Clonidine Hydrochloride: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

Clonidine hydrochloride was not carcinogenic when administered in the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of up to 1620 (male rats), 2040 (female rats), or 2500 (mice) mcg/kg/day. These doses are approximately 20, 25, and 15 times, respectively, the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis.

Mutagenesis

There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Impairment of Fertility

In a reproduction study fertility of female rats appeared to be adversely affected at dose levels of 500 and 2000 mcg/kg/day (10 and 40 times the MRHD on a mg/ m2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.

14 CLINICAL STUDIES

Efficacy of clonidine hydrochloride extended-release tablets 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)

Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD

The efficacy of clonidine hydrochloride extended-release tablets 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: clonidine hydrochloride extended-release tablets (CLON) 0.2 mg/day (N=78), clonidine hydrochloride extended-release tablets 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets-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: clonidine hydrochloride extended-release tablets adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride extended-release tablet 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 clonidine hydrochloride extended-release tablets 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 Number

Treatment Group

Primary Efficacy Measure: ADHDRS-IV Total Score

Mean Baseline Score

LS Mean Change from

Placebo-subtracted

(SD)

Baseline (SE)

Differencea (95% CI)

Study 1

Clonidine Hydrochloride Extended-Release Tablets (0.2 mg/day)

43.8 (7.47)

-15.0 (1.38)

-8.5 (-12.2, -4.8)

Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day)

44.6 (7.73)

-15.6 (1.33)

-9.1 (-12.8, -5.5)

Placebo

45.0 (8.53)

-6.5 (1.35)

-­-

Study 2

Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) +

Psychostimulant

38.9 (6.95)

-15.8 (1.18)

-4.5 (-7.8, -1.1)

Psychostimulant alone

39.0 (7.68)

-11.3 (1.24)

-­-

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

Maintenance Monotherapy for ADHD

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, clonidine hydrochloride extended-release tablets (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine hydrochloride extended-release tablets (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)

Double-Blind Full Analysis Set

Study 3

Clonidine Hydrochloride

Extended-Release Tablets

Placebo

Number of subjects

68

67

Number of treatment failures

31 (45.6%)

42 (62.7%)

Basis of Treatment Failure

Clinical criteriaa,b

11 (16.2%)

9 (13.4%)

Lack of efficacyc

1 (1.5%)

3 (4.5%)

Withdrawal of informed assent/consent

4 (5.9%)

20 (29.9%)

Other early termination

15 (22.1%)

10 (14.9%)

ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition; CGI-S = Clinical Global Impression-Severity
a At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S.

b Two subjects (1 placebo and 1 Clonidine Hydrochloride Extended-Release Tablets) withdrew consent, but met the clinical criteria for treatment failure.

c Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.

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

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Clonidine Hydrochloride Extended-Release Tablets are supplied as follows:

0.1 mg — Each pink, round, unscored tablet debossed with bceb3bbb-figure-05 on one side and 241 on the other side contains 0.1 mg of clonidine hydrochloride, USP. Tablets are supplied in bottles of 60 (NDC 0228-4241-06) with a child-resistant closure.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). See USP Controlled Room Temperature.

Dispense in a tight, light-resistant container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved Patient Labeling (Patient Information)

Dosage and Administration

Advise patients that clonidine hydrochloride extended-release tablets must be swallowed whole, never crushed, cut, or chewed, and may be taken with or without food. When initiating treatment, provide dosage escalation instructions [see Dosage and Administration (2.1)].

Missed Dose

If patients miss a dose of clonidine hydrochloride extended-release tablets, advise them to skip the dose and take the next dose as scheduled and not to take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period [see Dosage and Administration (2.4)].

Hypotension/Bradycardia

Advise patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, to avoid becoming dehydrated or overheated [see Warnings and Precautions (5.1)].

Sedation and Somnolence

Instruct patients to use caution when driving a car or operating hazardous machinery until they know how they will respond to treatment with clonidine hydrochloride extended-release tablets. Also advise patients to avoid the use of clonidine hydrochloride extended-release tablets with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2)].

Rebound Hypertension

Advise patients not to discontinue clonidine hydrochloride extended-release tablets abruptly [see Warnings and Precautions (5.3)].

Allergic Reactions

Advise patients to discontinue clonidine hydrochloride extended-release tablets and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur, such as generalized rash, urticaria, or angioedema [see Warnings and Precautions (5.4) ].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to clonidine hydrochloride extended-release tablets during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using clonidine hydrochloride extended-release tablets to monitor infants for excess sedation, decreased muscle tone, and respiratory depression and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Fertility

Advise females and males of reproductive potential that clonidine hydrochloride extended-release tablets may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Brands listed are the trademarks of their respective owners.

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Rev. A 2/2020

Patient Information

Clonidine Hydrochloride (klon’ i deen hye” droe klor’ ide )
Extended-Release Tablets

Rx Only

Read the Patient Information that comes with clonidine hydrochloride extended-release tablets 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 are clonidine hydrochloride extended-release tablets ?

Clonidine hydrochloride extended-release tablets are a prescription medicine used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Your doctor may prescribe clonidine hydrochloride extended-release tablets alone or together with certain other ADHD medicines.

  • Clonidine hydrochloride extended-release tablets are not a central nervous system (CNS) stimulant.
  • Clonidine hydrochloride extended-release tablets should be used as part of a total treatment program for ADHD that may include counseling or other therapies.

Who should not take clonidine hydrochloride extended-release tablets ?

  • Do not take clonidine hydrochloride extended-release tablets if you are allergic to clonidine in clonidine hydrochloride extended-release tablets. See the end of this leaflet for a complete list of ingredients in clonidine hydrochloride extended-release tablets.

What should I tell my doctor before taking clonidine hydrochloride extended-release tablets ?

Before you take clonidine hydrochloride extended-release tablets, 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 clonidine hydrochloride extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.

    • There is a pregnancy registry for females who are exposed to ADHD medications, including clonidine hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to clonidine hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with clonidine hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhdmedications/.
  • are breastfeeding or plan to breastfeed. Clonidine hydrochloride passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take clonidine hydrochloride extended-release tablets.

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

Clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets.

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 clonidine hydrochloride extended-release tablets ?

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

What should I avoid while taking clonidine hydrochloride extended-release tablets ?

  • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking clonidine hydrochloride extended-release tablets until you talk with your doctor. Clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets will affect you.
  • Avoid becoming dehydrated or overheated.

What are possible side effects of clonidine hydrochloride extended-release tablets ?

Clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets.
  • Sleepiness.
  • Withdrawal symptoms. Suddenly stopping clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets. 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 clonidine hydrochloride extended-release tablets ?

  • Store clonidine hydrochloride extended-release tablets between 68° to 77°F (20° to 25°C).
  • Keep clonidine hydrochloride extended-release tablets in a tightly closed container.

Keep clonidine hydrochloride extended-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of clonidine hydrochloride extended-release tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use clonidine hydrochloride extended-release tablets for a condition for which it was not prescribed.

Do not give clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets. If you would like more information, talk with your doctor. You can also ask your doctor or pharmacist for information about clonidine hydrochloride extended-release tablets that is written for healthcare professionals.

For more information about clonidine hydrochloride extended-release tablets, call Actavis at 1-888-838-2872.

What are the ingredients in clonidine hydrochloride extended-release tablets ?

Active Ingredient: clonidine hydrochloride

Inactive Ingredients: colloidal silicon dioxide, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 0.1 mg tablets also contain red iron oxide and titanium dioxide.

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.Parsippany, NJ 07054 USA

Rev. A 2/2020

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