Agrylin: Indications, Dosage, Precautions, Adverse Effects
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Agrylin - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Thrombocythemia
Class: Miscellaneous uncategorized agents
Form: Capsules
Ingredients: anagrelide hydrochloride, black iron oxide, crospovidone, gelatine, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, silicone dioxide, sodium lauryl sulphate, titanium dioxide

anagrelide hydrochloride capsules

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients
oralCapsule 0.5mgBlack iron oxide, crospovidone, gelatine,
lactose anhydrous, lactose monohydrate,
magnesium stearate, microcrystalline
cellulose, povidone, silicone dioxide, sodium
lauryl sulphate, titanium dioxide

Indications and Clinical Use

AGRYLIN (anagrelide hydrochloride capsules) are indicated for:

  • Treatment of patients with thrombocythemia secondary to myeloproliferative disorders to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms, including thrombo-hemorrhagic events.

AGRYLIN is intended for chronic usage and has not been evaluated for treatment of the acute life threatening complications of thrombocytosis.

Geriatrics (>65 years of age)

The safety and effectiveness of AGRYLIN have not been evaluated in studies specific to the elderly.

Pediatrics (<16 years of age)

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

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container (see Dosage Forms, Composition and Packaging).
  • Anagrelide is contraindicated in patients with severe hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied. Anagrelide must be used with caution in patients with moderate hepatic impairment as exposure to anagrelide is increased 8-fold in such patients (see Action and Clinical Pharmacology; Warnings and Precautions, Hepatic/Biliary/Pancreatic).

Warnings and Precautions

General

The decision to treat asymptomatic young adults with thrombocythemia secondary to myeloproliferative disorders should be individualized.

Sudden discontinuation or interruption of AGRYLIN (anagrelide hydrochloride capsules) treatment is followed by an increase in platelet count. Following discontinuation, an increase in platelet count can be observed within four days.

Cardiovascular

Due to the positive inotropic and chronotropic effects and cardiovascular side-effects (see Adverse Reactions) of AGRYLIN, it should be used with caution in patients with known or suspected heart disease, and only if the potential benefits of therapy outweigh the potential risks.

A pre-treatment cardiovascular examination (including investigations such as echocardiograph, electrocardiogram) is recommended for all patients, along with careful monitoring during treatment and further investigations carried out as necessary. In humans, therapeutic doses of AGRYLIN may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.

Anagrelide has been shown to increase the heart rate, resulting in an apparent increase in QTc interval of the electrocardiogram in healthy volunteers. The clinical impact of this effect is unknown (see Action and Clinical Pharmacology, Pharmacodynamics – Effects on Heart Rate and QTc Interval).

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 hypokalemia.

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 (see Action and Clinical Pharmacology, Special Populations and Conditions) or use with CYP1A2 inhibitors (see Drug Interactions, Drug-Drug Interactions).

Hepatic/Biliary/Pancreatic

Hepatic metabolism represents the major route of anagrelide clearance and liver function may therefore be expected to influence this process. AGRYLIN has not been studied in patients with severe hepatic impairment and is contraindicated (see Contraindications). Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see Action and Clinical Pharmacology, Special Populations and Conditions – Hepatic Insufficiency). It is recommended that patients with mild and moderate hepatic impairment receive AGRYLIN only if, in the physician's judgment, the potential benefits of therapy outweigh the potential risks. Patients with mild or moderate hepatic impairment should be carefully and regularly monitored for cardiovascular effects and hepatic toxicity while receiving AGRYLIN (see Warnings and Precautions, Cardiovascular, and Adverse Reactions). In patients with moderate hepatic impairment, a dosage reduction is required (see Dosage and Administration, Recommended Dose and Dosage Adjustment).

