Summary Basis of Decision for Intuniv XR

 

Clinical Pharmacology

Guanfacine (medicinal ingredient in Intuniv XR) is a known antihypertensive agent and a selective alpha_2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha_2B or alpha_2C subtypes. By stimulating alpha_2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

An affinity of guanfacine for the 5-HT_2B receptor was assessed in two separate studies. Guanfacine demonstrated a moderate in vitro affinity for the 5-HT_2B receptor, an identified likely molecular target for drug-induced valvular heart disease. Regurgitant cardiac valvular disease, primarily affecting the mitral and/or aortic valves, and other fibrotic complications have been reported in patients who took serotonergic drugs with 5-HT_2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT_2B receptors on cardiac interstitial cells.

While a very small number of possible fibrotic complications, including pleural or pericardial effusion, and cardiac valvulopathy in adult patients treated with immediate release guanfacine (a compound which has been available in the United States of America for more than 24 years with an exposure of over 3 million person years) for hypertension have been reported, the evidence is not sufficient to establish a causal relationship between guanfacine and these fibrotic complications but a contribution of guanfacine cannot be completely ruled out in rare cases. Guanfacine has not been studied in combination with drugs that are potent 5-HT_2B receptor agonists.

For further information, please refer to the Intuniv XR Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical development program of Intuniv XR for the treatment of ADHD consisted of several phase II and III studies conducted in children and adolescents with ADHD, in addition to several supportive studies conducted in healthy adult volunteers.

For this New Drug Submission, (NDS), evaluation of the efficacy of Intuniv XR in the treatment of ADHD in children and adolescents, aged 6 to 17 years, was based primarily on three pivotal studies, SPD503-301, SPD503-304 and SPD503-313.

The efficacy of Intuniv XR as monotherapy was evaluated in two short-term, randomized, multi-centre, double-blind, parallel-group, placebo-controlled and forced dose escalation studies, SPD503-301 [number of patients (n) = 345] and SPD503-304 (n = 322). In both short-term studies, the patient population consisted of children and adolescents, aged 6 to 17 years, who met Diagnostic and Statistical Manual of Mental Disorders, fourth Edition - Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD. In Study SPD503-304 only, patients were also required to have a minimum baseline visit Attention Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) score of 24.

In the SPD503-301 study, patients were randomized to receive either 2 mg, 3 mg, or 4 mg Intuniv XR daily or a placebo for 8 weeks; while in the SPD503-304 study patients were randomized to receive either 1 mg (only patients <110 lbs), 2 mg, 3 mg, or 4 mg Intuniv XR daily or a placebo for 9 weeks. Both studies consisted of a 3-week dose titration period followed by a dose maintenance period (2 weeks for Study SPD503-301 and 3 weeks for Study SPD503-304). Both studies then had a 3-week dose-tapering period followed by either a 30-day final study visit (SPD503-301) or a 30-day follow-up telephone contact (SPD503-304). Therefore, the primary dose-response analyses were based on the first 5 weeks of double-blind treatment from Study SPD503-301 and the first 6 weeks from Study SPD503-304 (dose titration and dose maintenance periods only).

The efficacy of Intuniv XR as an adjunctive therapy in children and adolescents aged 6 to 17 years with ADHD was assessed in a double-blind, randomized, placebo-controlled, multicenter, dose-optimization study, SPD503-313 (n = 455). In this study, patients were randomized to receive either 1 mg, 2, mg, 3 mg, or 4 mg Intuniv XR daily or a placebo for 9 weeks co-administered with a pre-specified, long-acting, oral psychostimulant. The study design consisted of a 5-week dose-optimization phase followed by 3-week dose maintenance phase and then a 9-day dose-tapering phase, followed by a final follow-up visit 7-9 days after their final dose of study drug for safety assessments.

The primary outcome for all three studies was the mean change from baseline to endpoint in the Attention Deficit Hyperactivity Disorder - Rating Scale-4th Edition (ADHD-RS-IV).

