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| Product NDC Code | 68180-606 | ||||
|---|---|---|---|---|---|
| Drug Name | Clonidine hydrochloride |
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| Type | Generic | ||||
| Pharm Class | Adrenergic alpha2-Agonists [MoA], Central alpha-2 Adrenergic Agonist [EPC] |
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| Active Ingredients |
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| Route | ORAL | ||||
| Dosage Form | TABLET, EXTENDED RELEASE | ||||
| RxCUI drug identifier | 1013930 | ||||
| Application Number | ANDA209285 | ||||
| Labeler Name | Lupin Pharmaceuticals, Inc. | ||||
| Packages |
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Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Clonidine hydrochloride extended-release tablets are not a controlled substance and has no known potential for abuse or dependence.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Clonidine hydrochloride extended-release tablets are not a controlled substance and has no known potential for abuse or dependence.
Overdosage of Clonidine Hydrochloride
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. Treatment Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia [see Warnings and Precautions ( 5.1 )] Sedation and somnolence [see Warnings and Precautions ( 5.2 )] Rebound hypertension [see Warnings and Precautions ( 5.3 )] Allergic reactions [see Warnings and Precautions ( 5.4 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth. ( 6.1 ) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two clonidine hydrochloride extended-release tablets ADHD clinical studies (Study 1, CLON-301 and Study 2, CLON-302) evaluated 256 patients in two 8-week placebo-controlled studies. A third clonidine hydrochloride extended-release tablets ADHD clinical study (Study 3, SHN-KAP-401) evaluated 135 children and adolescents in a 40- week placebo-controlled randomized-withdrawal study. Study 1: Fixed-dose Clonidine Hydrochloride Extended-Release Tablets Monotherapy Study 1 (CLON-301) was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine hydrochloride extended-release tablets in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Events Leading to Discontinuation of Clonidine Hydrochloride Extended-Release Tablets –Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation. The most common adverse reactions that led to discontinuation were somnolence and fatigue. Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2. Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment Period (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) PSYCHIATRIC DISORDERS Somnolence Somnolence includes the terms "somnolence" and "sedation". 38% 31% 4% Nightmare 4% 9% 0% Emotional Disorder 4% 4% 1% Aggression 3% 1% 0% Tearfulness 1% 3% 0% Enuresis 0% 4% 0% Sleep Terror 3% 0% 0% Poor Quality Sleep 0% 3% 1% NERVOUS SYSTEM DISORDERS Headache 20% 13% 16% Insomnia 5% 6% 1% Tremor 1% 4% 0% Abnormal Sleep-Related Event 3% 1% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 15% 10% 12% Nausea 4% 5% 3% Constipation 1% 6% 0% Dry Mouth 0% 5% 1% GENERAL DISORDERS Fatigue Fatigue includes the terms "fatigue" and "lethargy". 16% 13% 1% Irritability 9% 5% 4% CARDIAC DISORDERS Dizziness 7% 3% 5% Bradycardia 0% 4% 0% INVESTIGATIONS Increased Heart Rate 0% 3% 0% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3% 4% 4% Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper Period Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6 to 8; Placebo dose, weeks 6 to 8 (Study 1) Preferred Term Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) Abdominal Pain Upper 0% 6% 3% Headache 5% 2% 3% Gastrointestinal Viral 0% 5% 0% Somnolence 2% 3% 0% Heart Rate Increased 0% 3% 0% Otitis Media Acute 3% 0% 0% Study 2: Flexible-dose Clonidine Hydrochloride Extended-Release Tablets as Adjunctive Therapy to Psychostimulants Study 2 (CLON-302) was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride extended-release tablets as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes during which clonidine hydrochloride extended-release tablets were initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine hydrochloride extended-release tablets treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, decreased appetite, dizziness. Adverse Events Leading to Discontinuation –There was one patient in the CLON+STM group (1%) who discontinued because of an adverse event (severe bradyphrenia, with severe fatigue). Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4. Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2) Preferred Term Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets + STM (N=102) PBO + STM (N=96) PSYCHIATRIC DISORDERS Somnolence Somnolence includes the terms: "somnolence" and "sedation". 19% 7% Aggression 2% 1% Affect Lability 2% 1% Emotional Disorder 2% 0% GENERAL DISORDERS Fatigue Fatigue includes the terms "fatigue" and "lethargy". 14% 4% Irritability 2% 7% NERVOUS SYSTEM DISORDERS Headache 7% 12% Insomnia 4% 3% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 7% 4% RESPIRATORY DISORDERS Nasal Congestion 2% 2% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6% 3% CARDIAC DISORDERS Dizziness 5% 1% Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5. Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2) * Taper Period: weeks 6 to 8 Preferred Term Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets + STM (N=102) PBO + STM (N=96) Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0% Rash 2% 0% Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release tablets discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine hydrochloride extended-release tablets monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events exclude those already mentioned in 6.1: Psychiatric: hallucinations Cardiovascular: Q-T prolongation
| | |||
| PSYCHIATRIC DISORDERS | |||
| Somnolence | 38% | 31% | 4% |
| Nightmare | 4% | 9% | 0% |
| Emotional Disorder | 4% | 4% | 1% |
| Aggression | 3% | 1% | 0% |
| Tearfulness | 1% | 3% | 0% |
| Enuresis | 0% | 4% | 0% |
| Sleep Terror | 3% | 0% | 0% |
| Poor Quality Sleep | 0% | 3% | 1% |
| NERVOUS SYSTEM DISORDERS | |||
| Headache | 20% | 13% | 16% |
| Insomnia | 5% | 6% | 1% |
| Tremor | 1% | 4% | 0% |
| Abnormal Sleep-Related Event | 3% | 1% | 0% |
| GASTROINTESTINAL DISORDERS | |||
| Upper Abdominal Pain | 15% | 10% | 12% |
| Nausea | 4% | 5% | 3% |
| Constipation | 1% | 6% | 0% |
| Dry Mouth | 0% | 5% | 1% |
| GENERAL DISORDERS | |||
| Fatigue | 16% | 13% | 1% |
| Irritability | 9% | 5% | 4% |
| CARDIAC DISORDERS | |||
| Dizziness | 7% | 3% | 5% |
| Bradycardia | 0% | 4% | 0% |
| INVESTIGATIONS | |||
| Increased Heart Rate | 0% | 3% | 0% |
| METABOLISM AND NUTRITION DISORDERS | |||
| Decreased Appetite | 3% | 4% | 4% |
| | |||
| Abdominal Pain Upper | 0% | 6% | 3% |
| Headache | 5% | 2% | 3% |
| Gastrointestinal Viral | 0% | 5% | 0% |
| Somnolence | 2% | 3% | 0% |
| Heart Rate Increased | 0% | 3% | 0% |
| Otitis Media Acute | 3% | 0% | 0% |
| PSYCHIATRIC DISORDERS | ||
| Somnolence | 19% | 7% |
| Aggression | 2% | 1% |
| Affect Lability | 2% | 1% |
| Emotional Disorder | 2% | 0% |
| GENERAL DISORDERS | ||
| Fatigue | 14% | 4% |
| Irritability | 2% | 7% |
| NERVOUS SYSTEM DISORDERS | ||
| Headache | 7% | 12% |
| Insomnia | 4% | 3% |
| GASTROINTESTINAL DISORDERS | ||
| Upper Abdominal Pain | 7% | 4% |
| RESPIRATORY DISORDERS | ||
| Nasal Congestion | 2% | 2% |
| METABOLISM AND NUTRITION DISORDERS | ||
| Decreased Appetite | 6% | 3% |
| CARDIAC DISORDERS | ||
| Dizziness | 5% | 1% |
| Nasal Congestion | 4% | 2% |
| Headache | 3% | 1% |
| Irritability | 3% | 2% |
| Throat Pain | 3% | 1% |
| Gastroenteritis Viral | 2% | 0% |
| Rash | 2% | 0% |
Clonidine Hydrochloride Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS The following have been reported with other oral immediate release formulations of clonidine: Table 6 Clinically Important Drug Interactions Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Tricyclic antidepressants Increase blood pressure and may counteract clonidine's hypotensive effects Monitor blood pressure and adjust as needed Antihypertensive drugs Potentiate clonidine's hypotensive effects Monitor blood pressure and adjust as needed CNS depressants Potentiate sedating effects Avoid use Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use Sedating Drugs: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. ( 7 ) Tricyclic Antidepressants: May reduce the hypotensive effect of clonidine. ( 7 ) Drugs Known to Affect Sinus Node Function or AV Nodal Conduction: Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects such as bradycardia and AV block. ( 7 ) Antihypertensive drugs: Use caution when coadministered with clonidine hydrochloride extended-release tablets. ( 7 )
