Nexiclon XR

Tris Pharma, Inc.
Tris Pharma, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Nexiclon XR safely and effectively. see full prescribing information for Nexiclon XR. Nexiclon XR (Clonidine) FOR SUSPENSION, EXTENDED RELEASE for ORAL use.Initial U.S. Approval: 2009INDICATIONS AND USAGENEXICLON XR® (Clonidine Extended Release) Oral Suspension is a central alpha-adrenergic agonist indicated for: Treatment of hypertension (1) DOSAGE AND ADMINISTRATION Initial dose: 0.17 mg (2 mL) once daily. Elderly patients may benefit from a lower initial dose. Initial dose is recommended to be administered at bedtime. (2.1) Patients with renal impairment: Uptitrate slowly (2.3) DOSAGE FORMS AND STRENGTHS 0.09 mg/mL Extended Release Oral SuspensionCONTRAINDICATIONS Known hypersensitivity to clonidine (rash, angioedema) WARNINGS AND PRECAUTIONS Patients should not discontinue therapy without consulting a physician.  Dose reduction should be performed gradually over a 2- to 4-day period to avoid withdrawal symptomatology. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. (5.1) Monitor closely and uptitrate slowly in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure. (5.2) Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. (5.2) In perioperative use, NEXICLON XR may be administered up to 28 hours prior to surgery and resumed the following day. Side Effects There is very little experience with NEXICLON XR in controlled trials. Based on this limited experience, the adverse event profile appears similar with the immediate release clonidine formulation. The most commonly expected adverse reactions are dry mouth, drowsiness, and dizziness. (6) To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at 1-732-940-0358 and http://www.trispharma.com/ or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma Inc at 1-732-940-0358 and www.trispharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS 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, necessitating an increase in clonidine dose. (7) Drugs known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers, beta-blockers): Additive effects such as bradycardia and AV block. (7) USE IN SPECIFIC POPULATIONS Pregnancy Category C (8.1) Clonidine is secreted in human milk. (8.2) Safety and effectiveness in children have not been established. (8.3) Renal impairment: Dose may need adjustment. (2.3)

FULL PRESCRIBING INFORMATION

NEXICLON XR is indicated in the treatment of hypertension. NEXICLON XR may be employed alone or concomitantly with other antihypertensive agents.

• Maintenance dose: Further increments of 0.09 mg (1 mL) once daily may be made at weekly intervals if necessary until the desired response is achieved. The therapeutic doses most commonly employed have ranged from 0.17 mg to
• 0.52 mg once daily (2.2)

The dose of NEXICLON XR must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration in adults.

Dosing with NEXICLON XR should be initiated 0.17 mg (2 mL) once daily. Elderly patients may benefit from a lower initial dose [see Use is Specific Populations (8.4) ]. Initial dose is recommended to be administered at bedtime.

Further increments of 0.09 mg (1 mL) once daily may be made at weekly intervals if necessary until the desired response is achieved. The therapeutic doses most commonly employed have ranged from 0.17 mg (2 mL to 0.52 mg (6 mL) once daily.

NEXICLON XR was studied at doses of 0.17 to 0.52 mg to 0.52 mg (2 to 6 mL) once daily. Doses higher than 0.52 mg (6 mL) per day were not evaluated and are not recommended.

The recommended does of NEXICLON XR for patients who are currently taking clonidine hydrochloride immediate-release tablets is provided in the table below.

Adjust dosage according to the degree of impairment. In patients with end stage kidney disease on maintenance dialysis, start at 0.09 mg (1 mL) per day and up-titrate slowly to minimize dose related adverse events.

Monitor patients carefully, especially for bradycardia, sedation and hypotension. Only a minimal amount of clonidine is removed during routine hemodialysis.

In patients with moderate to severe kidney impairment not undergoing dialysis, initiate clonidine at the same dose as for patients without renal impairment. Up-titrate slowly and monitor for dose-related adverse events.

NEXICLON XR should not be used in patients with known hypersensitivity to clonidine [see Warnings and Precautions (5.2) ]

Instruct patients not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with NEXICLON XR, reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms.

An excessive rise in blood pressure following discontinuation of NEXICLON XR can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of NEXICLON XR.

Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.

In patients who have developed localized contact sensitization to a clonidine transdermal system, substitution of oral clonidine therapy may be associated with the development of a generalized skin rash.

In patients who develop an allergic reaction to a clonidine transdermal system, substitution of oral clonidine may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Monitor carefully and uptitrate slowly in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. The sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

NEXICLON XR may be administered up to 28 hours prior to surgery and resumed the following day. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required.

The following serious adverse reactions are discussed in detail elsewhere in the labeling:

• Withdrawal [see Warnings and Precautions (5.1) ]
• Allergic reactions [see Warnings and Precautions (5.2) ]

There is very limited experience with NEXICLON XR in controlled trials.  Based on this limited experience, the adverse event profile appears similar with to the immediate-release clonidine formulation.

Most adverse reactions are mild and tend to diminish with continued therapy. The most frequent (which also appear to be dose-related) are dry mouth (approximately 40%); drowsiness (approximately 33%; dizziness (approximately 16%); constipation and sedation (approximately 10% each).

The following less frequent adverse reactions have also been reported in patients receiving immediate-release clonidine, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome.  Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol.

Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Central Nervous System (CNS): Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares.

Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.

Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting.

Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention.

Hematologic: Thrombocytopenia.

Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain.

Musculoskeletal: Leg cramps and muscle or joint pain.

Oro-otolaryngeal: Dryness of the nasal mucosa.

Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes.

No drug interaction studies have been conducted with NEXICLON XR. The following have been reported with other oral formulations of clonidine.

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.

Monitor heart rate 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. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats [see Nonclinical Toxicology (13.2) ].

Alcohol: Based on in vitro studies, high concentration of alcohol may increase the rate of release of NEXICLON XR.

Pregnancy Category C. Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m² basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m² basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 mcg/kg).

No adequate, well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Clonidine is secreted in human milk.

Safety and effectiveness in pediatric patients have not been established.

Elderly patients may benefit from a lower initial dose [see Dosage and Administration (2) ].

The initial dosage should be based on the degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Only a minimal amount of clonidine is removed during routine hemodialysis.

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. As little as 0.1 mg of clonidine has produced signs of toxicity in children.

There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD₅₀ of clonidine is 206 and 465 mg/kg, respectively.

NEXICLON XR (clonidine) Extended-Release Oral Suspension is available for oral administration in one extended-release dose strength 0.09 mg/mL. The 0.09 mg/mL suspension is equivalent to 0.1 mg/mL of immediate-release clonidine hydrochloride.

Clonidine hydrochloride, a centrally active alpha-adrenergic agonist, 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:

[IC]

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

The inactive ingredients are: citric acid anhydrous, flavor, glycerin, high fructose corn syrup, methylparaben, modified food starch, polyvinyl acetate, polysorbate 80, povidone, propylparaben, purified water, sodium polystyrene sulfonate, sucrose, triacetin, and xanthan gum.

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. The patient’s maximum blood pressure decrease occurred within 6 to 8 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.

NEXICLON XR was studied in an open-label crossover, force titration, partially randomized trial in patients with mild and moderate essential hypertension who were on two or fewer antihypertensive medications.   The trial was designed to compare steady-state exposures between the NEXICLON XR and clonidine immediate-release tablets.  There were up- and down-titration phases.  There was no washout period between phases or treatments.

Studies with immediate-release clonidine hydrochloride have demonstrated a moderate reduction (15% to 20%) in cardiac output in the supine position with no change in the peripheral resistance. At a 45° tilt, there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.

Tolerance to the antihypertensive effect may develop in some patients, necessitating a re-evaluation of therapy.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.

Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.

Following single doses of NEXICLON XR Oral Suspension 0.17 mg, clonidine mean (S.D.) peak plasma concentrations of 0.49 (±0.09) ng/mL occurred at 7.8 (±1.7) hours. The plasma half-life of clonidine was 13.7 (±3.0) hours. There was no effect of food on the pharmacokinetic parameters.

[IC] [/IC]

A = NEXICLON XR Oral Suspension (0.17 mg QD) Fasted

B = Clonidine IR Tablet (0.1 mg clonidine hydrochloride Q 12h) Fasted

C = NEXICLON XR Oral Suspension (0.17 mg QD) Fed

In the multi-dose study, mild to moderate hypertensive patients were randomized to ER and BID IR clonidine formulations. The following plot shows the sitting blood pressure values for each treatment group at Day 22.

[IC] [/IC]

The half-life may increase up to 41 hours in patients with severe impairment of renal function. Following oral administration of clonidine 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.

Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m² basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m² basis).

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.

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

In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

[see Clinical Pharmacology (12.3) ]

NEXICLON XR (Clonidine Extended Release) Oral Suspension 0.09 mg/mL is supplied as light beige to tan viscous suspension containing 0.09 mg clonidine base per mL in bottles of 4 fl oz (118 mL). NDC 27808-029-01.

Store at 25ºC (77ºF); excursions permitted from 15º to 30ºC (59º to 86ºF). [See USP Controlled Room Temperature.]

Dispense in tight, light-resistant container.

Distributed By: NextWave Pharmaceuticals, Inc.

• Cupertino, CA 95014

•  

  • www.nextwavepharma.com

   

Manufactured By: Tris Pharma, Inc.

• Monmouth Junction, NJ 08852

•  

  • www.trispharma.com

   

LB8151

Rev 00

10/10

Caution patients against interruption of NEXICLON XR therapy without their healthcare provider’s advice.

Advise patients who engage in potentially hazardous activities, such as operating machinery or driving, of a possible sedative effect of clonidine. The sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

• Shake bottle well with vigorous back and forth motion for 5 to 10 seconds and then insert adapter into the neck of bottle.
• Insert syringe tip into the adapter and invert the bottle.
• Draw out amount of suspension as prescribed by doctor or physician. Dispense directly into mouth.

NEXICLON XR ^® (Clonidine Extended Release) Oral Suspension

0.09 mg/mL