Kapvay

Appropriate studies have not been performed on the relationship of age to the effects of clonidine in children younger than 18 years of age and Kapvay® extended-release tablets in children younger than 6 years of age. Safety and efficacy have not been established.

Kapvay is part of the drug class:

• Imidazoline receptor agonists

Clonidine lowers blood pressure by decreasing the levels of certain chemicals in your blood. This allows your blood vessels to relax and your heart to beat more slowly and easily.

Clonidine is used to treat hypertension (high blood pressure). The Kapvay brand of clonidine is used to treat attention deficit hyperactivity disorder (ADHD).

Clonidine is sometimes given with other medications.

Clonidine may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Swallow whole. Do not chew, break, or crush.
• If you have trouble swallowing, talk with your doctor.
• Take Kapvay at the same time of day.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Do not stop taking Kapvay all of a sudden without calling your doctor. You may have a greater risk of signs of withdrawal. If you need to stop this medicine, you will want to slowly stop it as ordered by your doctor.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

2.1 General Dosing Information

Kapvay is an extended-release tablet to be taken orally with or without food. Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of clonidine release.

Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of Kapvay for other clonidine products on a mg-per-mg basis is not recommended [see Clinical Pharmacology (12.3)].

2.2 Dose Selection

The dose of Kapvay, administered either as monotherapy or as adjunctive therapy to a psychostimulant, should be individualized according to the therapeutic needs and response of the patient. Dosing should be initiated with one 0.1 mg tablet at bedtime, and the daily dosage should be adjusted in increments of 0.1 mg/day at weekly intervals until the desired response is achieved. Doses should be taken twice a day, with either an equal or higher split dosage being given at bedtime (see Table 1).

Doses of Kapvay higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.

When Kapvay is being added-on to a psychostimulant, the dose of the psychostimulant can be adjusted depending on the patient's response to Kapvay.

2.3 Discontinuation

When discontinuing Kapvay, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension [see Warnings and Precautions (5.3)].

2.4 Missed Doses

If patients miss a dose of Kapvay, they should skip that dose and take the next dose as scheduled. Do not take more than the prescribed total daily amount of Kapvay in any 24-hour period.

8.1 Pregnancy

Pregnancy Category C:

Risk Summary
There are no adequate or well-controlled studies with Kapvay in pregnant women. In animal embryofetal studies, increased resorptions were seen in rats and mice administered oral clonidine hydrochloride from implantation through organogenesis at 10 and 5 times, respectively, the maximum recommended human dose (MRHD). No embryotoxic or teratogenic effects were seen in rabbits administered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD. Kapvay should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data
Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study.

8.3 Nursing Mothers

Clonidine hydrochloride is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kapvay and any potential adverse effects on the breastfed child from Kapvay or from the underlying maternal condition. Exercise caution when Kapvay is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of Kapvay in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of Kapvay in pediatric patients 6 to 17 years of age is supported by three adequate and well-controlled studies; a short-term, placebo-controlled monotherapy trial, a short-term adjunctive therapy trial and a longer-term randomized monotherapy trial [see Clinical Studies (14)]. Safety and efficacy in pediatric patients below the age of 6 years has not been established.

Juvenile Animal Data

In studies in juvenile rats, clonidine hydrochloride alone or in combination with methylphenidate had an effect on bone growth at clinically relevant doses and produced a slight delay in sexual maturation in males at 3 times the maximum recommended human dose (MRHD) for clonidine and methylphenidate.

In a study where juvenile rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood, a slight delay in onset of preputial separation (delayed sexual maturation) was seen in males treated with 300 mcg/kg/day, which is approximately 3 times the MRHD of 0.4 mg/day on a mg/m2 basis. The no-effect dose was 100 mcg/kg/day, which is approximately equal to the MRHD. There was no drug effects on fertility or on other measures of sexual or neurobehavioral development.