Pulmonary

Interstitial Lung Diseases

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 associated with lung infiltrations. The time of onset ranges from 1 week to several years after initiating anagrelide. In most cases, the symptoms improved after discontinuation of anagrelide (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Renal

It is recommended that patients with renal insufficiency (creatinine ≥ 2mg/μL) receive AGRYLIN when, in the physician's judgment, the potential benefits of therapy outweigh the potential risks. These patients should be monitored closely for signs of renal toxicity while receiving AGRYLIN (see Adverse Reactions).

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. AGRYLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

AGRYLIN 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 fetus. Women of child-bearing potential should be instructed that they must not be pregnant and that they should use contraception while taking AGRYLIN. AGRYLIN may cause fetal harm when administered to a pregnant woman.

Nursing Women

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants from AGRYLIN, 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.

Geriatrics (>65 years of age)

Pharmacokinetic (PK) differences between elderly and younger patients with essential thrombocythemia (ET) have been observed (see Action and Clinical Pharmacology, Special Populations and Conditions – Geriatrics; Dosage and Administration).

Pediatrics (<16 years of age)

The safety and efficacy of AGRYLIN in patients under 16 years of age have not been established. Myeloproliferative disorders are uncommon in pediatric patients and limited data are available in this population. An open-label study conducted in 17 pediatric patients 7-14 years of age and 18 adult patients (67% of which were elderly patients, i.e., 65 years of age and older) with essential thrombocythemia indicated that dose and body weight-normalized exposure, Cmax and AUC of anagrelide were lower in children/adolescents compared to adults (Cmax 48%, AUC55%) (see Action and Clinical Pharmacology, Pharmacokinetics). AGRYLIN should be used in this patient group with caution.

Monitoring and Laboratory Tests

AGRYLIN therapy requires close clinical supervision of the patient. To monitor the effect of AGRYLIN 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. The time to complete response, defined as platelet count ≤600,000/μL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3.0mg/day. In case of overdose, close clinical supervision of the patient is required, including monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped as appropriate, until platelet count returns to within the normal range. However, in patients with hepatic insufficiency or renal insufficiency, liver function and kidney function tests should be performed at least once per month or when deemed necessary in the physician’s judgement. Electrolytes (potassium, magnesium and calcium) should also be monitored.

As cases of hepatitis have been reported from post-marketing surveillance, it is recommended that liver functions (ALT and AST) tests are performed before anagrelide treatment is initiated and at regular intervals thereafter.

Carcinogenesis and Mutagenesis

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

Anagrelide produced no detectable or reproducible increases in gene mutational activity in studies conducted in vitro with mutant strains of Salmonella typhimurium in the Ames test, or in a mouse lymphoma mutagenesis assay, with or without a rat hepatic drug metabolising enzyme system.

In addition, no clastogenic activity was seen in vitro using cultured human peripheral lymphocytes or in vivo in a mouse bone marrow erythrocyte micronucleus assay. At the concentrations and doses employed in these studies, there was no indication that anagrelide was a potential mutagen either directly or after metabolic activation.

Adverse Reactions

Adverse Drug Reaction Overview

Analysis of the adverse events in a population consisting of 942 patients diagnosed with myelo-proliferative diseases of varying etiology [Essential Thrombocythemia (ET): 551; Polycythemia Vera (PV): 117; other myeloproliferative disorders (OMPD): 274] has shown that all disease groups have the same adverse event profile. While most reported adverse events during AGRYLIN (anagrelide hydrochloride capsules) therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events reported were reported in these patients. These include the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.

The mean duration of AGRYLIN therapy for ET, PV, Chronic Myelogenous Leukemia (CML) and OMPD patients was 65, 67, 40 and 44 weeks, respectively. Of the 942 patients treated with AGRYLIN, 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, 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 AGRYLIN.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The most frequently reported adverse reactions to AGRYLIN (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials are included in Table 1:

Table 1: Adverse events with an incidence of ≥5%
AGRYLIN
Body as a WholeHeadache(43.5%)
Asthenia(23.1%)
Abdominal pain(16.5%)
Pain, other(15.0%)
Fever(8.9%)
Chest pain(8.0%)
Malaise(6.4%)
Back pain(5.9%)
CardiovascularPalpitations(26.1%)
Tachycardia(7.5%)
DigestiveDiarrhea(25.7%)
Nausea(17.1%)
Flatulence(10.2%)
Vomiting(9.7%)
Anorexia(7.7%)
Dyspepsia(5.2%)
MetabolicEdema, other(20.6%)
Peripheral edema(8.5%)
NervousDizziness(15.4%)
Paresthesia(5.9%)
RespiratoryDyspnea(11.9%)
Pharyngitis(6.8%)
Cough(6.3%)
Skin and AppendagesPruritus(5.5%)
Rash, including urticaria(8.3%)

Table 2: Adverse events with an incidence of 1% to <5%
AGRYLIN
Body as a WholeAccidental injury, cellulitis, chills, flu symptoms, infection, neck
pain, photosensitivity.
CardiovascularAngina pectoris, arrhythmia, cardiovascular disease, congestive
heart failure, heart failure, hemorrhage, hypertension, hypotension,
migraine, postural hypotension, syncope, thrombosis,
vasodilatation.
DigestiveConstipation, dry mouth, dysphagia, eructation, gastritis, GI
distress, GI hemorrhage, melena, nausea and vomiting.
Hemic & LymphaticAnemia, ecchymosis, lymphadenoma, thrombocytopenia,
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 AGRYLIN therapy.
Thrombocytopenia promptly recovered upon discontinuation of
AGRYLIN.
HepaticElevated liver enzymes were observed in 3 patients (ET: 2;
OMPD: 1) during AGRYLIN therapy.
MusculoskeletalArthralgia, arthritis, bone pain, leg cramps, myalgia.
NervousAmnesia, confusion, depression, insomnia, nervousness,
somnolence.
Nutritional DisordersDehydration, edema, weight gain, weight loss.
RespiratoryAsthma, bronchitis, epistaxis, pneumonia, respiratory disease,
rhinitis, sinusitis.
Skin and AppendagesAlopecia, skin discoloration, skin disease, skin ulcer, sweating.
Special SensesAbnormal vision, amblyopia, conjunctivitis, diplopia, ear disorder,
eye disorder, tinnitus, visual field abnormality.
UrogenitalDysuria, hematuria, nocturia, urinary frequency, urinary
incontinence, urinary tract disorder, urinary tract infection.

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 AGRYLIN treatment; in 4 cases, the renal failure was considered to be possibly related to AGRYLIN treatment. The remaining 11 were found to have pre-existing renal impairment and were successfully treated with AGRYLIN. Doses ranged from 1.5-6.0mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.

Other adverse drug reactions seen in these or other clinical studies: supraventricular tachycardia (uncommon), ventricular tachycardia (uncommon), hypoesthesia (common).

Post-Market Adverse Drug Reactions

In individual case reports, a causal relationship has been established between acute pulmonary reactions (severe hypersensitivity pneumonia ‘allergic alveolitis’, pulmonary infiltrates/fibrosis, and dyspnea) and the use of anagrelide. AGRYLIN should be discontinued in patients showing acute pulmonary reactions. Cases of torsade de pointes have been reported (see Warnings and Precautions, Cardiovascular). Congestive heart failure, cardiomyopathy, myocardial infarction and tubulointerstitial nephritis have occurred in a small number of patients with the use of anagrelide. Hepatitis has also been reported in patients who have taken anagrelide treatment. The incidence of these events is not known.

Drug Interactions

Overview

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase (PDE) III. The effects of medicinal products with similar properties, such as the inotrope milrinone, may be exacerbated by anagrelide.

Drug-Drug Interactions

Limited pharmacokinetic and/or pharmacodynamic 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.

Apart from acetylsalicylic acid discussed further below, additional drug interaction studies have not been conducted, with the other most common medications used concomitantly with AGRYLIN (anagrelide hydrochloride) in clinical trials, which were acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. The most frequently used concomitant cardiac medication has been digoxin. There is no clinical evidence to suggest that AGRYLIN interacts with any of these compounds.

