Summary Basis of Decision for Thelin ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
ThelinTM
Sitaxsentan sodium, 100 mg, Tablet, Oral
Encysive Pharmaceuticals Inc.
Submission control no: 101934
Date issued: 2007-09-18
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre :Sommaire des motifs de décision (SMD), PrTHELINMD , Sodium sitaxsentan, 100 mg comprimés, Encysive Pharmaceuticals, Inc. N° de contrôle de la présentation 101934
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02295636
Therapeutic Classification:
Non-medicinal ingredients:
Film coating: microcrystalline cellulose, hydroxypropyl methylcellulose, stearic acid, anatase titanium dioxide, yellow iron oxide, red iron oxide, and pharmaceutical talc.
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On May 30, 2007, Health Canada issued a Notice of Compliance to Encysive Pharmaceuticals Inc. for the drug product Thelin.
Thelin contains the medicinal ingredient sitaxsentan sodium which is an endothelin receptor antagonist.
Thelin is indicated for treatment of primary pulmonary arterial hypertension (PAH) or pulmonary hypertension secondary to connective tissue disease, in patients with WHO functional class III who have not responded to conventional therapy. Thelin is also indicated in patients with WHO functional class II who did not respond to conventional therapy and for whom no appropriate alternative can be identified. Patients with PAH have increased levels of endothelin-1, which increase the blood pressure in the blood vessels leading to the lungs. Thelin blocks the action of endothelin-1 and lowers the blood pressure by widening the blood vessels to the lungs.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Two randomized, double-blind, multi-centre, placebo-controlled studies (n=425) were conducted to demonstrate efficacy and safety. Compared to placebo, treatment with Thelin resulted in a significant increase in exercise capacity. The placebo-corrected increases in 6-minute walk distance compared to baseline were 35 metres and 31 metres for the two pivotal studies. Compared to placebo-treatment, Thelin demonstrated improvements to the cardiac index, pulmonary vascular resistance, and systemic vascular resistance, after 12 weeks of treatment. Compared to placebo, there were significant improvements in Functional Class and significant reductions in the rate of clinical worsening in patients treated with Thelin.
Thelin (100 mg, sitaxsentan sodium) is presented in tablet form. The adult dose (100 mg) is to be taken orally once a day. Dosing guidelines are available in the Product Monograph. The safety and efficacy of Thelin in pediatric patients have not been established.
Thelin is contraindicated for pregnant women or women intending to become pregnant, nursing women, patients with prior liver impairment (mild to severe, Child-Pugh Class A-C), and patients with elevated liver aminotransferases (AST and/or ALT >3x upper limit of normal) prior to initiation of treatment. Thelin is also contraindicated in patients on cyclosporin treatment, and patients hypersensitive to sitaxsentan sodium or any component of the drug product. Thelin should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Thelin are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Thelin is favourable for treatment of primary PAH or pulmonary hypertension secondary to connective tissue disease, in patients with WHO functional class III who have not responded to conventional therapy, as well as in patients with WHO functional class II who did not respond to conventional therapy and for whom no appropriate alternative can be identified.
3 Scientific and Regulatory Basis for Decision
The New Drug Submission for sitaxsentan sodium was filed with Health Canada October 24, 2006 (Control No. 101934). Due to a number of quality deficiencies a Notice of Non-Compliance (NON) was issued on December 12, 2006. In the sponsor's response to the NON, all of the quality concerns that led to the NON were satisfactorily addressed. The timeline of these events are reported in section 4 Submission Milestones.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Sitaxsentan sodium, the medicinal ingredient of Thelin, is an endothelin receptor antagonist. Patients with pulmonary arterial hypertension (PAH) have increased levels of endothelin-1, which increase the blood pressure in the blood vessels leading to the lungs. Thelin blocks the action of endothelin-1 and lowers blood pressure by widening the blood vessels to the lungs. 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.