| Tricyclic antidepressants | Increase blood pressure and may counteract clonidine's hypotensive effects | Monitor blood pressure and adjust as needed |
| Antihypertensive drugs | Potentiate clonidine's hypotensive effects | Monitor blood pressure and adjust as needed |
| CNS depressants | Potentiate sedating effects | Avoid use |
| Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) | Potentiate bradycardia and risk of AV block | Avoid use |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clonidine stimulates alpha 2 -adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known. 12.2 Pharmacodynamics Clonidine is a known antihypertensive agent. By stimulating alpha 2 -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. 12.3 Pharmacokinetics Single-dose Pharmacokinetics in Adults Immediate-release clonidine hydrochloride and clonidine hydrochloride extended-release tablets 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 max is 50% lower for clonidine hydrochloride extended-release tablets 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 to 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 clonidine hydrochloride extended-release tablets, results are likely to be similar to those of the immediate release formulation. The pharmacokinetic profile of clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets under fasted conditions, 0.1 mg of clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets, 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 clonidine hydrochloride extended-release tablets 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 CATAPRES-Fasted n=15 Clonidine Hydrochloride Extended-Release Tablets -Fed n=15 Clonidine Hydrochloride Extended-Release Tablets -Fasted n=14 Parameter Mean SD Mean SD Mean SD C max (pg/mL) 443 59.6 235 34.7 258 33.3 AUC inf (hr*pg/mL) 7313 1812 6505 1728 6729 1650 hT max (hr) 2.07 0.5 6.80 3.61 6.50 1.23 T 1/2 (hr) 12.57 3.11 12.67 3.76 12.65 3.56 Figure 1 Mean Clonidine Concentration-Time Profiles after Single Dose Administration Multiple-dose Pharmacokinetics in Children and Adolescents 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. Image-02
| Cmax (pg/mL) | 443 | 59.6 | 235 | 34.7 | 258 | 33.3 |
| AUCinf (hr*pg/mL) | 7313 | 1812 | 6505 | 1728 | 6729 | 1650 |
| hTmax (hr) | 2.07 | 0.5 | 6.80 | 3.61 | 6.50 | 1.23 |
| T 1/2 (hr) | 12.57 | 3.11 | 12.67 | 3.76 | 12.65 | 3.56 |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Clonidine stimulates alpha 2 -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
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Clonidine is a known antihypertensive agent. By stimulating alpha 2 -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
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Single-dose Pharmacokinetics in Adults Immediate-release clonidine hydrochloride and clonidine hydrochloride extended-release tablets 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 max is 50% lower for clonidine hydrochloride extended-release tablets 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 to 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 clonidine hydrochloride extended-release tablets, results are likely to be similar to those of the immediate release formulation. The pharmacokinetic profile of clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets under fasted conditions, 0.1 mg of clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets, 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 clonidine hydrochloride extended-release tablets 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 CATAPRES-Fasted n=15 Clonidine Hydrochloride Extended-Release Tablets -Fed n=15 Clonidine Hydrochloride Extended-Release Tablets -Fasted n=14 Parameter Mean SD Mean SD Mean SD C max (pg/mL) 443 59.6 235 34.7 258 33.3 AUC inf (hr*pg/mL) 7313 1812 6505 1728 6729 1650 hT max (hr) 2.07 0.5 6.80 3.61 6.50 1.23 T 1/2 (hr) 12.57 3.11 12.67 3.76 12.65 3.56 Figure 1 Mean Clonidine Concentration-Time Profiles after Single Dose Administration Multiple-dose Pharmacokinetics in Children and Adolescents 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.
