Thelin 100 mg film-coated tablets

Each film-coated tablet contains 100 mg sitaxentan sodium.

Excipients:

Also contains 166.3mg of lactose monohydrate.

For a full list of excipients, see section 6.1

Film-coated tablet

Capsule shaped yellow-to-orange film-coated tablets, debossed with T100 on one side.

Treatment of patients with pulmonary arterial hypertension (PAH) classified as WHO functional class III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and in pulmonary hypertension associated with connective tissue disease.

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Thelin is to be taken orally as a dose of 100 mg once daily. It may be taken with or without food and without regard to the time of day.

In the case of clinical deterioration despite Thelin treatment for at least 12 weeks, alternative therapies should be considered. However, a number of patients who showed no response by week 12 of treatment with Thelin responded favourably by week 24, so an additional 12 weeks of treatment may be considered.

Higher doses did not confer additional benefit sufficient to offset the increased risk of adverse reactions, particularly liver injury (see section 4.4).

Discontinuation of treatment

There is limited experience with abrupt discontinuation of sitaxentan sodium. No evidence for acute rebound has been observed.

Dosage in hepatic impairment:

Studies in patients with pre-existing liver impairment have not been conducted. Thelin is contraindicated in patients with elevated liver aminotransferases prior to initiation of treatment (> 3 x Upper Limit of Normal (ULN)) or with elevated direct bilirubin > 2 x ULN prior to initiation of treatment (see section 4.3).

Dosage in renal impairment:

No dose adjustment is required in patients with renal impairment.

Use in children and adolescents (< 18 years).

Thelin is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Elderly patients:

No dosage adjustment is needed in patients over the age of 65 years.

Use in patients using other medicines:

The efficacy and safety of Thelin co-administration with other treatments for PAH (eg, epoprostenol, sildenafil, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

Hypersensitivity to the active substance or to any of the excipients.

Mild to severe hepatic impairment (Child-Pugh Class A-C).

Elevated aminotransferases prior to initiation of treatment (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 x ULN).

Elevated direct bilirubin > 2 x ULN prior to initiation of treatment.

Concomitant administration with ciclosporin A (see section 4.5).

Lactation (see section 4.6).

The efficacy of Thelin as monotherapy has not been established in patients with NYHA/WHO functional class IV PAH. Transfer to a therapy that is recommended at the severe stage of the disease (eg, epoprostenol) should be considered if the clinical condition deteriorates (see section 4.2).

Liver function:

Liver function abnormalities have been associated with PAH. Endothelin receptor antagonists, as a class, have been associated with liver function abnormalities.

Elevations of AST and/or ALT associated with Thelin occur both early and late in treatment, usually progress slowly, and are typically asymptomatic. During clinical trials, these changes were usually reversible when monitoring and discontinuation guidelines were followed. Liver aminotransferase elevations may reverse spontaneously while continuing treatment with sitaxentan sodium.

The mechanism of liver toxicity is not fully documented and it might vary between endothelin receptor antagonists. Appropriate care should be exercised when initiating sitaxentan in patients who discontinued other endothelin receptor antagonists due to liver enzyme abnormalities (see section 4.8).

Pre-existing liver impairment

Studies in patients with pre-existing liver impairment have not been conducted. Thelin is contraindicated in patients with elevated liver aminotransferases prior to initiation of treatment (> 3 x ULN), or with elevated direct bilirubin> 2 x ULN prior to initiation of treatment, see section 4.3.

Bleeding

There is an increased risk of bleeding with Thelin, mainly in the form of epistaxis and gingival bleeding.

Vitamin K antagonists

Thelin increases the plasma levels of Vitamin K antagonists such as warfarin, acenocoumarol and fenprocoumon (see section 4.5).

Drugs which inhibit Organic Anion Transporting Polypeptides (OATP)

The extent of interaction with potent OATP inhibitors (e.g. some statins, proteinase inhibitors, tuberculostatics) is unknown. As this could result in raised plasma levels of sitaxentan sodium, patients in need of the combination should be closely monitored for adverse events related to sitaxentan sodium (see section 4.5).

Oral contraceptive agents

Thelin increases oestrogen exposure when given concomitantly with oral contraceptive agents (see Section 4.5). Therefore, especially in women who smoke, there is an increased risk for thromboembolism. Given a theoretical higher risk for thromboembolism, traditional concomitant use of vitamin K antagonists should be considered.

Pregnancy

Due to possible teratogenicity, Thelin must not be initiated in women of child-bearing potential unless they practise reliable contraception. If necessary, pregnancy testing should be undertaken (see Section 4.6).