Anagrelide 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 anagrelide and its active metabolite BCH24426. Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism, e.g., theophylline. Drug-drug interactions with CYP1A2 substrates and inhibitors cannot be excluded.

There is a single case report which suggests that sucralfate may interfere with AGRYLIN absorption.

Two clinical interaction studies in healthy subjects, a single-dose study of co-administered anagrelide 1mg and acetylsalicylic acid 900mg and a repeat-dose dose study of co-administered anagrelide 1mg once daily and acetylsalicylic acid 75mg once daily, demonstrated greater anti-platelet aggregation effects than administration of acetylsalicylic acid alone. In the repeat-dose study, anagrelide alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet aggregation by acetylsalicylic acid. There was a short-lived decrease in platelet aggregation beyond the effects of acetylsalicylic acid alone for the first 2 hours after administration. The clinical relevance of this interaction in essential thrombocythemia patients is unknown.

Co-administered anagrelide 1mg and acetylsalicylic acid 900mg single-dose was generally well tolerated. There was no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT). No clinically relevant pharmacokinetic interactions between anagrelide and acetylsalicylic acid were observed. In that same study, acetylsalicylic acid alone produced a marked inhibition in platelet aggregation ex vivo.

In some essential thrombocythemia patients concomitantly treated with acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, the potential risks and benefits of the concomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with a high risk profile for haemorrhage and/or with a platelet count greater than 1000x109/L before treatment is commenced.

Drug-Food Interactions

Food decreased the Cmax of anagrelide by 14%, but increased the AUC0-∞ by 20%. For both parameters, the exposure after food was not equivalent to that in the fasted state. Food decreased the Cmax of the active metabolite BCH24426 by 29%, but had no effect on the AUC0-∞ . The most marked effects of food were evident in a longer time lag before absorption (or appearance, in the case of BCH24426), a slower rate of absorption and a later time of peak for plasma concentration of both anagrelide and BCH24426.

Grapefruit juice has been shown to inhibit CYP1A2 and therefore could also reduce the clearance of anagrelide.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Recommended Dose and Dosage Adjustment

Treatment with AGRYLIN (anagrelide hydrochloride capsules) should be initiated under close medical supervision. The recommended starting dosage of AGRYLIN is 0.5mg qid or 1mg bid, which should be maintained for at least one week. Dosage should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count below 600,000/μL, and ideally to the normal range. The dosage should be increased by not more than 0.5mg/day in any one week. Dosage should not exceed 10mg/day or 2.5mg in a single dose (see Warnings and Precautions, Monitoring Laboratory Tests). The decision to treat asymptomatic young adults with thrombocythemia secondary to myeloproliferative disorders should be individualized.

It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a dose of 0.5mg/day and be maintained for a minimum of one week with careful and regular monitoring of cardiovascular effects and hepatic toxicity. The dosage increment must not exceed more than 0.5mg/day in any one-week. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate impairment of hepatic function should be assessed before treatment is commenced. Use of anagrelide in patients with severe hepatic impairment has not been studied. Use of anagrelide in patients with severe hepatic impairment is contraindicated (see Contraindications).

The observed pharmacokinetic differences between the elderly and younger patients with ET would not be expected to require alteration of the recommended dosing regimen of AGRYLIN (see Action and Clinical Pharmacology, Special Populations and Conditions – Geriatrics).

To monitor the effect of AGRYLIN 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. The time to complete response, defined as platelet count ≤600,000/μL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3.0mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

Overdosage

Acute Toxicity and Symptoms

There have been a small number of post-marketing case reports of intentional overdose with AGRYLIN (anagrelide hydrochloride capsules). Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Platelet reduction from AGRYLIN 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 to within the normal range.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

The mechanism by which AGRYLIN (anagrelide hydrochloride capsules) reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters.