| Cmax (pg/mL) | 443 | 59.6 | 235 | 34.7 | 258 | 33.3 |
| AUCinf (hr*pg/mL) | 7313 | 1812 | 6505 | 1728 | 6729 | 1650 |
| hTmax (hr) | 2.07 | 0.5 | 6.80 | 3.61 | 6.50 | 1.23 |
| T 1/2 (hr) | 12.57 | 3.11 | 12.67 | 3.76 | 12.65 | 3.56 |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Clonidine hydrochloride extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Adverse Reactions ( 6 )]. History of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, angioedema.( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Clonidine hydrochloride extended-release tablets USP are a centrally acting alpha 2 -adrenergic agonist available as 0.1 mg extended-release tablets for oral administration. Each 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. 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: C 9 H 9 Cl 2 N 3 •HCl Mol. Wt. 266.56 Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. Clonidine hydrochloride extended-release tablets USP meet USP Dissolution Test 2. image-01
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Start with one 0.1 mg tablet at bedtime for one week. Increase daily dosage in increments of 0.1 mg/day at weekly intervals until the desired response is achieved. Take twice a day, with either an equal or higher split dosage being given at bedtime, as depicted below ( 2.2 ) Total Daily Dose Morning Dose Bedtime Dose 0.1 mg/day 0.1 mg 0.2 mg/day 0.1 mg 0.1 mg 0.3 mg/day 0.1 mg 0.2 mg 0.4 mg/day 0.2 mg 0.2 mg Do not crush, chew or break tablet before swallowing. ( 2.1 ) Do not substitute for other clonidine products on a mg-per-mg basis, because of differing pharmacokinetic profiles. ( 2.1 ) When discontinuing, taper the dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension. ( 2.3 ) 2.1 General Dosing Information Clonidine hydrochloride extended-release tablets are 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 clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets, 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). Table 1 Clonidine Hydrochloride Extended-Release Tablets Dosing Guidance Total Daily Dose Morning Dose Bedtime Dose 0.1 mg/day 0.1 mg 0.2 mg/day 0.1 mg 0.1 mg 0.3 mg/day 0.1 mg 0.2 mg 0.4 mg/day 0.2 mg 0.2 mg Doses of clonidine hydrochloride extended-release tablets higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended. When clonidine hydrochloride extended-release tablets are being added-on to a psychostimulant, the dose of the psychostimulant can be adjusted depending on the patient's response to clonidine hydrochloride extended-release tablets. 2.3 Discontinuation When discontinuing clonidine hydrochloride extended-release tablets, 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 clonidine hydrochloride extended-release tablets, they should skip that dose and take the next dose as scheduled. Do not take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period.
| 0.1 mg/day | 0.1 mg | |
| 0.2 mg/day | 0.1 mg | 0.1 mg |
| 0.3 mg/day | 0.1 mg | 0.2 mg |
| 0.4 mg/day | 0.2 mg | 0.2 mg |
| 0.1 mg/day | 0.1 mg | |
| 0.2 mg/day | 0.1 mg | 0.1 mg |
| 0.3 mg/day | 0.1 mg | 0.2 mg |
| 0.4 mg/day | 0.2 mg | 0.2 mg |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Clonidine hydrochloride extended-release tablets USP are available in 0.1 mg strength. The 0.1 mg tablets are white to off white round shaped biconvex tablets, debossed with 'LU' on one side and 'Z55' on other side. Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed. Extended-release tablets: 0.1 mg, not scored. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Clonidine hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies ( 14 )]. Clonidine hydrochloride extended-release tablets are a centrally acting alpha 2 -adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Clonidine Hydrochloride Clonidine Hydrochloride CLONIDINE HYDROCHLORIDE CLONIDINE CELLULOSE, MICROCRYSTALLINE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2208 (15000 MPA.S) MAGNESIUM STEARATE SILICON DIOXIDE SODIUM LAURYL SULFATE (White to off white) LU;Z55
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis Clonidine HCl 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/m 2 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/ m 2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis Clonidine HCl 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/m 2 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/ m 2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68180-606-06 Clonidine Hydrochloride Extended-Release Tablets 0.1 mg Bottle of 30 tablets NDC 68180-606-07 Clonidine Hydrochloride Extended-Release Tablets 0.1 mg Bottle of 60 tablets NDC 68180-606-09 Clonidine Hydrochloride Extended-Release Tablets 0.1 mg Bottle of 90 tablets image-04 Image-05 Image-06
Clonidine Hydrochloride: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.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 during pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise breastfeeding women using clonidine hydrochloride 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 may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology ( 13.1 )].
