Sanctura

trospium chloride

Dosage Form: tablet
PRESCRIBING INFORMATION


Sanctura® (trospium chloride) 20 mg tablets

DESCRIPTION

Sanctura® (trospium chloride) is a quaternary ammonium compound with the chemical name of Spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium], 3-[(hydroxydiphenylacetyl)oxy]-, chloride, (1α, 3β, 5α). The empirical formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.97. The structural formula of trospium chloride is represented below:

Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. The compound's solubility in water is approximately 1 g/2 mL.

Each Sanctura® tablet contains 20 mg of trospium chloride and is to be given orally. Each tablet also contains the following inactive ingredients: sucrose, wheat starch, microcrystalline cellulose, talc, lactose monohydrate, calcium carbonate, titanium dioxide, stearic acid, croscarmellose sodium, povidone, polyethylene glycol 8000, colloidal silicon dioxide, ferric oxide, carboxymethylcellulose sodium, white wax, magnesium stearate, and carnauba wax.

CLINICAL PHARMACOLOGY

Sanctura® is a muscarinic antagonist.

Trospium chloride antagonizes the effect of acetylcholine on muscarinic receptors in cholinergically innervated organs including the bladder. Its parasympatholytic action reduces the tonus of smooth muscle in the bladder. Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.

Pharmacodynamics

Placebo-controlled studies employing urodynamic variables were conducted in patients with conditions characterized by involuntary detrusor contractions. The results demonstrate that Sanctura® increases maximum cystometric bladder capacity and volume at first detrusor contraction.

Pharmacokinetics

Absorption: After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0-16.1%). Peak plasma concentrations (Cmax) occur between 5 to 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Sanctura® exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.

Effect of Food: Administration with a high fat meal resulted in reduced absorption, with AUC and Cmax values 70-80% lower than those obtained when Sanctura® was administered while fasting. Therefore, it is recommended that Sanctura® should be taken at least one hour prior to meals or on an empty stomach (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Information for Patients).

Distribution: Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5-50 ng/mL) were incubated with human serum in vitro.

The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma. The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.

Metabolism: The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.

Excretion: The plasma half-life for Sanctura® following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium.

The mean renal clearance for trospium (29.07 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated (see PRECAUTIONS: Drug Interactions).

A summary of mean (± standard deviation) pharmacokinetic parameters for a single 20 mg dose of Sanctura® is provided in Table 1.

Table 1. Mean (± SD) Pharmacokinetic Parameter Estimates for a Single 20 mg Sanctura® Dose in Healthy Volunteers

Cmax (ng/mL)	AUC0-∞ (ng/mL•hr)	Tmax (hr)	t½ (hr)
3.5 ± 4.0	36.4 ± 21.8	5.3 ± 1.2	18.3 ± 3.2

The mean plasma concentration-time (+ SD) profile for Sanctura® is shown in Figure 1.

Figure 1 - Mean (+ SD) Concentration-Time Profile for a Single 20 mg Oral Dose of Sanctura® in Healthy Volunteers

Pharmacokinetics in Special Populations

Age: Age did not appear to significantly affect the pharmacokinetics of Sanctura®, however, increased anticholinergic side effects unrelated to drug exposure were observed in patients greater than or equal to 75 years of age (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION).

Pediatric: The pharmacokinetics of Sanctura® were not evaluated in pediatric patients.

Gender: Studies comparing the pharmacokinetics in different genders had conflicting results. When a single 40 mg Sanctura® dose was administered to 16 elderly subjects, exposure was 45% lower in elderly females compared to elderly males. When 20 mg Sanctura® was dosed twice daily for 4 days to 6 elderly males and 6 elderly females (60 to 75 years), AUC and Cmax were 26% and 68% higher, respectively, in females without hormone replacement therapy than in males.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Severe renal impairment significantly altered the disposition of Sanctura®. A 4.2-fold and 1.8-fold increase in mean AUC0-∞ and mean Cmax, respectively, and the appearance of an additional elimination phase with a long half-life (~33 hr) was detected in patients with severe renal impairment (creatinine clearance less than 30 mL/min) compared with healthy, nearly age-matched subjects. The different pharmacokinetic behavior of Sanctura® in patients with severe renal impairment necessitates adjustment of dosage frequency. The pharmacokinetics of Sanctura® have not been studied in people with creatinine clearance ranging from 30-80 mL/min. (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).

Hepatic Impairment: There is no information regarding the effect of severe hepatic impairment on exposure to Sanctura®. In a study of patients with mild (Child-Pugh score 5-6) and with moderate (Child-Pugh score 7-8) hepatic impairment, given 40 mg of immediate-release trospium chloride, mean Cmax increased 12% and 63%, respectively, and mean AUC0-∞ decreased 5% and 15%, respectively, compared to healthy subjects. The clinical significance of these findings is unknown. Caution should be used when administering Sanctura® to patients with moderate and severe hepatic impairment (see PRECAUTIONS: General).

Electrophysiology

The effect of 20 mg twice daily and up to 100 mg twice daily Sanctura® on QT interval was evaluated in a single-blind, randomized, placebo and active (moxifloxacin 400 mg once daily) controlled 5 day parallel trial in 170 male and female healthy volunteer subjects aged 18 to 45 years. The QT interval was measured over a 24-hour period at steady state. The 100 mg twice daily dose of Sanctura® was chosen because this achieves the Cmax expected in severe renal impairment. Sanctura® was not associated with an increase in individual corrected (QTcI) or Fridericia corrected (QTcF) QT interval at any time during steady state measurement, while moxifloxacin was associated with a 6.4 msec increase in QTcF.