Results from the SPD503-301 study demonstrated improvement ADHD-RS-IV total scores at endpoint in all randomized Intuniv XR treatment groups was statistically significantly greater than in placebo treatment groups (p<0.001) for each of the 2 mg, 3 mg, and 4 mg Intuniv XR randomized treatment groups. Improvements in ADHD-RS-IV scores were observed in patients taking Intuniv XR beginning 2 to 3 weeks after initiation of dosing.

When data were examined by age subgroups, only children aged 6 to 12 years demonstrated clinically relevant improvements. Therefore, the approved indication for Intuniv XR was authorized for use in children between the ages of 6 and 12 years only, inclusive.

When data were examined on a weight-adjusted (mg/kg) basis and evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.

The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results for the ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales, Clinical Global Impression of Improvement (CGI-I), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S) and Conners' Teachers Rating Scale results.

Results from the SPD503-304 study also demonstrated statistically significant improvements in ADHD-RS-IV total scores at endpoint in all randomized Intuniv XR treatment groups compared to the placebo treatment groups (p<0.02) for each of the 2 mg, 3 mg, and 4 mg Intuniv XR randomized treatment groups, and for the 1mg Intuniv XR treatment group [for patients 55-110 lbs (24.95-49.89 kg)].

When data were examined by age subgroups, only children aged 6 to 12 years demonstrated clinically relevant improvements

When data were examined on a weight-adjusted (mg/kg) basis and evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.

The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results for the ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales, Clinical Global Impression of Improvement (CGI-I), and Conners' Parent Rating Scale Revised Short Form (CPRS-R:S) results.

Results from the SPD503-313 study also showed mean reductions in ADHD-RS-IV total scores at endpoint that were significantly greater for Intuniv XR given as an adjunct to a stable dose of psychostimulant compared to placebo given with a psychostimulant, for both morning and evening Intuniv XR dosing (p = 0.002 and p<0.001 respectively). Both treatment groups had significantly greater improvement on the Hyperactivity/Impulsivity and Inattentive subscales of the ADHD-RS-IV compared with the placebo group regardless of time of administration. The majority of subjects reached their optimal doses in the 0.05-0.12 mg/kg/day range.

The percentage of responders, (defined as a percentage reduction from Baseline in the ADHD-RS-IV Total Score of ≥25%), were 69.7% for placebo, 79.2% for Intuniv XR taken in the morning (AM), and 83.1% for Intuniv XR in the evening (PM) group. The results indicated a statistically significant difference from placebo in the evening Intuniv XR dosing group but not the morning Intuniv XR dosing group.

When data were examined on a weight-adjusted (mg/kg) basis improvements were observed beginning at doses in the range 0.01-0.04 mg/kg/day once daily.

Conners' Global Index-Parent (CGI-P) total score results were supportive of the primary endpoint.

The original indication proposed by the sponsor in the New Drug Submission (NDS) was as follows: Intuniv XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients aged 6-17 years (children and adolescents) as both monotherapy and when co-administered with psychostimulants.

Following review of the submission, Health Canada revised the indication to:

Intuniv XR (guanfacine hydrochloride extended-release tablets) is indicated as monotherapy for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 to 12 years. Intuniv XR is also indicated as adjunctive therapy to psychostimulants for the treatment of ADHD in children, aged 6 to 12 years, with a sub-optimal response to psychostimulants.

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

Clinical Safety

In evaluating the safety and efficacy of Intuniv XR, a total of 14 studies were conducted in children and adolescents with ADHD. Across these 14 studies, a total of 1,533 subjects (1,192 pediatric patients aged 6 to 12 years and 341 adolescents aged 13 to 17 years) received Intuniv XR. In addition, 13 studies were also performed in healthy adult volunteers.

The clinical safety evaluation was based primarily on data from the three pivotal studies (SPD503-301, 304 and 313; previously described in the Clinical Efficacy section), in addition to several supportive studies.

In the SPD503-301 and SPD503-304 studies, treatment-emergent adverse events (TEAEs) with the highest patient incidence rates in the Intuniv XR treatment group combined included somnolence/sedation (38%), headache (23.8%), and fatigue (14%). Additional common TEAEs included: abdominal pain upper (9.9%), dizziness (6.4%), decreased appetite (6%), lethargy (5.7%), and irritability (5.8%). Other common TEAEs (1% to 5%) included diarrhea, vomiting, and insomnia.

Of the 513 Intuniv XR-treated patients in the two monotherapy studies, three (0.6%) patients experienced serious adverse events (SAE), which were severe but considered not related to Intuniv XR; one of these SAEs (pneumothorax) led to discontinuation.

In the SPD503-313 study, when administering Intuniv XR with the psychostimulant treatment, TEAEs with the highest patient incidence rate were that of headache (21.2%), and somnolence (13.6%). Additional common TEAEs were: fatigue (9.6%), insomnia (8.6%), abdominal pain upper (8.3%), dizziness (7.6%), decreased appetite (6.6%), nausea (5%), sedation (4.3%), and orthostatic hypotension (2.3%). Other common TEAEs (1% to 5%) included vomiting, stomach discomfort, irritability, and enuresis.

Safety results from this also showed no evidence of additive or unique adverse effects when co-administering Intuniv XR along with a psychostimulants relative to what is observed with either medication alone. In addition, there were no SAEs in this study.

Of the 75 patients enrolled, 5 (7%) patients discontinued due to adverse events. There were no evident patterns of clinical importance with regard to hematology, clinical chemistry, urinalysis or physical examination results.

Sedative events, including somnolence and sedation, were commonly reported adverse reactions in clinical studies (38% for Intuniv XR vs. 12% for placebo in monotherapy studies and 18% for Intuniv XR vs. 7% for placebo in the adjunctive study), especially during initial use. These sedative events showed a clear dose-relationship in the 2-4 mg/day range.

Safety Topics of Special Interest

Cardiovascular

The cardiac safety of guanfacine was characterized in non-clinical studies, a thorough QTc prolongation study in healthy adult subjects and periodic ECG measurements from the Phase 2/3 studies in pediatric patients with ADHD. Guanfacine has not been demonstrated to inhibit hERG potassium channels. In the thorough QT/QTc study using immediate release guanfacine, the maximal placebo-adjusted mean change in the QTcF interval was 5 msec at 12 h post-dosing on day 1 in subjects receiving 4 mg/day and 8 msec at 12 h post-dosing on day 6 at the supratherapeutic dose of 8 mg/day. The 12 h post-dose time point at which maximal QTcF effects are seen occurs 7 hours or more after peak plasma guanfacine concentrations. An increase in the QTc interval (placebo-adjusted mean change from baseline approximately 5 msec) has been observed in patients aged 6 to 17 years with ADHD receiving therapeutic doses of Intuniv XR at steady-state. In clinical trials of Intuniv XR in ADHD patients, there were no reports of torsade de pointes.

In the monotherapy studies (SPD503-301 and 304), the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure and pulse were decreases by 5 mmHg, 3 mmHg, and 6 bpm, respectively, for all dose groups combined.

Syncope cases occurred in the long-term, open-label studies (SPD503-303 and 305). Maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy, which became less pronounced over time.

In the 9-week controlled adjunctive therapy (co-administered with a psychostimulant), the maximum mean changes from baseline in supine systolic blood pressure, diastolic blood pressure, and pulse were decreases of 4 mmHg, 3 mmHg and 9 bpm, respectively for the Intuniv XR morning and evening administration groups combined, occurring between weeks 3 and 5 of the study.

In both the monotherapy and adjunctive therapy studies, it was noted that decreases in blood pressure and heart rate were usually asymptomatic. However, hypotension and bradycardia can occur.

A Notice of Non-Compliance (NON) was issued given the need for labelling to address the concern of cardiac disorders discussed above. Most of the issues have been resolved through strong wording in the Warning and Precautions section of the Product Monograph.

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