Other antihypertensives

Sitaxentan

Each film-coated tablet contains 100 mg sitaxentan sodium. Excipients: Also contains 166.3mg of lactose monohydrate.

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.

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)).

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.

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.

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

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).

Concomitant administration with ciclosporin A.

Lactation.

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.

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.

Because treatment-associated elevations of AST and/or ALT are a marker for potential serious liver injury, liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals. If AST and/or ALT are > 3 x ULN prior to initiation of therapy, use of Thelin is contraindicated. The mechanism of liver toxicity is not fully documented and it might vary between endothelin antagonists. Appropriate care should be exercised when initiating Sitaxentan in patients who discontinued other endothelin receptor antagonists due to liver enzyme abnormalities.

Recommendations in case of treatment-emergent ALT/AST elevations:

If ALT/AST measurements rise to the following levels then changes to the monitoring or treatment are given

>3 and ?5 x ULN: Confirm by another liver test within 2 weeks. If confirmed, continue to monitor aminotransferases at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, return to monthly liver testing.

> 5 and 8 x ULN:Confirm by another liver test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks until levels have normalised. If the aminotransferase levels return to pre-treatment values, consider reintroducing Thelin according to the conditions described below.

>8 x ULN: treatment must be stopped and reintroduction of Thelin is not to be considered.

If liver transferase 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 > 2x ULN, treatment should be stopped and re-introduction of Thelin is not to be considered.

Re-introduction of treatment:

Re-introduction of treatment with Thelin should only be considered if the potential benefits of treatment with Thelin outweigh the potential risks and when liver aminotransferase levels are within pre-treatment values. The advice of a hepatologist is recommended. Aminotransferase levels must then be checked within 3 days after re-introduction, then again after a further 2 weeks, and thereafter according to the recommendations above.

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.

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.

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.

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.

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. 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. 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 sitaxenten 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.

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.

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

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

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.

Encysive (UK) Limited

(POM)

29 June 2009