In this study, asymptomatic, non-specific T wave inversions were observed more often in subjects receiving Sanctura® than in subjects receiving moxifloxacin or placebo following five days of treatment. This finding was not observed during routine safety monitoring in 2 other placebo-controlled clinical trials in 591 Sanctura® treated overactive bladder patients (see CLINICAL STUDIES). The clinical significance of T wave inversion in this study is unknown. Sanctura® is associated with an increase in heart rate that correlates with increasing plasma concentrations. In the study described above, Sanctura® demonstrated a mean increase in heart rate compared to placebo of 9.1 bpm for the 20 mg dose and of 18.0 bpm for the 100 mg dose. In the two U.S. placebo-controlled trials in patients with overactive bladder, the mean increase in heart rate compared to placebo in Study 1 was observed to be 3.0 bpm and in Study 2 was 4.0 bpm.

CLINICAL STUDIES

Sanctura® was evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency, and urge incontinence in two U.S. 12-week, placebo-controlled studies and one 9-month open label extension.

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group study in 523 patients. A total of 262 patients received Sanctura® 20 mg twice daily and 261 patients received placebo. The majority of patients were Caucasian (85%) and female (74%) with a mean age of 61 years (range: 21 to 90 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of at least 7 per week, and greater than 70 micturitions per week. The patient's medical history and urinary diary during the treatment-free baseline confirmed the diagnosis. Reductions in urinary frequency, urge incontinence episodes and urinary void volume for placebo and Sanctura® treatment groups are summarized in Table 2 and Figures 2 and 3.

Table 2. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 1

a Treatment differences assessed by analysis of variance for ITT:LOCF data set.
b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.
c Placebo N=253, Sanctura® N=248.
* Denotes co-primary endpoint
ITT=intent-to-treat, LOCF=last observation carried forward.
Efficacy endpoint	Placebo N=256	Sanctura® N=253	P-value
Urinary frequency/24 hours a,*
Mean baseline	12.9	12.7
Mean change from baseline	-1.3 (0.2)	-2.4 (0.2)	<0.001
Urge incontinence episodes/week b,*
Mean baseline	30.1	27.3
Mean change from baseline	-13.9 (1.2)	-15.4 (1.1)	0.012
Urinary void volume/toilet void (mL) a,c
Mean baseline	156.6	155.1
Mean change from baseline	7.7 (3.1)	32.1 (3.1)	<0.001

Figure 2 – Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 1

Figure 3 – Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 1

Study 2 was nearly identical in design to Study 1. A total of 329 patients received Sanctura® 20 mg twice daily and 329 patients received placebo. The majority of patients were Caucasian (88%) and female (82%) with a mean age of 61 years (range: 19 to 94 years). Entry criteria were identical to Study 1. Reductions in urinary frequency, urge incontinence episodes, and urinary void volume for placebo and Sanctura® treatment groups are summarized in Table 3 and Figures 4 and 5.

Table 3. Mean (SE) change from baseline to end of treatment (Week 12 or last observation carried forward) for urinary frequency, urge incontinence episodes, and void volume in Study 2

a Treatment differences assessed by analysis of variance for ITT:LOCF data set.
b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.
c Placebo N=320, Sanctura® N=319.
* Denotes primary endpoint
ITT=intent-to-treat, LOCF=last observation carried forward.
Efficacy endpoint	Placebo N=325	Sanctura® N=323	P-value
Urinary frequency/24 hours a,*
Mean baseline	13.2	12.9
Mean change from baseline	-1.8 (0.2)	-2.7 (0.2)	<0.001
Urge incontinence episodes/week b
Mean baseline	27.3	26.9
Mean change from baseline	-12.1 (1.0)	-16.1 (1.0)	<0.001
Urinary void volume/toilet void (mL) a, c
Mean baseline	154.6	154.8
Mean change from baseline	9.4 (2.8)	35.6 (2.8)	<0.001

Figure 4 – Mean Change from Baseline in Urinary Frequency/24 Hours, by Visit: Study 2

Figure 5 – Mean Change from Baseline in Urge Incontinence/Week, by Visit: Study 2

INDICATIONS AND USAGE

Sanctura®, a muscarinic antagonist, is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

CONTRAINDICATIONS

Sanctura® is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Sanctura® is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

WARNINGS

Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride. In one case, 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, trospium chloride should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

PRECAUTIONS

General

Risk of Urinary Retention: Sanctura® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

Decreased Gastrointestinal Motility: Sanctura® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS). Sanctura®, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis.

Controlled Narrow-angle Glaucoma: In patients being treated for narrow-angle glaucoma, Sanctura® should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring.

Patients with Renal Impairment: Dose modification is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min). In such patients, Sanctura® should be administered as 20 mg once a day at bedtime (see DOSAGE AND ADMINISTRATION).

Patients with Hepatic Impairment: Caution should be used when administering Sanctura® in patients with moderate or severe hepatic impairment (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Specific Populations).

Information for Patients

Patients should be informed that trospium chloride may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue trospium chloride and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.