Manufacturing Process and Process Controls
Sitaxsentan sodium is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
Detailed characterization studies were performed. The drug substance is poorly soluble over the physiological pH range and has three potential polymorphic forms. The desired polymorph form A is the most thermodynamically stable and is consistently produced by the manufacturing process. Impurities and degradation products arising from manufacturing and/or storage were reported, characterized, and found to be within qualified limits.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of sitaxsentan sodium.
Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
The drug substance packaging is considered to be acceptable.
Stability
Based on long-term and accelerated stability studies, the suggested re-test period and storage conditions for sitaxsentan sodium are supported and considered to be acceptable.
3.1.2 Drug Product
Description and Composition
Thelin (100 mg sitaxsentan sodium) tablets are presented as capsule-shaped
yellow-to-orange film-coated tablets, debossed with T-100 on one side of the tablet. The tablets are packaged in PVC/Aclar blisters and in high-density polyethylene (HDPE) bottles with induction seals and child-resistant caps.
The non-medicinal ingredients in Thelin tablets include microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, sodium starch glycolate, magnesium stearate, dibasic sodium phosphate, ascorbyl palmitate, edetate disodium dihydrate, and monobasic sodium phosphate. The film coating contains microcrystalline cellulose, hydroxypropyl methylcellulose, stearic acid, anatase titanium dioxide, yellow iron oxide, red iron oxide, and pharmaceutical talc.
All non-medicinal ingredients found in Thelin are acceptable for use in drugs according to the Food and Drug Regulations.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
Thelin tablets are manufactured using a wet granulation process. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable.
Control of Drug Product
Thelin is tested to verify that the identity, appearance, content uniformity, water content, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Thelin.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life of 24-months is considered acceptable when the product (packaged in HDPE bottles or PVC/Aclar blisters) is stored at 15-25 °C, protected from heat and moisture.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Thelin has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The pharmacodynamic properties of sitaxsentan sodium were evaluated in vitro and in vivo in multiple animal models of PAH.
In vitro, sitaxsentan was approximately 6,500-fold more selective for the human ETA receptor than the human ETB receptor. Administration of sitaxsentan sodium prevented and reversed acute changes in pulmonary hypertension in rats and pigs. The overall results varied depending on the timing of the administration. Administration before hypoxia appeared to attenuate the effects of hypoxia, and administration after hypoxia appeared to reduce the effects.
Sitaxsentan lowered the resting mean blood pressure (BP) and heart rate (HR) in a rat model of heart failure. In rats that had undergone an experimentally-induced myocardial infarction (MI), sitaxsentan sodium appeared to attenuate some of the effects of MI; i.e., cardiac function of the heart with MI was more depressed in the vehicle treated group. In hypertensive rats, sitaxsentan sodium lowered BP without affecting HR or locomotor activity and did not alter circadian rhythms in HR, locomotor activity, or BP.
Safety Pharmacology
The potential for sitaxsentan sodium to interact with biologically important targets and cause potential adverse side effects was evaluated in vitro and in vivo in multiple animal models of PAH. Congestive heart failure, as well as cardiovascular, respiratory, and central nervous system safety pharmacology studies were conducted with rats, mice, and dogs. These studies suggested that sitaxsentan sodium does not pose a risk of producing adverse effects on respiration, HR, BP, action potential prolongation or QT interval, or arrhythmia activity. Sitaxsentan sodium given intravenously to mice appeared to cause a
dose-dependent decrease in spontaneous locomotor activity. This effect was small but statistically significant at doses of 50 and 100 mg/kg, and was more pronounced at 200 mg/kg.
3.2.2 Pharmacokinetics
Absorption
Sitaxsentan had high oral bioavailability in all species tested, and was rapidly absorbed following oral administration.
Distribution
At concentrations of 100 µg/mL, >98% was bound to mouse, rat, dog and human plasma. The percentage decreased slightly at 500 µg/mL. Sitaxsentan appeared to be widely distributed in the rat following IV or oral administration. Distribution to the brain was limited, indicating sitaxsentan and/or its metabolites did not effectively cross the blood-brain barrier. Quantifiable levels of sitaxsentan were found in the pre-weaning pup plasma indicating that sitaxsentan was transferred in breast milk.
