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Agrylin

Last reviewed on RxList: 1/9/2019
Drug Description

AGRYLIN
(anagrelide hydrochloride) Capsules, for Oral Use

DESCRIPTION

AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro- 1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate. The molecular formula is C10H7Cl2N3O•HCl•H2O which corresponds to a molecular weight of 310.55. The structural formula is:

AGRYLIN® (anagrelide hydrochloride) - Structural Formula  - Illustration

Anagrelide hydrochloride is an off-white powder. It is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and dimethylformamide.

AGRYLIN is supplied as capsules for oral administration, containing 0.5 mg of anagrelide base (as anagrelide hydrochloride). The capsules also contain anhydrous lactose NF, crospovidone NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and povidone NF as inactive ingredients. The capsule shell contains gelatin, titanium dioxide and black iron oxide.

Indications & Dosage

INDICATIONS

AGRYLIN is indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.

DOSAGE AND ADMINISTRATION

Recommended Starting Dosage

Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.

Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.

Dose Titration Based Upon Platelet Response

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 AGRYLIN therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY]. Patients with moderate hepatic impairment who have tolerated AGRYLIN 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 AGRYLIN in patients with severe hepatic impairment.

Clinical Monitoring

AGRYLIN 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

Capsules: White, opaque capsule, containing 0.5 mg anagrelide (as anagrelide hydrochloride), imprinted Logo with “063” in black ink.

Storage And Handling

AGRYLIN is available as: 0.5 mg, opaque, white capsules imprinted Logo with “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), [See USP Controlled Room Temperature]. Store in a light resistant container.

Manufactured for Shire US Inc., 300 Shire Way, Lexington, MA 02421, USA. Revised: Dec 2018

Side Effects

SIDE EFFECTS

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

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-armclinical studies, 942 patients [see Clinical Trials] diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to AGRYLIN 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 AGRYLIN, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions resulting in treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.

The most frequently reported adverse reactions to AGRYLIN (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 of AGRYLIN in at least 5% of Patients

Adverse Reactions AGRYLIN
(N=942) (%)
Cardiac disorders
Palpitations 26%
Tachycardia 8%
Chest pain 8%
General disorders and administration site conditions
Asthenia 23%
Edema 21%
Pain 15%
Fever 9%
Peripheral edema 9%
Malaise 6%
Gastrointestinal disorders
Diarrhea 26%
Nausea 17%
Abdominal pain 16%
Vomiting 10%
Flatulence 10%
Anorexia 8%
Dyspepsia 5%
Respiratory, thoracic and mediastinal disorders
Dyspnea 12%
Cough 6%
Skin and subcutaneous tissue disorders
Rash 8%
Pruritus 6%
Musculoskeletal and connective tissue disorders
Back pain 6%
Nervous system disorders
Headache 44%
Dizziness 15%
Paresthesia 6%

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 reactions observed in pediatric patients was similar to adult patients. The most common adverse reactions observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month AGRYLIN 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. Other adverse reactions reported in these pediatric patients receiving AGRYLIN treatment 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 reactions in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity, and elevated leukocyte count.

Drug Interactions

DRUG INTERACTIONS

Drugs That Prolong QT

Avoid use of AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide, and pimozide) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

PDE3 Inhibitors

AGRYLIN is a phosphodiesterase 3 (PDE3) inhibitor. Avoid use of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Aspirin And Drugs That Increase Bleeding Risk

Co-administration of single-dose or repeat-dose AGRYLIN and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone [see CLINICAL PHARMACOLOGY]. Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with AGRYLIN is higher than in those subjects treated with another cytoreductive treatment. The majority of the major hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily, aspirin). Therefore, the potential risks of the concomitant use of AGRYLIN with aspirin should be assessed, particularly in patients with a high-risk profile for hemorrhage, before treatment is initiated [see WARNINGS AND PRECAUTIONS].

Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

CYP450 Interactions

CYP1A2 Inhibitors

AGRYLIN and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of AGRYLIN. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.

CYP1A2 Inducers

CYP1A2 inducers could decrease the exposure of AGRYLIN. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in AGRYLIN exposure.

CYP1A2 Substrates

AGRYLIN demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Toxicity

Torsades de pointes and ventricular tachycardia have been reported with AGRYLIN. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular effects and evaluate as necessary.

AGRYLIN increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see CLINICAL PHARMACOLOGY].

Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia [see DRUG INTERACTIONS].

Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of AGRYLIN therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Avoid use of AGRYLIN in patients with severe hepatic impairment.

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms [see CLINICAL PHARMACOLOGY].

AGRYLIN is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure [see DRUG INTERACTIONS].

In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.

Pulmonary Hypertension

Cases of pulmonary hypertension have been reported in patients treated with AGRYLIN. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during AGRYLIN therapy [see ADVERSE REACTIONS].

Bleeding Risk

Use of concomitant AGRYLIN and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of AGRYLIN with aspirin, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors) [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

Pulmonary Toxicity

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of AGRYLIN in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating AGRYLIN. If suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation [see ADVERSE REACTIONS.]

Nonclinical Toxicology

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 1 mg twice daily dose). Adrenal pheochromocytomas 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.

Use In Specific Populations

Pregnancy

Risk Summary

Available data from case reports with AGRYLIN use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal embryo-fetal studies, delayed fetal development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses approximately 97 times the maximum clinical dose (10 mg/day) based on body surface area (see Data). There are adverse effects on maternal and fetal outcomes associated with thrombocythemia in pregnancy (see Clinical Considerations).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Thrombotic events, such as stroke, deep vein thrombosis, or myocardial infarction, can be complications of thrombocythemia. Thrombocythemia in pregnancy is associated with an increased risk for miscarriage, stillbirth, and other maternal outcomes, such as preeclampsia.

Data

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 administered at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher during organogenesis through lactation 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 (3 mg/kg) was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.

Lactation

Risk Summary

There is no information regarding the presence of anagrelide in human milk, the effect on the breastfed child, or the effects on milk production. Anagrelide or its metabolites have been detected in the milk of lactating rats (see Data). Because of the potential for serious adverse reactions, including thrombocytopenia, in a breastfed child, advise patients that breastfeeding is not recommended during treatment with AGRYLIN, and for one week following the last dose.

Data

In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride (3 mg/kg) was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.

Females And Males Of Reproductive Potential

Infertility

Females

Based on findings from animal studies, AGRYLIN may impair female fertility [see Nonclinical Toxicology].

Pediatric Use

The safety and effectiveness of AGRYLIN have been established in pediatric patients 7 years of age and older. There are no data for pediatric patients less than 7 years of age. Use of AGRYLIN in these pediatric patients is supported by evidence from adequate and well-controlled studies of AGRYLIN in adults with additional pharmacokinetic, pharmacodynamic, and safety data in 18 pediatric patients aged 7-16 years with thrombocythemia secondary to ET [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY and Clinical Studies].

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].

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] and dose reduction is required [see DOSAGE AND ADMINISTRATION]. Use of AGRYLIN in patients with severe hepatic impairment has not been studied. Avoid use of AGRYLIN in patients with severe hepatic impairment. The potential risks and benefits of AGRYLIN therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during AGRYLIN treatment [see WARNINGS AND PRECAUTIONS].

Overdosage & Contraindications

OVERDOSE

At higher than recommended doses, AGRYLIN has been shown to cause hypotension. There have been postmarketing case reports of intentional overdose with AGRYLIN. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with supportive management. Platelet reduction from AGRYLIN therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.

In case of overdosage, stop AGRYLIN dosing and monitor platelet counts for thrombocytopenia and observe for possible complications such as bleeding. Consider resumption of AGRYLIN dosing once the platelet count returns to the normal range.

CONTRAINDICATIONS

None.

Clinical Pharmacology
Agrylin
Medication Guide

PATIENT INFORMATION

  • Dose: Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted [see DOSAGE AND ADMINISTRATION].
  • Cardiovascular effects: Tell the patient to contact a doctor immediately if they experience chest pain, palpitations, or feel their heartbeat is irregular [see WARNINGS AND PRECAUTIONS].
  • Risk of Pulmonary Hypertension: Tell the patient to contact a doctor immediately if they experience shortness of breath, swelling in legs or ankles, or lips and skin turn a bluish color [see WARNINGS AND PRECAUTIONS].
  • Risk of bleeding: Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise more easily than usual [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
  • Lactation: Advise women not to breastfeed during treatment with AGRYLIN, and for one week following the last dose [see Use In Specific Populations].
  • Infertility: Advise females of reproductive potential treatment with AGRYLIN may impair fertility [see Use In Specific Populations, Nonclinical Toxicology].
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