Patients should be informed that anticholinergic agents, such as Sanctura®, may produce clinically significant adverse effects related to anticholinergic pharmacological activity. For example, heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as Sanctura® are used in a hot environment. Because anticholinergics such as Sanctura® may also produce dizziness or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.

Sanctura® should be taken 1 hour prior to meals or on an empty stomach. If a dose is skipped, patients are advised to take their next dose 1 hour prior to their next meal.

Drug-Drug Interactions

Sanctura® is metabolized by ester hydrolysis and excreted by the kidneys through a combination of tubular secretion and glomerular filtration. Based on in vitro data, no clinically relevant metabolic drug-drug interactions are expected with trospium. However, some drugs which are actively secreted by the kidney may interact with trospium by competing for renal tubular secretion. Co-administration of 500 mg metformin immediate release tablets twice daily with Sanctura XR® (trospium chloride 60 mg extended release) reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax.

The concomitant use of Sanctura® with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Sanctura® may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

Concomitant use of Sanctura® and digoxin did not affect the pharmacokinetics of either drug.

Drugs Eliminated by Active Tubular Secretion: Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, Sanctura® has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g., procainamide, pancuronium, morphine, vancomycin, and tenofovir). Coadministration of Sanctura® with these drugs may increase the serum concentration of Sanctura® and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs (see CLINICAL PHARMACOLOGY: Excretion).

Drug-Laboratory-Test Interactions

Interactions between Sanctura® and laboratory tests have not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day, approximately 9 times the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 40 mg.

Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the rat micronucleus test.

No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).

Pregnancy: Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies of Sanctura® in pregnant women.

Trospium chloride was not teratogenic at statistically significant levels in rats or rabbits administered doses up to 200 mg/kg/day. This corresponds to systemic exposures up to approximately 9 and 16 times, respectively (based on AUC), the clinical exposure at the maximum recommended human dose (MRHD) of 40 mg. However, in rabbits, one fetus in each of the three treated dose groups (0.5, 0.3, and 16 times the exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A no effect level (20 mg/kg/day in rats and rabbits) for maternal and fetal toxicity was observed at levels approximately equivalent to the clinical exposure at the MRHD. No developmental toxicity was observed in the offspring of female rats exposed pre- and post-natally to up to 200 mg/kg/day. Sanctura® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Trospium chloride (2 mg/kg PO and 50 mcg/kg IV) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sanctura® is administered to a nursing woman. Sanctura® should be used during lactation only if the potential benefit justifies the potential risk to the newborn.

Pediatric Use

The safety and effectiveness of Sanctura® in pediatric patients have not been established.

Geriatric Use

Of the 591 patients with overactive bladder who received treatment with Sanctura® in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight Sanctura® treated patients (15%) were greater than or equal to 75 years of age.

In these 2 studies, the incidence of commonly reported anticholinergic adverse events in patients treated with Sanctura® (including dry mouth, constipation, dyspepsia, UTI, and urinary retention) was higher in patients 75 years of age and older as compared to younger patients. This effect may be related to an enhanced sensitivity to anticholinergic agents in this patient population (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION). Therefore, based upon tolerability, the dose frequency of Sanctura® may be reduced to 20 mg once daily in patients 75 years of age and older.

Adverse Reactions

The safety of Sanctura® was evaluated in Phase 2 and 3 controlled clinical trials in a total of 2975 patients, who were treated with Sanctura® (N=1673), placebo (N=1056) or active control medications (N=246). Of this total, 1181 patients participated in two, 12-week, Phase 3, U.S., efficacy and safety studies and a 9-month open-label extension. Of this total, 591 patients received Sanctura® 20 mg twice daily. In all controlled trials combined, 232 and 208 patients received treatment with Sanctura® for at least 24 and 52 weeks, respectively.

In all placebo-controlled trials combined, the incidence of serious adverse events was 2.9% among patients receiving Sanctura® 20 mg twice daily and 1.5% among patients receiving placebo. Of these, 0.2% and 0.3% were judged to be at least possibly related to treatment with Sanctura® or placebo, respectively, by the investigator.

Table 4 lists treatment emergent adverse events from the combined 12-week U.S. safety and efficacy trials that were judged to be at least possibly related to treatment with Sanctura® by the investigator, were reported by at least 1% of patients, and were reported more frequently in the Sanctura® group than in the placebo group.

The two most common adverse events reported by patients receiving Sanctura® 20 mg twice daily were dry mouth and constipation. The single most frequently reported adverse event for Sanctura®, dry mouth, occurred in 20.1% of Sanctura® treated patients and 5.8% of patients receiving placebo. In the two Phase 3 U.S. studies, dry mouth led to discontinuation in 1.9% of patients treated with Sanctura® 20 mg twice daily. For the patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.

