anagrelide 0.5 MG (as anagrelide hydrochloride) Oral Capsule
DRUG INTERACTIONS
7 Other PDE 3 inhibitors: Exacerbation of inotropic effects ( 7.2 ) Aspirin and Drugs that Increase Bleeding Risk : Increased risk of bleeding with concomitant use ( 7.3 ) 7.1 Drugs that Prolong QT Do not use anagrelide 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 ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .
7.2 PDE3 Inhibitors Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor.
The effects of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .
7.3 Aspirin and Drugs that Increase Bleeding Risk Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone [see Clinical Pharmacology ( 12.3 )] .
Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with anagrelide 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 anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is initiated [see Warnings and Precautions ( 5.2 )] .
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).
7.4 CYP450 Interactions CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2.
Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide.
Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.
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.
CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g.
theophylline, fluvoxamine, ondansetron).
OVERDOSAGE
10 At higher than recommended doses, this medicine has been shown to cause hypotension.
There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride.
Reported symptoms include sinus tachycardia and vomiting.
Symptoms resolved with supportive management.
Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
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 stopped, as appropriate, until the platelet count returns to within the normal range.
DESCRIPTION
11 Anagrelide hydrochloride, USP is a platelet-reducing agent.
Its chemical name is 6,7-dichloro-1,5-dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate and it has the following structural formula: C 10 H 7 Cl 2 N 3 O·HCl·H 2 O M.W.
310.56 Anagrelide hydrochloride, USP is an off white powder that is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and in dimethylformamide.
Each Anagrelide Capsule USP, for oral administration, contains either 0.5 mg or 1 mg of anagrelide base (as anagrelide hydrochloride, USP) and has the following inactive ingredients: black iron oxide, crospovidone, D&C Yellow #10 Aluminum Lake, FD&C Blue #1/Brilliant Blue Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Red #40/Allura Red Aluminum Lake, gelatin, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, shellac glaze and titanium dioxide.
Structural Formula
CLINICAL STUDIES
14 Clinical Studies in Adult Patients: A total of 942 patients with myeloproliferative neoplasms including 551 patients with Essential Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative neoplasms (OMPN), were treated with anagrelide in three clinical trials.
Patients with OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unclassified myeloproliferative neoplasms.
Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/μL on two occasions or ≥ 650,000/μL on two occasions with documentation of symptoms associated with thrombocythemia.
The mean duration of anagrelide therapy for ET, PV, CML, and OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years.
Patients were treated with anagrelide starting at doses of 0.5 to 2 mg every 6 hours.
The dose was increased if the platelet count was still high, but to no more than 12 mg each day.
Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000 to 400,000/μL).
The criteria for defining subjects as “responders” were reduction in platelets for at least 4 weeks to ≤600,000/μL, or by at least 50% from baseline value.
Subjects treated for less than 4 weeks were not considered evaluable.
The results are depicted graphically below: *x 10 3 /μL †Nine hundred and forty-two subjects with myeloproliferative neoplasms were enrolled in three research studies.
Of these, 923 had platelet counts measured over the duration of the studies.
Anagrelide was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
Clinical Study in Pediatric Patients: An open label safety and PK/PD study was conducted in 18 pediatric patients 7 to 16 years of age (8 patients 7 to 11 years of age and 10 patients 12 to 16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females).
Prior to entry on to the study, 17 of 18 pediatric patients and 12 of 17 adult patients had received anagrelide treatment for an average of 2 years.
The median starting total daily dose, determined by retrospective chart review, for pediatric and adult patients with ET who had received anagrelide prior to study entry was 1 mg for each of the three age groups (7 to 11 and 12 to 16 year old patients and adults).
The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily.
At study completion, the median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7 to 11 years of age, 2.25 mg in patients 12 to 16 years of age, and 1.5 mg for adults.
figure 1
HOW SUPPLIED
16 /STORAGE AND HANDLING Anagrelide Capsules USP, 0.5 mg are available as light gray opaque cap/white opaque body hard gelatin capsules, spin printed in black ink “Ivax hourglass logo” “5241” on the cap and “0.5 mg” on the body containing 0.5 mg of anagrelide base (as anagrelide hydrochloride, USP).
NDC 0172- 5241 -60 0.5 mg packaged in bottles of 100 capsules NDC 69189-5241-1 single dose pack with 1 capsule as repackaged by Avera McKennan Hospital Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
RECENT MAJOR CHANGES
Dosage and Administration ( 2 ) 10/2014 Contraindications ( 4 ) 10/2014 Warnings and Precautions ( 5 ) 10/2014
GERIATRIC USE
8.5 Geriatric Use Of the 942 subjects in clinical studies of anagrelide, 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.
DOSAGE FORMS AND STRENGTHS
3 Anagrelide Capsules, 0.5 mg are available as light gray opaque cap/white opaque body hard gelatin capsules, spin printed in black ink “Ivax hourglass logo” “5241” on the cap and “0.5 mg” on the body containing 0.5 mg of anagrelide base (as anagrelide hydrochloride).
