Consumer medicine information

Anagrelide SCP

Anagrelide

BRAND INFORMATION

Brand name

Anagrelide SCP

Active ingredient

Anagrelide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Anagrelide SCP.

What is in this leaflet

This leaflet answers some common questions about ANAGRELIDE SCP.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ANAGRELIDE SCP against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What ANAGRELIDE SCP is used for

ANAGRELIDE SCP capsules contain a medicine called anagrelide (as hydrochloride monohydrate) which 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. ANAGRELIDE SCP capsules can help prevent these problems.

Before you take ANAGRELIDE SCP

When you must not take it

Do not take ANAGRELIDE SCP if you:

  • have an allergy to anagrelide or any of the ingredients listed at the end of this leaflet
  • have severe liver problems
  • are pregnant or breast feeding.

Do not take ANAGRELIDE SCP if the expiry date (Exp.) printed on the pack has passed.

Do not take ANAGRELIDE SCP if the packaging is torn or shows signs of tampering.

Do not use ANAGRELIDE SCP to treat any other complaint unless your doctor tells you to.

Before you start to take it

Tell your doctor if you have any of the following:

  • you have any allergies,
  • you have had or now have any liver or kidney disease
  • you have heart disease, heart failure or are at high risk of vascular events (thrombosis or bleeding).

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

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

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

Do not give this medicine to anyone else even if they have the same condition as you.

Taking other medicines

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

Some medicines may be affected by ANAGRELIDE SCP, or may affect how well it works. These include:

  • aspirin or a medicine containing aspirin
  • medicined used to treat depression such as fluvoxamine
  • medicine 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 can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ANAGRELIDE SCP.

How to take ANAGRELIDE SCP

How much to take

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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 day should not exceed 2.5 mg. Your total daily dose should not exceed four times this, ie 10 mg (20 of the 0.5 mg capsules).

If you are elderly, you should take the normal adult dose.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

When to take it

Take your capsules the same time each day. This will help you remember when to take the capsules.

Food reduces the absorption of ANAGRELIDE SCP slightly, but this does not have any effect on the ability of ANAGRELIDE SCP to reduce your platelet count.

How long to take it

You should not normally stop taking ANAGRELIDE SCP capsules unless your doctor tells you to. If ANAGRELIDE SCP capsules have been successfully reducing the excess of platelets in your blood, stopping ANAGRELIDE SCP capsules 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.

If you fell unwell during your course of treatment, tell your doctor.

If you forget to take ANAGRELIDE SCP

If you forget to take a dose of ANAGRELIDE SCP capsules, 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 that you missed.

If you have trouble remembering to ANGARELIDE SCP capsules, ask your pharmacist for some hints.

If you have any questions about this, check with your doctor or pharmacist.

If you take too much ANAGRELIDE SCP (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ANAGRELIDE SCP capsules. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

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

While you are taking ANAGRELIDE SCP

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ANAGRELIDE SCP.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking ANAGRELIDE SCP.

Things you must not do

Do not take ANAGRELIDE SCP capsules to treat any complaint other than that directed by your doctor. It may not be safe to take ANAGRELIDE SCP capsules 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 ANAGRELIDE SCP capsules.

Do not stop taking your ANAGRELIDE SCP capsules or change the dosage without checking with your doctor.

Things to be careful of

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ANAGRELIDE SCP.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • aches and pains, including the back and the chest
  • palpitations, an usually 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 events, persist you should consult your doctor.

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

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • heart problems, including heart attack or a disturbed 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
  • allergic coughing
  • abdominal pain or tenderness, stomach discomfort, vomiting blood or passing black stools
  • yellowing of the skin and eyes caused by inflammation of the liver (hepatitis)
  • bleeding, which can sometimes be serious if you are also taking aspirin.

These may be serious side effects. You may need urgent medical attention.

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

After using ANAGRELIDE SCP

Storage

Keep ANAGRELIDE SCP 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.

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store ANAGRELIDE SCP or any other medicine in the bathroom or near a sink.

Do not leave ANAGRELIDE SCP in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking ANAGRELIDE SCP, or your capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ANAGRELIDE SCP is a capsule with an opaque white body and cap. The capsule is filled with white to off-white powder.

Each bottle contains 100 capsules.

Ingredients

The active ingredient in ANAGRELIDE SCP is anagrelide (as hydrochloride monohydrate). Each capsule contains 0.5 mg of anagrelide.

The capsule also contains:

  • lactose monohydrate
  • cellulose microcrystalline
  • povidone
  • croscarmellose sodium
  • silica colloidal anhydrous
  • purified talc
  • magnesium stearate
  • anhydrous lactose.

The capsule shell contains:

  • gelatin
  • titanium dioxide.

The capsules do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Southern Cross Pharma Pty Ltd
Suite 5/118 Church Street
Hawthorn VIC 3122
Australia

Australian registration numbers:
ANAGRELIDE SCP
AUST R 276297

Date of preparation:
July 2017.

Published by MIMS April 2018

BRAND INFORMATION

Brand name

Anagrelide SCP

Active ingredient

Anagrelide

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Anagrelide.

2 Qualitative and Quantitative Composition

Anagrelide capsules contain the active ingredient anagrelide (as hydrochloride monohydrate) equivalent to 0.5 mg of anagrelide.
Excipients with known effect: lactose and lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Anagrelide Lupin is a capsule with an opaque white body and cap.
Each Anagrelide Lupin capsules contain 0.5 mg of anagrelide as the active ingredient.

