Chemical formula: C₁₈H₁₅ClN₂O₆S₂ Molecular mass: 454.905 g/mol PubChem compound: 216235
Sitaxentan interacts in the following cases:
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.
Sitaxentan is metabolised in the liver by cytochrome P450 CYP2C9 and CYP3A4/5 isoenzymes. Sitaxentan 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 co-administration.
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.
The clearance of nifedipine was not clinically significantly changed when given concomitantly with sitaxentan. This was tested for low-dose nifedipine only. Therefore, at higher doses of nifedipine, an increase in exposure cannot be excluded.
Concomitant administration of sitaxentan and 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.
Concomitant administration of sitaxentan with omeprazole increased the omeprazole AUC0-24 by 30%; Cmax was unchanged. The change in AUC was not considered clinically significant.
A single dose of sildenafil 100 mg coadministered with sitaxentan 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.
There is an increased risk of bleeding with sitaxentan, mainly in the form of epistaxis and gingival bleeding.
Treatment with sitaxentan 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 sitaxentan 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.
No data are available with sitaxentan 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 sitaxentan is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.
There are no human data regarding the use of sitaxentan sodium during pregnancy. Sitaxentan sodium caused teratogenicity in rats. Potential effects in humans are unknown. Sitaxentan 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 sitaxentan.
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 sitaxentan has been evaluated in clinical trials of more than 1,200 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 sitaxentan 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).
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 sitaxentan 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 sitaxentan-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 sitaxentan (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 sitaxentan 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.
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