Anagrelide Capsules, 1 mg are available as white opaque hard gelatin capsules, spin printed in black ink “Ivax hourglass logo” “5240” on the cap and “1 mg” on the body containing 1 mg of anagrelide base (as anagrelide hydrochloride).
Capsules: 0.5 mg, 1 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism by which anagrelide reduces blood platelet count is unknown.
In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.
INDICATIONS AND USAGE
1 Anagrelide capsules USP are 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 [see Clinical Studies ( 14 ), Dosage and Administration ( 2 )] .
Anagrelide is a platelet reducing agent indicated for the treatment of 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.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Experience with anagrelide in pediatric patients was based on an open label safety and PK/PD study conducted in 18 pediatric patients aged 7 to 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 )].
PREGNANCY
8.1 Pregnancy Teratogenic Effects Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with anagrelide 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.
Anagrelide 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/m 2 /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 [ 14 C]-anagrelide hydrochloride was administered to pregnant rats on gestation Day 17.
Drug-related radioactivity was detected in maternal and fetal tissue.
NUSRING MOTHERS
8.3 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 [ 14 C]-anagrelide hydrochloride was administered to lactating female rats on postnatal Day 10.
Drug-related radioactivity was detected in the maternal milk and blood.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have been reported with anagrelide.
Obtain a pre-treatment cardiovascular examination including an ECG in all patients.
Monitor patients for cardiovascular effects.
( 5.1 ) Bleeding Risk: Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding ( 5.2 ) 5.1 Cardiovascular Toxicity Torsades de pointes and ventricular tachycardia have been reported with anagrelide.
Obtain a pre-treatment cardiovascular examination including an ECG in all patients.
During treatment with anagrelide monitor patients for cardiovascular effects and evaluate as necessary.
Torsades de pointes and ventricular tachycardia have been reported with anagrelide.
Obtain a pre-treatment cardiovascular examination including an ECG in all patients.
During treatment with anagrelide monitor patients for cardiovascular effects and evaluate as necessary.
Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see Clinical Pharmacology ( 12.2 )] .
Do not use anagrelide 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 ( 7.1 )] .
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 anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced.
Reduce anagrelide dose in patients with moderate hepatic impairment.
Use of anagrelide in patients with severe hepatic impairment has not been studied [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.2 , 12.3 )] .
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms [see Clinical Pharmacology ( 12.2 )] .
Anagrelide 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 .
Anagrelide 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 ( 7.2 )] .
In patients with cardiac disease, use anagrelide only when the benefits outweigh the risks.In patients with cardiac disease, use anagrelide only when the benefits outweigh the risks.
5.2 Bleeding Risk Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study.
Assess the potential risks and benefits for concomitant use of anagrelide 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 ( 7.3 ), Clinical Pharmacology ( 12.3 )] .
5.3 Pulmonary Toxicity Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide 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 anagrelide.
If suspected, discontinue anagrelide and evaluate.
Symptoms may improve after discontinuation [see Adverse Reactions ( 6 )].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING 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 ( 2 )].
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 ( 5.1 )].
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 ( 5.2 ), Drug Interactions ( 7.1 )] .
Manufactured For: TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454 Rev.
I 7/2015
DOSAGE AND ADMINISTRATION
2 The starting dose for adults is 0.5 mg four times a day or 1 mg twice a day ( 2.1 ) The starting dose for pediatric patients is 0.5 mg per day ( 2.1 ) Maintain the starting dose for at least one week and then titrate to maintain target platelet counts ( 2.2 ) Do not exceed a dose increment of 0.5 mg/day in any one week.
Do not exceed 10 mg/day or 2.5 mg in a single dose.
( 2.2 ) Moderate hepatic impairment: Start with 0.5 mg per day ( 2.3 ) 2.1 Starting Dose Adults: The recommended starting dosage of anagrelide capsules is 0.5 mg four times daily or 1 mg twice daily.
Adults: The recommended starting dosage of anagrelide capsules is 0.5 mg four times daily or 1 mg twice daily.
Pediatric Patients: The recommended starting dosage of anagrelide capsules is 0.5 mg daily.
2.2 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 [see Warnings and Precautions ( 5 )] .
Most patients will experience an adequate response at a dose of 1.5 to 3 mg/day.
Monitor platelet counts weekly during titration then monthly or as necessary.
2.3 Dose Modifications for Hepatic Impairment In patients with moderate hepatic impairment (Child Pugh score 7 to 9) start anagrelide capsules therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .
Patients with moderate hepatic impairment who have tolerated anagrelide capsules 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 anagrelide capsules in patients with severe hepatic impairment.
2.4 Clinical Monitoring Anagrelide capsules 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.