Anagrelide was shown to inhibit PDE III found in platelets and as a result raises cAMP levels, which in turn may explain the inhibitory effect on platelet aggregation. Platelet aggregation is inhibited in humans at doses higher than those required to reduce platelet count. Two major metabolites, one active and one inactive, have been identified. The active metabolite, BCH24426 or 3-hydroxy anagrelide, shows similar potency and efficacy as anagrelide in the platelet lowering effect. Exposure as measured by plasma AUC is approximately 2-fold higher for 3-hydroxy anagrelide (BCH24426) compared to anagrelide. The inactive metabolite, RL603 or 5,6-dichloro-3,4-dihydroquinazolin-2-ylamine, does not participate in the overall affect of AGRYLIN.

Pharmacodynamics

Oral administration of single and multiple doses of anagrelide in healthy volunteers caused dose-related reductions in platelet count during treatment. In addition, dose-related reductions occur in platelet aggregation. These effects were reversible following cessation of treatment. No clinically important changes in other study variables were noted, i.e., bleeding time, platelet survival time, bone marrow morphology, blood pressure, pulse rate, urinalysis, and EKG. Anagrelide is well tolerated at low doses. A 5mg dose caused orthostatic hypotension and dizziness in healthy volunteers; doses of 1 to 2mg/day were tolerable.

In most cases, the incidence of adverse effects is dose-related, intensity is mild, duration is transient, and treatment is unnecessary.

In 9 subjects receiving a single 5-mg dose of anagrelide, standing blood pressure decreased an average of 22/15mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2mg.

Pharmacological evaluation of anagrelide and its metabolites showed that 3-hydroxy anagrelide (BCH24426) had a comparable inhibitory effect to the parent drug on megakaryocytopoiesis – and therefore platelet formation – while RL603 was inactive. Anagrelide and 3-hydroxy anagrelide (BCH24426) were also found to be inhibitors of PDEIII although 3-hydroxy anagrelide (BCH24426) was almost forty times more potent than the parent drug while RL603 was again virtually inactive.

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, randomized, placebo- and active-controlled, cross-over study in 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 occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg . The evidence suggests that this increase in QTc may be due to the physiological effect of the increasing heart rate and the corresponding QT-RR hysteresis, rather than a direct effect on repolarization.

Pharmacokinetics

Absorption

Single oral-dose administration of either 1 or 2mg of anagrelide resulted in Cmax values ranging between 7 and 13ng/mL, about 1 hour after administration.

Pharmacokinetic data obtained from healthy subjects comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%. For both parameters, the exposure after food was not equivalent to that in the fasted state. Food decreased the Cmax of the active metabolite BCH24426 by 29%, but had no effect on the AUC0-∞ . The most marked effects of food were evident in a longer time lag before absorption (or appearance, in the case of BCH24426), a slower rate of absorption and a later time of peak for plasma concentration of both anagrelide and BCH24426.

Distribution

The available plasma concentration time data at the steady state in patients showed no evidence of anagrelide accumulation in plasma after repeated administration. Long-term oral administration ( ≥2 months to >5 years) of anagrelide at doses of 2 to 4mg/day resulted in plasma levels within the range expected after a single dose.

Metabolism

The drug is extensively metabolized; less than 1% is recovered in the urine as anagrelide. At fasting and at a dose of 0.5mg of anagrelide, the plasma half-life is 1.3 hours.

Excretion

Following oral administration of 14C-anagrelide in humans, more than 70% of the radioactivity was recovered in urine. Urinary excretion was monophasic, while the plasma half-life of anagrelide was in the range of 1 to 2 hours. This pharmacokinetic half-life is consistent with the clinical dose frequency of 2 to 4 times per day. The plasma half-life of the pharmacologically active metabolite, 3-hydroxy anagrelide (BCH24426), was approximately 3 hours.

There was a statistically greater amount of anagrelide metabolite excreted in the urine during the 24-hour period after fasted administration of anagrelide, compared to after the fed state. These differences, however, were not considered to be clinically significant.

