PrDom-ANAGRELIDE Anagrelide hydrochloride monohydrate Capsules 0.5 mg Capsules
Date of Preparation:
6111 Royalmount Ave. # 100 June 2, 2006 Montreal, Quebec H4P 2T4
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 5 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 9 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 10 DOSAGE FORMS, COMPOSITION AND PACKAGING 11
PHARMACEUTICAL INFORMATION 12 CLINICAL TRIALS 12 DETAILED PHARMACOLOGY 14 TOXICOLOGY 19 REFERENCES 23
PrDom-ANAGRELIDE Anagrelide hydrochloride monohydrate Capsules 0.5 mg Capsules Platelet Reducing Agent
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| oral | capsules 0.5 mg | Lactose For a complete listing see Dosage Forms, Composition and Packaging section. |
Dom-ANAGRELIDE (anagrelide hydrochloride) capsules are indicated for the 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. Dom-ANAGRELIDE 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):
No data is available.
Pediatrics (< 16 years of age):
Safety and efficacy of Dom-ANAGRELIDE in patients under the age of 16 has not been established.
Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
General
The decision to treat asymptomatic young adults with thrombocythemia secondary to myeloproliferative disorders should be individualized. Sudden discontinuation or interruption of anagrelide hydrochloride treatment is followed by an increase in platelet count. Following discontinuation, an increase in platelet count can be observed within four days.
Cardiovascular
Anagrelide hydrochloride 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 anagrelide hydrochloride, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of anagrelide hydrochloride may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Hepatic/Biliary/Pancreatic
It is recommended that patients with evidence of hepatic dysfunction (bilirubin, SGOT, or measures of liver function >1.5 times the upper limit of normal) receive anagrelide hydrochloride when, in the physician's judgment the potential benefits of therapy outweigh the potential risks. These patients should be monitored closely for signs of hepatic toxicity while receiving anagrelide hydrochloride (see ADVERSE REACTIONS, Hepatic System).
Renal
It is recommended that patients with renal insufficiency (creatinine $ 2 mg/dL) receive anagrelide hydrochloride 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 anagrelide hydrochloride (see ADVERSE REACTIONS, Urogenital System).
Special Populations
Pregnant Women:
There are no adequate and well-controlled studies in pregnant women. Anagrelide hydrochlroide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Anagrelide hydrochloride 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 anagrelide hydrochloride. Anagrelide hydrochloride may cause fetal harm when administered to a pregnant woman.
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 anagrelide hydrochloride, 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.
:
The safety and efficacy of anagrelide hydrochloride in patients under the age of 16 years have not been established.
Anagrelide hydrochloride therapy requires close clinical supervision of the patient. To monitor the effect of anagrelide hydrochloride 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/uL, 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.
Carcinogenesis and Mutagenesis
No long term studies in animals have been performed to evaluate carcinogenic potential of anagrelide. 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 metabolizing 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.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug 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.
Analysis of the adverse events in a population consisting of 942 patients diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease groups have the same adverse event profile. While most reported adverse events during anagrelide hydrochloride 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 anagrelide hydrochloride therapy for ET, PV, CML and OMPD patients was 65, 67, 40 and 44 weeks, respectively. Of the 942 patients treated with anagrelide hydrochloride, 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 doses of anagrelide hydrochloride. The most frequently reported adverse reactions to anagrelide hydrochloride (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were:
| Headache | 43.5% |
| Palpitations | 26.1% |
| Diarrhea | 25.7% |
| Asthenia | 23.1% |
| Edema, other | 20.6% |
| Nausea | 17.1% |
| Abdominal Pain | 16.5% |
| Dizziness | 15.4% |
| Pain, other | 15.0% |
| Dyspnea | 11.9% |
| Flatulence | 10.2% |
| Vomiting | 9.7% |
| Fever | 8.9% |
| Peripheral Edema | 8.5% |
| Rash, including urticaria | 8.3% |
| Chest Pain | 8.0% |
| Anorexia | 7.7% |
| Tachycardia | 7.5% |
| Pharyngitis | 6.8% |
| Malaise | 6.4% |
| Cough | 6.3% |
| Paresthesia | 5.9% |
| Back Pain | 5.9% |
| Pruritus | 5.5% |
| Dyspepsia | 5.2% |
Adverse events with an incidence of 1% to < 5 % included the following:
Body as a Whole System:
Chills, flu symptoms, infection, neck pain, accidental injury, photosensitivity, cellulitis.
Cardiovascular System:
Arrhythmia, hemorrhage, cardiovascular disease, angina pectoris, heart failure, congestive heart failure, vasodilatation, postural hypotension, migraine, syncope, hypotension, thrombosis, hypertension.
Digestive System:
Constipation, GI hemorrhage, GI distress, dry mouth, melena, nausea and vomiting, gastritis, dysphagia, eructation.
Hemic & Lymphatic System:
Anemia, thrombocytopenia, ecchymosis, lymphadenoma. Platelet counts below 100 000/uL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below
50 000/uL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide hydrochloride therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide hydrochloride.
Hepatic System:
Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide hydrochloride therapy.
Musculoskeletal System:
Arthralgia, myalgia, leg cramps, arthritis, bone pain.
Nervous System:
Depression, somnolence, insomnia, confusion, hypertension, nervousness, amnesia.
Nutritional Disorders:
Weight loss, dehydration, weight gain, edema.
Respiratory System:
Rhinitis, epistaxis, respiratory disease, asthma, sinusitis, pneumonia, bronchitis.
Skin and Appendages System:
Sweating, skin disease, alopecia, skin ulcer, skin discoloration.
Special Senses:
Amblyopia, abnormal vision, ear disorder, conjunctivitis, diplopia, visual field abnormality, tinnitus, eye disorder.
Urogenital System:
Urinary tract disorder, urinary frequency, hematuria, urinary tract infection, dysuria, nocturia, urinary incontinence.
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 anagrelide hydrochloride treatment; in 4cases, the renal failure was considered to be possibly related to anagrelide hydrochloride treatment. The remaining 11 were found to have pre-existing renal impairment and were successfully treated with anagrelide hydrochloride. Doses ranged from 1.5-6.0 mg/day, with exposure periods of 2 to 12 months. No dose-adjustment was required because of renal insufficiency. The adverse event profile for the 942 patients in clinical trials on anagrelide hydrochloride therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:
Drug-Drug Interactions
Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interaction 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 and warfarin. Bioavailability studies evaluating possible interactions between anagrelide hydrochloride and other drugs have not been conducted. The most common medications used concomitantly with anagrelide hydrochloride have been aspirin, acetarninophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. The most frequently used concomitant cardiac medication has been digoxin. Although drug to drug interaction studies have not been conducted, there is no clinical evidence to suggest that anagrelide hydrochloride interacts with any of these compounds. 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 aspirin 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, aspirin 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 aspirin. The potential risk and benefits of the concomitant use of anagrelide with acetcylsalycic acid in patients with a platelet count greater than 1000 x 109/L and/or history of hemorrahge should be assessed before treatment is commenced. There is a single case report which suggests that sucralfate may interfere with anagrelide hydrochloride absorption. 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. 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. Anagrelide hydrochloride is an inhibitor of cyclic AMP, PDE III. The effects of medicinal products with similar properties such as inotropes, milrinone may be exacerbated by anagrelide.
Drug-Food Interactions
Food has no clinically significant effect on the bioavailability of anagrelide hydrochloride.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
Treatment with Dom-ANAGRELIDE (anagrelide hydrochloride) Capsules should be initiated under close medical supervision. The recommended starting dosage of Dom-ANAGRELIDE is 0.5 mg qid or 1 mg 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/uL, and ideally to the normal range. The dosage should be increased by not more than 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). The decision to treat asymptomatic young adults with thrombocythemia secondary to rnyeloproliferative disorders should be individualized. To monitor the effect of Dom-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/uL, 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.
There are no reports of overdosage with anagrelide hydrochloride. Platelet reduction from anagrelide hydrochloride, 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.
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.
Mechanism of Action:
The mechanism by which anagrelide 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. Platelet aggregation is inhibited in humans at doses higher than those required to reduce platelet count. Anagrelide inhibits cyclic AMP phosphodiesterase, as well as ADP- and collagen-induced platelet aggregation.
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 5 mg 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 fell 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.
Pharmacokinetics
Following oral administration of 14C-anagrelide in humans, more than 70% of the radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5mg and 2.0 mg. At fasting and at a dose of 0.5mg of anagrelide, the plasma half-life is 1.3 hours. The available plasma concentration time data at the steady state in patients showed that anagrelide does not accumulate in plasma after repeated administration. The drug is extensively metabolized; less than 1 % is recovered in the urine as anagrelide. Single oral-dose administration of either 1 or 2 mg of anagrelide resulted in Cmax, values ranging between 7 and 13 ng/mL, about 1 hour after administration, values consistent with estimates from preclinical studies. Urinary excretion was monophasic, the half-life of anagrelide being in the range of 1 to 2 hours. This PK half-life is consistent with the clinical dose frequency of 2 to 4 times per day. When a 0.5-mg dose of anagrelide was taken after food, its bioavailability (based on AUC values) was modestly reduced by an average of 13.8 % and its plasma half-life slightly increased (to 1.8 hours), when compared with drug administered to the same subjects in the fasted state. The peak plasma level was lowered by an average of 45% and delayed by 2 hours. The presence of food caused a slowing of the absorption from the gut after a single oral-dose administration of 0.5 mg of anagrelide. This led to the presence of anagrelide in the blood for a longer time, as compared to fasted administration. In addition, 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 plasma levels that showed no evidence of anagrelide accumulation. Mean excretion values for the major metabolite in the 24-hour urine sample were similar to those values obtained following single oral-dose administration of 0.5 mg of anagrelide.
Capsules: Store at controlled room temperature (15/ to 30/C) in a light resistant container.
Availability of Dosage Forms
Dom-ANAGRELIDE (anagrelide hydrochloride) capsules are supplied as follows: 0.5 mg capsules: White to off-white free flowing granules filled in size "4", hard gelatin, white opaque capsules. The body and cap is printed with the label claim "0.5 mg" in black colour. Bottles of 100 capsules
Composition
Active ingredient: anagrelide hydrochloride Non-medicinal ingredients (alphabetically): Crospovidone, lactose, magnesium stearate, microcrystalline cellulose, and povidone. Capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, and titanium dioxide.