(sitaxsentan sodium tablets) 100 mg Endothelin receptor antagonist Date of preparation: November 4, 2008 (r) Registered trademark of Encysive Pharmaceuticals Inc. Pfizer Canada Inc. 17 300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control Number: 125736

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY OF PRODUCT INFORMATION

CONTRAINDICATIONS

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. The co-administration of THELIN with cyclosporine is contraindicated, as cyclosporine induces a 6-fold increase in the pre-dose plasma concentrations of sitaxsentan Hypersensitivity to sitaxsentan sodium or any component of the drug product (for a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph). Nursing Women Prior Liver Impairment (mild to severe, Child-Pugh Class A-C) Elevated liver aminotransferases prior to initiation of treatment (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Liver toxicity (see Hepatic/Biliary/Pancreatic)

THELIN has been associated with a reversible, dose-related increase in aspartate aminotransferase (AST) and alanine aminotransferase (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.

THELIN is to be taken orally. The adult dose is 100 mg once daily. THELIN may be taken with or without food and without regard to the time of day. Higher doses did not confer additional benefit sufficient to offset the increased risk of side effects, particularly liver injury (see WARNINGS and PRECAUTIONS). A dose of 50 mg once daily did not demonstrate sufficient efficacy to support its use. Safety and efficacy in pediatric patients have not been established.

THELIN should be initiated with caution if the patient has a systemic systolic blood pressure lower than 85 mm Hg.

Treatment with THELIN has been associated with a dose-related decrease in hemoglobin and hematocrit. The overall mean decrease in hemoglobin concentration in 149 THELIN-treated patients during placebo-controlled trials was 0.5 g/dL (change from baseline to end of treatment).

Most of the decrease in hemoglobin concentration was detected during the first few weeks of THELIN treatment and hemoglobin levels normally stabilized by week 4 of THELIN treatment. In the placebo-controlled studies, marked decreases in hemoglobin (> 15% decrease from baseline with values below the lower limit of normal) were observed in 7% of patients treated with THELIN (10/149) and in 3% of placebo-treated patients (5/155).

A decrease in hemoglobin concentration by at least 1 g/dL was observed in 60% of patients treated with THELIN (83/149) as compared to 32% of placebo-treated patients (48/155). The

origin of the change in hemoglobin is not known, but it does not appear to be due to hemorrhage or hemolysis.

It is recommended that hemoglobin concentrations be monitored 1 and 3 months following the initiation of THELIN and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, a further evaluation should be undertaken to determine the cause and need for specific treatment.

Use in patients with baseline values of liver aminotransaminases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (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 (see CONTRAINDICATIONS).

ALT/AST levels and treatment/monitoring recommendations are as follows: > 3 and <= 8 x 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 x ULN - Treatment must be stopped and reintroduction of THELIN is not to be considered. If liver aminotransferase 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 reintroduction 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 aminotransferase levels are within pretreatment values. The advice of a hepatologist is recommended. Aminotransferase levels must then be checked within 3 days after reintroduction, then again after further 2 weeks, and thereafter according to the recommendations above.

Pregnant Women: CONTRAINDICATIONS)

THELIN is contraindicated in pregnant women or in women intending to become pregnant (see

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 (see CONTRAINDICATIONS).

Pediatrics:

Use in Elderly Patients:

Of the 1487 patients treated with THELIN in clinical studies, 169 (11%) were aged 65 and over. The overall frequency of events and types of adverse events were similar in patients above and below 65 years of age.

In the 512 patients studied in the placebo-controlled PAH trials, the efficacy of THELIN in the geriatric population (>=65 years of age) was comparable to the efficacy observed in the non- elderly. Therefore, THELIN may be used in the patients aged 65 years and over as long as haematology and liver function assessments are performed regularly (see WARNINGS AND PRECAUTIONS).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most commonly reported adverse events with THELIN treatment were headache, peripheral oedema, nasal congestion, nausea,

constipation, epistaxis, insomnia; prothrombin time prolonged and increased INR (Refer to Table 1).

Overall treatment discontinuations were less frequent in THELIN-treated patients (3%; 4/149 patients) than in placebo-treated patients (8%; 12/155 patients). In the STRIDE-2 study (see PART II: CLINICAL TRIALS), 2/61 (3%) patients taking THELIN discontinued treatment due to adverse events, as compared to 6/62 (10%) placebo-treated. During continued treatment in the extension study following completion of STRIDE-2, 13/145 (9%) patients treated with THELIN were discontinued due to adverse events.

Serious Adverse Drug Reactions Related to the Administration of THELIN:

Hepatobiliary disorders (hepatitis), Hepatic Failure, Investigations (elevated Liver function test abnormal/Hepatic enzymes increased [ALT/AST]).

Discontinuations Related to THELIN:

Of the 774 subjects treated in the sitaxsentan > 50 to <= 100 mg group, 34 (4%) discontinued study drug due to a drug-related, treatment-emergent AE. The only drug-related, treatment-emergent AE associated with discontinuation of study drug in at least 2% of subject in the > 50 to <= 100 mg sitaxsentan group was LFT abnormal (13 subjects, 2%). None of the specific drug-related, treatment-emergent AEs associated with discontinuation of study drug were experienced in at least 2% of placebo subjects.

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 reaction information from clinical trials is useful for identifying drug-related adverse events and for approximate rates. Safety data were obtained from 29 clinical studies, which comprised a total of 1487 subjects, including healthy volunteers and patients. Doses ranged from 50 mg to more than 1000 mg per day, and duration of treatment ranged from 1 day to 2.8 years (N=148 for 1 year or more). In PAH studies, safety data were obtained from 899 patients receiving THELIN. Table 1 presents the adverse drug reactions that occurred during placebo-controlled PAH trials in > 1% of THELIN patients, at a rate greater than placebo, and that were considered to be at least possibly related to THELIN treatment.

Table 1

: Adverse Drug Reactions Occurring in > 1% of Patients Treated with THELIN, More Frequently Than Placebo, and Related to THELIN Treatment

System Organ Class Preferred Term	THELIN 100 mg N = 149 (%)	Placebo N = 155 (%)
Gastrointestinal
Nausea	10 (6.7%)	6 (3.9%)
Constipation	5 (3.4%)	0
Upper Abdominal Pain	3 (2.0%)	2 (1.3%)
Vomiting	4 (2.7%)	2 (1.3%)
Dyspepsia	3 (2.0%)	1 (0.6%)
General Disorders and Administration Site Conditions
Fatigue	4 (2.7%)	3 (1.9%)
Investigations
INR Increased	9 (6.0%)	4 (2.6%)
PT Prolonged	7 (4.7%)	0
Metabolism and Nutrition
Peripheral Oedema	13 (8.7%)	5 (3.2%)
Musculoskeletal, Connective Tissue and Bone
Muscle Cramp	3 (2.0%)	1 (0.6%)
Nervous System
Headache	23 (15.4%)	21 (13.5%)
Insomnia	3 (2.0%)	0
Respiratory, Thoracic, and Mediastinal
Nasal Congestion	13 (8.7%)	7 (4.5%)
Epistaxis	5 (3.4%)	0
Skin and Subcutaneous Tissue
Flushing	6 (4.0%)	1 (0.6%)

Less Common Adverse Drug Reactions (<1%)

Blood and Lymphatic System Disorders:

Eosinophilia, Leukopenia, Myeloproliferative disorder, Thrombocytopenia, Lymphoma, Pancytopenia

Cardiac Disorders:

Bradycardia, Chest discomfort, Right ventricular failure, Angina pectoris, Atrial flutter, Atrioventricular block first degree, Myocardial infarction, Pericardial effusion, Sinus bradycardia, Supraventricular tachycardia, Tachycardia, Ventricular bigeminy, Ventricular extrasystoles, Ventricular tachycardia, Cardiac disorder, Cardiac failure, Cardiac failure congestive, Cardiac flutter, Dilatation atrial, Supraventricular extrasystoles

Ear and Labyrinth Disorders:

Tinnitus, Cerumen impaction, Deafness, Ear congestion, Ear pain, Sensation of block in ear, Otitis media

Endocrine Disorders:

Goiter

Eye Disorders:

Conjunctival haemorrhage, Lacrimation increased, Photophobia, Conjunctival hyperaemia, Conjunctivitis, Eye infection, Eye oedema, Visual disturbance, Eye inflammation, Eye irritation, Eye pruritus, Keratoconjunctivitis sicca, Retinal tear, Vitreous floaters

Gastrointestinal Disorders:

Dry mouth, Gastroenteritis viral, Gingivitis, Haematochezia, Gastrointestinal discomfort, Gingival pain, Abdominal strangulated hernia, Anal skin tags, Appendicitis, Colitis, Colonic polyp, Diverticulum, Eructation, Faecal incontinence, Food poisoning, Gastroenteritis bacterial, Gastrointestinal fungal infection, Gastrointestinal haemorrhage, Gastrointestinal infection, Glossodynia, Haemorrhoids, Mouth haemorrhage, Oesophageal spasm, Peptic ulcer, Proctalgia, Pruritus ani, Retching, Tongue blistering, Tongue discolouration, Tongue disorder, Tongue ulceration, Tooth abscess, Abdominal hernia, Abdominal tenderness, Abscess, Aptyalism, Ascites, Enteritis, Frequent bowel movements, Gastritis viral, Gastroenteritis, Gastrointestinal disorder, Hiccups, Oral pruritus, Pancreatic pseudocyst, Pancreatitis acute, Stomatitis

General Disorders and Administration Site Conditions:

Malaise, Feeling hot, Puncture site haemorrhage, Feeling cold, Inflammation localized, Injection site dermatitis, Venipuncture site inflammation, Application site bruising, Hyperthermia, Multi-organ failure, Pain, Sensation of foreign body

Hepatobiliary Disorders:

Gallbladder disorder, Hepatomegaly, Jaundice, Cholecystitis chronic, Cholelithiasis, Cholestasis, Hyperbilirubinaemia

Immune System Disorders:

Hypersensitivity, Conjunctivitis allergic, Drug hypersensitivity, Systemic lupus erythematosus

Infections and Infestations:

Viral infection, Candidiasis, Fungal infection, Oral candidiasis

Injury, Poisoning and Procedural Complications:

Arthropod bite, Joint injury, Laceration, Arthropod sting, Drug toxicity, Fall, Head injury, Sunburn, Animal bite, Ligament injury, Post procedural haemorrhage, Skin laceration, Soft tissue injury, Thermal burn

Investigations:

Activated partial thromboplastin time prolonged, Blood bicarbonate decreased, Haemoglobin decreased, Weight decreased, Blood bilirubin increased, Blood creatinine increased, Blood glucose increased, Blood pressure decreased, Cardiac murmur, Eosinophil count

increased, Haematocrit decreased, White blood cell count decreased, Aspartate aminotransferase increased, Blood creatine phosphokinase increased, Blood lactate dehydrogenase increased, Blood phosphorus increased, Blood potassium decreased, Blood potassium increased, Blood pressure increased, Body temperature increased, Electrocardiogram QT prolonged, Heart rate increased, Heart rate irregular, Oxygen saturation decreased, Pregnancy test positive, Red blood cell count decreased, Venous pressure jugular increased, Alanine aminotransferase increased, Blood creatine phosphokinase-MB increased, Blood uric acid increased, Coagulation time prolonged, Crystal urine, Haematocrit increased, Haemoglobin increased

Metabolism and Nutrition Disorders:

Decreased appetite, Anorexia, Fluid retention, Oedema, Gout, Hyperglycaemia, Hyperkalaemia, Hypocalcaemia, Hypoglycaemia, Increased appetite, Lactic acidosis, Localised oedema, Weight fluctuation, Dehydration, Hypercholesterolaemia, Hypernatraemia, Polydipsia

Musculoskeletal and Connective Tissue Disorders:

Flank pain, Chest wall pain, Facial pain, Localised infection, Osteochondrosis, Arthritis, Arthritis bacterial, Arthritis infective, Limb discomfort, Muscle fatigue, Muscle haemorrhage, Muscle twitching, Muscular weakness, Musculoskeletal pain, Musculoskeletal stiffness, Osteoarthritis, Pain in jaw, Polyarthritis, Rib fracture, Tendonitis, Connective tissue inflammation, Fibromyalgia, Groin pain, Joint sprain, Joint stiffness, Muscle atrophy, Musculoskeletal chest pain

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps):

Ovarian cyst, Skin papilloma, Uterine leiomyoma, Basal cell carcinoma

Nervous System Disorders:

Sinus headache, Somnolence, Tremor, Dizziness postural, Ataxia, Disturbance in attention, Dysphonia, Memory impairment, Partial seizures, Vertigo, Confusional state, Dysaesthesia, Facial palsy, Head discomfort, Ischaemic stroke, Paraesthesia oral, Restless legs syndrome, Restlessness, Sciatica

Pregnancy, Puerperium and Perinatal Conditions:

Abortion spontaneous

Psychiatric Disorders:

Nervousness, Agitation, Sleep disorder, Thinking abnormal

Renal and Urinary Disorders:

Haematuria, Pollakiuria, Bladder disorder, Dysuria, Nephritis interstitial, Renal impairment, Renal insufficiency, Proteinuria, Urosepsis

Reproductive System and Breast Disorders:

Menorrhagia, Metrorrhagia, Vaginal haemorrhage, Amenorrhoea, Nipple pain, Breast tenderness, Genital pruritus female, Menopausal symptoms, Testicular pain, Vaginal mycosis, Breast microcalcification, Breast pain, Vaginal infection, Vaginal prolapse

Respiratory, Thoracic and Mediastinal Disorders:

Sinusitis, Hypoxia, Sinus congestion, Hoarseness, Orthopnoea, Pleurisy, Rhinitis, Acute sinusitis, Alveolitis allergic, Asthma, Lower respiratory tract infection, Nasal sinus drainage, Nocturnal dyspnea, Pleural effusion, Pleuritic pain, Pneumonia aspiration, Pneumothorax, Respiratory tract infection, Sneezing, Sputum purulent, Wheezing, Bronchitis acute, Dry throat, Dyspnoea exertional, Dyspnoea paroxysmal nocturnal, Lobar pneumonia, Lung infection, Nasal discomfort, Paranasal sinus hypersecretion, Pulmonary embolism, Respiratory failure, Sinus pain, Sputum discoloured, Tachypnoea, Throat irritation

Skin and Subcutaneous Tissue Disorders:

Contusion, Alopecia, Herpes simplex, Herpes zoster, Onychomycosis, Urticaria, Cellulitis, Dermatitis allergic, Dry skin, Night sweats, Petechiae,

Pruritus generalised, Rash papular, Rosacea, Skin disorder, Skin hyperpigmentation, Skin necrosis, Skin ulcer, Subcutaneous abscess, Dermatitis contact, Furuncle, Gouty tophus, Intertrigo, Nail hypertrophy, Pallor, Palmar erythema, Paronychia, Psoriasis, Rash macular, Rash pustular, Skin desquamation, Skin irritation, Skin lesion

Surgical and Medical Procedures:

Tooth extraction, Endodontic procedure, Medical device implantation, Nasal polypectomy, Radiofrequency ablation, Stent placement, Aneurysmectomy, Atrial septal defect repair, Detached retina repair

Vascular Disorders:

Hypertension, Haematoma, Arteriovenous fistula-acquired, Haemorrhage, Migraine, Orthostatic hypotension, Phlebothrombosis, Post thrombotic syndrome, Thrombophlebitis superficial, Catheter site haemorrhage, Peripheral artery aneurysm

Abnormal Hematologic and Clinical Chemistry Findings

Chemistry: WARNINGS

During all PAH placebo-controlled trials, elevations in ALT or AST by more than 3 x ULN were observed in 2% of THELIN-treated PAH patients at the 100 mg dose (N = 149) compared to 5% of placebo-treated patients (N = 155). A higher dose of THELIN (300 mg), evaluated in STRIDE-1, demonstrated an increased frequency and severity of liver abnormalities (see

). In STRIDE-2, elevated LFTs > 3 x ULN were observed in 2 patients (3%) treated with THELIN 100 mg per day versus 4 patients in the placebo group (6%).

Elevations in AST and/or ALT occurred both early and late in treatment with THELIN and usually progressed slowly. These changes were typically asymptomatic and were reversible when monitoring and discontinuation guidelines were followed. Liver aminotransferase elevations have reversed spontaneously while continuing treatment with THELIN. (see Management of Patients with Increased Liver Aminotransaminases; Hepatic/Biliary/Pancreatic; WARNINGS AND PRECAUTIONS: and DOSAGE AND ADMINISTRATION)

Table 2: Treatment-Emergent Bleeding AEs Experienced by >= 1.0% of Subjects in THELIN 100 mg/day Combined Group (Phase 3, Long-Term, Oral Studies in Subjects with PAH Exposed >= 6 Months)

Preferred Term	Subjects (N=438)
Subjects with >= 1 Bleeding AE	74 (17%)
Epistaxis	35 (8%)
Haemoptysis	9 (2%)
Menorrhagia	6 (1%)
Haematoma	3 (1%)
Gingival Bleeding	6 (1%)
Haematuria	4 (1%)
Vaginal Haemorrhage	3 (1%)

Hematology: (sWarnings and Precautions)

DRUG INTERACTIONS

Serious Drug Interactions

Cyclosporin : Drug-Drug Interactions CONTRAINDICATIONS)

CONTRAINDICATED due to a significant increase in the exposure of sitaxsentan (see

Warfarin : Drug-Drug Interactions DOSAGE AND ADMINISTRATION

REDUCED DOSAGE of warfarin is recommended due to enhanced effect on PT and INR (see

Sitaxsentan is also a moderate inhibitor of CYP2C9 (Ki = 0.46 uM) and, to a lesser extent, of CYP2C19 (Ki = 1-4 uM) and CYP3A4/5 (Ki = 20 uM). Plasma concentrations of drugs principally metabolized by these isoforms, particularly CYP2C9 (such as warfarin, phenytoin), may be increased during THELIN co-administration.

CyclosporineCONTRAINDICATIONS

: 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 (see

Digoxin

: Concomitant administration of digoxin 0.25 mg once daily and THELIN 100 mg did not alter the pharmacokinetics of digoxin, indicating no effect on the p-glycoprotein transporter.

Fluconazole: Concomitant administration of THELIN 100 mg once daily with fluconazole 400 mg once daily resulted, on average, in moderate increases in the Cmax (17%) and AUC0-24 (9%) of sitaxsentan. These effects, however, varied on an individual basis, unrelated to genotype; although 52% of the subjects exhibited an increase in Cmax and 38% exhibited an increase in AUC0-24, the remaining subjects had either no change or a decrease in these parameters. Sitaxsentan is metabolized by CYP2C9 and CYP3A4/5, both of which are inhibited by fluconazole. While it is possible the predominant isoform may vary among individuals, this redundancy in metabolic pathways may minimize the effect of inhibition of either isoform on the overall clearance of sitaxsentan. There was no clinically significant effect on AEs. The results of this study, as well as an earlier study, indicate that it is not likely that a significant drug interaction would result when sitaxsentan and fluconazole are co-administered. Ketoconazole: Ketoconazole is metabolized by CYP3A4/5. Co-administration of THELIN 100 mg once daily with ketoconazole 400 mg once daily resulted in reduced clearance of ketoconazole. The increases in mean Cmax and AUC0-24 were approximately 18% and 20%, respectively. These changes were not considered clinically significant. Ketoconazole is also a CYP3A4/5 inhibitor. During concomitant administration, sitaxsentan Cmax was unchanged, but AUC0-24 was increased by approximately 20%, consistent with ketoconazole inhibiting CYP3A4/5 in vivo. This change was not considered clinically significant. Nelfinavir: Nelfinavir is metabolized by both CYP2C19 and CYP3A4/5. Concomitant administration of THELIN 100 mg once daily and nelfinavir 1250 mg twice daily reduced the clearance of nelfinavir, resulting in a 14% increase in mean Cmax and a 15% increase in mean AUC0-12. In the one subject classified as a CYP2C19 poor metabolizer, mean Cmax and mean AUC0-12 increased by 18% and 36%, respectively. These changes were not considered clinically significant. Nelfinavir is also a CYP3A4/5 inhibitor. The sitaxsentan mean Cmax decreased by 7% and mean AUC0-24 decreased by 17%. These changes were not considered clinically significant. Nifedipine: THELIN 100 mg co-administered with nifedipine 10 mg every 8 hours increased Cmax of nifedipine by 12% and mean AUC0-8 by 21%, while clearance was reduced. These changes were not considered clinically significant. Omeprazole: THELIN 100 mg once daily co-administered with omeprazole 41.2 mg once daily increased the mean AUC0-24 by 27%; Cmax was unchanged. The change in AUC was not considered clinically significant.

Oral contraceptives

: Concomitant administration of THELIN 100 mg once daily and Ortho- Novum 1/35 for a 28-day cycle resulted in increases in the mean exposure to ethinyl estradiol (59%) and norethindrone (47%). THELIN had no effect on the anti-ovulatory activity of the oral contraceptive as assessed by plasma concentrations of FSH, LH, and progesterone.

Sildenafil: A single dose of sildenafil 100 mg co-administered with THELIN 100 mg increased the mean Cmax and AUC[?] of sildenafil by 18% and 28%, respectively. There was no change in mean Cmax or AUC[?] for the active metabolite, n-desmethylsildenafil. These changes in sildenafil plasma concentrations were not considered clinically significant. 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 (see DOSAGE AND ADMINISTRATION). 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.

DOSAGE AND ADMINISTRATION

General

Subjects receiving warfarin achieve therapeutic anticoagulation (International Normalised Ratio (INR) target) with lower doses of the anticoagulant in the presence of THELIN. The mean dose of warfarin at study endpoint in STRIDE-2 (18 weeks of dosing) was 3.6 mg/day for patients treated with placebo, compared to 2.2 mg/day for patients receiving THELIN (approximately 40% lower). When initiating warfarin therapy in a patient taking THELIN, it is recommended to start at the lowest available dose of warfarin. In patients already taking warfarin, it is recommended that the warfarin dose be reduced when starting THELIN. In all cases, INR should be monitored on a regular schedule. Increases in the warfarin dose should be done in small increments to reach an appropriate target INR (see Drug Interactions).

Monitoring and Discontinuing THELIN in Patients Developing Liver Aminotransferase Abnormalities

In women of child-bearing potential, THELIN treatment must only be initiated following a negative pregnancy test and only in those who practice adequate contraception. Monthly pregnancy tests during treatment with THELIN are recommended.

Studies in patients with pre-existing liver impairment have not been conducted. THELIN is contraindicated with elevated liver aminotransferases prior to initiation of treatment (>3 x ULN) (see CONTRAINDICATIONS).

Sixty-two patients discontinuing bosentan due to liver function abnormalities (of whom 32 failed attempts at dose reduction and/or interruption and re-challenge with bosentan) were treated using THELIN in clinical trials. Of these patients, 19% (12/62) experienced a recurrence of abnormalities during treatment with THELIN following a mean exposure of 28 weeks. Appropriate care should be exercised when initiating THELIN in this patient population.

OVERDOSAGE:

There is no specific experience with the management of THELIN overdose. In the event of an overdose, symptomatic and supportive measures should be employed. At doses greater than or equal to 300 mg daily THELIN has been associated with 4 cases of mild to severe hepatitis, with one case resulting in hepatic failure and death. These patients had multiple co-morbidities and drug therapies; however, the contribution of THELIN in these cases could not be excluded.

ACTION AND CLINICAL PHARMACOLOGY

Endothelin-1 (ET-1) is a potent vasoconstricting paracrine and autocrine peptide found in the lungs. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH). Additionally, PAH also is characterized by reduced nitric oxide activity. ET-1 actions are mediated through endothelin A receptors (ETA), present on smooth muscle cells, and endothelin B receptors (ETB), present on endothelial cells. Predominant actions of ET-1 binding to ETA are vasoconstriction and vascular remodeling, while binding to ETB results in ET-1 clearance, and vasodilatory/antiproliferative effects, due in part to nitric oxide and prostacyclin release. Sitaxsentan is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500- fold more selective for ETA as compared to ETB).

Absorption and Distribution

THELIN is rapidly absorbed following oral administration. In PAH patients, peak plasma concentrations are generally achieved within 1-4 h. The absolute bioavailability of THELIN is between 70 and 100%. When administered with a high fat meal, the rate of absorption of THELIN was decreased as evidence by a 43% decrease in Cmax and a delay in Tmax (2-fold increase) compared to fasted conditions, but the extent of absorption (AUC) was the same.

THELIN is widely distributed in tissues and more than 99% protein bound to plasma proteins, predominantly albumin. The degree of binding is independent of concentration in the clinically relevant range. Sitaxsentan sodium does not penetrate into erythrocytes and does not appear to cross the blood- brain barrier.

Following oral administration to healthy volunteers, sitaxsentan is highly metabolized. The 2 most common circulating metabolites (1, 3 keto and 1-keto-2-hydroxy derivatives) account for approximately 3 and 8.5%, respectively, of the parent compound activity. They are at least 20 and 30 times, respectively, less potent than sitaxsentan on ETA receptors and inactive on ETB receptors. In vitro, sitaxsentan is metabolized via CYP2C9 and CYP3A4. However, administration of sitaxsentan with inhibitors of these isoforms is not expected to result in clinically significant changes in sitaxsentan plasma concentrations. Approximately 50-60% of an oral dose is excreted in the urine with the remainder eliminated in the feces. Approximately 1% of the dose is excreted as unchanged drug. The terminal elimination half-life (t1/2) is 10 hours. Steady state in PAH subjects is expected to be reached within 4-6 days. Apparent clearance increases with body weight in PAH subjects; however, no adjustment in dose is warranted. No unexpected accumulation in the plasma was observed after multiple dosing at the recommended dose of 100 mg once daily. At doses of 300 mg or above non-linear pharmacokinetics resulted in disproportionately higher plasma concentrations of sitaxsentan, which may results in an increased incidence of liver injury. (see WARNINGS).

Based on results of the population pharmacokinetic analysis and pooled pharmacokinetic data over several studies, it was found that sex, race, and age do not significantly affect the pharmacokinetics of sitaxsentan sodium.

The influence of liver impairment on the pharmacokinetics of sitaxsentan sodium has not been evaluated. THELIN is contraindicated with elevated liver aminotransferases prior to initiation of treatment (>3 x ULN) (see CONTRAINDICATIONS).

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

THELIN 100 mg is supplied as capsule-shaped yellow-to-orange film-coated oral tablets, debossed with T-100 on one side. Available in bottles of 28 tablets. Nonmedicinal ingredients in THELIN tablets include microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, sodium starch glycolate, magnesium stearate, dibasic sodium phosphate, ascorbyl palmitate, edetate disodium dehydrate, and monobasic sodium phosphate. The film coating contains microcrystalline cellulose, hydroxypropyl methylcellulose, stearic acid, anatose titanium dioxide, yellow iron oxide dehydrate, and pharmaceutical talc.

Route of administration	Dosage Form / Strength	Clinically Relevant Non- medicinal Ingredients
Oral	Tablet 100 mg	Lactose monohydrate

PRODUCT MONOGRAPH

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