Nexiclon XR

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

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.

2.1 Initial Dose

Dosing with Nexiclon XR should be initiated at 0.17 mg 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.

2.2 Maintenance Dose

Further increments of 0.09 mg 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.

Nexiclon XR was studied at doses of 0.17 to 0.52 mg per day. Doses higher than

0.52 mg per day were not evaluated and are not recommended.

2.3 Patients Currently Using Clonidine Hydrochloride Immediate Release Tablets

The recommended dose of Nexiclon XR for patients who are currently taking clonidine hydrochloride immediate-release tablets is provide in the table below.

2.4 Renal Impairment

Adjust dosage according to the degree of impairment. In patients with end stage kidney disease on maintenance dialysis, start at 0.09 mg 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.

Extended-Release Tablet 0.17 and 0.26 mg clonidine base

0.17 mg Extended-Release tablet (clonidine base)

0.26 mg Extended-Release tablet (clonidine base)

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

5.1 Withdrawal

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.

5.2 General Precautions

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.

5.3 Perioperative Use

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.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Following single doses of Nexiclon XR 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.

A = Nexiclon XR Tablets (0.17 mg QD) Fasted

B = Clonidine IR Tablet (0.1 mg clonidine hydrochloride Q12h) Fasted

C = Nexiclon XR Tablets (017 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.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

13.2 Animal Toxicology and/or Pharmacology

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

In 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 Tablet is supplied as splitable, scored, capsule-shaped coated tablets containing 0.17 mg or 0.26 mg clonidine base in bottles of 90 tablets.

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

   

LB8155

Rev 00

10/10

Applies to clonidine: compounding powder, injectable solution, oral suspension extended release, oral tablet, oral tablet extended release, transdermal film extended release

Cardiovascular

Very common (10% or more): Hypotension (45%), orthostatic hypotension (32%)
Common (1% to 10%): Chest pain, tachycardia
Uncommon (0.1% to 1%): Sinus bradycardia, Raynaud's phenomenon, palpitations
Rare (0.01% to 0.1%): Atrioventricular block, palpitations, bradycardia, syncope, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, high degree AV block), cerebrovascular accident
Frequency not reported: Bradyarrhythmia, hypertension, rebound hypertension[Ref]

Dermatologic

Very common (10% or more): Contact dermatitis with the patch formulation (19%)
Common (1% to 10%): Sweating
Uncommon (0.1% to 1%): Pruritus, rash (localized or generalized), urticaria, erythema
Rare (0.01% to 0.1%): Alopecia, excoriation, burning
Very rare (less than 0.01%): Papules, throbbing, blanching, generalized macular rash, facial/tongue angioedema
Frequency not reported: Hives, localized hypo or hyper pigmentation[Ref]

Endocrine

Rare (0.01% to 0.1%): Gynecomastia[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (40%), upper abdominal pain (15%), nausea (13%), vomiting (10%)
Common (1% to 10%): Constipation, parotid gland pain
Uncommon (0.1% to 1%): Colonic pseudo-obstruction
Very rare (less than 0.01%): Parotitis[Ref]

Genitourinary

Common (1% to 10%): Erectile dysfunction
Frequency not reported: Micturition difficulty, loss of libido, decreased sexual activity, nocturia, urinary retention[Ref]

General

Most adverse effects are mild and diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth (40%), drowsiness (33%), dizziness (16%), constipation (10%), and sedation (10%).[Ref]

Hematologic

Rare (0.01% to 0.1%): Peripheral blood flow disturbance, thrombocytopenia[Ref]

Hepatic

Frequency not reported: Mild transient abnormalities of liver function tests, hepatitis[Ref]

Metabolic

Rare (0.01% to 0.1%): Blood glucose increased, serum creatine phosphokinase increased
Frequency not reported: Weight gain, anorexia[Ref]

Musculoskeletal

Frequency not reported: Muscle pain, joint pain, leg cramps[Ref]

Nervous system

Very common (10% or more): Drowsiness (33%), dizziness (16%), somnolence (13%), sedation (10%)
Common (1% to 10%): Headache
Uncommon (0.1% to 1%): Paresthesia
Frequency not reported: Headache, localized numbness[Ref]

Ocular

Rare (0.01% to 0.1%): Lacrimation decreased (dry eyes)
Frequency not reported: Accommodation disorder, ocular burning, vision blurred[Ref]

Other

Common (1% to 10%): Fatigue, tinnitus
Uncommon (0.1% to 1%): Malaise
Frequency not reported: Fever, pallor, weakness, positive Coombs' test, increased sensitivity to alcohol[Ref]

Psychiatric

Very common (10% or more): Confusion (13%)
Common (1% to 10%): Depression, tearfulness, sleep disorder, hallucinations (both visual and auditory), nervousness, agitation
Uncommon (0.1% to 1%):
Rare (0.01% to 0.1%): Delusional perception, nightmare
Frequency not reported: Libido decreased, restlessness, anxiety, irritability, behavior changes[Ref]

Respiratory

Common (1% to 10%): Hypoventilation
Rare (0.01% to 0.1%): Nasal dryness[Ref]

Some side effects of Nexiclon XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.