Sitaxsentan (patient information)

Encysive Pharmaceuticals Inc., in consultation with Health Canada, wishes to highlight important safety information for the safe and appropriate prescribing and use of THELIN™ (sitaxsentan sodium).

THELIN (sitaxsentan sodium) is indicated for treatment of primary pulmonary arterial hypertension or pulmonary hypertension secondary to connective tissue disease, in patients with WHO functional class III who have not responded to conventional therapy. THELIN is also indicated in patients with WHO functional class II who did not respond to conventional therapy and for whom no appropriate alternative can be identified.


 * THELIN has been associated with a reversible, dose-related increase in aspartate aminotranferase (AST) and alanine aminotranferase (ALT), accompanied in some cases by elevated bilirubin. THELIN has been associated with 4 cases of mild to severe hepatitis, with one case resulting in hepatic failure and death. These patients were taking doses ≥ 300 mg daily and had multiple co-morbidities and drug therapies; however, the contribution of THELIN in these cases could not be excluded. Doses of THELIN above 100 mg once daily are not recommended.
 * Aminotransaminase (AST and ALT) levels must be measured prior to initiation of treatment with THELIN and subsequently at monthly intervals.
 * Use of THELIN is CONTRAINDICATED in patients with prior liver impairment (mild to severe, Child-Pugh Class A-C)
 * Use of THELIN is CONTRAINDICATED in patients with elevated liver aminotranferases prior to initiation of treatment AST and/or ALT > 3 x ULN.
 * Use of THELIN is CONTRAINDICATED in pregnant women or in women intending to become pregnant.
 * Use of THELIN is CONTRAINDICATED in Nursing Women.
 * Use of THELIN with cyclosporine is CONTRAINDICATED due to an interaction leading to a significant increase in the exposure of sitaxsentan.
 * Reduced dosage of warfarin is recommended due to enhanced effect on prothrombin time (PT) and international normalized ratio (INR).

Hepatic/Biliary/Pancreatic
THELIN has been associated with a reversible, dose-related increase in aspartate aminotranferase (AST) and alanine aminotranferase (ALT), accompanied in some cases by elevated bilirubin. THELIN has been associated with 4 cases of mild to severe hepatitis, with one case resulting in hepatic failure and death. These patients were taking doses ≥ 300 mg daily and had multiple co-morbidities and drug therapies; however, the contribution of THELIN in these cases could not be excluded. Doses of THELIN above 100 mg once daily are not recommended.

Liver transaminase levels must be measured prior to initiation of treatment and subsequently at monthly intervals.

Pre-existing Liver Impairment
Use in patients with baseline values of liver aminotransaminases, i.e., aspartate aminotranferase (AST) and/or alanine aminotranferase (ALT), greater than 3 times the upper limit of normal (ULN), particularly when the total bilirubin is increased to greater than 2 times the ULN, is contraindicated.

Management of Patients with Increased Liver Aminotransaminases
ALT/AST levels and treatment/monitoring recommendations are as follows:

> 3 and ≤ 8 × ULN - Confirm by another liver function test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values consider reintroducing THELIN (see Reintroduction of treatment below). > 8 × ULN - Treatment must be stopped and reintroduction of THELIN is not to be considered.

If liver aminotranferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, anorexia, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in total bilirubin above 2 x ULN, treatment should be stopped and re-introduction of Thelin is not to be considered.

Reintroduction of treatment
Reintroduction of treatment with THELIN should only be considered if the potential benefits of treatment with THELIN outweigh the potential risks and when aminotranferase levels are within pretreatment values. The advice of a hepatologist is recommended. Aminotranferase levels must then be checked within 3 days after reintroduction, then again after further 2 weeks, and thereafter according to the recommendations above.

Use in Women of Child-bearing Potential
Endothelin-1 receptor antagonists, as a class, have consistently produced teratogenic effects in animals. Results from reproductive toxicology studies performed with sitaxsentan indicate that dosing during pregnancy in the rat results in several fetal malformations. Although the effects of THELIN on human development are unknown, THELIN is likely to produce major birth defects if used by pregnant women. Therefore, pregnancy must be excluded before the start of treatment with THELIN and prevented thereafter by the use of a reliable method of contraception. Monthly pregnancy tests during treatment with THELIN are recommended.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the fetus.

Use in Nursing Women
Sitaxsentan was detected in the plasma of nursing pups from female rats treated with sitaxsentan, indicating that sitaxsentan was present in the breast milk. It is unknown whether sitaxsentan is excreted in human milk, but breastfeeding while taking THELIN is contraindicated.

Drug-Drug Interactions
Cyclosporine: THELIN 100 mg once daily co-administered with cyclosporine 3.5 mg/kg twice daily did not alter the pharmacokinetic disposition of cyclosporine, which is extensively metabolized by CYP3A4/5. However, this co-administration resulted in a 6-fold increase in the pre-dose concentrations of sitaxsentan. The mechanism for this interaction is not known. Because of this increase in sitaxsentan exposure, the use of THELIN in patients receiving cyclosporine is contraindicated.

Warfarin: Sitaxsentan is an inhibitor of CYP2C9 and increases the AUC and Cmax of drugs metabolized by CYP2C9. The AUC∞ of S-warfarin was increased by approximately 96%, and clearance was decreased by approximately 63% when a single 25 mg dose was co-administered with THELIN 100 mg once daily. An enhanced effect on PT and INR was observed, consistent with the increase in exposure to S-warfarin.

In clinical trials, it was recommended that the warfarin dose be decreased by 80% when starting THELIN and then increased in increments of no greater than 0.5 mg/day while titrating to the desired INR. The mean dose of warfarin at study endpoint in STRIDE 2 (18 weeks of dosing) was 2.2 mg/day for patients receiving THELIN, compared to 3.6 mg/day for patients treated with placebo. In STRIDE 2, the need to change the warfarin dose due to changes in INR was similar among the THELIN-treated and, placebo-treated patients.

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any serious or unexpected adverse reactions in patients receiving

THELIN should be reported to Encysive Canada, Inc. or Health Canada at the following addresses
Encysive Canada, Inc.

50 Elm Rd.

Toronto, ON

M5M 3T4

Tel: 877-684-3546

Fax: 866-234-9213

Any suspected adverse reaction can also be reported to
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)

Marketed Health Products Directorate

HEALTH CANADA

Address Locator: 0701C

OTTAWA, Ontario, K1A 0K9

Tel: 613-957-0337 or Fax: 613-957-0335

To report an Adverse Reaction, consumers and health professionals may call toll free:

Tel: 866-234-2345

Fax: 866-678-6789

cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at
Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) E-mail: bcans_enquiries@hc-sc.gc.ca Tel.: 613-941-1499 Fax: 613-941-1668