4 Clinical Particulars

4.1 Therapeutic Indications

Anagrelide Lupin capsules are indicated for the treatment of essential thrombocythaemia.

4.2 Dose and Method of Administration

Treatment with Anagrelide Lupin capsules should be initiated under close medical supervision. The recommended starting dosage of Anagrelide Lupin 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 150-400 x 109/L. The dose should be increased by not more than 0.5 mg/day in any one week.
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. Anagrelide Lupin is not recommended for patients with severe hepatic impairment.
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.
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.

4.3 Contraindications

Anagrelide Lupin 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 Anagrelide Lupin 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. 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 (also see Patient monitoring).
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 (Cmax) 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.

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 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)).

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)).

Patient monitoring.

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 post-marketing 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 platelets), 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.

Cessation of Anagrelide Lupin 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 pretreatment levels occurs in some individuals, therefore platelet count should be monitored frequently.

Use in the elderly.

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

Paediatric use.

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

Effects on laboratory tests.

No data available.

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. 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.
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.
Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III. 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. Anagrelide demonstrated inhibitory activity towards CYP1A2 in vitro which presents a theoretical potential for interaction with other co-administered 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, furosemide, 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.

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 B31)
1 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
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 child-bearing 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

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

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.
The very common (≥ 10%), common (1% to < 10%) and uncommon (0.1% to < 1%) adverse events to anagrelide of 551 patients with ET in clinical trials were:

Body as a whole system.

Very common: headache (44.5%), asthenia (22.1%), pain, other than abdominal, chest or back (14.7%).
Common: fever, flu symptoms, chills, neck pain, photosensitivity, paraesthesia, back pain, malaise.

Cardiovascular system.

Very common: palpitations (27.2%), oedema (19.8%).
Common: arrhythmia, haemorrhage, cardiovascular disease, cerebrovascular accident, angina pectoris, heart failure, hypertension, postural hypotension, vasodilatation, migraine, syncope, chest pain, tachycardia, peripheral oedema.
Uncommon: supraventricular tachycardia.

Digestive system.

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.

Haemic and lymphatic system.

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.

Hepatic system.

Common: elevated liver enzymes.

Musculoskeletal system.

Common: arthralgia, myalgia, leg cramps.

Nervous system.

Very common: dizziness (14.5%).
Common: depression, somnolence, confusion, insomnia, nervousness, amnesia.
Uncommon: hypoaesthesia.

Nutritional disorders.

Common: dehydration, anorexia.

Respiratory system.

Very common: dyspnoea (10.5%).
Common: rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma, cough, pharyngitis.

Skin and appendages system.

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

Special senses.

Common: amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.

Urogenital system.

Common: dysuria, haematuria.
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 creatinines remained within normal limits and no dose adjustment was required because of renal insufficiency.
In addition to the cardiovascular adverse events described above, ventricular tachycardia has been reported as an uncommon adverse reaction (0.1% to < 1%) in individual case reports and clinical trials.
Pulmonary hypertension has been reported as an uncommon adverse reaction (0.1% to < 1%) in clinical trials.
Allergic alveolitis, including interstitial lung disease and pneumonitis associated with the use of anagrelide have been reported in individual case reports. However, no case reports have occurred during clinical trials, post-marketing studies, or compassionate use programmes, therefore, the incidence of these events is not known.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medical 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.
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 Poison Information Centre on 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 still under investigation. 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. 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, cross-over 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 (Cmax 55-75% higher; AUC 90% higher) and women had higher heart rate changes (and QTc changes) than men around the time of Tmax.

Note.

The recommended starting dosage of Anagrelide Lupin 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 and 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 Tmax 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.
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 Cmax by 14%, but increased the AUC by 20%. Food also reduced the Cmax of 3-hydroxy anagrelide.

Distribution.

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%.

Metabolism.

The drug is extensively metabolised; less than 1% is recovered in the urine as anagrelide. The pharmacological activity of the metabolites is unknown. Two major metabolites have been identified RL603 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. The half-life of 3-hydroxy anagrelide is approximately 3 hours.

Excretion.

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 co-administered drugs that are also mainly metabolised by CYP1A2 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Elderly.

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 Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax 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 presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients.

Children (7 to 14 years of age).

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 body weight-normalised exposure, Cmax and AUCt, of anagrelide were lower in the paediatric patients compared to the adult patients (Cmax 48%, AUCt 55%). There were no apparent differences between patient groups (paediatric versus adult patients) for Tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.

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 Cmax 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

Anagrelide Lupin capsules contain the following inactive ingredients: lactose monohydrate, croscarmellose sodium, povidone, microcrystalline cellulose, magnesium stearate and anhydrous lactose.
The capsule shells consist of gelatin, titanium dioxide, iron oxide black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (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

HDPE bottles with child resistant polypropylene closures containing 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

Chemical structure.


CAS number.

823178-43-4.
Chemical name: 6,7-dichloro-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one hydrochloride monohydrate.
Molecular formula: C10H7Cl2N3O.HCl.H2O.
Molecular weight: 310.56.
Anagrelide (as hydrochloride monohydrate) is an orally active quinazolin derivative.
Anagrelide hydrochloride monohydrate is a white to off-white powder. It is very slightly soluble in water, acetonitrile, slightly soluble in acetic acid and ethanol, sparingly soluble in methanol and soluble in formic acid solutions.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes