Intuniv XR - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Intuniv XR - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: ADHD (Attention Deficit Hyperactivity Disorder)
Class: Antiadrenergic agents, centrally acting
Form: Tablets
Ingredients: guanfacine hydrochloride, crospovidone, fumaric acid, glyceryl behenate, green pigment blend PB-1763 (3mg and 4mg tablets only), hypromellose, lactose, methacrylic acid copolymer, microcrystalline cellulose, and povidone

Pharmaceutical Information

Drug Substance

Proper name:guanfacine hydrochloride
Chemical name:N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride
Molecular formula and molecular mass:C9H9Cl2N3O·HCl282.56
Structural formula:
Physicochemical properties:Guanfacine hydrochloride is a white to off-white crystalline powder, sparingly soluble in water (approximately 1mg/mL). The only organic solvent in which it has relatively high solubility is methanol (≥30mg/mL).

Clinical Trials

Efficacy Studies

Study demographics and trial design

Table 1: Summary of patient demographics for clinical trials in ADHD
Study #Trial designDosage, route of
administration and
duration
Study subjects
(n=number)
Mean
age
(Range)
Gender
Study 1Randomized, double-blind, placebo-controlled, parallel-group, forced-dose titration study conducted in children and adolescents aged 6-17 years with ADHDOral, 2, 3 and 4mg, once daily, 8 weeks345

(6-12 yrs: 265)
(13-17yrs: 80)
10.5 yrs
(6-17)
257M: 88F
Study 2Randomized, double-blind, placebo-controlled, forced-dose study conducted in children and adolescents aged 6-17 years with ADHDOral, 1, 2, 3 and 4mg, once daily, 9 weeks322
(6-12 yrs: 241)
(13-17 yrs: 81)
10.5 yrs
(6-17)
233M: 89F
Study 3Randomized, doubleblind, placebocontrolled, dose-optimization study conducted in adolescents aged 13- 17 years with ADHD to confirm the efficacy, safety, and tolerabilityOral, 1, 2, 3, 4, 5, 6, 7mg, once daily, 15 weeks31214.5 yrs
(13-17)
202M: 110F
Study 4Randomized, double-blind, placebo-controlled, dose-optimization adjunctive study with psychostimulants in children and adolescents aged 6-17 years with ADHDOral, 1, 2, 3 and 4mg, once daily as an adjunct to a current, stable dose of psychostimulant, 9 weeks455
(6-12 yrs: 361)
(13-17 yrs: 94)
10.8 yrs
(6-17)
326M: 129F

Only patients weighing <110lbs could be randomized to 1mg.

The efficacy of INTUNIV XR in the treatment of ADHD was established in 2 placebo-controlled monotherapy trials (Studies 1 and 2) in pediatric patients (children and adolescents; aged 6-17 years, inclusive) and in 1 placebo-controlled monotherapy trial in adolescents (aged 13-17 years). Signs and symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale IV (ADHD-RS-IV) scores. Daily doses used in these studies were within the range of 1- 4mg for children and 1-7mg in adolescents.

In Study 4, the safety and efficacy of INTUNIV XR was evaluated as adjunctive therapy in patients treated with psychostimulants (longer-acting formulations of mixed salts of a single-entity amphetamine product, lisdexamfetamine dimesylate, methylphenidate hydrochloride extended-release, methylphenidate hydrochloride, and dexmethylphenidate hydrochloride). The study was conducted in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to psychostimulants. Patients continued to take their psychostimulant in the morning and were dosed either in the morning or the evening with INTUNIV XR or with placebo in addition to their psychostimulant. Symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale (ADHD-RS-IV) scores. Using the Conners` Global Index-Parent (CGI-P) scale, parents made separate weekly assessments of their child`s ADHD symptoms exhibited in the morning (before school) and evening (before bedtime).

Study results

Short-Term Monotherapy Trials
Table 2: Results of Studies 1, 2 and 3 in ADHD (Children and Adolescents aged 6-17 years)
Study No.Primary EndpointsAssociated value and statistical
significance for Drug at specific
dosages
Associated value and
statistical significance
for Placebo
Study 1ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the ITT populationMean (SD)
2mg: −15.40 (12.82)
3mg: −15.79 (13.00)
4mg: −18.96 (13.71)

Comparison (placebo-adjusted difference)⚹⚹⚹
LS mean (95% CI)
−7.42 (−12.07, −2.77) p=0.0006
−7.52 (−12.19, −2.85) p=0.0005
−9.99 (−14.67, −5.32) p<0.0001
Mean (SD)
−8.86 (12.90)
Study 2⚹⚹ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the ITT populationMean (SD)
1mg: −20.4 (14.00)
2mg: −18.0 (14.88)
3mg: −19.4 (14.62)
4mg: −20.9 (11.89)
Comparison (placebo-adjusted difference)⚹⚹⚹
LS mean (95% CI)
−6.75 (−11.3, −2.2) p=0.0041
−5.41 (−9.9, −0.9) p=0.0176
−7.31 (−11.8, −2.8) p=0.0016
−7.88 (−12.3, −3.4) p=0.0006
Mean (SD)
−12.2 (12.96)
Study 3ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the FAS populationMean (SD)
−25.7 (10.09)

Comparison (placebo-adjusted difference)
LS mean (95% CI)
−6.026 (−8.865, −3.187) p<0.001
Mean (SD)
−19.5 (12.63)

p-value and 95% CI from Dunnett`s adjustment for multiple means comparisons

⚹⚹Only patients weighing <110lbs could be randomized to 1mg

⚹⚹⚹Age subgroup analysis revealed statistically significant efficacy for only children aged 6 to 12 years

ITT: Intent to Treat

FAS: Full analysis set

In Study 1, the improvement in 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 2mg, 3mg, and 4mg 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.

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.

In Study 2, there were 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 2mg, 3mg, and 4mg INTUNIV XR randomized treatment groups, and for the 1mg INTUNIV XR treatment group (for patients 55-110lbs [24.95 – 49.89kg]).

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

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.

In Study 3, subjects receiving INTUNIV XR had a statistically significant greater improvement from baseline in ADHD-RS-IV total score compared with subjects who received placebo (p<0.001).

The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results of the Clinical Global Impression of Severity (CGI-S), ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales and Clinical Global Impression of Improvement (CGI-I).

Controlled, long-term efficacy studies (>9 weeks) have not been conducted in children aged 6 to 12 years and ( >15 weeks) in adolescents aged 13-17 years.

Short-Term Adjunctive Trial
Table 3: Results of Study 4 in ADHD (Children and Adolescents aged 6-17 years)
Primary EndpointsAssociated value and statistical
significance for Drug+
Psychostimulant at all dosages
Associated value and statistical
significance for Placebo
ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for FAS populationMean (SD)
All doses AM: −20.4 (12.77)
All doses PM: −21.0 (12.39)
Overall: −20.7 (12.56)

Comparison
(placebo-adjusted difference)
LS mean1 (95% CI)
−4.5 (−7.5, −1.4) p=0.0022
−5.3 (−8.3, −2.3) p<0.0012
−4.9 (−7.2, −2.6) p<0.0013
Mean (SD)
−16.0 (11.77)

FAS – Full analysis set

1.LS mean, and p-value were based on type III sum of squares from the ANCOVA model for the change from Baseline, including treatment group and psychostimulant type as fixed effects, and baseline value as a covariate.

2. p-value of INTUNIV XR AM and PM groups based on Dunnett`s multiple comparison procedure.

3. p-value for all INTUNIV XR was a t-test. This was a secondary efficacy analysis.

Mean reductions in ADHD-RS-IV total scores at endpoint were significantly greater for INTUNIV XR given as an adjunct to a stable dose of psychostimulant compared to placebo given with a psychostimulant for Study 4, 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 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 (PM) INTUNIV XR dosing group but not the morning (AM) INTUNIV XR dosing group.

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

Controlled long-term efficacy studies (>9 weeks) for adjunctive treatment have not been conducted.

Detailed Pharmacology

Safety Pharmacology

Guanfacine demonstrates a moderate in vitro affinity for the 5-HT2B 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-HT2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT2B 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 USA 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-HT2B receptor agonists.

Mechanism of Action

Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) psychostimulant. The mechanism of action of guanfacine in ADHD is not known.

Pharmacodynamics

Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.

Guanfacine is a known antihypertensive agent. By stimulating alpha2A-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.

Pharmacokinetics

Guanfacine is rapidly and well absorbed in rat and dog after oral administration. In rats, the absorbed drug was widely distributed in various tissues including the brain, the fetuses of pregnant rats and the milk of lactating rats. Plasma protein binding was moderate, amounting to approximately 71% in rat plasma.

Following absorption, the drug is rapidly and extensively metabolised by epoxidation and hydroxylation of the aromatic moiety, followed by conjugation with glucuronic acid, sulphate and glutathione.

After oral or intravenous administration of the [14C]-labelled drug, radioactivity was excreted equally in urine and feces of rats, although urinary excretion was more important in dogs. Biliary excretion and recirculation were extensive in rats. Relatively little unchanged parent drug was found in rat urine. In dogs, about ¼ of the radioactivity in urine was the unchanged drug. No radioactivity was found in the expired air of the rat. The pattern of metabolism and excretion of radioactivity was not altered by repeated dosing. No accumulation of the drug and/or its metabolites was evident in these animal studies.

Guanfacine did not inhibit cytochromes P450 CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 in vitro, and is therefore unlikely to affect the in vivo clearance of other co-administered drugs metabolised by cytochrome P450s. Guanfacine is primarily metabolised by CYP3A4 in human liver microsomes, and has been studied in a clinical study.

Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12mg/kg/day on a mg/m² basis.

Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study.

No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m² basis.

Rat experiments have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose of 0.12mg/kg/day on a mg/m² basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.