Metabolism
Sitaxsentan was extensively metabolized by the hepatic cytochrome system in dogs, rats, and mice (both sexes), with very little being excreted unchanged (except for the female rat). The three main drug components found in the plasma were sitaxsentan and its two major metabolites, TBC4718 and TBC4814. It is unlikely that sitaxsentan will cause induction of any of the major CYP isoforms in man in vivo, but based on in vitro data, inhibition of CYP2C19, CYP3A4/5, and especially CYP2C9 is considered likely.
Elimination
The major route of excretion appears to be biliary, except in female rats where approximately 40% of the dose was excreted in the urine.
3.2.3 Toxicology
Acute Toxicity
The maximum tolerated oral dose was 800 mg/kg and 1200 mg/kg in female and male mice, respectively. In rats, the maximum tolerated oral dose was 750 mg/kg and 500 mg/kg in females and males, respectively. At the maximum tolerated doses, tremors, subdued behavior, hunched appearance, laboured breathing, and hypothermia were observed.
Long Term Toxicity
The repeat-dose toxicity studies were conducted in mice (oral administration), rats (oral and IV), and dogs (oral and IV). The durations of the toxicity studies were up to 26 weeks in mice and rats, and up to 39 weeks in dogs. In mice, rats, and dogs, there were dose-related increases in liver weights (centrilobular hypertrophy and occasionally necrosis), induction of hepatic drug metabolizing enzymes, decreases in hemoglobin and hematocrit, and increases in platelet count, activated partial thromboplastin times (APTT) and/or prothrombin times (PT). The effects on APTT and PT were seen at higher doses. In rats and dogs, there was coagulopathy (bleeding), but this was not seen in mice. Based on the effects on the liver in the pre-clinical studies, the liver appears to be a target organ for toxicity.
Carcinogenicity
Two carcinogenicity studies were performed. One was a 26-week carcinogenicity study in mice and the other was a traditional 99-week study in rats. Sitaxsentan did not demonstrate any conclusive evidence of carcinogenic potential in the two studies.
Mutagenicity
Sitaxsentan demonstrated no evidence of mutagenic potential in the Ames test and in the mouse micronucleus test. In the chromosome aberration test, sitaxsentan exhibited clastogenic effects at doses toxic to cells. In the mouse lymphoma test, the results were equivocal following short-term exposure to sitaxsentan.
Reproductive and Developmental Toxicity
Sitaxsentan did not affect fertility in male and female rats. In the embryo-toxicity studies in rats, there were dose-dependent malformations of the head, mouth, face and large blood vessels. Teratogenic effects were seen at the lowest dose tested (20 mg/kg twice a day) which gives a 24-hour exposure that is estimated to be 30 times higher than the total exposure in PAH patients taking 100 mg once daily.
At the lowest dose of 20 mg/kg BID, sitaxsentan decreased pup survival, delayed female sexual maturity, and produced tubular atrophy/aplasia in the testes. Higher doses in F1 animals resulted in decreases in weight gain during lactation, an increased incidence of large, abnormally-shaped livers in males, delays in male sexual maturity, delays in auditory function, and a decreased number of implants in mating females.
3.2.4 Summary and Conclusion
The non-clinical studies for this drug submission are considered acceptable. Sitaxsentan is an endothelin receptor antagonist that appears to prevent and reverse acute changes in pulmonary hypertension in the animals tested.
Thelin (sitaxsentan sodium) is rapidly absorbed and is extensively metabolized by the cytochrome P450 system in the liver. Based on the effects of the non-clinical studies, the liver appears to be the primary organ of toxicity. The increase in liver weights and blood clotting times, and the histopathology findings of hepatocyte hypertrophy and centrilobular necrosis in the liver are all indicative that the liver is a target organ of toxicity for sitaxsentan. Sitaxsentan was also shown to be teratogenic in rats. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns. Overall, the non-clinical pharmacology and toxicology studies support the use of sitaxsentan for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Sitaxsentan has been shown to selectively bind to human endothelin type A (ETA) receptors compared to endothelin Type B (ETB) receptors. The binding affinity was approximately 6,500 fold more to ETA receptors than to ETB receptors.
Using an adequate model to evaluate the effects of sitaxsentan on QT duration, it was shown that sitaxsentan had no significant effects on QT interval. The subjects received either a placebo, sitaxsentan 100-1000 mg once daily for 7 days as well as a positive control drug (moxifloxacin) known to increase QT. No clinically relevant effects on QT interval or other ECG parameters occurred. The Phase III studies confirmed this observation.
3.3.2 Pharmacokinetics
Absorption
Sitaxsentan was rapidly and extensively absorbed. It can be taken with or without food as there were no significant effects of food on drug exposure (AUC) under both conditions. The minimum possible bioavailability was approximately 55% which compared to the amount that was excreted in the urine. The drug exposure increased disproportionately with the dose administered. Evidence of saturation was seen with repeated administration. In vitro studies indicated that sitaxsentan is not transported bypermeability-glycoproteins
Distribution
Sitaxsentan has a large volume of distribution (>60L). The circulating drug or its metabolites are predominately found in plasma as shown by the ratio of concentration in plasma and whole blood. In animals, sitaxsentan was found in breast milk and it may also cross the placenta.
Metabolism
In vitro tests have shown that sitaxsentan is metabolized by the liver cytochrome isoenzymes CYP2C9 and CYP3A4/5. Sitaxsentan is a relatively strong inhibitor of CYP2C9 and to a lesser extent an inhibitor of CYP2C19 and CYP3A4/5.
The two main circulating metabolites were identified as 1,2-diketo-sitaxsentan and 1-keto-2-hydroxy-sitaxsentan which account for approximately 3% and 8.5% of the parent drug, respectively. These two metabolites were less active than sitaxsentan on ETA receptors (20 and 30 times, respectively), and inactive on ETB receptors.
Elimination
The main routes of excretion for radiolabelled sitaxsentan were renal (49-62%) and fecal (34-48%). The clearance increased with body weight, decreased in patients that received higher doses. Clearance was also decreased in PAH patients compared to healthy individuals.
Special Populations
No dose adjustment is required due to race, sex, and renal impairment. There is no data available for pediatric patients.
3.3.3 Clinical Efficacy
Three pivotal studies (FPH01, FPH02 and FPH04) were submitted, however only two of them (FPH01, FPH02) proved to be useful for the assessment. All three studies were multicentre, double-blind, placebo-controlled, randomized studies that used patients with primary or secondary (connective tissue disease and congenital heart disease) pulmonary arterial hypertension (PAH), with World Health Organization (WHO) functional class II, III and IV. There were very few class IV patients (12 patients) enrolled in the three pivotal studies. Study FPH01 (a study duration of 12 weeks) compared the dosing of Thelin 100 mg and 300 mg once daily to placebo in 178 PAH patients, and Study FPH02 (18 weeks) and Study FPH04 (18 weeks) compared the dosing of Thelin 50 and 100 mg once daily to placebo in 245 and 98 PAH patients, respectively. Study FPH02 also had an open-label bosentan arm; however, the study was not designed to directly compare bosentan to sitaxsentan. The non-pivotal studies included two open-label studies and three long-term extension studies.
The primary endpoint in Study FPH01 was the change from baseline to Week 12 in percent of predicted peak oxygen uptake during cycle ergometry, which is not currently accepted as a validated surrogate endpoint for PAH. There was a small increase (3.1%) in percent of predicted peak oxygen uptake at the higher (300 mg) dose when compared to placebo; however, there was no apparent effect at the 100 mg dose level.
