Anagrelid Zentiva

Anagrelid Zentiva is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It also has been used in the treatment of chronic myeloid leukemia. [Wikipedia]

Anagrelid Zentiva is a medicine which interferes with the development of platelets. It reduces the number of platelets produced by the bone marrow, which results in a decrease in the platelet count in the blood towards a more normal level. For this reason it is used to treat patients with essential thrombocythaemia.

Essential thrombocythaemia is a condition which occurs when the bone marrow produces too many of the blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems with blood circulation and clotting.

Anagrelid Zentiva lowers the number of blood clotting cells (platelets) in the body, which helps prevent blood clots from forming.

Anagrelid Zentiva is used to treat a condition called thrombocythemia (also called thrombocytosis). Thrombocythemia is a blood cell disorder in which too many platelet cells are produced, causing bleeding or blood-clotting problems.

Anagrelid Zentiva may also be used for purposes not listed in this medication guide.

Starting Dose

Adults

The recommended starting dosage of Anagrelid Zentiva is 0.5 mg four times daily or 1 mg twice daily.

Pediatric Patients

The recommended starting dosage of Anagrelid Zentiva is 0.5 mg daily.

Titration

Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/μL, and ideally between 150,000/μL and 400,000/μL. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.

Dose Modifications For Hepatic Impairment

In patients with moderate hepatic impairment (Child Pugh score 7-9) start Anagrelid Zentiva therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events. Patients with moderate hepatic impairment who have tolerated Anagrelid Zentiva therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of Anagrelid Zentiva in patients with severe hepatic impairment.

Clinical Monitoring

Anagrelid Zentiva therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes.

To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤ 600,000/μL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.

How supplied

Dosage Forms And Strengths

White, opaque capsule, containing 0.5 mg Anagrelid Zentiva (as Anagrelid Zentiva hydrochloride), imprinted with “063” in black ink.

Storage And Handling

Anagrelid Zentiva is available as 0.5 mg, opaque, white capsules imprinted “063” in black ink: NDC 54092-063-01 = bottle of 100

Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F),. Store in a light resistant container.

Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA. 1-800-828-2088. Revised: July 2015.

See also:
What is the most important information I should know about Anagrelid Zentiva?

Do not take Anagrelid Zentiva

• If you are allergic (hypersensitive) to Anagrelid Zentiva or any of the other ingredients of Anagrelid Zentiva. Check the ingredients of Anagrelid Zentiva listed in Section 6 of this leaflet. An allergic reaction may be recognised as a rash, itching, swollen face or lips, or shortness of breath.

• If you have moderate or severe liver problems.

• If you have moderate or severe kidney problems.

Take special care with Anagrelid Zentiva

Before treatment with Anagrelid Zentiva, tell your doctor

• If you have or think you might have a problem with your heart.

• If you have any problems with your liver or kidneys.

• If you are pregnant or breastfeeding.

• If you have been told by a doctor that you have an intolerance to some sugars.

Use Anagrelid Zentiva as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Anagrelid Zentiva by mouth with or without food.
• Take Anagrelid Zentiva on a regular schedule to get the most benefit from it. It may take several weeks (4 to 12 weeks) before you get the full effect from Anagrelid Zentiva.
• If you miss a dose of Anagrelid Zentiva, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Anagrelid Zentiva.

Use: Labeled Indications

Essential thrombocythemia: Treatment of thrombocythemia secondary to myeloproliferative neoplasms to reduce elevated platelets and the risk of thrombosis and to reduce associated symptoms (including thrombo-hemorrhagic events).

Note: The use of hydroxyurea and low-dose aspirin may be preferred over Anagrelid Zentiva for the initial treatment of essential thrombocythemia; however, Anagrelid Zentiva may be appropriate in patients who are resistant or intolerant to hydroxyurea (ESMO [Vannucchi 2015]).

See also:
What other drugs will affect Anagrelid Zentiva?