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.Patient Information Clonidine Hydrochloride (klon' i deen hye" droe klor' ide) Extended-Release Tablets USP 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, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to clonidine hydrochloride and their baby. If you or your child becomes pregnant during treatment with clonidine hydrochloride, 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 much 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 or Lupin Pharmaceuticals, Inc. at 1-800-399-2561. How should I store clonidine hydrochloride extended-release tablets? Store clonidine hydrochloride extended-release tablets between 68°-77°F (20°-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, go to www.lupinpharmaceuticals.com or call 1-800-399-2561 What are the ingredients in clonidine hydrochloride extended-release tablets? Active Ingredient: clonidine hydrochloride Inactive Ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Nagpur 441108 India June 2022 ID#: 270530
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.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 tablets 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 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. Study Number Treatment Group Primary Efficacy Measure: ADHDRS-IV Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (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) - 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) ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4 th 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. Study 3 Double-Blind Full Analysis Set 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 criteria a,b 11 (16.2%) 9 (13.4%) Lack of efficacy c 1 (1.5%) 3 (4.5%) Withdrawal of informed assent/consent 4 (5.9%) 20 (29.9%) Other early terminations 15 (22.1%) 10 (14.9%) Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3) image-03
| 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) | - | |
| Study 3 | ||
| 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 terminations | 15 (22.1%) | 10 (14.9%) |
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 Females and Males of Reproductive Potential Infertility Based on findings in Animal studies revealed that clonidine hydrochloride may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology ( 13.1 )].
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of clonidine hydrochloride extended-release tablets 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/m 2 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/m 2 basis. All these effects in males 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.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including clonidine hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866961-2388 or visiting https://womensmentalhealth.org/adhd-medications/. Risk Summary Prolonged experience with clonidine in pregnant women over several decades, based on published literature, including controlled trials, a retrospective cohort study and case reports, have not identified a drug associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. 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) given to adolescents on a mg/m 2 basis. No developmental effects were seen in rabbits administered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data 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 given to adolescents on a mg/m 2 basis) produced no developmental effects. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD given to adolescents on a mg/m 2 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 to 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 to 14; 500 mcg/kg/day was the lowest dose employed in this study.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Renal Impairment: The dosage of clonidine hydrochloride extended-release tablets must be adjusted according to the degree of impairment, and patients should be carefully monitored. ( 8.6 , 12.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including clonidine hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866961-2388 or visiting https://womensmentalhealth.org/adhd-medications/. Risk Summary Prolonged experience with clonidine in pregnant women over several decades, based on published literature, including controlled trials, a retrospective cohort study and case reports, have not identified a drug associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. 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) given to adolescents on a mg/m 2 basis. No developmental effects were seen in rabbits administered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data 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 given to adolescents on a mg/m 2 basis) produced no developmental effects. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD given to adolescents on a mg/m 2 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 to 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 to 14; 500 mcg/kg/day was the lowest dose employed in this study. 8.2 Lactation Risk Summary Based on published lactation studies, clonidine hydrochloride is present in human milk at relative infant doses ranging from 4.1 to 8.4% of the maternal weight-adjusted dosage. Although in most cases, there were no reported adverse effects in breastfed infants exposed to clonidine, there is one case report of sedation, hypotonia, and apnea in an infant exposed to clonidine through breast milk. If an infant is exposed to clonidine hydrochloride through breastmilk, monitor for symptoms of hypotension and bradycardia, such as sedation, lethargy, tachypnea and poor feeding (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clonidine hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from clonidine hydrochloride extended-release tablets or from the underlying maternal condition. Exercise caution when clonidine hydrochloride extended-release tablets are administered to a nursing woman. Clinical Considerations Monitor breastfeeding infants exposed to clonidine hydrochloride through breast milk for symptoms of hypotension and/or bradycardia such as sedation, lethargy, tachypnea, and poor feeding. 8.3 Females and Males of Reproductive Potential Infertility Based on findings in Animal studies revealed that clonidine hydrochloride may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of clonidine hydrochloride extended-release tablets 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/m 2 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/m 2 basis. All these effects in males 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 clonidine hydrochloride extended-release tablets 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 clonidine hydrochloride extended-release tablets following dialysis.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Clonidine hydrochloride extended-release tablets USP are white to off white round shaped biconvex tablets, debossed with 'LU' on one side and 'Z55' on other side. NDC 68180-606-06 – 0.1 mg round tablets supplied in bottles containing 30 tablets. NDC 68180-606-07 – 0.1 mg round tablets supplied in bottles containing 60 tablets. NDC 68180-606-09 – 0.1 mg round tablets supplied in bottles containing 90 tablets. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Dispense in a tight container.
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