Summary Basis of Decision for Rupall (Formerly Rupatadine)

Clinical Pharmacology

Rupatadine is a second-generation antihistamine, long-acting histamine antagonist with selective peripheral H1-receptor and platelet activating factor (PAF) antagonistic activities. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain an antihistaminic activity and may partially contribute to the overall efficacy of the drug, maintaining activity for up to 24 hours.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

Studies were not conducted in patients with renal and hepatic insufficiency. Since rupatadine is metabolised by the cytochrome P450 (CYP) enzyme CYP3A4 to active metabolites, which include desloratadine, it is uncertain whether rupatadine and desloratadine concentrations will be significantly affected in patients with hepatic and/or renal insufficiency. This uncertainty has been addressed in the Rupatadine Product Monograph.

Rupatadine is subject to CYP3A4 metabolism and its administration with ketoconazole and other potent CYP3A4 inhibitors is contraindicated. Co-administration of Rupatadine with erythromycin and other moderate CYP3A4 inhibitors should be avoided as stated in the Rupatadine Product Monograph.

The sponsor has conducted studies to examine the central nervous system (CNS) effects of Rupatadine, as well as its ability to enhance the effects of CNS depressants, and on the ability to drive or operate machinery. Although no specific effects of Rupatadine on the CNS have been observed in the dedicated studies, possible effects on the CNS cannot be excluded; therefore a general warning was included in the Rupatadine Product Monograph.

A "thorough QT study" was conducted by the sponsor. The sponsor provided a set of QTcF analyses using contemporary methods which showed no evidence of a dose-dependent QTcF prolongation with Rupatadine, although statistically significant prolongation was observed at isolated time points. Letters of expert opinions were provided to Health Canada that confirmed that the data had been reanalyzed using contemporary methods and the resulting analyses did not show evidence of QT prolongation. Nevertheless, the standardized Product Monograph content for drugs with QT/QTc prolongation potential was applied to ensure that relevant safety information is available for health professionals and patients.

Overall, the clinical pharmacological data support the use of Rupatadine for the specified indication.

For further details, please refer to the Rupatadine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical program for Rupatadine assessed the efficacy of Rupatadine 10 mg tablets for adults and adolescents 12 years of age and older, and Rupatadine oral solution (1 mg/mL), for children 2-11 years of age for the following conditions:

• Seasonal Allergic Rhinitis (SAR)
• Perennial Allergic Rhinitis (PAR)
• Chronic Spontaneous Urticaria (CSU)

Efficacy of Rupatadine Tablets for Adults and Adolescents

Allergic Rhinitis (SAR and PAR)

To support the indication of Rupatadine 10 mg tablets for the treatment of allergic rhinitis (AR) in adults and adolescents 12 years of age and older, the sponsor has identified as "pivotal" one SAR study, Study IC05/RUP/4/03, and one PAR study, Study IC06/RUP/3/04. Based on current international regulatory guidelines, this approach is acceptable. Both pivotal studies were Phase III, multicentre, double-blind, randomized, parallel-group, placebo- and active-controlled studies. The inclusion and exclusion criteria for the study populations were appropriate and the patient population was representative of the general population of patients with SAR or PAR. Baseline characteristics were very similar for all treatment arms for both clinical studies. The study durations (4 weeks for SAR and 12 weeks for PAR) were considered appropriate.

Three hundred and seventy nine patients 12 years of age and older with a history of SAR and a clinically symptomatic diagnosis, were randomized to treatment with Rupatadine 10 mg, desloratadine 5 mg, or placebo once daily in the pivotal SAR Study IC05RUP/4/03. The 12-week pivotal PAR study IC06/RUP/3/04 was conducted in 736 patients over 12 years of age with moderate or severe PAR. Patients were randomized to treatment with Rupatadine 10 mg, cetirizine 10 mg, or placebo once daily. Change from baseline in the Total Symptom Score (TSS), which included the Total Nasal Symptom Score (TNSS) and Total Non-Nasal Symptom Score (TNNSS) was the primary efficacy endpoint.

The pivotal SAR study demonstrated that the Rupatadine 10 mg tablet once daily (QD) is effective in controlling both the nasal and non-nasal symptoms of SAR, with results better than placebo and very similar to desloratadine 5 mg. Rupatadine tablets resulted in a statistically significant reduction in the mean TSS (reflective evaluation) from baseline compared to placebo (p = 0.03) over the 4-week treatment period. Rupatadine 10 mg reduced baseline reflective symptoms by 46.1%, compared to placebo (37.3%). Several secondary variables were evaluated in this study and confirmed the results from the primary endpoint. Rupatadine resulted in statistically significant improvements in instantaneous TSS (p = 0.014), and in a clinically significant improvement in the reflective TNSS (difference greater than 0.55 units) compared to placebo. In addition, the mean change from baseline in reflective and instantaneous TNSS following rupatadine treatment was greater than the minimal clinically important difference (MCID) of a decrease of 3 points on a 0-12 point TNSS scale. Treatment with Rupatadine also resulted in statistically significant reductions in TNNSS (reflective and instantaneous evaluation) compared to placebo (p = 0.024, p = 0.033 respectively).

In the pivotal PAR study, the Rupatadine 10 mg tablet reduced the instantaneous TSS, by 47.8% from baseline compared to 38.8% for placebo. The primary endpoint achieved statistical significance (p = 0.008) compared to placebo and the results were considered clinically meaningful for Rupatadine 10 mg. Secondary endpoints (TNSS, TNNSS, as well as individual symptoms) also showed improvement over placebo. Instantaneous TNSS at the end of the 12-week period was reduced from baseline with a difference between Rupatadine and placebo of 0.54 units. Rupatadine and cetirizine reduced the baseline reflective TNSS scores more than placebo (50.1%, 49.1%, and 43.5% respectively). Following 12 weeks of treatment with Rupatadine tablets in patients with PAR, the mean change from baseline in instantaneous and reflective TNSS score was greater than 3 points on a 0-12 point TNSS scale. Rupatadine and cetirizine reduced the baseline instantaneous and reflective TNNSS more than placebo, after 12 weeks in the intention-to-treat (ITT) analysis, although the changes were not statistically significant.

Chronic Spontaneous Urticaria (CSU)

Two randomized, multicentre, double-blind, parallel group, placebo controlled clinical studies in adults and adolescent patients (12 years and older) were conducted to evaluate the efficacy and safety of Rupatadine 10 mg tablets in the treatment of chronic spontaneous urticaria (CSU). These studies included one 4-week dose ranging study (IC02RUP/II/02) and one 6-week pivotal efficacy study (IC010RUP/3/04). Both studies were multicentre, double-blind, randomized, placebo-controlled, parallel-group studies. A total of 587 patients (176 males and 410 females) with CSU were treated with rupatadine 5 mg, 10 mg, 20 mg tablets, or placebo. Of these patients, 176 received rupatadine 10 mg tablets QD. Approximately 98% of patients were Caucasian. The primary efficacy endpoint for both studies was the change from baseline in mean pruritus score (MPS) over the 4-week treatment period. Secondary efficacy endpoints included Mean Number of Wheals (MNW), Mean Total Symptom Score (MTSS), as well as Dermatology Life Quality Index (DLQI; a measure of quality of life). Rupatadine 10 mg was statistically better than placebo in reducing the MPS (primary endpoint), decreasing the MNW score, and improving the DLQI over the 4 weeks of treatment.

Efficacy of Rupatadine Oral Solution for Children

To study the effects of Rupatadine in children 2-11 years of age, four clinical studies with Rupatadine oral solution (1 mg/mL), were conducted; one pivotal study in children 6-11 years of age with persistent allergic rhinitis, one pivotal study in children 2-11 years of age with CSU, as well as a safety and a pharmacokinetics study in children 2-5 years of age with AR.

In both pivotal studies, treatment with Rupatadine was shown to be effective in the treatment of AR and CSU in patients aged 2-11 years old. The doses of 2.5 mL and 5 mL are considered effective in children when stratified by body weight; i.e., 2.5 mL for children of ≥10 kg up to <25 kg (mainly children 2-5 years of age) and 5 mL for children ≥25 kg (mainly children 6-11 years of age).

Indication

The New Drug Submission for Rupatadine was filed with the following indications:

Rupatadine tablets are indicated for:

• Symptomatic treatment of allergic rhinitis in adults and adolescents (over 12 years of age) providing a fast 24-hour relief of nasal and non-nasal symptoms such as sneezing, runny nose, nasal congestion, itching in the eyes and nose, watery and red eyes.
• Symptomatic treatment of urticaria in adults and adolescents (over 12 years of age) providing a rapid relief of symptoms such as itching and hives.

Rupatadine oral solution is indicated for:

• Symptomatic treatment of allergic rhinitis in children (2 to 11 years of age) providing a fast 24-hour relief of nasal and non-nasal symptoms such as sneezing, runny nose, nasal congestion, itching in the eyes, nose, mouth, throat and/or ears, watery and red eyes.
• Symptomatic treatment of urticaria in children (2 to 11 years of age) providing a rapid relief of symptoms such as itching and hives.

The final recommended indications are as follows:

Allergic Rhinitis

Rupatadine is indicated for the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) in patients 2 years of age and older.

Chronic Spontaneous Urticaria

Rupatadine is indicated for the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (e.g., pruritus and hives), in patients 2 years of age and older.

For more information, refer to the Rupatadine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Rupatadine 10 mg tablets was based on information from 15 studies in patients with AR, 4 studies in patients with urticaria, two long-term studies, four "other" studies in healthy subjects (which included a "thorough" QT study), and 16 pharmacokinetic and pharmacodynamic studies. A total of 3,823 subjects, including 2,898 patients and 925 healthy volunteers were exposed to the active ingredient, rupatadine, at doses ranging from 2 mg to 100 mg with 2,141 subjects exposed to rupatadine 10 mg. Treatment duration in the randomized controlled studies ranged from 1 to 12 weeks. The long-term safety studies in patients with PAR lasted for 12 months. These studies were performed to comply with the recommendations of the International Council for Harmonisation Guideline E1 to assess clinical safety of drugs intended for long term treatment of non-life-threatening conditions. The majority of subjects (patients and healthy volunteers) (>90%), were 18-64 years of age, the remainder of subjects were 12-17 years old or ≥65 years old. There were 149 adolescents included in clinical studies; 28 of them were treated for 6 months and 26 of them were treated for 12 months.

A total of 626 pediatric patients 2-11 years of age, were included in the Rupatadine oral solution clinical studies. Of them, 306 patients received rupatadine oral solution at the doses of 2.5 mL or 5 mL (1 mg/mL), adjusted by body weight. One hundred forty-seven subjects were exposed to rupatadine oral solution 2.5 mg and 159 subjects were exposed to rupatadine solution 5 mg. The period of exposure ranged between 1 and 9 weeks.

The most common adverse reactions reported with Rupatadine 10 mg tablets were somnolence, headache, tiredness, asthenia, dry mouth, nausea, and dizziness. The majority of the adverse reactions observed in the clinical studies were mild to moderate in severity and they usually did not require cessation of therapy.

Two pivotal double-blind, randomized, controlled clinical studies were conducted in patients with SAR and PAR. Together these two studies had a safety population of 902 patients aged 12 years and older (302 patients received Rupatadine 10 mg, 307 placebo, 118 desloratadine 5 mg, and 175 cetirizine 10 mg). The treatment period was 4 to 12 weeks. Somnolence and headache were common CNS adverse reactions in the controlled studies of patients 12 years or older with AR. Somnolence was reported in 8.8% of Rupatadine-treated patients compared to 2.0% of placebo treated patients. Headache was reported in 5.8% of Rupatadine-treated patients compared to 4.9% of the placebo treated patients.

Across all studies conducted with Rupatadine tablets and all treatment groups, there were 617 subject withdrawals. Of these 617 subjects, 106 were withdrawn from the study due to an adverse event. Sixty-eight subjects treated with rupatadine in the clinical studies were discontinued due to an adverse event. Adverse events leading to treatment discontinuation occurred in thirty-eight subjects treated with rupatadine 10 mg in the clinical studies. The most common adverse events leading to discontinuation in the patients treated with rupatadine were severe headache, daytime sleepiness and weakness, and severe drowsiness. One patient who suffered from Wolf Parkinson White Syndrome withdrew from the study due to ECG abnormalities.

In two long-term safety studies conducted with PAR patients, 337 patients 12 years and older were treated with Rupatadine 10 mg tablets once daily up to at least 6 months with 121 patients exposed for at least 12 months. The most common adverse events (>5%) were headache, nasopharyngitis/common cold symptoms, somnolence, allergic rhinoconjunctivitis, gastroenteritis, catarrh, pharyngolaryngeal pain, acute tonsillitis, odynophagia, flu-like symptoms, fatigue, cough, and dysmenorrhea. There were 6 patients who experienced 8 serious adverse events (SAEs), all in the Rupatadine 10 mg group, one of which was reported during the 28-day controlled period of the study (ligament sprain). Of the 8 SAEs, 3 were possibly related to Rupatadine (aspartate aminotransferase increased, alanine aminotransferase increased and creatine phosphokinase increased).

The most common adverse reactions in children were related to the CNS; headaches and somnolence. In the AR pivotal study, study DC04/RUP/3/08, the most frequently reported adverse events were headache (5.6% of patients) and cough (3.9% of patients) in the placebo group; whereas headache (12.8% of patients) was the most frequently adverse event reported in the Rupatadine solution (1 mg/mL) group.

Post-marketing data includes one case of torsade de pointes following the use of Rupatadine when administered with concomitant medications known to have the potential for QT prolongation. In post-marketing experience the following adverse reactions have been reported: arthralgia, atrial fibrillation, back pain, blood creatine phosphokinase increased, cough, dyspnoea, epistaxis, fatigue, headache, hypersensitivity reactions (including anaphylactic reactions, angioedema and urticaria), hypertension, increased appetite, myalgia, muscular weakness, nausea, off-label use, palpitations, QT prolongation, rhabdomyolysis, rash, somnolence, syncope, tachycardia, urticaria, increased weight, and vertigo.

Overall, the safety data supports the approval of Rupatadine for the specified indication. Appropriate contraindications, warnings and precautions are in place in the approved Rupatadine Product Monograph to address the identified safety concerns.

For more information, refer to the Rupatadine Product Monograph, approved by Health Canada and available through the Drug Product Database.