GEN-ANAGRELIDE

Anagrelide hydrochloride capsules 0.5 mg anagrelide as anagrelide hydrochloride Platelet-Reducing Agent Genpharm ULC Date of Revision: 85 Advance Road June 16, 2008 Etobicoke, Ontario M8Z 2S6 Control # 121164

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION.............................3

SUMMARY PRODUCT INFORMATION........................................ 3 INDICATIONS AND CLINICAL USE............................................ 3 CONTRAINDICATIONS............................................................. 4 WARNINGS AND PRECAUTIONS................................................ 4 ADVERSE REACTIONS.............................................................. 6 DRUG INTERACTIONS.............................................................. 9 DOSAGE AND ADMINISTRATION..............................................10 OVERDOSAGE......................................................................... 11 ACTION AND CLINICAL PHARMACOLOGY................................. 11 STORAGE AND STABILITY........................................................14 DOSAGE FORMS, COMPOSITION AND PACKAGING..................... 15

PART II: SCIENTIFIC INFORMATION.............................................. 16

PHARMACEUTICAL INFORMATION........................................... 16 CLINICAL TRIALS.................................................................... 17 DETAILED PHARMACOLOGY ...................................................19 TOXICOLOGY......................................................................... 21

REFERENCES.......................................................................... 24

PART III: CONSUMER INFORMATION............................................. 26

GEN-ANAGRELIDE Anagrelide hydrochloride capsules

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. 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, and 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 GEN-ANAGRELIDE (anagrelide hydrochloride) treatment is followed by an increase in platelet count. Following discontinuation, an increase in platelet count can be observed within four days.

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 30 mg/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 3 mg/kg/day and above), and in females receiving the doses of 10 and 30 mg/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.

Cardiovascular

GEN-ANAGRELIDE 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. Because of the positive inotropic effects and side-effects of GEN-ANAGRELIDE, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of GEN-ANAGRELIDE may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.

Hepatic/Biliary/Pancreatic

Hepatic metabolism represents the major route of anagrelide clearance and liver function may therefore be expected to influence this process. GEN-ANAGRELIDE 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). It is recommended that patients with mild and moderate hepatic impairment receive GEN-ANAGRELIDE 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 GEN-ANAGRELIDE (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).

Renal

It is recommended that patients with renal insufficiency (creatinine >= 2 mg/dL) receive GEN- ANAGRELIDE 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 GEN-ANAGRELIDE (see ADVERSE REACTIONS, Urogenital System).

Special Populations

Pregnant Women:

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

GEN-ANAGRELIDE 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 foetus. Women of child-bearing potential should be instructed that they must not be pregnant and that they should use contraception while taking GEN-ANAGRELIDE. GEN-ANAGRELIDE may cause foetal 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 GEN-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.

Pediatrics (<16 years of age): The safety and efficacy of GEN-ANAGRELIDE in patients under the age of 16 years 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%, AUCt 55%). (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). GEN-ANAGRELIDE should be used in this patient group with caution.

Monitoring and Laboratory Tests

GEN-ANAGRELIDE therapy requires close clinical supervision of the patient. To monitor the effect of GEN-ANAGRELIDE 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/mL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/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.

DRUG INTERACTIONS

Overview

Anagrelide is an inhibitor of cyclic AMP 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. Although additional drug interaction studies have not been conducted, the most common medications used concomitantly with GEN-ANAGRELIDE (anagrelide hydrochloride) in clinical trials have been acetylsalicylic acid, 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 GEN-ANAGRELIDE 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 GEN- ANAGRELIDE absorption. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single 900 mg dose of acetylsalicylic acid was generally well tolerated. There was no effect on bleeding time, PT or 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.

Anagrelide alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet aggregation by acetylsalicylic acid. The potential risks and benefits of the

concomitant use of anagrelide with acetylsalicylic acid in patients with a platelet count greater than 1000x109/L and/or a history of haemorrhage should be assessed 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 GEN-ANAGRELIDE (anagrelide hydrochloride) Capsules should be initiated under close medical supervision. The recommended starting dosage of GEN-ANAGRELIDE is mg 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/mL, 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 10 mg/day or 2.5 mg in a single dose (see PRECAUTIONS). 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 0.5 mg/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 0.5 mg/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). To monitor the effect of GEN-ANAGRELIDE 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/mL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1 .5 to 3.0 mg/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 GEN-ANAGRELIDE (anagrelide hydrochloride). Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Platelet reduction from GEN-ANAGRELIDE 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 GEN-ANAGRELIDE (anagrelide hydrochloride) 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 phosphodiesterase 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 than 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 GEN-ANAGRELIDE.

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 2 mg/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 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2 mg. 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.

Pharmacokinetics

Absorption: Single oral-dose administration of either 1 or 2 mg of anagrelide resulted in Cmax values ranging between 7 and l3 ng/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 4 mg/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 0.5 mg 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 4 mg/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 0.5 mg of anagrelide.

Special Populations and Conditions

Geriatrics:

No specific pharmacokinetic studies have been conducted in this patient population.

Pediatrics: 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%, AUCt 55%).

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 15deg to 25degC in a light-resistant container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

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

GEN-ANAGRELIDE 0.5 mg capsules:

White opaque capsules imprinted with "G 063" in black ink and supplied in bottles of 100.

COMPOSITION

Each capsule of GEN-ANAGRELIDE (anagrelide hydrochloride) contains 0.5 mg of anagrelide as anagrelide hydrochloride and the following non-medicinal ingredients: crospovidone, black iron oxide, gelatine, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, silicone dioxide, sodium lauryl sulfate, titanium dioxide.