Ditropan XL: Package Insert and Label Information

DITROPAN XL- oxybutynin chloride tablet, extended release
Janssen Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

DITROPAN XL® (oxybutynin chloride) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

DITROPAN XL® is also indicated for the treatment of pediatric patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).

2 DOSAGE AND ADMINISTRATION

DITROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

DITROPAN XL® may be administered with or without food.

2.1 Adults

The recommended starting dose of DITROPAN XL® is 5 or 10 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.

2.2 Pediatric Patients Aged 6 Years of Age and Older

The recommended starting dose of DITROPAN XL® is 5 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

3 DOSAGE FORMS AND STRENGTHS

DITROPAN XL® extended-release tablets are available as 5 and 10 mg tablets for oral use:

5 mg: Pale yellow, round, tablet with “5 XL” printed on one side with black ink.

10 mg: Pink, round, tablet with “10 XL” printed on one side with black ink.

4 CONTRAINDICATIONS

DITROPAN XL® is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma.

DITROPAN XL® is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product. There have been reports of hypersensitivity reactions, including anaphylaxis and angioedema.

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

5.2 Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6)]. A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how DITROPAN XL® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

DITROPAN XL® should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

DITROPAN XL® should be used with caution in patients with Parkinson’s disease due to the risk of aggravation of symptoms.

5.3 Worsening of Symptoms of Myasthenia Gravis

DITROPAN XL® should be used with caution in patients with myasthenia gravis due to the risk of aggravation of symptoms.

5.4 Worsening of Symptoms of Decreased Gastrointestinal Motility in Patients with Autonomic Neuropathy

DITROPAN XL® should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility.

5.5 Urinary Retention

DITROPAN XL® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].

5.6 Gastrointestinal Adverse Reactions

DITROPAN XL® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)].

DITROPAN XL® , like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis and intestinal atony.

DITROPAN XL® should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

As with any other nondeformable material, caution should be used when administering DITROPAN XL® to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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 clinical practice.

The safety and efficacy of DITROPAN XL® (5 to 30 mg/day) was evaluated in 774 adult subjects who participated in five double-blind, controlled clinical trials. In four of the five studies, Ditropan IR (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by ≥ 1% of subjects are shown in Table 1.

Table 1: Adverse Drug Reactions Reported by ≥ 1% of DITROPAN XL® -treated Adult Subjects in Five Double-blind, Controlled Clinical Trials of DITROPAN XL®
System/Organ ClassPreferred Term DITROPAN XL® 5 to 30 mg/dayn=774% Ditropan IR *5 to 20 mg/dayn=199%
*
IR = immediate release
The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.
Psychiatric Disorders
Insomnia 3.0 5.5
Nervous System Disorders
Headache 7.5 8.0
Somnolence 5.6 14.1
Dizziness 5.0 16.6
Dysgeusia 1.6 1.5
Eye Disorders
Vision blurred 4.3 9.6
Dry eye 3.1 2.5
Respiratory, Thoracic and Mediastinal Disorders
Cough 1.9 3.0
Oropharyngeal pain 1.9 1.5
Dry throat 1.7 2.5
Nasal dryness 1.7 4.5
Gastrointestinal Disorders
Dry mouth 34.9 72.4
Constipation 8.7 15.1
Diarrhea 7.9 6.5
Dyspepsia 4.5 6.0
Nausea 4.5 11.6
Abdominal pain 1.6 2.0
Vomiting 1.3 1.5
Flatulence 1.2 2.5
Gastro-esophageal reflux disease 1.0 0.5
Skin and Subcutaneous Tissue Disorders
Dry skin 1.8 2.5
Pruritus 1.3 1.5
Renal and Urinary Disorders
Dysuria 1.9 2.0
Urinary hesitation 1.9 8.5
Urinary retention 1.2 3.0
General Disorders and Administration Site Conditions
Fatigue 2.6 3.0
Investigations
Residual urine volume 2.3 3.5

The discontinuation rate due to adverse reactions was 4.4% with DITROPAN XL® compared to 0% with Ditropan IR. The most frequent adverse reaction causing discontinuation of study medication was dry mouth (0.7%).

The following adverse reactions were reported by <1% of DITROPAN XL® -treated patients and at a higher incidence than placebo in clinical trials: Metabolism and Nutrition Disorders: anorexia, fluid retention; Vascular disorders: hot flush; Respiratory, thoracic and mediastinal disorders: dysphonia; Gastrointestinal Disorders: dysphagia, frequent bowel movements; General disorders and administration site conditions: chest discomfort, thirst.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported from worldwide postmarketing experience with DITROPAN XL®. Because postmarketing 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.

Infections and Infestations: Urinary tract infection; Psychiatric Disorders: psychotic disorder, agitation, confusional state, hallucinations, memory impairment, abnormal behavior; Nervous System Disorders: convulsions; Eye Disorders: glaucoma; Respiratory, Thoracic and Mediastinal Disorders: nasal congestion; Cardiac Disorders: arrhythmia, tachycardia, palpitations, QT interval prolongation; Vascular Disorders: flushing, hypertension; Skin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; anaphylactic reactions requiring hospitalization for emergency treatment; Injury, poisoning and procedural complications: fall.

Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation. In one reported case, concomitant use of oxybutynin with carbamazepine and dantrolene was associated with adverse events of vomiting, drowsiness, confusion, unsteadiness, slurred speech and nystagmus, suggestive of carbamazepine toxicity.

7 DRUG INTERACTIONS

The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects.

Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide.

Mean oxybutynin plasma concentrations were approximately 2 fold higher when DITROPAN XL® was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies using DITROPAN XL® in pregnant women. DITROPAN XL® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during DITROPAN XL® treatment are encouraged to contact their physician.

Risk Summary

Based on animal data, oxybutynin is predicted to have a low probability of increasing the risk of adverse developmental effects above background risk.

Animal Data

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility or harm to the animal fetus.

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