Clonidine Hydrochloride Extended-Release Tablets

KAPVAY (clonidine hydrochloride) extended-release is a centrally acting alpha2-adrenergic agonist available as 0.1 mg or 0.2 mg extended-release tablets for oral administration. Each 0.1 mg and 0.2 mg tablet is equivalent to 0.087 mg and 0.174 mg, respectively, of the free base.

The inactive ingredients are sodium lauryl sulfate, lactose monohydrate, hypromellose type 2208, partially pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. The formulation is designed to delay the absorption of active drug in order to decrease peak to trough plasma concentration differences. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)2-imidazoline hydrochloride. The following is the structural formula:

Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol.

KAPVAY® (clonidine hydrochloride) extended-release is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies].

Mechanism Of Action

Clonidine stimulates alpha2-adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known.

Pharmacodynamics

Clonidine is a known antihypertensive agent. By stimulating alpha2-adrenergic receptors in the brain stem, clonidine reduces sympathetic outflow from the central nervous system and decreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure.

Pharmacokinetics

Immediate-release clonidine hydrochloride and KAPVAY 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 Cmax is 50% lower for KAPVAY compared to immediate-release clonidine hydrochloride.

Following oral administration of an immediate release formulation, plasma clonidine concentration peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours.

About 50% of the absorbed dose is metabolized in the liver. Although studies of the effect of renal impairment and studies of clonidine excretion have not been performed with KAPVAY, results are likely to be similar to those of the immediate release formulation.

The pharmacokinetic profile of KAPVAY administration was evaluated in an open-label, three-period, randomized, crossover study of 15 healthy adult subjects who received three single-dose regimens of clonidine: 0.1 mg of KAPVAY under fasted conditions, 0.1 mg of KAPVAY following a high fat meal, and 0.1 mg of clonidine immediate-release (Catapres®) under fasted conditions. Treatments were separated by one-week washout periods.

Mean concentration-time data from the 3 treatments are shown in Table 7 and Figure 1. After administration of KAPVAY, maximum clonidine concentrations were approximately 50% of the Catapres maximum concentrations and occurred approximately 5 hours later relative to Catapres. Similar elimination half-lives were observed and total systemic bioavailability following KAPVAY was approximately 89% of that following Catapres.

Food had no effect on plasma concentrations, bioavailability, or elimination half-life.

Table 7 : Pharmacokinetic Parameters of Clonidine in Healthy Adult Volunteers

Figure 1 : Mean Clonidine Concentration-Time Profiles after Single Dose Administration

Plasma clonidine concentrations in children and adolescents (0.1 mg bid and 0.2 mg bid) with ADHD are greater than those of adults with hypertension with children and adolescents receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in children and adolescents was higher than CL/F observed in adults with hypertension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day.

Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of “sedation-like” AEs (somnolence and fatigue) appeared to be independent of clonidine dose or concentration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.

Animal Toxicology And/Or Pharmacology

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 adult patients before, and periodically after, the start of clonidine therapy for hypertension. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.

Clinical Studies

Efficacy of KAPVAY in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:

• One short-term, placebo-controlled monotherapy trial (Study 1)
• One short-term adjunctive therapy to psychostimulants trial (Study 2)
• One randomized withdrawal trial as monotherapy (Study 3)

The efficacy of KAPVAY in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes. Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales.

Study 1 (CLON-301), was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary efficacy endpoint. Patients were randomly assigned to one of the following three treatment groups: KAPVAY (CLON) 0.2 mg/day (N=78), KAPVAY 0.4 mg/day (N=80), or placebo (N=78). Dosing for the KAPVAY groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses). Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment. At both doses, improvements in ADHD symptoms were statistically significantly superior in KAPVAY-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Study 2 (CLON-302) was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary efficacy end point. Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response. Patients were randomly assigned to one of two treatment groups: KAPVAY adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The KAPVAY dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response. The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment. ADHD symptoms were statistically significantly improved in KAPVAY plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Table 8 : Short-Term Trials

Study 3 (SHN-KAP-401), was a double-blind, placebo-controlled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD. The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase. All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses). Eligible patients had to demonstrate treatment response as defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase. Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, KAPVAY (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of KAPVAY in the double-blind phase. The primary efficacy endpoint was the percentage of patients with treatment failure defined as a ≥ 30% increase (worsening) in ADHD-RS-IV total score and ≥ 2 points increase (worsening) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason. A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the KAPVAY group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring KAPVAY (Table 9). The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.

Table 9 : Treatment Failure: Double-Blind Full Analysis Set (Study 3)

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)

KAPVAY®
(KAP-vay)
(clonidine hydrochloride) Extended-Release Tablets

Read the Patient Information that comes with KAPVAY before you start taking it and each time you get a refill. There may be new information. This Patient Information leaflet does not take the place of talking to your doctor about your medical condition or treatment.

What is KAPVAY?

KAPVAY is a prescription medicine used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Your doctor may prescribe KAPVAY alone or together with certain other ADHD medicines.

• KAPVAY is not a central nervous system (CNS) stimulant.
• KAPVAY should be used as part of a total treatment program for ADHD that may include counseling or other therapies.

Who should not take KAPVAY?

• Do not take KAPVAY if you are allergic to clonidine in KAPVAY. See the end of this leaflet for a complete list of ingredients in KAPVAY.

What should I tell my doctor before taking KAPVAY?

Before you take KAPVAY, tell your doctor if you:

• have kidney problems
• have low or high blood pressure
• have a history of passing out (syncope)
• have heart problems, including history of heart attack
• have had a stroke or have stroke symptoms
• had a skin reaction (such as a rash) after taking clonidine in a transdermal form (skin patch)
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if KAPVAY will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. KAPVAY can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take KAPVAY.

Tell your doctor about all of the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

KAPVAY and certain other medicines may affect each other causing serious side effects. Sometimes the doses of other medicines may need to be changed while taking KAPVAY.

Especially tell your doctor if you take:

• anti-depression medicines
• heart or blood pressure medicine
• other medicines that contain clonidine
• a medicine that makes you sleepy (sedation)

Ask your doctor or pharmacist for a list of these medicines, if you are not sure if your medicine is listed above.

Know the medicines that you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

How should I take KAPVAY?

• Take KAPVAY exactly as your doctor tells you to take it.
• Your doctor will tell you how many KAPVAY tablets to take and when to take them. Your doctor may change your dose of KAPVAY. Do not change your dose of KAPVAY without talking to your doctor.
• Do not stop taking KAPVAY without talking to your doctor.
• KAPVAY can be taken with or without food.
• KAPVAY should be taken 2 times a day (in the morning and at bedtime).
• If you miss a dose of KAPVAY, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time.
• Take KAPVAY tablets whole. Do not chew, crush or break KAPVAY tablets. Tell your doctor if you cannot swallow KAPVAY tablets whole. You may need a different medicine.
• If you take too much KAPVAY, call your Poison Control Center or go to the nearest hospital emergency room right away.

What should I avoid while taking KAPVAY?

• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking KAPVAY until you talk with your doctor. KAPVAY taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive, operate heavy machinery or do other dangerous activities until you know how KAPVAY will affect you.
• Avoid becoming dehydrated or overheated.

Ware possible side effects of KAPVAY?

KAPVAY may cause serious side effects, including:

• Low blood pressure and low heart rate. Your doctor should check your heart rate and blood pressure before starting treatment and regularly during treatment with KAPVAY.
• Sleepiness.
• Withdrawal symptoms. Suddenly stopping KAPVAY may cause withdrawal symptoms including: increased blood pressure, headache, increased heart rate, lightheadedness, tightness in your chest and nervousness.

The most common side effects of KAPVAY include:

• sleepiness
• tiredness
• irritability
• trouble sleeping (insomnia)
• nightmare
• constipation
• dry mouth
• decreased appetite
• dizziness

Tell your doctor if you have any side effects that bother you or that does not go away.

These are not all of the possible side effects of KAPVAY. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store KAPVAY?

• Store KAPVAY between 68°-77°F (20°-25°C).
• Keep KAPVAY in a tightly closed container.

Keep KAPVAY and all medicines out of the reach of children.

General information about the safe and effective use of KAPVAY

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use KAPVAY for a condition for which it was not prescribed.

Do not give KAPVAY to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about KAPVAY. If you would like more information, talk with your doctor. You can also ask your doctor or pharmacist for information about KAPVAY that is written for healthcare professionals.

For more information about KAPVAY, go to www.KAPVAY.com or call 1-877-370-1142.

What are the ingredients in KAPVAY?

• Active Ingredient: clonidine hydrochloride
• Inactive Ingredients: sodium lauryl sulfate, lactose monohydrate, hypromellose type 2208, partially pregelatinized starch, colloidal silicon dioxide, and magnesium stearate