Secondary endpoints included the 6-minute walk (the standard parameter for evaluation of PAH), time to clinical worsening, the New York Heart Association (NYHA) functional class improvement, and various cardiopulmonary hemodynamic parameters. There was a statistically significant improvement in the 6-minute walk at 12 weeks, compared to placebo (35 m and 33 m for the Thelin 100 and 300 mg dose groups, respectively). The improvements in the 6-minute walk at six weeks were not significant. There were too few events to analyze the time to clinical worsening. Compared to placebo, both doses of Thelin were associated with a statistically significant improvement in NYHA functional class by the end of Week 12 (15%, 29%, and 30% improvements were reported in the placebo, 100 mg and 300 mg groups, respectively). With regards to the improvements in cardiopulmonary hemodynamics, both doses of Thelin showed significant improvements in pulmonary vascular resistance, systemic vascular resistance and cardiac index. The 300 mg dose group showed significant improvements in mean arterial pressure and mean right atrial pressure, and the 100 mg dose group showed an increase in mean pulmonary capillary wedge pressure.
The primary endpoint of Study FPH02 was the improvement in 6-minute walk distance. Patients treated with Thelin 100 mg for 18 weeks demonstrated statistically significant improvements in exercise capacity compared to the placebo group (31.4 m). This result was comparable to the 6-minute walk distance achieved in Study FPH01. Improvements in the 6-minute walk over placebo were also statistically significant at Week 12 (22.43 m), but not at Week 6 (5.48 m). None of the differences seen with the Thelin 50 mg dose group were statistically significant.
Statistically significant improvements (patients remaining stable or improved) in WHO functional class were reported in the 100 mg dose group as compared to the placebo group at Week 18 (98.3% vs. 86.8%). No significant differences were observed at Weeks 6 and 12. In the 50 mg dose group, there were no significant differences compared to placebo. With regard to time to clinical worsening, none of the treatments were significantly different from placebo. Significant improvements in Borg Dyspnea Score were observed at Weeks 6 and 12 in the 100 mg dose group vs. the placebo group. At Week 18, the difference was no longer significant. In the 50 mg dose group, there were no significant differences in the Borg Dyspnea Score compared to placebo.
The final pivotal study, Study FPH04, also used the 6-minute walk as the primary endpoint, however, due to a larger than expected placebo effect, none of the differences between Thelin treatments and placebo were statistically significant. With regards to time to clinical worsening and the Borg Dyspnea Score, none of the differences were statistically significant. Overall, Study FPH04 did not offer much support to the overall efficacy of Thelin in the treatment of PAH.
Study FPH02 was the most important study, since the 6-minute walk was the primary outcome measure and the positive study results confirmed the results of the first pivotal study (FPH01) where the 6-minute walk was only a secondary endpoint. Without this confirmation it would be difficult to accept the results of a secondary endpoint, when the primary endpoint in study FPH01 (change from baseline to Week 12 in percent of predicted peak oxygen uptake during cycle ergometry) was not statistically significant at the 100 mg dose level. Other secondary endpoints that were statistically significant in one or both studies included: improvements in WHO functional class compared to placebo, improvements in Borg Dyspnea Score at Weeks 6 and 12, and improvements in cardiopulmonary hemodynamics (significant improvements in pulmonary vascular resistance, systemic vascular resistance and cardiac index).
Two pivotal studies demonstrated that there was a significant benefit to WHO functional class III patients, the patients with primary pulmonary hypertension and the patients with pulmonary hypertension secondary to connective tissue disease. However, the number of class IV patients studied (n =12) was insufficient to grant an authorization for this subset of patients. There were also an insufficient number of patients with PAH secondary to congenital heart disease to grant authorization in this subset of patients. Patients with WHO functional class II did not show a significant benefit from sitaxsentan treatment (placebo subtracted 6-minute walk of 24.8 and 15.5 m in Studies FPH01 and FPH02). However, it was decided that a more restricted indication along with restrictions on prescribing and distribution of Thelin would help mitigate the risk to these patients.