Table 4. Incidence (%) of adverse events judged at least possibly related to treatment with Sanctura®, reported in greater than or equal to 1% of all patients treated with Sanctura® and more frequent with Sanctura® (20 mg twice daily) than placebo in Studies 1 and 2 combined

Adverse Event	Placebo (N=590)	Sanctura® 20 mg twice daily (N=591)
Abbreviations: NOS=not otherwise specified
Gastrointestinal Disorders
Dry mouth	34 ( 5.8)	119 (20.1)
Constipation	27 (4.6)	57 (9.6)
Abdominal pain upper	7 (1.2)	9 (1.5)
Constipation aggravated	5 (0.8)	8 (1.4)
Dyspepsia	2 (0.3)	7 (1.2)
Flatulence	5 (0.8)	7 (1.2)
Nervous System Disorders
Headache	12 (2.0)	25 (4.2)
General Disorders
Fatigue	8 (1.4)	11 (1.9)
Renal and Urinary Disorders
Urinary retention	2 (0.3)	7 (1.2)
Eye Disorders
Dry eyes NOS	2 (0.3)	7 (1.2)

Other adverse events from the Phase 3, U.S., placebo-controlled trials judged possibly related to treatment with Sanctura® by the investigator, occurring in greater than or equal to 0.5% of Sanctura® treated patients, and more common with Sanctura® than placebo are: tachycardia NOS, vision blurred, abdominal distension, vomiting NOS, dysgeusia, dry throat, and dry skin.

During controlled clinical studies, one event of angioneurotic edema was reported.

Postmarketing Surveillance

Additional spontaneous adverse events, regardless of relationship to drug, reported from marketing experience with trospium chloride include: Gastrointestinal – gastritis; Cardiovascular – palpitations, supraventricular tachycardia, chest pain, syncope, “hypertensive crisis”; Immunological – Stevens-Johnson syndrome, anaphylactic reaction, angioedema; Nervous System – vision abnormal, hallucinations and delirium; Musculoskeletal – rhabdomyolysis; General – rash.

OVERDOSAGE

Management of Overdosage

Overdosage with antimuscarinic agents, including Sanctura®, can result in severe anticholinergic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, ECG monitoring is recommended.

A 7-month-old baby experienced tachycardia and mydriasis after administration of a single dose of trospium 10 mg given by a sibling. The baby's weight was reported as 5 kg. Following admission into the hospital and about 1 hour after ingestion of the trospium, medicinal charcoal was administered for detoxification. While hospitalized, the baby experienced mydriasis and tachycardia up to 230 beats per minute. Therapeutic intervention was not deemed necessary. The baby was discharged as completely recovered the following day.

DOSAGE AND ADMINISTRATION

The recommended dose is 20 mg twice daily. Sanctura® should be dosed at least one hour before meals or given on an empty stomach.

Dosage modification is recommended in the following patient populations:

• For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended dose is 20 mg once daily at bedtime (see PRECAUTIONS: General).


• In geriatric patients greater than or equal to 75 years of age, dose may be titrated down to 20 mg once daily based upon tolerability (see PRECAUTIONS: Geriatric Use).

HOW SUPPLIED

Sanctura® tablets 20 mg (brownish yellow, biconvex, glossy coated tablets printed with black ink) are supplied as follows: 60 count HDPE bottle - NDC 0023-3513-60

Store at controlled room temperature 20° to 25°C (68° to 77°F) (see USP).

Rx only

Revised: 09/2011

Manufactured for:

Allergan, Inc.

Irvine, CA

92612

Manufactured by:

Madaus GmbH

Troisdorf, Germany

Address Medical Inquiries to:

1-800-433-8871

© 2011 Allergan, Inc., Irvine, CA 92612, U.S.A.

® marks owned by Allergan, Inc.

72157US12C

20 mg

NDC 0023-3513-60

60 tablets

Sanctura ®

Trospium Chloride Tablets

® ALLERGAN

Sanctura   trospium chloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0023-3513 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength trospium chloride (trospium) trospium chloride 20 mg

Inactive Ingredients Ingredient Name Strength sucrose   starch, wheat   cellulose, microcrystalline   talc   lactose monohydrate   calcium carbonate   titanium dioxide   stearic acid   croscarmellose sodium   povidone   polyethylene glycol 8000   silicon dioxide   ferric oxide red   carboxymethylcellulose sodium   white wax   magnesium stearate   carnauba wax

Product Characteristics Color yellow (yellow) Score 2 pieces Shape BULLET (BULLET) Size 7mm Flavor Imprint Code S Contains

Packaging # NDC Package Description Multilevel Packaging 1 0023-3513-60 60 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021595	12/01/2007

Labeler - Allergan, Inc. (144796497)

Establishment
Name	Address	ID/FEI	Operations
Madaus GmbH		537523859	MANUFACTURE

Revised: 09/2011Allergan, Inc.

More Sanctura resources

• Sanctura Side Effects (in more detail)
• Sanctura Dosage
• Sanctura Use in Pregnancy & Breastfeeding
• Drug Images
• Sanctura Drug Interactions
• Sanctura Support Group
• 11 Reviews for Sanctura - Add your own review/rating

• Sanctura Advanced Consumer (Micromedex) - Includes Dosage Information


• Sanctura Consumer Overview


• Sanctura MedFacts Consumer Leaflet (Wolters Kluwer)


• Sanctura Monograph (AHFS DI)


• Sanctura XR Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

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Neotricin HC

Generic Name: bacitracin, neomycin, polymyxin B, and hydrocortisone ophthalmic (BAS i TRAY sin, NEE oh MYE sin, POL ee MIX in, HYE droe KOR ti sone off THAL mik)

Brand Names: Ocu-Cort

What is bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

Bacitracin, neomycin, and polymyxin B are antibiotics that kill bacteria.

Hydrocortisone is a steroid. It prevents the release of substances in the body that cause inflammation.

Bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic (for the eyes) is used to treat eye infections caused by bacteria, injury, burns, or contamination by a foreign body in the eye. This medication is also used to treat an eye condition called chronic uveitis.

Bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

You should not use this medication if you are allergic to bacitracin, neomycin, polymyxin B, or hydrocortisone. Do not use this medication if you have a fungal or viral infection that affects your eyes, including herpes, chickenpox, or smallpox.

Before using this medication, tell your doctor if you have glaucoma, cataracts, or a viral or fungal infection anywhere in your body.

Do not allow the tip of the ointment tube to touch any surface, including the eyes or hands. If the tip becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Bacitracin, neomycin, polymyxin B, and hydrocortisone will not treat a viral or fungal infection of the eye.

To make sure this medication is helping your condition and is not causing harmful effects, your eyes will need to be checked on a regular basis during treatment. This will help your doctor determine how long to treat you with bacitracin, neomycin, polymyxin B, and hydrocortisone. Do not miss any follow-up visits to your doctor.

Call your doctor if your symptoms do not improve, or if your infection gets worse while using this medication.

Bacitracin, neomycin, polymyxin B and hydrocortisone should not be used on a child.

What should I discuss with my healthcare provider before using bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

You should not use this medication if you are allergic to bacitracin, neomycin, polymyxin B, or hydrocortisone. Do not use this medication if you have a fungal or viral infection that affects your eyes, including herpes, chickenpox, or smallpox.

Before using bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic, tell your doctor if you have:

• 
  

  glaucoma;

  
  


• 
  

  cataracts; or

  
  


• 
  

  a viral or fungal infection anywhere in your body.

  
  

FDA pregnancy category C. It is not known whether bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Bacitracin, neomycin, polymyxin B and hydrocortisone should not be used on a child.

How should I use bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before using bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic ointment.

To use the ointment:

• 
  

  You may warm the ointment by holding the medicine tube in your hand for a few minutes before use. Do not remove the cap from the tube until you are ready to apply the ointment.

  
  


• 
  

  Tilt your head back slightly, and pull down gently on your lower eyelid. Apply a thin film of the ointment into your lower eyelid.

  
  


• 
  

  Close your eye and roll your eyeball around for 1 to 2 minutes.

  
  

Do not allow the tip of the ointment tube to touch any surface, including the eyes or hands. If the tip becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye. Do not share the ointment with another person.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Bacitracin, neomycin, polymyxin B, and hydrocortisone will not treat a viral or fungal infection of the eye.

To make sure this medication is helping your condition and is not causing harmful effects, your eyes will need to be checked on a regular basis during treatment. This will help your doctor determine how long to treat you with bacitracin, neomycin, polymyxin B, and hydrocortisone. You may need frequent eye exams if you use this medication for longer than 10 days. Do not miss any follow-up visits to your doctor.

Call your doctor if your symptoms do not improve, or if your infection gets worse while using this medication.

Store bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic at room temperature away from moisture and heat. Keep the tube tightly capped when not in use.

What happens if I miss a dose?

Use the medication as soon as you remember the missed dose. If it is almost time for your next dose, skip the missed dose and use the medicine at your next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

An overdose of bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic is not likely to occur.

What should I avoid while using bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

Do not use any other eye medications unless your doctor has prescribed them.

Bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic can cause temporary blurred vision. Be careful if you drive or do anything that requires you to be able to see clearly.

Bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  blurred vision, eye pain, or seeing halos around lights;

  
  


• 
  

  severe itching, watering, redness, or swelling of your eyes;

  
  


• 
  

  vision changes, increased sensitivity to light;

  
  


• 
  

  white patches on your eyes;

  
  


• 
  

  crusting or drainage from your eyes; or

  
  


• 
  

  any new signs of infection.

  
  

Less serious side effects may include temporary blurred vision and mild eye irritation after using the ointment.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic?

It is not likely that other drugs you take orally or inject will have an effect on bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic used in the eyes. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Neotricin HC resources

• Neotricin HC Side Effects (in more detail)
• Neotricin HC Use in Pregnancy & Breastfeeding
• Neotricin HC Drug Interactions
• Neotricin HC Support Group
• 0 Reviews for Neotricin HC - Add your own review/rating

Compare Neotricin HC with other medications

• Conjunctivitis, Bacterial
• Uveitis

Where can I get more information?

• Your pharmacist can provide more information about bacitracin, neomycin, polymyxin B and hydrocortisone ophthalmic.

See also: Neotricin HC side effects (in more detail)

Scholl Athlete's Foot Powder

1. Name Of The Medicinal Product

Scholl Athlete's Foot Powder.

2. Qualitative And Quantitative Composition

Tolnaftate BP 1.0% w/w.

3. Pharmaceutical Form

Powder for topical application.

4. Clinical Particulars

4.1 Therapeutic Indications

Prevention and treatment of Athlete's Foot.

4.2 Posology And Method Of Administration

Wash and dry infected area and apply twice daily, or as directed by a doctor. Dust feet liberally, especially between toes. For added protection dust on socks, hosiery and inside shoes. Continue treatment for two weeks after symptoms disappear.

4.3 Contraindications

Not recommended for nail or scalp infections.

4.4 Special Warnings And Precautions For Use

Keep out of the reach of children. For external use only. Keep out of the eyes. If symptoms do not improve within 10 days, discontinue use and consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not relevant to topical use.

4.6 Pregnancy And Lactation

No known restrictions.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

None stated.