Long-term oral administration ( ≥2 months to >5 years) of anagrelide at doses of 2 to 4mg/day resulted in mean excretion values for the major metabolite in the 24-hour urine sample similar to those values obtained following single oral-dose administration of 0.5mg of anagrelide.

Special Populations and Conditions

Geriatrics

Pharmacokinetic data from fasting elderly patients with ET (age range 65 to 75 years) compared to fasting adult patients (age range 22 to 50 years) indicate that the C max 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 caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients.

Pediatrics

An open-label study conducted in 17 pediatric patients 7 to 14 years of age and 18 adult patients (67% of which were elderly patients, i.e., 65 years of age and older) with essential thrombocythemia indicated that dose and body weight-normalized exposure, Cmax and AUC of anagrelide were lower in children/adolescents compared to adults (Cmax 48%, AUCt 55%).

Summary of PK Parameters for Anagrelide and Metabolite in Adolescent/Adult and
Pediatric/Adolescent Subjects on 0.5mg bid Regimen
AnagrelideBCH24426
PK
Parameter
AA (n=4)
Mean (SD)
PA (n=4-6)
Mean (SD)
AA (n=4)
Mean (SD)
PA (n=4-6)
Mean (SD)
Tmax
(h)
1.9 (1.5)3.9 (3.1)2.4 (1.1)4.0 (3.1)
Cmax
(ng/mL)
3.1 (1.3)1.9 (0.6)4.5 (1.8)5.5 (2.8)
Cmin
(ng/mL)
00.03 (0.04)0.2 (0.1)0.4 (0.2)
AUC
(ng.h/mL)
8.6 (3.3)8.2 (3.3)19.9 (3.7)24.4 (8.3)
T1/2z(h)1.5 (0.5)3.9 (3.7)2.8 (0.7)4.2 (1.6)
Cavg
(ng/mL)
0.7 (0.3)0.7 (0.3)1.7 (0.3)2.0 (1.7)
FI4.3 (1.0)3.2 (2.2)2.5 (0.6)1.1 (0.9)
CI/F
(mL/min)
1062 (315)1169 (465)429 (71)1004 (455)

AA: Adolescent/adult subject group; PA: Pediatric/adolescent subject group.

Hepatic Insufficiency

Hepatic metabolism represents the major route of anagrelide clearance and liver function is expected to influence this process. Accordingly, an open label pharmacokinetic study has been performed on subjects with moderate hepatic impairment (and otherwise healthy) vs. healthy subjects. A single dose of 1mg anagrelide was administered to each individual. Though a limited number of patients were enrolled for the study, the results show that AUC0-∞ was nearly 8 times higher in subjects with moderate hepatic impairment (n=10) than in healthy subjects (n=10). A strong correlation has been established between the AUC measurements and the Child-Pugh Score (indicator of hepatic impairment severity). Pharmacokinetic measurements performed on 3-hydroxy anagrelide (BCH24426, the active metabolite of anagrelide) and RL603 (the inactive metabolite of anagrelide) show approximately a doubling of AUC in patients with moderate hepatic impairment as compared to healthy subjects. No study has been performed either on patients with severe or on patients with mild hepatic impairment, therefore, no data are available.

Storage and Stability

Store from 15°C to 25°C in a light-resistant container.

Dosage Forms, Composition and Packaging

AGRYLIN (anagrelide hydrochloride capsules) is available in capsules containing 0.5mg of anagrelide as anagrelide hydrochloride for oral administration.

AGRYLIN 0.5mg capsules: White, opaque capsules imprinted with Shire logo “S” and “063" in black ink and supplied in bottles of 100.

Each capsule of AGRYLIN (anagrelide hydrochloride capsules) contains 0.5mg of anagrelide as anagrelide hydrochloride and the following non-medicinal ingredients:

  • Black iron oxide, crospovidone, gelatine, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, silicone dioxide, sodium lauryl sulfate, titanium dioxide.