3.3.4 Clinical Safety
Three dose levels of Thelin (50 mg, 100 mg, and 300 mg once daily) were used in the clinical program with a total of 238 patients exposed (94, 149 and 56 patients, respectively). The clinical program is described is section 3.3.3 Clinical Efficacy.
The majority of patients studied (approximately 90%) experienced at least one adverse event (AE) in the various treatment groups, across the three pivotal studies and similar trends were seen in the non-pivotal extension studies. The most commonly reported AEs with Thelin treatment (≥2%) were headache, peripheral edema, nasal congestion, nausea, epistaxis, constipation, insomnia, increased international normalized ratio (INR), and prolonged prothrombin time (PT).
Dose-related increases in the incidence of increased INR, prolonged PT, and abnormal liver function tests were seen in Study FPH01. In study FPH02, there were a number of AEs that were seen more frequently in the sitaxsentan 100 mg group than in the sitaxsentan 50 mg group; suggesting that the AEs might be dose-related. These included peripheral edema, nasopharyngitis, insomnia, upper respiratory tract infection, nasal congestion, epistaxis, diarrhea, muscle cramps, increased INR, and abdominal cramps.
Overall, the majority of the serious adverse events (SAEs) reported in the three pivotal trials were considered to be related to deterioration of PAH. There were a total of 3 deaths during the three pivotal studies (one 300 mg sitaxsentan patient and two placebo patients) and none of them were considered related to treatment.
One of the major safety concerns identified during the clinical development of Thelin is the potential for hepatic injury. In the pivotal and long-term extension trials, 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. In the long-term extension trials Thelin was associated with four 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. Consequently doses of Thelin above 100 mg once daily are not recommended.
Other safety topics of interest included reductions in hemoglobin and hematocrit, coagulation problems, and bleeding events. In the three pivotal studies, the maximum mean reductions in hemoglobin (-1 to -2 g/dL) and hematocrit (-3 to -5%) were generally reached within the first four weeks and stabilized thereafter. The sponsor attributes these changes to hemodilution as a general mechanism, but occult bleeding could not be ruled out. The most frequent bleeding event was epistaxis (17%), followed by hemoptysis (2%), menorrhagea (1%), hematoma (1%), gingival bleeding (1%), hematuria (1%) and vaginal hemorrhage (1%). The majority of patients were on concomitant anticoagulant therapy, usually warfarin. However, not all bleeding AEs occurred in patients with anticoagulants and the majority occurred in patients with an international normalized ratio (INR) of <3.5.
There were dose-related increases in both INR and prothrombin time (PT) but this usually occurred in patients on anticoagulant therapy, which is likely the result of a drug-drug interaction with warfarin through the inhibition of CYP2C9. The sponsor has recommended a dose reduction of warfarin when starting patients on Thelin that are already on warfarin (decrease by 80%) and starting warfarin at a greatly reduced dosage (starting at 0.5 mg) in patients already on Thelin. In all cases, the INR should be monitored closely and the dose of warfarin be adjusted in increments of no greater than 0.5 mg to reach an appropriate target INR. This risk mitigation strategy (described in the Product Monograph) appears to be appropriate based on the results of the pivotal studies when this strategy was implemented; i.e., the incidence of INR exceeding 3.5 was greatly reduced.
The potential of harmful effects of Thelin on the unborn fetus, should be mentioned. There are no human data regarding the use of sitaxsentan sodium during pregnancy; therefore, the potential effects in humans are unknown. However, from animal data, sitaxsentan did cause teratogenicity in rats. Therefore, the use of Thelin during pregnancy is contraindicated. Women of child-bearing age receiving Thelin treatment should use two forms of reliable contraception.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Two of the three pivotal studies demonstrated a modest (35 m and 31 m), but statistically significant improvement in exercise tolerance (6-minute walk) as compared to placebo. The third pivotal study demonstrated a small (24 m) improvement over placebo, however, this difference was not statistically significant because of a larger than expected placebo effect. Compared to placebo-treatment, Thelin demonstrated improvements to the cardiac index, pulmonary vascular resistance, and systemic vascular resistance, after 12 weeks of treatment. There were also significant improvements in Functional Class and significant reductions in the rate of clinical worsening in patients treated with Thelin.