4.9 Overdose

Not relevant to topical use.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tolnaftate: topical antifungal agent (ATC Classification D01AE).

5.2 Pharmacokinetic Properties

Not applicable for a topical dosage form of this type.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Talc; Starch.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 25^oC.

6.5 Nature And Contents Of Container

High density poly-ethylene powder bottle with sifter assembly. Pack size: 75g

6.6 Special Precautions For Disposal And Other Handling

No special precautions required.

7. Marketing Authorisation Holder

Scholl Consumer Products Ltd. Venus, 1 Old Park Lane, Trafford Park, Manchester M41 7HA

8. Marketing Authorisation Number(S)

PL 0587/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th April 1985 / 13^th January 2005

10. Date Of Revision Of The Text

May 2006

Bupivacaine Hydrochloride Infusion Solution BP 0.125% w / v

1. Name Of The Medicinal Product

Bupivacaine Hydrochloride Infusion Solution 0.125% w/v.

2. Qualitative And Quantitative Composition

Each 100ml contains anhydrous bupivacaine hydrochloride 0.125g equivalent to 0.1319g of bupivacaine hydrochloride.

For excipients, see 6.1

3. Pharmaceutical Form

Solution for Infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Bupivacaine Hydrochloride Infusion Solution 0.125% w/v may be used:

1) for continuous infusion lumbar epidural analgesia to relieve pain during labour.

2) for continuous infusion epidural analgesia to control postoperative pain.

4.2 Posology And Method Of Administration

Route of Administration : Epidural infusion.

Bupivacaine Hydrochloride Infusion Solution should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Every precaution should be taken to avoid accidental intravascular administration; careful aspiration is essential. Prior to commencing a continuous epidural infusion, satisfactory epidural block should be established with test and loading doses of local anaesthetic. A test dose containing adrenaline is recommended, since an intravascular injection of an adrenaline-containing solution may be recognised by an increase in heart rate. A test dose of 7.5mg of bupivacaine 0.25% (3ml) or 10mg of bupivacaine 0.5% (2ml) containing adrenaline may be used. Verbal contact with the patient and repeated measurements of heart rate (ECG) should be maintained following the test dose. Aspiration should be repeated prior to administration of the loading dose and before starting the infusion. Epidural block can usually be established with test and loading doses (total volume 8 – 12ml of bupivacaine 0.25%) and sufficient time should be allowed to confirm that a satisfactory block has been established before commencing the infusion. If symptoms of toxicity or signs of an intrathecal blockade occur, the infusion should be stopped immediately.

Following the start of an infusion a continuous review of the patient is required with adequate clinical monitoring, (a minimum being the recording of blood pressure/pulse pain and sedation assessments). Segmental testing of the level of the block is required at least at 2 hourly intervals throughout the time the infusion is administered. For obstetric analgesia the test level T5/T6 should be clearly marked, for postoperative analgesia the level of block should be determined relative to the site of surgery. Appropriate monitoring should be carried out to detect progressive spread of the block or an increasing density of block.

Adequate filtering should be an integral part of the infusion line. The infusion line should be clearly marked to avoid confusion with intravenous lines. Also to avoid confusion, consideration should be given to using a different brand of proprietary pump to that used for IV infusions. In addition, the following pump specifications should be considered:-

- accurate infusion rates down to 1ml/hour should be able to be set.

- positive pressure drive, (not gravity feed), should be present.

- a back-up battery should be present.

- an automatic infusion shut-off should be present in case power is lost or the front of the pump is accidentally opened.

The lowest dose required to provide adequate analgesia should be given. A maximum dose of bupivacaine 2mg/kg should not be exceeded in any 4 hour period. The total dose of bupivacaine over 24 hours should not exceed 400 mg.

The length of continuous epidural infusions given post-operatively should be minimised, due to the increased risks of reaching a toxic plasma concentration, inducing local neural injury or local infection. Administration of bupivicaine epidural infusion has not been adequately studied for more than 72 hours

The dosages in the following table are recommended as a guide for use in healthy adults during labour and in the post operative period. It should not be necessary to exceed an infusion dosage of bupivacaine 20mg/hour. The dosgae should be titrated to meet the individual requirements and the lowest effective dosage should be used.

In the management of post-operative pain, the dose given during surgery should be taken into account.

It may be possible to reduce the dose of bupivacaine when epidural opioids are co-administered.

Children : Not recommended

Indication	Type of Block	% Concentration	Infusion rate per Hour
ml	mg
Analgesia in labour	Continuous infusion lumbar epidural	0.125	8-12	10–15
Control of post operative pain	Continuous infusion epidural: Thoracic, upper abdominal, lower abdominal	0.125	4-12	5-15

4.3 Contraindications

Bupivacaine hydrochloride solutions are contra-indicated in patients with a known hypersensitivity to local anaesthetic agents of the amide group or to other components of the infusion formulation. Solutions of bupivacaine hydrochloride are contra-indicated for intravenous regional anaesthesia (Bier's block).