In a study where juvenile rats were treated with clonidine alone (300 mcg/kg/day) or in combination with methylphenidate (10 mg/kg/day in females and 50/30 mg/kg/day in males; the dose was lowered from 50 to 30 mg/kg/day in males due to self-injurious behavior during the first week of treatment) from day 21 of age to adulthood, decreases in bone mineral density and mineral content were observed in males treated with 300 mcg/kg/day clonidine alone and in combination with 50/30 mg/kg/day methylphenidate and a decrease in femur length was observed in males treated with the combination at the end of the treatment period. These doses are approximately 3 times the MRHD of 0.4 mg/day clonidine and 54 mg/day methylphenidate on a mg/m2 basis. All these effects in male were not reversed at the end of a 4-week recovery period. In addition, similar findings were seen in males treated with a lower dose of clonidine (30 mcg/kg/day) in combination with 50 mg/kg/day of methylphenidate and a decrease in femur length was observed in females treated with clonidine alone at the end of the recovery period. These effects were accompanied by a decrease in body weight gain in treated animals during the treatment period but the effect was reversed at the end of the recovery period. A delay in preputial separation (sexual maturation) was observed in males treated with the combination treatment of 300 mcg/kg/day clonidine and 50/30 mg/kg/day methylphenidate. There was no effect on reproduction or sperm analysis in these males.

8.6 Renal Impairment

The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of Kapvay should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental Kapvay following dialysis.

9.1 Controlled Substance

Kapvay is not a controlled substance and has no known potential for abuse or dependence.

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:

C9H9Cl2N3•HCl                     Mol. Wt. 266.56

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

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dangerously high blood pressure (severe headache, pounding in your neck or ears, nosebleed, anxiety, chest pain, shortness of breath) followed by low blood pressure (feeling like you might pass out). Other overdose symptoms may include feeling cold, extreme weakness or drowsiness, weak or shallow breathing, pinpoint pupils, fainting, or seizure (convulsions).

Applies to clonidine: oral suspension extended release, oral tablet, oral tablet extended release

Other dosage forms:

• epidural injectable, epidural solution
• transdermal patch extended release

Along with its needed effects, clonidine (the active ingredient contained in Kapvay) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking clonidine:

• Mental depression
• swelling of the feet and lower legs

• Anxiety
• blistering, burning, crusting, dryness, or flaking of the skin
• chest pain or discomfort
• confusion as to time, place, or person
• decreased urine output
• dilated neck veins
• drowsiness
• dry mouth
• fast, pounding, or irregular heartbeat or pulse
• fever
• general feeling of discomfort or illness
• holding false beliefs that cannot be changed by fact
• hyperventilation
• irregular breathing
• irritability
• itching, scaling, severe redness, soreness, or swelling of the skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lightheadedness, dizziness, or fainting
• mental depression
• paleness or cold feeling in the fingertips and toes
• pounding, slow heartbeat
• problems in urination or increase in the amount of urine
• raised red swellings on the skin, lips, tongue, or in the throat
• restlessness
• seeing or hearing things that are not there
• shaking
• shortness of breath
• skin rash
• swelling of the face, fingers, feet, or lower legs
• tightness in the chest
• tingling or pain in the fingers or toes when exposed to cold
• trouble with sleeping
• troubled breathing
• unusual excitement, nervousness, or restlessness
• unusual tiredness or weakness
• vivid dreams or nightmares
• weight gain
• wheezing

Get emergency help immediately if any of the following symptoms of overdose occur while taking clonidine:

• Dizziness (extreme) or faintness
• feeling cold
• pinpoint pupils of the eyes
• unusual tiredness or weakness (extreme)

Some side effects of clonidine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Constipation

• Darkening of the skin
• decreased sexual ability
• dry, itching, or burning eyes
• loss of appetite
• nausea or vomiting

• Blurred vision
• decreased interest in sexual intercourse
• hair loss or thinning of the hair
• inability to have or keep an erection
• leg cramps
• loss in sexual ability, desire, drive, or performance
• muscle or joint pain
• pale skin
• swelling of the breasts or breast soreness in both females and males
• weakness