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Intuniv (Guanfacine Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

INTUNIV is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C H Cl N O·HCl corresponding to a molecular weight of 282.55. The chemical structure is: ® 9 9 2 3

Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.

CLINICAL PHARMACOLOGY

Mechanism of Action

Guanfacine is a central alpha -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. 2A

Pharmacodynamics

Guanfacine is a selective central alpha -adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha or alpha subtypes. 2A 2B 2C

Guanfacine is a known antihypertensive agent. By stimulating central alpha -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. 2A

Effects on Height, Weight, and Body Mass Index (BMI)

Patients taking INTUNIV demonstrated similar growth compared to normative data. Patients taking INTUNIV had a mean increase in weight of 0.5 kg (1 lb) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV.  ® ® ® ®

Effect on ECG

The effect of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg.  An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs. This finding has no known clinical relevance.

Pharmacokinetics

Absorption and Distribution

Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. ®

Immediate-release guanfacine and INTUNIV have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure. ®

A comparison across studies suggests that the C is 60% lower and AUC 43% lower, respectively, for INTUNIV compared to immediate-release guanfacine.  Therefore, the relative bioavailability of INTUNIV to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 5. max 0-∞ ® ® ®

Table 5: Pharmacokinetic Parameters in Adults
  Parameter   INTUNIV ®
       1 mg once daily       
(n=52)
     Immediate-release     
guanfacine
1 mg once daily
(n=12)
  C (ng/mL)   max
  1.0 ± 0.3   2.5 ± 0.6
  AUC (ng.h/mL)                  0-∞
  32 ± 9   56 ± 15
  t (h)   max
  6.0 (4.0 - 8.0)   3.0 (1.5-4.0)
  t (h)   1/2
  18 ± 4   16 ± 3

Note: Values are mean +/- SD, except for t which is median (range)   max

Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV 4 mg, the C was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. ® max

The pharmacokinetics were affected by intake of food when a single dose of INTUNIV 4 mg was administered with a high-fat breakfast. The mean exposure increased (C ~75% and AUC ~40%) compared to dosing in a fasted state. ® max

Dose Proportionality

Following administration of INTUNIV in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C and AUC of guanfacine were proportional to dose. ® max 0-∞

Metabolism and Elimination

In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5).  Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.

Renal and Hepatic Impairment

The impact of renal impairment on PK of guanfacine in children was not assessed. [] see Use in Specific Populations

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6-7 times the maximum recommended human dose of 4 mg/day on a mg/ m basis.
2

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

Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 30 times the maximum recommended human dose on a mg/ m basis.
2

CLINICAL STUDIES

Safety and Efficacy Studies

The efficacy of INTUNIV in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2, and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population. Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years. ®

Studies 1 and 2: Fixed-dose INTUNIV Monotherapy ®

Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345). Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324). In both studies, randomized subjects in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started  The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs).  Patients who weighed less than 25 kg (55 lbs) were not included in either study. ® ®

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).

The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies, as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 6).  ® ® ®

Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When 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.

Controlled, monotherapy long-term efficacy studies (>9 weeks) have not been conducted.

In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17).  Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender.  Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. ®

Table 6: Fixed dose Studies

Study                    

(Age Range)  

     Primary Efficacy Measure

  Treatment Group
 Placebo           Intuniv ®            1mg
    Intuniv ®              2mg
    Intuniv ®               3mg
    Intuniv ®               4mg
  (6 – 17 years)

1


Mean Baseline (SD)  


 38.1 (9.34)
 -- 36.1   (9.99)  36.8   (8.72)  38.4  (9.21) 

LS Mean Change from Baseline (SE)  




 -8.5 (1.42)
 -- -15.9 (1.37)  -16.0 (1.38)  -18.5 (1.39) 
LS Mean Difference from Placebo (95% CI)


 --  -- -7.4 (-11.3, -3.5) 
-7.5 (-11.4, -3.6) 
-10.0 (-13.9, -6.1) 
             
  (6 – 17 years)

2


Mean Baseline (SD)  


 39.3  (8.85)
 41.7  (7.81) 
 39.9   (8.74) 
 39.1   (9.22) 
 40.6   (8.57) 

LS Mean Change from Baseline (SE)  




 -12.7 (1.60)
 -19.4 (1.69)  -18.1   (1.60) 
-20.0 (1.64)  -20.6 (1.60) 
LS Mean Difference from Placebo (95% CI)



 --  -6.8 (-11.3, -2.2) 
 -5.4    (-9.9, -0.9)  a
 -7.3 (-11.8, -2.8) 
 -7.9 (-12.3, -3.4) 
 

LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Doses were shown to be statistically significantly superior to placebo.   

a

Study 3: Flexible-dose INTUNIV as Adjunctive Therapy to Psychostimulants ®

Study 3 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Subjects were started at the 1 mg INTUNIV dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering.  Subjects took INTUNIV either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning.  Allowable psychostimulants in the study were ADDERALL XR, VYVANSE, CONCERTA, FOCALIN XR, RITALIN LA, METADATE CD or FDA-approved generic equivalents. ® ® ® ® ® ® ® ® ® ®

Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8).

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV dosing (see Table 7). Nearly two-thirds (64.2%) of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range. ® ®

Study 4: Flexible-dose INTUNIV Monotherapy ®

Study 4 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years  (n=340). ®

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). 

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo in both AM and PM dosing groups of INTUNIV (see Table 7). ® ®


Table 7: Flexible-Dose studies

         Study (Age Range)

                                           Treatment Group                                        
        Placebo                           Intuniv ® 1mg – 4mg               
        AM  
  PM  
  (6 – 17 years)

3   a


Mean Baseline (SD)           

 37.7 (7.75)
 37.6 (8.13)
 37.0 (7.65)
LS Mean Change from Baseline (SE)          


 -15.9 (0.96)
 -20.3 (0.97)
 -21.2 (0.97)
LS Mean Difference from Placebo (95% CI)  



 --  -4.5 (-7.5, -1.4) b
 -5.3 (-8.3, -2.3) b
 
  (6 – 12 years)

4  


Mean Baseline (SD)  

 42.9 (6.21)
 41.7 (6.39)
 41.6 (6.66)
LS Mean Change from Baseline (SE)  


 -10.6 (1.20)
 -20.0 (1.23)
 -20.4 (1.19)
LS Mean Difference from Placebo (95% CI)


 --  -9.4 (-12.8, -6.0) b
 -9.8 (-13.1, -6.4) b
 

LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Treatment was given in combination with a psychostimulant. Doses were shown to be statistically significantly superior to placebo.

a

b

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