Epidural anaesthesia, regardless of the local anaesthetic used, has its own contra-indications which include: Active disease of the central nervous system such as meningitis, poliomyelitis, intracranial haemorrhage, subacute combined degeneration of the cord due to pernicious anaemia, and cerebral or spinal tumors. Tuberculosis of the spine. Pyogenic infection of the skin at or adjacent to the site of lumbar puncture. Spina bifida or meningomyelocele. A diagnosed arteriovenous malformation in the vertebral column in close proximity to the proposed puncture site. Cardiogenic or hypovolaemic shock. Coagulation disorders or ongoing anticoagulant therapy. Epidural and spinal anaesthesia is contra-indicated in patients with an expanding cerebral lesion, a tumor, cyst or abscess, which may, if the intracranial pressure is suddenly altered, cause obstruction to the cerebrospinal fluid or blood circulation (the pressure cone).

4.4 Special Warnings And Precautions For Use

Before any nerve block is attempted, an open vein must be guaranteed (by an indwelling needle, cannula, drip etc.). Adequate resuscitative equipment (oxygen, suction, means of intubation and appropriate emergency drugs) must be available. Epidural and spinal block techniques should only be carried out by clinicians with the necessary knowledge and experience.

Clinicians should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications (see 4.9 & 4.8).

Major peripheral nerve blocks may require the administration of a large volume of local anaesthetic in areas of high vascularity, often close to large vessels where there is an increased risk of intravascular injection and/or systemic absorption. This may lead to high plasma concentrations.

Like all local anaesthetic drugs, bupivacaine may cause acute toxicity effects on the central nervous and cardiovascular systems if utilised for local anaesthetic procedures resulting in high blood concentrations of the drug. This is especially the case after unintentional intravascular administration or injection into highly vascular areas. Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in connection with high systemic concentrations of bupivacaine.

There have been reports of cardiac arrest with difficult resuscitation or death during the use of bupivacaine for epidural anaesthesia in obstetrical patients. Resuscitation has been difficult or impossible despite adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity presumably following inadvertent intravascular injection.

Administration of repeated doses of bupivacaine hydrochloride may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug. Tolerance varies with the status of the patient. Debilitated, elderly or acutely ill patients should be given reduced doses commensurate with their physical status.

Only in rare cases have amide local anaesthetics been associated with allergic reactions (with anaphylactic shock developing in most severe instances). Patients allergic to ester-type local anaesthetics such as procaine have not shown cross-sensitivity to amide-type agents such as bupivacaine.

Since bupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow.

Local anaesthetics should be used with caution for epidural or spinal anaesthesia in the following situations: severe shock, severe renal dysfunction, hypovolaemia, dehydration, hypotension below 90mm systolic or a level less than 30% of their average systolic blood pressure, gross hypotension, marked obesity, senility, cerebral atheroma, myocardial degeneration, toxaemia and severe ischaemic heart disease, (especially with a history of recent infarction) because of the dangers of hypotension.

Similar caution is required in patients with a known or suspected abnormality in their acid-base status and in cases of impaired cardiovascular function, such as patients with a fixed cardiac output (severe valvular stenosis, partial or complete heart block, beta-blocking therapy), resulting in decreased ability to respond to dilatation of the vascular bed or to compensate for functional changes associated with the prolongation of A-V conduction produced by local anaesthetics.

Epidural and spinal anaesthesia with any local anaesthetic can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include preloading the circulation with crystalloid or colloid solution. Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration or aorta-caval occlusion in patients with massive ascites, large abdominal tumours or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring, since cardiac effects may be additive.

Epidural and spinal anaesthesia, properly performed, is generally well tolerated by obese patients and by those with obstructive lung disease. However, patients with a splinted diaphragm which interferes with breathing, such as those with hydramnios, large ovarian or uterine tumours, pregnancy, ascites or omental obesity are at risk from hypoxia due to respiratory inadequacy and aortocaval compression due to tumour mass. Lateral tilt, oxygen and mechanical ventilation should be used when indicated. Dosage should be reduced in such patients.

Epidural anaesthesia can cause intercostal paralysis and patients with pleural effusions may suffer respiratory embarrassment. Septicaemia can increase the risk of intraspinal abscess formation in the postoperative period.

When bupivacaine is administered as intra-articular injection, caution is advised when recent major intra-articular trauma is suspected or extensive raw surfaces within the joint have been created by the surgical procedure, as that may accelerate absorption and result in higher plasma concentrations.

Paracervical block may have a greater adverse effect on the foetus, than other nerve blocks used in obstetrics. Due to the systemic toxicity of bupivacaine, special care should be taken when using bupivacaine for para cervical block.

Small doses of local anaesthetics injected into the head and neck, including retrobulbar, dental and stellate ganglion blocks, may produce systemic toxicity due to inadvertent intra-arterial injection.

Retrobulbar injections may very rarely reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnoea, convulsions etc.

Prior to retrobulbar block, necessary equipment, drugs and personnel should be immediately available as with all other regional procedures.

Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular muscle dysfunction. The primary causes include trauma and/or local toxic effects on muscles and/or nerves. The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anaesthetic and the duration of exposure of the tissue to the local anaesthetic. For this reason, as with all local anaesthetics, the lowest effective concentration and dose of local anaesthetic should be used.

Vasoconstrictors may aggravate tissue reactions and should be used only when indicated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Bupivacaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive.

Epidural anaesthesia is contra-indicated in patients receiving anticoagulant therapy. Patients taking aspirin should have their bleeding time measured before epidural anaesthesia, as aspirin can prolong the bleeding time by inhibiting thromboxane A2 formation in platelets. (Refer section 4.3)

Specific interaction studies with bupivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution should be advised.(see also section 4.4).

