SYNONYM(S):

None

COMMON TRADE NAME(S): (r)

AGRYLIN

CLASSIFICATION:

miscellaneous, noncytotoxic

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

The exact mechanism of action is not known. It is thought that a reduction in platelet production is the result of decreased megakaryocyte hypermaturation.1 Anagrelide disrupts the postmitotic phase of megakaryocyte development, resulting in a reduction in the size of these cells.2,3 Anagrelide is also thought to inhibit adenosine diphosphate (ADP) and collagen induced platelet aggregation.4

PHARMACOKINETICS:

Interpatient variability
Oral Absorption > 70% absorbed, food decreases the extent and rate of absorption, but this is not considered to be clinically significant 5
time to peak plasma concentration 1-8 hours 2,4,6
Distribution cross blood brain barrier? no information found
volume of distribution 12 + 3 L/kg 4
plasma protein binding no information found
Metabolism extensively metabolized, <1% eliminated unchanged 4-5 metabolites have been identified, activity of these is not known 4
active metabolite(s) 2-amino-5,6-dichloro-3,4-dihydroquinazoline 7
inactive metabolite(s)
Excretion primarily renally eliminated
urine >70% eliminated via this route
feces 10-30% eliminated via this route 2
terminal half life 2-3 days 2
clearance no information found
Gender no information found
Elderly no information found
Children no information found
Ethnicity no information found

Adapted from reference 4 unless specified otherwise.

USES:

Primary uses: Other uses:
*Thrombocythemia secondary to myeloproliferative disorders 8 none

*Health Canada Therapeutic Products Programme approved indication

No pediatric indications are available.

SPECIAL PRECAUTIONS:

Contraindicated 2

in patients who have a history of hypersensitivity reaction to anagrelide.

Heart disease: 2

caution in patients with known or suspected heart disease, as anagrelide may cause cardiovascular effects (see table below).

Renal insufficiency: 2 Hepatic dysfunction: 2 Carcinogenicity: 2

caution in patients with renal insufficiency due to increased risk of renal toxicity.

caution in patients with hepatic dysfunction due to increased risk of hepatic toxicity.

no information found.

Mutagenicity: Not shown to be mutagenic in Ames test and in mammalian in vitro mutation test. Not shown to be clastogenic in mammalian in vitro and in vivo chromosome tests.2

Fertility: 2

Studies in male rats have shown no effect on fertility and reproduction. Studies in female rats have shown a higher rate of disruption of implantation if given early in pregnancy and retarded parturition if given late in pregnancy.

Pregnancy: 2

FDA Pregnancy Category C. The benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding 2

is not recommended due to the potential secretion into breast milk.

SIDE EFFECTS:

ORGAN SITE SIDE EFFECT ONSET
dose-limiting side effects are in bold, italics I= immediate (onset in hours to days); E = early (days to weeks) D= delayed (weeks to months); L= late (months to years)
auditory/hearing ear disorder (1-5%) 8 E D
tinnitus (1-5%) 8 E D
blood/bone marrow anemia (1-5%) 8 D
hemorrhage (1-5%) 8 E
thrombocytopenia (9%) 5 E
cardiovascular (arrhythmia) arrhythmia (1-5%) 8 D
cardiovascular (general) angina (1-5%) 8 D
cardiomegaly L
cardiomyopathy (rare) 9 L
complete heart block L
ORGAN SITE SIDE EFFECT ONSET
dose-limiting side effects are in bold, italics I= immediate (onset in hours to days); E = early (days to weeks) D= delayed (weeks to months); L= late (months to years)
heart failure (1-5%) 8 L
edema/fluid retention (20%) E
hypertension (1-5%) 8 E D
hypotension (1-5%) 8 E D
myocardial infarction D
palpitations (27%) L
pericarditis L
postural hypotension (1-5%) 8 I
syncope (1-5%) 8 E
tachycardia (7%) E
vasodilatation (1-5%) E
constitutional symptoms chills (1-5%) 8 I
fever (9%) 8 E
flu-like symptoms (1-5%) 8 I
malaise (6%) E
sweating (1-5%) 8 E
dermatology/skin alopecia (1-5%) 8 E D
cellulitis (1-5%) 8 E
ecchymosis (1-5%) 8 E
photosensitivity (1-5%) 8 E
pruritus (6%) 8 I
rash (8%) I
skin discolouration (1-5%) 8 D
skin ulcer (1-5%) 8 D
gastrointestinal emetogenic potential: low
anorexia (6%) I
belching (1-5%) 8 E
constipation (1-5%) 8 E
diarrhea (24%) E
dysphagia (1-5%) 8 E
dyspepsia (6%) I
flatulence (11%) E
gastritis (1-5%) 8 E
gastrointestinal distress (1-5%) 8 E
gastrointestinal hemorrhage (1-5%) 8 D
melena (1-5%) E
nausea (15%) I
pancreatitis D
pharyngitis (7%) D
vomiting (7%) I
ORGAN SITE SIDE EFFECT ONSET
dose-limiting side effects are in bold, italics I= immediate (onset in hours to days); E = early (days to weeks) D= delayed (weeks to months); L= late (months to years)
weight loss/weight gain (1-5%) 8 D
hepatic elevated liver function tests (rare) 2 D
infection infection (1-5%) 8 D
urinary tract infection (1-5%) 8 E D
lymphatics lymphadenoma (1-5%) 8 E D
musculoskeletal arthralgia (1-5%) 8 D
arthritis (1-5%) 8 D
leg cramps (1-5%) 8 D
myalgia (1-5%) 8 D
neurology amnesia (1-5%) 8 D
cerebrovascular accident D
confusion (1-5%) 8 I
depression (1-5%) 8 D
dizziness (15%) I
insomnia (1-5%) 8 E
migraine (1-5%) 8
nervousness (1-5%) 8 E
paresthesia (7%) D
seizures D
somnolence (1-5%) 8 E
ocular/visual abnormal vision (1-5%) 8 D
amblyopia (1-5%) 8 D
blurred vision D
conjunctivitis (1-5%) 8 D
eye disorder (1-5%) 8 D
visual field abnormality (1-5%) 8 D
pain abdominal pain (17%) I
back pain (6%) 8 E D
bone pain (1-5%) 8 E D
chest pain (8%) E D
headache (45%) I
neck pain (1-5%) 8 E D
pain (15%) E D
pulmonary bronchitis (1-5%) 8 D
cough (6%) 8 E D
dyspnea (11%) D
epistaxis (1-5%) 8 E D
pneumonia (1-5%) 8 E D
pneumonitis (rare) 10 D
pulmonary fibrosis D
ORGAN SITE SIDE EFFECT ONSET
dose-limiting side effects are in bold, italics I= immediate (onset in hours to days); E = early (days to weeks) D= delayed (weeks to months); L= late (months to years)
pulmonary hypertension D
rhinitis (1-5%) 8 E D
sinusitis (1-5%) 8 E D
renal/genitourinary dysuria (2%) 5 D
erectile dysfunction (rare) 11 D
hematuria (2%) 5 E D
incontinence (1-5%) 8 E D
nocturia (1-5%) 8 E D
renal failure (1-5%) 8 D
urinary frequency (1-5%) 8 E D
urinary tract disorder (1-5%) 8 E D