Limited PK and/or PD studies investigating possible interactions between Anagrelid Zentiva 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 Anagrelid Zentiva, nor does Anagrelid Zentiva affect the PK properties of digoxin or warfarin.

Although additional drug interaction studies have not been conducted, the most common medications used concomitantly with Anagrelid Zentiva in clinical trials were aspirin, acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. There is no clinical evidence to suggest that Anagrelid Zentiva interacts with any of these compounds.

An in vivo interaction study in humans demonstrated that a single 1mg dose of Anagrelid Zentiva administered concomitantly with a single 900 mg dose of aspirin was generally well tolerated. There was no effect on bleeding time, PT or aPTT. No clinically relevant pharmacokinetic interactions between Anagrelid Zentiva and acetylsalicylic acid were observed. In that same study, aspirin alone produced a marked inhibition in platelet aggregation ex vivo. Anagrelid Zentiva alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet aggregation by aspirin.

Anagrelid Zentiva is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of Anagrelid Zentiva. Anagrelid Zentiva demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other coadministered medicinal products sharing that clearance mechanism e.g. theophylline.

Anagrelid Zentiva is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by Anagrelid Zentiva.

There is a single case report, which suggests that sucralfate may interfere with Anagrelid Zentiva absorption.

Food has no clinically significant effect on the bioavailability of Anagrelid Zentiva.

See also:
What are the possible side effects of Anagrelid Zentiva?

Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease groups have the same adverse event profile. While most reported adverse events during Anagrelid Zentiva therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events were reported in these patients. These include the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atriala fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.

Of the 942 patients treated with Anagrelid Zentiva for a mean duration of approximately 65 weeks, 161 (17%) were discontinued from the study because of adverse events or abnormal laboratory test results. The most common adverse events for treatment discontinuation were headache, diarrhea, edema, palpitations, 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 Anagrelid Zentiva. The most frequently reported adverse reactions to Anagrelid Zentiva (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were:

Headache................................43.5%

Palpitations............................26.1%

Diarrhea.................................25.7%

Asthenia.................................23.1%

Edema, other..........................20.6%

Nausea....................................17.1%

Abdominal Pain.....................16.4%

Dizziness................................15.4%

Pain, other..............................15.0%

Dyspnea.................................11.9%

Flatulence...............................10.2%

Vomiting................................9.7%

Fever......................................8.9%

Peripheral Edema...................8.5%

Rash, including urticaria........8.3%

Chest Pain..............................7.8%

Anorexia................................7.7%

Tachycardia............................7.5%

Pharyngitis.............................6.8%

Malaise...................................6.4%

Cough.....................................6.3%

Paresthesia.............................5.9%

Back Pain...............................5.9%

Pruritus...................................5.5%

Dyspepsia...............................5.2%

Adverse events with an incidence of 1% to < 5% included:

Body as a Whole System: Flu symptoms, chills, photosensitivity.

Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.

Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis, eructation.

Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy. Platelet counts below 100,000/μL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/μL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on Anagrelid Zentiva therapy. Thrombocytopenia promptly recovered upon discontinuation of Anagrelid Zentiva.

Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during Anagrelid Zentiva therapy.

Musculoskeletal System: Arthralgia, myalgia, leg cramps.

Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.

Nutritional Disorders: Dehydration.

Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.

Skin and Appendages System: Skin disease, alopecia.

Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.

Urogenital System: Dysuria, hematuria.

Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD experienced renal failure (approximately 1%) while on Anagrelid Zentiva treatment; in 4 cases, the renal failure was considered to be possibly related to Anagrelid Zentiva treatment. The remaining 11 were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency. The adverse event profile for patients in three clinical trials on Anagrelid Zentiva therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:

All Patients with Myeloproliferative Disease (N=942)

Postmarketing Reports

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported in patients who have taken Anagrelid Zentiva treatment in post-marketing reports