYLIN. Remind them if any new medicines are about to be started.

Tell your doctor immediately if you experience shortness of breath and fatigue while taking AGRYLIN.

Things you must not do

Do not take AGRYLIN to treat any complaint other than that directed by your doctor. It may not be safe to take AGRYLIN for another complaint.
Do not give your medicine to anyone else, even if they have the same condition as you. It may not be safe for another person to take AGRYLIN.
Do not stop taking your AGRYLIN or change the dosage without checking with your doctor.

Driving or using machines

AGRYLIN may cause dizziness in some patients. Be careful driving or operating machinery until you know how AGRYLIN affects you.

Looking after your medicine

Keep AGRYLIN capsules in their bottle until it is time to take your dose.
Keep AGRYLIN in a cool dry place where the temperature stays below 25°C.
Do not store it or any other medicine in the bathroom or near a sink.
Do not leave it on a windowsill or in the car on hot or cold days. Heat, cold and dampness can destroy some medicines.
Keep AGRYLIN where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Ask your pharmacist what to do with any unused medicines.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking AGRYLIN. Like all medicines, AGRYLIN may have some side effects. Most side effects are mild, and patients often find that these wear off after a few weeks.

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

Some serious side effects that may occur are shown below:

Less serious side effects

Less serious side effects	What to do
Headache Aches and pains, including the back and the chest Palpitations, an unusually rapid heartbeat Water retention, swelling of the hands or feet Abdominal pain Difficult or painful breathing Loss of appetite Rash Wind, diarrhoea, nausea, vomiting Feeling unwell Weakness, dizziness Fever Worsening of a cough Tingling sensation like pins and needles Alopecia (hair loss)	If these side effects persist, you should consult your doctor.

Serious side effects

Serious side effects

What to do

Heart problems, including heart attack, stroke or a disturbed heart heartbeat, enlargement of the heart. As a precaution, your doctor may have to order some special straightforward heart function tests, both before and during your treatment.
Chest pain with or without rapid breathing.
Lung problems, including shortness of breath, wheezing or difficulty breathing.
Severe abdominal or back pain (pancreatitis)
Abdominal pain or tenderness, stomach discomfort, vomiting blood or passing black stools.
Allergic coughing.
Yellowing of the skin and eyes caused by inflammation of the liver (hepatitis).
Unexplained bruising or bleeding, which can sometimes be serious if you are also taking aspirin.

Call your doctor immediately.

As a precaution, your doctor may have your blood, liver and kidney tested regularly during treatment with AGRYLIN.

Other side effects not listed here may also occur in some patients. tell your doctor if you notice anything else that is making you feel unwell.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

What AGRYLIN contains

Active ingredient (main ingredient)	Anagrelide hydrochloride
Other ingredients (inactive ingredients)	Crospovidone, lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone.

Do not take this medicine if you are allergic to any of these ingredients.

What AGRYLIN looks like

AGRYLIN 0.5 mg capsule (AUST R 71752): White, opaque capsules, containing white powder. They are marked with logo "S" on the cap and "063" on the body in black ink.

AGRYLIN are available in plastic bottles containing 100 capsules.

Who distributes AGRYLIN

Takeda Pharmaceuticals Australia Pty Ltd
Level 39, 225 George Street
Sydney, NSW 2000
Australia
Telephone: 1800 012 612
www.takeda.com/en-au

AGRYLIN capsules are supplied in New Zealand by:

Takeda New Zealand Limited
Level 10, 21 Queen Street
Auckland,
New Zealand
Telephone: 0508 169 077

This leaflet was prepared in September 2022.

AGRYLIN^® is a registered trademark or Takeda Pharmaceuticals U.S.A, Inc.

TAKEDA^® and the TAKEDA Logo^® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Agrylin

Active ingredient

Anagrelide

Schedule

1 Name of Medicine

Anagrelide hydrochloride.

2 Qualitative and Quantitative Composition

Agrylin capsules is available in the following strength: 0.5 mg. Each capsule of Agrylin contains 0.5 mg of anagrelide base (as anagrelide hydrochloride).
Agrylin (anagrelide hydrochloride) is an orally active quinazoline derivative.

Excipient(s) with known effect.

Contains sugars as lactose.
Each capsule contains lactose monohydrate (53.7 mg) and lactose (65.8 mg). For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule.
Agrylin is available as 0.5 mg white opaque capsule, containing white powder and printed with Shire logo "S" on the cap and "063" on the body in blank ink (AUST R 71752).

4 Clinical Particulars

4.1 Therapeutic Indications

Agrylin capsules are indicated for the treatment of essential thrombocythaemia.

4.2 Dose and Method of Administration

Treatment with Agrylin capsules should be initiated under close medical supervision. The recommended starting dosage of Agrylin for adult patients is 1 mg/day, which should be administered orally in two divided doses (0.5 mg/dose). The starting dose should be maintained for at least a week. The dose should then be adjusted to the lowest effective dose required to reduce and maintain platelet count below 600 x 10⁹/L and ideally at levels between 150 x 10⁹/L and 400 x 10⁹/L. The dose should be increased by not more than 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose because of the hypotensive effect of anagrelide (see Section 5.1 Pharmacodynamic Properties).
The decision to treat asymptomatic young adults with essential thrombocythaemia should be individualised (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

For patients with moderate hepatic impairment, the recommended starting dose is 0.5 mg/day, to be maintained for a minimum of one week with close monitoring of cardiovascular effects. Agrylin is not recommended for patients with severe hepatic impairment.

Patient monitoring.

To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached.
Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely. Where immediate reduction of the platelet count is required, pheresis may be a more appropriate therapeutic intervention (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Agrylin is contraindicated in patients who have developed hypersensitivity to anagrelide hydrochloride or any of its excipients (see Section 6.1 List of Excipients) and in patients with severe hepatic impairment. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied.

4.4 Special Warnings and Precautions for Use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Agrylin as it contains lactose.

Cardiovascular.

Therapeutic doses of anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations and congestive cardiac failure. A pre-treatment cardiovascular examination (including investigations such as echocardiography, electrocardiogram) is recommended for all patients. Patients should be monitored during treatment of cardiovascular effects and further investigations carried out as necessary. Hypokalaemia or hypomagnesaemia must be corrected prior to anagrelide administration. Anagrelide should be used with caution in patients with known or suspected heart disease or at high risk of vascular events, and only if the potential benefits of therapy outweigh the potential risks (see also Patient monitoring/effects on laboratory tests in this section).
Anagrelide has been shown to increase both the heart rate and QTc interval in healthy volunteers. The clinical impact of this effect is unknown (see Section 5.1 Pharmacodynamic Properties).
Caution should be taken when using anagrelide in patients with known risk factors for prolongation of the QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalaemia.
Care should also be taken in populations that may have a higher maximum plasma concentration (C_max) of anagrelide or its active metabolite, 3-hydroxy-anagrelide, e.g. hepatic impairment or use with CYP1A2 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pulmonary hypertension.

Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy.

Bleeding.

Use of concomitant anagrelide and aspirin (acetylsalicylic acid) has been associated with major haemorrhagic events (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

Patients with renal impairment (serum creatinine ≥ 0.18 mmol/L) should be monitored closely since they are at greater risk of renal toxicity while receiving anagrelide (see Section 4.8 Adverse Effects (Undesirable Effects), Renal and urinary disorders).

Use in hepatic impairment.

Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild or moderate impairment of hepatic function should be assessed before and during treatment is commenced. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for cardiovascular effects (see Section 4.2 Dose and Method of Administration for specific dosing recommendations).
Patients with hepatic impairment (serum bilirubin, AST or other measures of hepatic function > 1.5 times the upper limit of normal) should be monitored closely while receiving anagrelide since anagrelide may worsen hepatic impairment (see Section 4.8 Adverse Effects (Undesirable Effects), Hepatobiliary disorders).

Patient monitoring/effects on laboratory tests.

Anagrelide therapy requires close clinical supervision of the patient. While the platelet count is being lowered (usually during the first two weeks of treatment), platelet count should be performed every 2 days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached (see Section 4.2 Dose and Method of Administration). As cases of hepatitis have been reported from postmarketing surveillance, it is recommended that liver function tests (ALT and AST) are performed before anagrelide treatment is initiated and at regular intervals thereafter. A full blood count (haemoglobin, white blood cells and platelet count), renal function (serum creatinine, urea) tests and electrolytes (potassium, magnesium and calcium) should continue to be monitored during anagrelide therapy. Patients should be regularly assessed during anagrelide therapy for the emergence of cardiovascular effects which may require further examination and investigation. The QTc interval should be closely monitored during anagrelide treatment.

Paediatric use.

The efficacy and safety of anagrelide in patients under the age of 16 years have not been established.

Use in the elderly.

The observed pharmacokinetic differences between elderly and young patients with essential thrombocythemia (ET) do not warrant using a different starting regimen or different dose titration step to achieve an individual patient optimised anagrelide regimen.

Cessation of Agrylin treatment.

In general, interruption of anagrelide treatment is followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count can be observed within four days. It should be noted that there is risk of thromboembolic events during this rebound phase. The dynamics of the rise in platelet count following interruption of therapy have been studied in only a very small number of patients, and data from normal controls suggests that a rebound to beyond pre-treatment levels occurs in some individuals. Therefore, platelet count should be monitored frequently.

Thrombotic risk.

Abrupt treatment discontinuation or substantial reduction of anagrelide's dose should be avoided due to the risk of sudden increase in platelet counts, which may lead to potentially fatal thrombotic complications, such as cerebral infarction (see Section 4.2 Dose and Method of Administration). Patients should be advised how to recognise early signs and symptoms suggestive of thrombotic complications, such as cerebral infarction, and if symptoms occur to seek medical assistance.

Treatment discontinuation.

In the event of dosage interruption or treatment withdrawal, platelets should be monitored frequently (see Section 4.2 Dose and Method of Administration).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted.

Warfarin or digoxin.

In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.

Aspirin (acetylsalicylic acid) and drugs that increase bleeding risk.

At therapeutic doses, anagrelide may potentiate the effects of other medicinal products that inhibit platelet aggregation. In two clinical interaction studies in healthy subjects, co-administration of single dose anagrelide 1 mg and aspirin 900 mg or repeat dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater anti-platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1 mg and aspirin 900 mg single doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT). In the repeat dose study, there was a short lived decrease in ex vivo collagen induced platelet aggregation beyond the effects of aspirin alone for the first 2 hours after administration. In some ET patients concomitantly treated with aspirin and anagrelide, major haemorrhages have occurred. The potential risks and benefits of concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high-risk profile for haemorrhage, before treatment is commenced.

Other PDE3 inhibitors.

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE3). The effects of drugs with similar properties such as inotropes (e.g. milrinone) may be exacerbated by anagrelide.

CYP1A2 inhibitors.

Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and ciprofloxacin, and such medicinal products could theoretically adversely influence the clearance of anagrelide, thereby increasing plasma concentrations. Anagrelide demonstrated inhibitory activity towards CYP1A2 in vitro which presents a theoretical potential for interaction with other coadministered medicinal products sharing that clearance mechanism, e.g. theophylline.

CYP1A2 inducers.

CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g. omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.
Preclinical data indicate an augmented anticoagulant effect when heparin and anagrelide were used in combination.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Although additional drug interaction studies have not been conducted, the most common medications used concomitantly with anagrelide in clinical trials have been aspirin, paracetamol, frusemide, iron, ranitidine, hydroxyurea, and allopurinol. The most frequently used concomitant cardiac medication has been digoxin. Other than aspirin, there is no clinical evidence to suggest that anagrelide interacts with any of these compounds.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in animals have shown reproductive toxicity. Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m²/day, 195 times the maximum recommended human dose based on body surface area) had no effect on fertility of male rats. However, in female rats, given oral doses of 60 mg/kg/day (360 mg/m²/day, 49 times the maximum recommended human dose based on body surface area) or higher, it disrupted implantation when administered in early pregnancy. A no effect dose level was not established.
(Category B3)
Anagrelide is not recommended in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the foetus. Women of childbearing potential should be instructed that they must not be pregnant and that they should use contraception while taking anagrelide. Anagrelide may cause foetal harm when administered to a pregnant woman. There are no adequate studies of anagrelide use in pregnant women.
Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day. Treatment was stopped as soon as it was realised they were pregnant. All delivered normal, healthy babies.
No teratogenic effects were observed in pregnant rats at oral doses up to 900 mg/kg/day (5400 mg/m²/day, 730 times the maximum recommended human dose based on body surface area), or in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m²/day, 32 times the maximum recommended human dose based on body surface area). However, increased embryonic deaths and suppression of foetal growth were seen in rats at oral doses of 60 mg/kg/day (360 mg/m²/day, 49 times the maximum recommended human dose based on body surface area) or greater, and ossification was retarded at 100 mg/kg/day or greater. When administered to rats in late pregnancy at oral doses of 60 mg/kg/day or higher, it retarded or blocked parturition, resulting in maternal and neonatal deaths.
It is not known whether this drug is excreted in human milk. When administered to lactating rats, anagrelide hydrochloride at doses greater than 60 mg/kg/day (360 mg/m²/day, 49 times the maximum recommended human dose based on body surface area) decreased survival of the offspring. Because many drugs are excreted in human milk and in view of the unknown risks of anagrelide to the infant, a decision to discontinue nursing or to discontinue the drug should be seriously considered, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Agrylin may cause dizziness in some patients. Caution should be shown when driving or operating machinery whilst on treatment with Agrylin.

4.8 Adverse Effects (Undesirable Effects)

While most reported adverse events during anagrelide therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events reported in patients with ET and/or in patients with thrombocythaemias or other aetiologies include: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, torsades de pointes, ventricular tachycardia, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, hepatitis, gastric/duodenal ulceration, tubulointerstitial nephritis and seizure.
Of the 551 patients treated with anagrelide for a mean duration of 65 weeks, 82 (15%) were discontinued from the study because of adverse events or abnormal laboratory test results. The most common adverse events for treatment discontinuation were headache, diarrhoea, oedema, palpitation and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.
Adverse reactions arising from clinical studies, post-authorisation safety studies, and spontaneous reports are presented below. Within the system organ classes, they are listed under the following headings: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

General disorders and administration site conditions.

Very common: headache (44.5%), asthenia (22.1%), pain, other than abdominal, chest or back (14.7%).
Common: Fever, Influenza-like illness, chills, neck pain, photosensitivity, paraesthesia, back pain, malaise.
Uncommon: oedema, chest pain.

Cardiac and vascular disorders.

Very common: palpitations (27.2%), oedema (19.8%).
Common: arrhythmia, haemorrhage, cardiovascular disease, cerebrovascular accident, angina pectoris, congestive heart failure, hypertension, orthostatic hypotension, vasodilatation, chest pain, tachycardia, peripheral oedema.
Uncommon: ventricular tachycardia, supraventricular tachycardia, atrial fibrillation.
Rare: myocardial infarction, cardiomyopathy, cardiomegaly, pericardial effusion.
Not known: torsade de pointes*, Prinzmetal angina*.

Gastrointestinal disorders.

Very common: diarrhoea (24.3%), abdominal pain (17.4%), nausea (15.1%), flatulence (10.5%).
Common: constipation, GI distress, GI haemorrhage, gastritis, melena, aphthous stomatitis, eructation, nausea, vomiting, dyspepsia.
Uncommon: pancreatitis.

Blood and lymphatic system disorders.

Common: anaemia, thrombocytopenia, ecchymosis, lymphadenoma.
Platelet counts below 100 x 10⁹/L occurred in 35 patients and reduction below 50 x 10⁹/L occurred in 7 of the 551 ET patients while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide.

Hepatobiliary disorders.

Common: elevated liver enzymes.
Not known: hepatitis*.

Musculoskeletal and connective tissue disorders.

Common: arthralgia, myalgia, leg cramps.
Uncommon: back pain.

Nervous system disorders.

Very common: dizziness (14.5%), headache.
Common: depression, hypoesthesia, somnolence, confusion, insomnia, nervousness, amnesia, migraine, syncope.
Uncommon: paraesthesia.
Not known: cerebral infarction.

Psychiatric disorders.

Uncommon: depression, confusional state, insomnia, nervousness.

Metabolism and nutritional disorders.

Common: dehydration, decreased appetite.

Respiratory, thoracic and mediastinal disorders.

Very common: dyspnoea (10.5%).
Common: rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma, cough, pharyngitis.
Uncommon: pleural effusion, pulmonary hypertension.
Rare: lung infiltration.
Not known: interstitial lung disease including pneumonitis and allergic alveolitis*.

Skin and subcutaneous tissue disorders.

Common: pruritus, skin disease, alopecia, rash including urticaria.
Uncommon: ecchymosis.

Eye, ear and labyrinth disorders.

Common: amblyopia, visual impairment, tinnitus, visual field abnormality, diplopia.

Renal and urinary disorders.

Common: dysuria, haematuria.
Rare: renal failure.
Not known: tubulointerstitial nephritis*.

Investigations.

Uncommon: hepatic enzymes increased.
* Post-marketing ADRs.
Of the 551 patients, 10 were found to have renal abnormalities. Six of the 10 experienced renal failure (approximately 1%) while on anagrelide treatment; in two, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 4 were found to have pre-existing renal impairment and were successfully treated with anagrelide. Doses ranged from 1.5 - 6.0 mg/day, with exposure periods of 2 to 12 months. Serum creatinine remained within normal limits and no dose adjustment was required because of renal insufficiency.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute toxicity and symptoms.

Symptoms of acute toxicity were decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
At higher than recommended doses, anagrelide has been shown to cause reductions in blood pressure, with occasional hypotension. There have been a small number of post-marketing case reports of intentional overdose with anagrelide. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Platelet reduction from anagrelide therapy is dose related; therefore thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Should overdosage occur, cardiac, and central nervous system toxicity can also be expected.

Management and treatment.

In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as appropriate, until the platelet count returns within the normal range.
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Healthy male volunteers given anagrelide demonstrated dose related reductions in platelet counts. The reduction after 8-10 days treatment with anagrelide 0.5 mg bd was 24-30% and with 1 mg bd, 30-44%. After 1 mg mane for 30 days, the average reduction in platelet count was 15%. Platelet counts returned to normal within one week of ceasing treatment.

Mechanism of action.

The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.

Pharmacodynamic effects.

In vitro studies of the growth of human megakaryocyte colonies in tissue culture showed that anagrelide disrupted the postmitotic phase of megakaryocyte development reducing megakaryocyte size and ploidy. Anagrelide did not have a thrombocytopenic effect in the animal models tested, rats, dogs and monkeys, at doses ≤ 10 mg/kg/day.
Anagrelide at doses ≥ 1 mg inhibited ADP and collagen induced platelet aggregation in healthy volunteers. Anagrelide 0.5 mg twice daily for 14 days followed by anagrelide 1 mg twice daily for a further 14 days reduced haemoglobin concentration by a median 12 g/L. In in vitro studies of human blood, anagrelide inhibited cyclic AMP phosphodiesterase.
Anagrelide produces dose dependent vasodilation, decreasing blood pressure and increasing heart rate and ventricular contractility. In a pharmacodynamic study, a dose of 5 mg caused orthostatic hypotension and dizziness in nine healthy volunteers (average fall in standing blood pressure = 22/15 mmHg). Only minimal changes in blood pressure were observed following a dose of 2 mg.

Effects on heart rate and QTc interval.

The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double blind, randomised, placebo and active controlled, crossover study in 60 healthy adult men and women.
A dose related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximal concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
An apparent transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec (upper 2 sided 90% CI 8.0 msec) occurring at 2 hours for 0.5 mg and +10.0 msec (upper 2 sided 90% CI 12.7 msec) occurring at 1 hour for 2.5 mg. Anagrelide exposure was higher in women than men (C_max 55-75% higher; AUC 90% higher) and women had higher heart rate changes (and QTc changes) than men around the time of T_max.

Note.

The recommended starting dosage of Agrylin is 0.5 mg twice daily and should be increased by not more than 0.5 mg/day in any one week (see Section 4.2 Dose and Method of Administration).

Clinical trials.

A total of 551 patients with essential thrombocythaemia (ET) were treated with anagrelide in two uncontrolled trials and in compassionate use. Patients with ET were diagnosed based on the following criteria: platelet count ≥ 900 x 10⁹/L on two determinations; profound megakaryocytic hyperplasia in bone marrow; absence of Philadelphia chromosome; normal red cell mass; normal serum iron and ferritin, and normal marrow iron stores.
The mean duration of anagrelide therapy for study patients was 65 weeks; 23% of patients received treatment for 2 years. In the main trial, 274 ET patients were treated with anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤ 600 x 10⁹/L, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. 79% of evaluable patients (n = 254) responded and 73% of patients receiving at least one dose (n = 274) responded. The reduction in mean platelet count is depicted graphically in Figure 1. See Table 1.

In an investigator led randomised controlled trial, patients with ET who were at high risk of vascular events were randomized to either anagrelide + aspirin (n = 405) or hydroxyurea + aspirin (n = 404). Use of anagrelide monotherapy was not studied. Patients were high risk if they had one or more of the following: age ≥ 60 years, current or previous platelet count > 1,000 x 10⁹/L, history of ischaemia, thrombosis, embolism, haemorrhage caused by ET, hypertension requiring therapy or diabetes requiring a hypoglycaemic agent. The initial anagrelide dose was 0.5 mg twice daily and the initial hydroxyurea dose 0.5 to 1 g daily. The dose was then adjusted to maintain platelet count < 400 x 10⁹/L. The aspirin dose was 75-100 mg per day. Median follow up was 39 months (range 12-72).
Both groups achieved similar control of platelet count within 9 months of trial entry. Anagrelide + aspirin were associated with a significantly higher incidence of arterial thrombosis (9.1% vs 4.2%), serious haemorrhage (5.4% vs 2.0%) and transformation to myelofibrosis (4.0% vs 1.2%) in this high risk group compared to hydroxyurea + aspirin. Rates of death, from any cause, were not significantly different between the two groups.

5.2 Pharmacokinetic Properties

Absorption.

Single oral doses of 1-2 mg anagrelide are absorbed rapidly in healthy male volunteers, mean T_max being 0.9 h. Following administration of ¹⁴C-anagrelide in people, more than 70% of radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. The available plasma concentration time data at steady state in patients show that anagrelide does not accumulate in plasma after repeated administration. Anagrelide protein binding in human plasma is 91%.
Pharmacokinetic data obtained from healthy Caucasian volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the C_max by 14%, but increased the AUC by 20%. Food also reduced the C_max of 3-hydroxy anagrelide.

Metabolism.

The drug is extensively metabolised; less than 1% is recovered in the urine as anagrelide. Two major metabolites have been identified: RL 603 and 3-hydroxy anagrelide. RL603 is considered pharmacologically inactive whilst 3-hydroxy anagrelide is pharmacologically active, being equipotent as the parent compound in terms of platelet inhibition and 40 times more potent as an inhibitor of phosphodiesterase III.

Excretion.

The half-life of 3-hydroxy anagrelide is approximately 3 hours. Metabolites are excreted in urine (79%) and faeces (21%). Excretion is > 97% complete within 5 days. Anagrelide is metabolised by CYP1A2 and, therefore, there is potential for interaction with other coadministered drugs that alter (inhibit or induce) CYP1A2-mediated metabolism (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special populations pharmacokinetics.

Pharmacokinetic (PK) data from paediatric (age range 7-14 years) and adult (age range 16-86 years) patients with thrombocythaemia secondary to a myeloproliferative disorder (MPD), indicate that dose and bodyweight normalised exposure, C_max and AUC_t, of anagrelide were lower in the paediatric patients compared to the adult patients (C_max 48%, AUC_t 55%).
There were no apparent differences between patient groups (paediatric versus adult patients) for t_max and t_1/2 for anagrelide, 3-hydroxy anagrelide or RL603.
Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared to fasting adult patients (age range 22-50 years) indicate that the C_max and AUC of anagrelide were 36% and 61% higher, respectively in elderly patients, but that the C_max and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower, respectively in the elderly patients. These differences were likely to be caused by lower pre-systemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients.

Renal impairment.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance < 30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide. The pharmacokinetic results show that the exposure to 3-hydroxy anagrelide is higher (100% increase in plasma elimination half-life from 3 to 6 hours) in severe renally impaired patients although the C_max did not differ.

Hepatic impairment.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.

5.3 Preclinical Safety Data

Genotoxicity.

Anagrelide did not cause gene mutations in bacterial or mammalian cells, nor was it clastogenic in the human lymphocyte chromosome aberration test in vitro or the mouse micronucleus test in vivo.

Carcinogenicity.

In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma was observed in females receiving 30 mg/kg/day (99 times human AUC for anagrelide and 18 times human AUC for metabolite 3-hydroxyanagrelide) with a NOEL of 10 mg/kg/day (6 times human AUC for anagrelide and twice human AUC exposure for metabolite 3-hydroxyanagrelide after the maximum recommended clinical dose of 10 mg/day). Adrenal phaeochromocytomas were increased in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above. A NOEL was not established in males and for females was 3 mg/kg/day (1.6 times human AUC exposure to anagrelide and less than the human exposure to metabolite 3-hydroxyanagrelide after the maximum recommended clinical dose of 10 mg/day). Adrenal phaeochromocytomas were also found in a one-year rat study.
No long-term data in humans are available to evaluate the carcinogenic potential of anagrelide hydrochloride. The maximum duration of human exposure in clinical trials was 4 years.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each capsule of Agrylin contains the following non-medicinal ingredients: crospovidone, lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone.
For active ingredient, see Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Agrylin capsules are available in bottles of 100 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Anagrelide hydrochloride is an off white, non-volatile powder. It is practically insoluble in water and sparingly soluble in dimethyl sulfoxide and dimethylformamide.

Chemical structure.

CAS number.

The CAS Registry Number for anagrelide hydrochloride is 58579-51-4.

7 Medicine Schedule (Poisons Standard)

Prescription only Medicine (S4).

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Agrylin Capsules 0.5 mg