Agrylin

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to anagrelide.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Agrylin is a prescription medication used to treat a condition where the blood makes too many platelets. Agrylin belongs to a group of drugs called platelet-reducing agents. These work by slowing the production of platelets in the body.

Agrylin comes as a capsule to take by mouth. It is usually taken with or without food 2 to 4 times a day.

Common side effects of Agrylin include headache, irregular heart beats, diarrhea, weakness, and nausea. Agrylin can also cause dizziness. Do not drive or operate heavy machinery until you know how this medication affects you.

Anagrelide lowers platelets (blood-clotting cells) in the body, which helps prevent blood clots from forming.

Anagrelide is used to treat a blood cell disorder called thrombocythemia (also called thrombocytosis), which occurs when your body produces too many platelet cells.

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

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance for side effects.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For thrombocythemia:
    • Adults—At first, 0.5 milligram (mg) four times a day or 1 mg two times a day, taken for at least 1 week. Your doctor may adjust your dose if needed.
    • Children—At first, 0.5 mg per day. Your doctor may adjust your dose if needed.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will need to have your heart checked before starting Agrylin. This includes an ECG. Talk with your doctor.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Other drugs that work like this one have led to more deaths in people with very bad heart failure compared to people with very bad heart failure not taking those drugs. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Agrylin, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Agrylin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Agrylin.

Review Date: October 4, 2017

None.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Toxicity [see Warnings and Precautions (5.1)]
• Bleeding Risk [see Warnings and Precautions (5.2)]
• Pulmonary Toxicity [see Warnings and Precautions (5.3)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Studies in Adult Patients

In three single-arm clinical studies, 942 patients [see Clinical Trials (14)] diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion [see Warnings and Precautions (5.1)], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.

Adverse Reactions (frequency 1% to < 5%) included:

General disorders and administration site conditions: Flu symptoms, chills.

Cardiac disorders: Arrhythmia, angina pectoris, heart failure, syncope.

Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.

Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.

Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.

Hepatobiliary disorders: Elevated liver enzymes.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Psychiatric disorders: Depression, confusion, nervousness.

Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.

Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.

Skin and subcutaneous tissue disorders: Alopecia.

Eye disorders: Abnormal vision, diplopia.

Ear and labyrinth disorders: Tinnitus

Renal and urinary disorders: Hematuria, renal failure.

Other less frequent adverse reactions (<1%) were:

Cardiac disorders: Ventricular tachycardia, supraventricular tachycardia.

Nervous system disorders: Hypoesthesia.

Clinical Study in Pediatric Patients

The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.

Postmarketing Experience

The following adverse reactions have been identified during post-marketing use of Agrylin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of torsades de pointes, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see Warnings and Precautions (5)], tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.

Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with Agrylin in pregnant women. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10 mg/day. Agrylin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of 100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area. No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal clinical dose based on body surface area).

In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.

In a placental transfer study, a single oral dose of [14C]-anagrelide hydrochloride was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.

Nursing Mothers

Risk Summary

It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reaction in nursing infants from anagrelide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Data

In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.

Pediatric Use

Experience with Agrylin in pediatric patients was based on an open label safety and PK/PD study conducted in 18 pediatric patients aged 7-16 years with thrombocythemia secondary to ET [see Dosage and Administration (2.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients [see Adverse Reactions (6.1)].

Geriatric Use

Of the 942 subjects in clinical studies of Agrylin, 42.1% were 65 years and over, while 14.9% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and Administration (2.3)]. Use of Agrylin in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions (5.1)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30 mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily dose).

Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell (L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or the in vivo mouse micronucleus test.

Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies in female rats, oral doses of 30 mg/kg/day (29 times the recommended maximum human dose based on body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.

Animal Toxicology and/or Pharmacology

In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.

Do not take aspirin unless your doctor has told you to. Follow your doctor's instructions about how much aspirin to take, and how often to take it.

Ask a doctor or pharmacist before using any other pain, cold, allergy, or sleep medication. Aspirin (sometimes abbreviated as ASA) is contained in many combination medicines. Although aspirin is sometimes prescribed for use with anagrelide, taking these medications together may increase your risk of bleeding. Check the label to see if a medicine contains aspirin or ASA.

Grapefruit and grapefruit juice may interact with anagrelide and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Toxicity [see WARNINGS AND PRECAUTIONS]
• Bleeding Risk [see WARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In three single-arm clinical studies, 942 patients [see Clinical Trials] diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion [see WARNINGS AND PRECAUTIONS], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.

Table 1 : Adverse Reactions Reported in Clinical Studies in at least 5% of Patients

Adverse Reactions (frequency 1% to < 5%) included:

General disorders and administration site conditions: Flu symptoms, chills.

Cardiac disorders: Arrhythmia, angina pectoris, heart failure, syncope.

Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.

Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.

Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.

Hepatobiliary disorders: Elevated liver enzymes.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Psychiatric disorders: Depression, confusion, nervousness.

Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.

Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.

Skin and subcutaneous tissue disorders: Alopecia.

Eye disorders: Abnormal vision, diplopia.

Ear and labyrinth disorders: Tinnitus

Renal and urinary disorders: Hematuria, renal failure.

Other less frequent adverse reactions ( < 1%) were:

Cardiac disorders: Ventricular tachycardia, supraventricular tachycardia.

Nervous system disorders: Hypoesthesia.

The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.

Postmarketing Experience

The following adverse reactions have been identified during post-marketing use of AGRYLIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of torsades de pointes, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see WARNINGS AND PRECAUTIONS], tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.

Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

Read the entire FDA prescribing information for Agrylin (Anagrelide)