Source: European Medicines Agency (EU) Revision Year: 2011 Publisher: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom
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 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).
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, or direct bilirubin is >2 x ULN, use of sitaxentan is contraindicated (see section 4.3)
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; if confirmed, a decision should be made on an individual basis to continue or to stop Thelin administration. Continue to monitor aminotransferases at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, consider resuming the initial treatment schedule according to the conditions described below.
>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 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. Re-introduction must follow the guidelines detailed in section 4.2. 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.
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.
There is an increased risk of bleeding with Thelin, mainly in the form of epistaxis and gingival bleeding.
Thelin increases the plasma levels of Vitamin K antagonists such as warfarin, acenocoumarol and fenprocoumon (see section 4.5).
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).
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.
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).
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.
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.
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.
Co-administration with ciclosporin A, a potent OATP inhibitor, resulted in a 6-fold increase in Cmin 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.
Co-administration with Thelin did not cause a clinically significant change in the clearance of either sitaxentan sodium or ketoconazole.
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.
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.
Concomitant administration of Thelin and OrthoNovum 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).
A single dose of sildenafil 100 mg coadministered with Thelin increased Cmax and AUC∞ of sildenafil by 18% and 28%, respectively. There was no change in Cmax 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.
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.
Concomitant administration of Thelin with omeprazole increased the omeprazole AUC0-24 by 30%; Cmax was unchanged. The change in AUC was not considered clinically significant.
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.
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.
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.
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.
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:
Uncommon: Haemoglobin decrease (rarely resulting in anaemia), haematocrit decrease
Very common: Headache
Common: Insomnia, dizziness
Common: Gingival bleeding, flushing
Common: Nasal congestion, epistaxis
Common: Nausea, constipation, upper abdominal pain, vomiting, dyspepsia and diarrhoea
Common: Liver aminotransferases increase, bilirubin increase (associated with liver aminotransferase increase)
Rare: Symptomatic hepatitis
Rare: Rash (various types and presentations)
Common: Muscle cramp
Common: Fatigue, oedema (most commonly peripheral)
Common: INR increase (with concomitant vitamin K antagonist therapy). Prothrombin time (PT) increase (with concomitant vitamin K antagonist therapy).
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.
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.
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.
Not applicable.
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