Coagulation problems and bleeding events were identified as being a safety concern. The Product Monograph provides appropriate guidelines for patients on anticoagulant therapy. The majority of patients that had these events were on concomitant anticoagulant therapy, usually warfarin. The INR should be monitored carefully. However, there will always be a risk of bleeding as with any form of anticoagulation, even with the INR within an acceptable target range.
The major safety concern identified during the clinical studies was the potential for hepatic injury.
Through the risk mitigation strategy below, the risk of hepatic injury should be reduced:
- Prior liver impairment (mild to severe, Child-Pugh Class A-C) is contraindicated.
- Elevated aminotransferases prior to initiation of treatment (AST and/or ALT >3x ULN) is contraindicated
- Liver transaminase levels must be measured prior to initiation of treatment and subsequently at monthly intervals.
- The following management plan for patients with increased liver transaminases will be used:
| ALT/AST levels | Treatment and Monitoring Recommendations |
| >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. In the case of elevations of aminotransferases accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice or unusual lethargy or fatigue) or of increases in bilirubin ≥2 x ULN, treatment must 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 three days after reintroduction, then again after two weeks, and thereafter according to the recommendations above.
- The sponsor is proposing an access program through Calea (the distribution company) that:
- Fully educates both prescriber and patient about the hepatic risks of sitaxsentan before a prescription can be honoured.
- Dispenses the drug on a named patient basis only.
- Assures that under no circumstances can a patient receive a prescription for greater than 100 mg daily.
- Provides only a 28-day supply at any time.
- Has a web-based system in place to facilitate confirmation that monthly liver function testing has been completed prior to monthly dispensing of Thelin.
- Sends monthly reminders to physicians and clinic nurses regarding liver function testing for each patient 7-10 days before the next prescription is due to be released.
- Includes monthly reminders regarding liver function testing to patients along with each and every prescription.
- Contacts each patient's family physician and any other physician involved in their care to advise them of the potential risk of hepatotoxicity and of the requirements for monthly liver function testing.
- Provides a wallet card to each patient that outlines the potential risk of hepatotoxicity and the requirement for monthly liver function testing.
While the currently recommended dose of Thelin, 100 mg once daily, appears to be manageable with regard to risk of liver toxicity, doses only 3-6 times this recommended dosage have resulted in serious hepatic injury and death. Therefore, doses of Thelin above 100 mg once daily are not recommended.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Thelin is favourable for the treatment of primary pulmonary arterial hypertension (PAH) or pulmonary hypertension secondary to connective tissue disease, in patients with WHO functional class III who have not responded to conventional therapy. Thelin is also considered favourable for the treatment of patients with WHO functional class II who did not respond to conventional therapy and for whom no appropriate alternative can be identified. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: ThelinTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2005-08-30 |
| Request for priority status | |
| Filed | 2005-09-07 |
| Rejection issued by Bureau Director: | 2005-10-03 |
| Submission filed: | 2005-10-24 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2005-12-09 |
| Response filed: | 2005-12-22 |
| Screening Acceptance Letter issued: | 2006-02-22 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2006-10-12 |
| Quality Evaluation complete: | 2006-11-28 |
| Clinical Evaluation complete: | 2006-12-07 |
| NON issued by Director General (quality issues): | 2006-12-12 |
| Response filed: | 2006-12-27 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2007-01-03 |
| Review 2 | |
| Labelling Review complete: | 2007-05-07 |
| Quality Evaluation complete: | 2007-05-09 |
| Clinical Evaluation complete: | 2007-05-23 |
| NOC issued by Director General: | 2007-05-30 |