anagrelide

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)

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
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.

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

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

No long-term studies in animals have been performed to evaluate carcinogenic potential of anagrelide hydrochloride.

Anagrelide produced no detectable or reproducible increases in gene mutational activity in studies conducted in vitro with mutant strains of S. 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.

AGRYLIN 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 AGRYLIN, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of AGRYLIN may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.

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. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment . 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 .In patients with moderate hepatic impairment, a dosage reduction is required.

It is recommended that patients with renal insufficiency (creatinine ≥2 mg/dL) 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, Table 1, Urogenital)

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 foetus.

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 foetus. 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 foetal 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 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.

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

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 3.0 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.