Pulmonary veno-occlusive disease (PVOD)

No data are available with Thelin in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when Thelin is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.

Haemoglobin concentration

Treatment with Thelin was associated with a dose-related decrease in haemoglobin (see section 4.8). Most of this decrease of haemoglobin concentration was detected during the first few weeks of treatment and haemoglobin levels stabilized by 4 weeks of Thelin treatment. It is recommended that haemoglobin concentrations be checked prior to treatment, after 1 and 3 months, and every 3 months thereafter. If a marked decrease in haemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.

Excipients

Thelin tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Sitaxentan sodium is metabolised in the liver by cytochrome P450 CYP2C9 and CYP3A4/5 isoenzymes. Sitaxentan sodium is an inhibitor of CYP2C9 and, to a lesser extent, CYP2C19, CYP3A4/5 and CYP2C8. Plasma concentrations of drugs principally metabolized by CYP2C9 may be increased during sitaxentan sodium co-administration. Co-administration with drugs metabolized by CYP2C19 or CYP3A4/5 is not expected to result in clinically significant drug interactions. Sitaxentan sodium does not affect the p-glycoprotein transporter, but it is postulated to be a substrate of OATP transporter proteins.

Effects of other medicinal products on Thelin

Organic Anion Transporting Polypeptides (OATP) Inhibitors: Co-administration with ciclosporin A, a potent OATP inhibitor, resulted in a 6-fold increase in C_min and a 67% increase in AUC of sitaxentan therefore the use of Thelin in patients receiving systemic ciclosporin A is contraindicated (see section 4.3). Clearance of ciclosporin A was unchanged.

The extent of interaction with other OATP inhibitors (some HMG CoA reductase inhibitors eg, atorvastatin, protease inhibitors eg, ritonavir, tuberculostatics eg, rifamycin) is unknown but could result in raised plasma levels of sitaxentan. The clinical significance of this is unknown. Patients in need of the combination should be closely monitored. Moreover, Clinical interaction studies with nelfinavir, a moderately potent OATP inhibitor, and pravastatin, a low affinity OATP inhibitor, did not result in clinically significant changes in sitaxentan plasma levels.

Fluconazole (inhibitor of CYP2C19, CYP2C9 and CYP3A4/5): Co-administration of Thelin and fluconazole had no effect on the clearance of sitaxentan sodium.

Ketoconazole (substrate and inhibitor of CYP3A4/5): Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or ketoconazole.

Nelfinavir (substrate of CYP3A4/5, CYP2C19): Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or nelfinavir. The clearance of nelfinavir was not clinically significantly changed in one subject that was classified as a CYP2C19 poor metaboliser.

Effects of Thelin on other medicinal products

Warfarin (vitamin K antagonist, substrate of CYP2C9): Concomitant treatment with sitaxentan sodium resulted in a 2.4 fold increase in S-warfarin exposure. Subjects receiving warfarin achieve therapeutic anticoagulation (International Normalised Ratio [INR] target) with lower doses of the anticoagulant in the presence of sitaxentan sodium. It is expected that a similar increase in anticoagulant effect will be seen with warfarin analogues, including acenocoumarol, fenprocoumon and fluindione. When initiating vitamin K antagonist therapy in a patient taking sitaxentan sodium, it is recommended to start at the lowest available dose. In patients already taking a vitamin K antagonist, it is recommended that the dose of the vitamin K antagonist be reduced when starting sitaxentan sodium. In all cases, INR should be monitored on a regular schedule. Increases in the vitamin K antagonist dose should be done in small increments to reach an appropriate target INR. If INR is not properly monitored and increased exposure to vitamin K antagonists remains undetected, severe or life-threatening bleeding episodes may occur.

Oral contraceptives (substrate of CYP3A4/5): Concomitant administration of Thelin and Ortho-Novum 1/35 (1 mg norethindrone/ 0.035 mg ethinyl estradiol) resulted in increases in exposure to ethinyl estradiol (substrate of CYP3A4/5) and norethindrone (CYP3A4/5) of 59 % and 47%, respectively. However, sitaxentan sodium did not affect the anti-ovulatory activity of the oral contraceptive as assessed by the plasma concentrations of follicle stimulating hormone (FSH), luteinising hormone (LH), and progesterone (see section 4.4).

Sildenafil (substrate of CYP3A4): A single dose of sildenafil 100 mg coadministered with Thelin increased C_max and AUC of sildenafil by 18% and 28%, respectively. There was no change in C_max or AUC for the active metabolite, n-desmethylsildenafil. These changes in sildenafil plasma concentrations were not considered clinically significant. Interaction with sildenafil may be serious if hypotension occurs beyond a safe level. Study results suggest that the dose of sildenafil does not need to be adjusted during concomitant administration with sitaxentan sodium.

Nifedipine (substrate of CYP3A4/5): The clearance of nifedipine was not clinically significantly changed when given concomitantly with Thelin. This was tested for low-dose nifedipine only. Therefore, at higher doses of nifedipine, an increase in exposure cannot be excluded.

Omeprazole (substrate of CYP2C19): Concomitant administration of Thelin with omeprazole increased the omeprazole AUC0-24 by 30%; C_max was unchanged. The change in AUC was not considered clinically significant.

Digoxin (substrate of p-Glycoprotein): Concomitant administration of Thelin did not alter the pharmacokinetics of digoxin indicating no effect on the p-glycoprotein transporter

No clinical interaction study was performed with a substrate of CYP 2C8. Therefore an interaction with such a drug cannot be excluded.

Pregnancy

There are no human data regarding the use of sitaxentan sodium during pregnancy. Sitaxentan sodium caused teratogenicity in rats (see section 5.3). Potential effects in humans are unknown. Thelin should not be used during pregnancy unless clearly necessary ie, in case no alternative treatment options are available.

Lactation

Sitaxentan sodium was detected in the plasma of breast fed pups from female rats treated with sitaxentan sodium, indicating that sitaxentan sodium was present in the breast milk. It is unknown whether or not sitaxentan sodium is excreted into human milk. Women should not breastfeed while using Thelin.

Women of child-bearing potential

Treatment must not be initiated in women of child-bearing potential unless they practice reliable contraception, due to possible teratogenicity. If necessary, pregnancy testing should be undertaken.

No studies on the effects on the ability to drive and use machines have been performed. A known undesirable effect is dizziness, which could influence the ability to drive or use machines.

General description

Safety of Thelin has been evaluated in clinical trials of more than 1200 patients with PAH, as well as post-marketing safety data. At the recommended dose during placebo-controlled trials in pulmonary arterial hypertension PAH, the most common adverse drug reactions considered to be at least possibly related to Thelin treatment were headache in 15% of patients, and peripheral oedema and nasal congestion, each in 9% of patients.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are reported as very common ( 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, 1/100), rare (> 1/10,000, 1/1,000), and very rare ( 1/10,000).

Adverse reactions

Increased Liver Aminotransferases (see section 4.4)

Elevations of AST and/or ALT are associated with sitaxentan sodium. In phase 2 and 3 oral studies in patients with PAH, elevations in ALT and/or AST> 3 ULN were observed in 5% of placebo-treated patients (N = 155) and 7% of Thelin 100 mg-treated patients (N = 887). Elevations in ALT values> 5 ULN were 4% (36/887) for sitaxentan 100 mg QD and 0.6% in the placebo group (1/155).

The Sitaxentan population also included patients (N = 53) who had discontinued another endothelin receptor antagonist due to liver function abnormalities. This specific group had a higher risk (19%; N = 10/53) of developing elevations in ALT and/or AST> 3 x ULN indicating that appropriate care should be exercised when initiating sitaxentan in this patient population.

Decreased Haemoglobin (see section 4.4)

The overall mean decrease in haemoglobin concentration for Thelin -treated patients was 0.5 g/dl (change to end of treatment). In placebo-controlled studies, marked decreases in haemoglobin > 15% decrease from baseline with value < lower limit of normal) were observed in 7% of patients treated with Thelin (N = 149) and 3% of placebo-treated patients (N = 155). A decrease in haemoglobin concentration by at least 1 g/dl was observed in 60% of patients treated with Thelin as compared to 32% of placebo-treated patients.

Post marketing experience

Adverse events reported during the post-marketing period to date have been similar to those reported in clinical trials. Cases of concurrent elevations of transaminases (ALT and/or AST) > 8 x ULN and total bilirubin > 2 x ULN have been reported following administration of sitaxentan sodium. This may lead to hepatic failure, which can be fatal, and highlights the need for regular monitoring of transaminases and bilirubin.

There is no specific experience with the management of Thelin overdose. In the event of overdose, symptomatic and supportive measures should be employed.

During clinical trials, Thelin was given as a daily oral dose of 1000 mg/day for 7 days to healthy volunteers. The most common adverse effects at this dose were headache, nausea, and vomiting.

In an open-label hypertension study, 10 patients received 480 mg twice daily (approximately a 10fold increase in daily dose compared to the MRHD) for up to 2 weeks. Headaches (some severe), peripheral oedema, and anaemias were the most common adverse events reported in these patients, none of which were considered serious.

In an open-label PAH study, one fatal case of hepatic failure has been reported after chronic dosing of sitaxentan at 600 mg/day administered as 300 mg bid.

Pharmacotherapeutic group: Other antihypertensives, ATC code: C02KX03

Mechanism of action

Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodelling and is pro-inflammatory. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), as well as other cardiovascular disorders and connective tissue diseases, including scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension, and atherosclerosis, suggesting a pathogenic role of ET1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET1 concentrations are strongly correlated with the severity and prognosis of these diseases. 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 ET1 binding to ETA are vasoconstriction and vascular remodelling, while binding to ETB results in ET1 clearance, and vasodilatory/ antiproliferative effects due in part to nitric oxide and prostacyclin release.

Thelin is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB).

Efficacy

Two randomized, double-blind, multi-centre, placebo-controlled trials were conducted to demonstrate efficacy. STRIDE-1, which included 178 patients, compared 2 oral doses of Thelin (100 mg once daily and 300 mg once daily) with placebo during 12 weeks of treatment. The 18 week STRIDE-2 trial, conducted in 246 patients, included 4 treatment arms: placebo once daily, Thelin 50 mg once daily, Thelin 100 mg once daily, and open-label bosentan twice daily (efficacy-rater blinded, administered according to the approved package insert).

STRIDE-4 included 98 patients randomised to sitaxentan sodium 50 mg, 100 mg, and placebo once daily for 18 weeks. Efficacy endpoints included sub maximal exercise capacity, WHO functional class and Time to Clinical Worsening for all studies, and haemodynamics for STRIDE-1.

Patients had moderate to severe (NYHA/WHO functional class II-IV) PAH resulting from idiopathic pulmonary arterial hypertension (IPAH, also known as primary pulmonary hypertension), connective tissue disease (CTD), or congenital heart disease (CHD).

In these studies, the study medicine was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen, and vasodilators (eg, calcium channel blockers, ACE inhibitors). Patients with pre-existent hepatic disease and patients using non-conventional PAH treatments (eg, iloprost) were excluded.

Sub-maximal exercise capacity: This was assessed by measuring distance walked in 6 minutes (6minute walk test) at 12 weeks for STRIDE-1 and 18 weeks for STRIDE2 and STRIDE-4. In both STRIDE-1 and STRIDE-2 trials, treatment with Thelin resulted in a significant increase in exercise capacity. The placebo-corrected increases in walk distance in the whole cohort compared to baseline were 35 metres (p = 0.006; ANCOVA) and 31 metres (p < 0.05; ANCOVA), respectively. In STRIDE-4, a statistically non-significant placebo-corrected mean improvement of 24.3 metres (p = 0.2078) was observed in the whole cohort. Among patients with PAH associated with CTD in STRIDE-1 and STRIDE-2, a statistically significant difference versus placebo was observed (37.73 metres, p < 0.05).

Haemodynamic parameters: These were assessed in STRIDE-1 for both functional class II and III patients. Compared with placebo treatment, Thelin resulted in statistically significant improvement in pulmonary vascular resistance (PVR) and cardiac index (CI) after 12 weeks of treatment (see below).

Systemic vascular resistance (-276 dynes*sec/cm⁵ (16%)) was improved after 12 weeks of treatment. The reduction in mean pulmonary artery pressure of 3 mmHg (6%) was not statistically significant.

The effect of Thelin on the outcome of the disease is unknown.

Functional Class: A reduction in symptoms of PAH were observed with sitaxentan sodium 100 mg treatment. Improvements in functional class were observed across all studies (STRIDE-1, STRIDE-2 & STRIDE-4).

Long-term survival:There are no randomised studies to demonstrate beneficial effects on survival of treatment with sitaxentan sodium. However, patients completing STRIDE-2 were eligible to enrol in open-label studies (STRIDE-2X and STRIDE-3). A total of 145 patients were treated with sitaxentan sodium 100 mg and their long term survival status was assessed for a minimum of 3 years. In this total population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96%, 85% and 78% respectively. These survival estimates were similar in the subgroup of patients with PAH associated with CTD for the Thelin treated group (98%, 78% and 67% respectively). The estimates may have been influenced by the initiation of new or additional PAH therapies, which occurred in 24% of patients at one year.

Absorption

Sitaxentan sodium is rapidly absorbed following oral administration. In PAH patients, peak plasma concentrations are generally achieved within 1-4 hours. The absolute bioavailability of Thelin is between 70 and 100%. When administered with a high fat meal, the rate of absorption (C_max) of Thelin was decreased by 43% and the T_max delayed (2-fold increase) compared to fasted conditions, but the extent of absorption was the same.

Distribution

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

Metabolism and Elimination

Following oral administration to healthy volunteers, sitaxentan sodium is highly metabolised. The most common metabolic products are at least 10 times less potent as ET_A antagonists than sitaxentan sodium in a standard in vitro test of activity. In vitro, sitaxentan sodium is metabolized by CYP2C9 and CYP3A4/5.

In vitro studies using human liver microsomes or primary hepatocytes show that sitaxentan sodium inhibits CYP2C9, and, to a lesser extent, CYP 2C8, CYP2C19 and CYP3A4/5.

Approximately 50-60% of an oral dose is excreted in the urine with the remainder eliminated in the faeces. Less than 1% of the dose is excreted as unchanged active ingredient. The terminal elimination half-life (t_½) is 10 hours. Steady state in volunteers is reached within about 6 days.

No unexpected accumulation in the plasma was observed after multiple dosing at the recommended dose of 100 mg once daily. However, at doses of 300 mg or higher, non-linear pharmacokinetics result in disproportionately higher plasma concentrations of sitaxentan sodium.

Special Populations

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

Liver Function Impairment

The influence of liver impairment on the pharmacokinetics of sitaxentan sodium has not been evaluated. Refer to section 4.3.

In repeated-dose toxicity studies, dose-related liver changes (weight, centrilobular hypertrophy, occasionally necrosis), induction of hepatic drug metabolising enzymes and slightly decreased erythron parameters were seen in mice, rats and dogs. At high doses, dose-related increases in prothrombin time (PT) and activated partial thromboplastin time (APTT) were also seen, most prominently in rats, and coagulopathy (bleedings) in rats and dogs, but not mice. The significance of these findings for humans is unknown.

Testicular tubular atrophy was observed in rats, but not in mice or dogs. In the 26-week study, moderate to marked diffuse seminiferous tubular atrophy was present at a very low incidence, whereas in the 99-week study there was a dose-related, slightly increased incidence of minimal to mild focal atrophy at doses providing 29 to 94 times the human exposure.

Reproduction toxicity has been evaluated in rats only. Thelin did not affect fertility in males and females. Thelin was teratogenic at the lowest tested dose in rats, corresponding to exposures more than 30 times the human exposure. Dose-dependent malformations of the head, mouth, face and large blood vessels occurred. A NOAEL has not been established.

Administration of Thelin to female rats from late-pregnancy through lactation reduced pup survival, and caused testis tubular aplasia and delayed vaginal opening at the lowest exposure tested (1745 times the human exposure). Large / abnormally shaped livers, a delay in auditory function development, a delay in preputial separation and a reduction in the number of embryonic implants occurred at higher maternal doses.

In vitro and in vivo tests on genetic toxicology did not provide any evidence for a clinically relevant genotoxic potential.

Thelin was not carcinogenic when administered to rats for 97-99 weeks or when administered to p53(+/-) transgenic mice for 6 months.

Tablet core:

Cellulose, microcrystalline (E460)

Lactose monohydrate

Hypromellose (E464)

Sodium starch glycolate

Magnesium stearate (E470b)

Disodium phosphate, anhydrous (E339)

Ascorbyl palmitate (E304)

Disodium edetate

Monobasic sodium phosphate (E339)

Film coat:

Stearic acid (E570b)

Hypromellose (E464)

Cellulose, microcrystalline (E460)

Titanium dioxide (E171)

Yellow iron oxide dehydrate (E172)

Red iron oxide dehydrate (E172)

Talc (E553b)

Not applicable.

24 months

Store below 25°C.

PVC/ACLAR/paper-backed aluminium blisters containing 14 tablets.

Cartons contain 14, 28, 56, or 84 tablets.

High-density polyethylene (HDPE) bottles containing 28 tablets.

Not all pack sizes may be marketed.

No special requirements.

Pfizer Limited

Sandwich,

Kent, CT13 9NJ

United Kingdom

United Kingdom

EU/1/06/353/001

EU/1/06/353/002

EU/1/06/353/003

EU/1/06/353/004

EU/1/06/353/005

10 August 2006

July 2010

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments.

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