Adapted from reference 4 unless specified otherwise.

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT
sucralfate 3 unknown case report suggesting the sucralfate may interfere with absorption of anagrelide space administration of anagrelide and sucralfate by 2 hours

SUPPLY AND STORAGE:

Oral: 12

Sandoz Canada Inc. supplies anagrelide as a 0.5 mg capsule. Select non-medicinal ingredients: lactose. Store at room temperature in a light-resistant container.

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Adults:

BCCA usual dose noted in bold, italics
Oral: initial dosing : 0.5 mg PO four times daily or 1 mg PO twice daily 2 maintenance : 1-4 mg PO daily in 2-4 divided doses or 1.5-3 mg daily 2 Adjust dose according to the platelet count Platelet counts every 1-2 weeks during dosage titration and every 1-3 months during maintenance , or every 2 days during the first week of treatment and at least weekly until the maintenance dose is Do not increase dose by more than 0.5 mg/day in any one week. Maximum dose: 10 mg/day or 2.5 mg in a single dose. reached. 8

Dosage in renal failure: no information found Dosage in hepatic failure: no information found Dosage in dialysis: no information found

Children:

Initial dosing of 0.5 mg PO twice daily and maintenance dosing of 0.5-4 mg/day in 3 divided doses have been used.5,13-15 However, safety and efficacy have not been established.

REFERENCES:

  1. Yoon SY, Li CY, Mesa RA, et al. Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia. British Journal of Haematology 1999; 106(3):682-8.

  2. Shire. Agrylin Product Monograph. Laval, Quebec; 19 July 2003.

  3. Kastrup B, editor. Drug Facts and Comparisons. St Louis, Missouri: Facts and Comparisons; September 2003.

  4. Gaver RC, Deeb G, Pittman KA, et al. Disposition of anagrelide, an inhibitor of platelet aggregation. Clinical Pharmacology & Therapeutics 1981; 29(3):381-6.

  5. Anagrelide. USPDI. Volume 1. Drug Information for the health care professional. 22nd ed. Greenwood Village, Colorado: Thomson MICROMEDEX; 2002.

  6. Hong Y, Erusalimsky JD. Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review. Platelets 2002; 13(7):381-6.

  7. Lane WJ, Hattori K, Dias S, et al. Anagrelide metabolite induces thrombocytopenia in mice by inhibiting megakaryocyte maturation without inducing platelet aggregation. Experimental Hematology 2001; 29(12):1417-24.

  8. Repchinsky C, editor. Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2003.

  9. James CW. Anagrelide-induced cardiomyopathy. Pharmacotherapy 2000; 20(10):1224-7.

  10. Raghavan M, Mazer MA, Brink DJ. Severe hypersensitivity pneumonitis associated with anagrelide. Annals of Pharmacotherapy 2003; 37(9):1228-1231.

  11. Braester A, Laver B. Anagrelide-induced erectile dysfunction. Annals of Pharmacotherapy 2002; 36(7):1291.

  12. Sandoz Canada Inc. Sandoz anagrelide product monograph. Boucherville, Quebec; 10 January 2006.

  13. Hermann J, Fuchs D, Sauerbrey A, et al. Successful treatment of essential thrombocythemia with anagrelide in a child. Medical & Pediatric Oncology 1998; 30(6):367-70; discussion 370-1.

  14. Scherer S, Ferrari R. Treatment Of Essential Thrombocythemia in Childhood. Pediatric Hematology & Oncology 2003; 20:361- 365.

  15. Lackner H, Urban C, Beham-Schmid C, et al. Treatment of children with anagrelide for thrombocythemia. Journal of Pediatric Hematology/Oncology 1998; 20(5):469-73.