4.6 Pregnancy And Lactation

There is no evidence of untoward effects in human pregnancy. In large doses there is evidence of decreased pup survival in rats and an embryological effect in rabbits if bupivacaine is administered in pregnancy. Bupivacaine should not therefore be given in early pregnancy unless the benefits are considered to outweigh the risks.

Foetal adverse effects due to local anaesthetics, such as foetal bradycardia, seem to be most apparent in paracervical block anaesthesia. Such effects may be due to high concentrations of anaesthetic reaching the foetus. (See also Section 4.4)

Bupivacaine enters the mother's milk, but in such small quantities that there is no risk of affecting the child at therapeutic dose levels.

4.7 Effects On Ability To Drive And Use Machines

In general, it is sufficient to allow 2 - 4 hours post nerve block or until full functions have returned following regional nerve block. In many situations, patients receive a sedative or other CNS (central nervous system) depressant drug e.g. diazepam, midazolam to allow the block to be performed. One must allow adequate time for the effects of these drugs to clear. Depending on dosage, local anaesthetics may have a very mild effect on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

Accidental sub-arachnoid injection can lead to very high spinal anaesthesia possibly with apnoea and severe hypotension.

The adverse reaction profile for Bupivacaine hydrochloride is similar to those for other long acting local anaesthetics. Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (e.g., decrease in blood pressure, bradycardia), events caused directly (e.g., nerve trauma) or indirectly (e.g., epidural abscess) by needle puncture.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to several causes, e.g. direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance, or an injection of a non-sterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Occasionally these are permanent.

The adverse reactions considered at least possibly related to treatment with Bupivacaine hydrochloride from clinical trials with related products and post-marketing experience are listed below by body system organ class and absolute frequency. Frequencies are defined as very common (1/10), common (1/100, < 1/10), uncommon (1/1,000, < 1/100), rare (1/10,000, < 1/1,000) or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).

Table of Adverse Drug Reactions (ADR)

System Organ Class	Frequency Classification	Adverse Drug Reaction
Immune system disorders	Rare	Allergic reactions, anaphylactic reaction/shock (see section 4.4)
Nervous system disorders	Common	paraesthesia, dizziness
	Uncommon	Signs and symptoms of CNS toxicity (convulsions, circumoral paraesthesia, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremor, light headedness, tinnitus, dysarthria, muscle twitching)
	Rare	Neuropathy, peripheral nerve injury, arachnoiditis, paresis and paraplegia
Eye disorders	Rare	Diplopia
Cardiac disorders	Common	Bradycardia (see section 4.4)
	Rare	Cardiac arrest (see section 4.4), cardiac arrhythmias
Vascular disorders	Very Common	Hypotension (see section 4.4)
	Common	Hypertension (see section 4.5)
Respiratory disorders	Rare	Respiratory depression
Gastrointestinal disorders	Very Common	Nausea
	Common	Vomiting
Renal and Urinary	Common	Urinary retention

Hepatic dysfunction, with reversible increases of SGOT, SGPT, alkaline phosphatase and bilirubin, has been observed following repeated injections or infusions of bupivacaine. If signs of hepatic dysfunction are observed during treatment with bupivacaine, the drug should be discontinued.

4.8.1 Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system. Such reactions are caused by high blood concentrations of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularised areas (see section 4.4). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually light-headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular twitching or tremors are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with respiration and possible loss of functional airways. In severe cases apnoea may occur. Acidosis, hyperkalaemia and hypoxia increase and extend the toxic effects of local anaesthetics.

Recovery is due to redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity may be seen in severe cases and is generally preceded by signs of toxicity in the central nervous system. In patients under heavy sedation or receiving a general anaesthetic, prodromal CNS symptoms may be absent. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics, but in rare cases cardiac arrest has occurred without prodromal CNS effects.

4.8.2 Treatment of acute toxicity

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.

Treatment of a patient with systemic toxicity consists of arresting convulsions and ensuring adequate ventilation with oxygen, if necessary by assisted or controlled ventilation (respiration).

Once convulsions have been controlled and adequate ventilation of the lungs ensured, no other treatment is generally required.

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Cardiac arrest due to bupivacaine can be resistant to electrical defibrillation and resuscitation must be continued energetically for a prolonged period.

High or total spinal blockade causing respiratory paralysis and hypotension during epidural anaesthesia should be treated by ensuring and maintaining a patent airway and giving oxygen by assisted or controlled ventilation.

If cardiovascular depression occurs (hypotension, bradycardia) appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

4.9 Overdose

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration. (See sections 4.8.1 amp; 4.8.2).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group (ATC code): N01B B51

Bupivacaine Hydrochloride is a long acting local anaesthetic of the amide type. It prevents the generation and conduction of the nerve impulse by decreasing the permeability of the nerve cell membrane to sodium ions. As well as blocking conduction in nerve axons in the peripheral nervous system, local anaesthetics interfere with the function of all organs in which conduction or transmission of impulses occur.

At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with less pronounced motor block.

Following absorption, bupivacaine may cause stimulation of the CNS followed by depression and in the cardiovascular system it acts primarily on the myocardium where it may decrease electrical excitability, conduction rate, force of contraction and eventually cardiac arrest.

5.2 Pharmacokinetic Properties

Like other local anaesthetics, the rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration administered, the route of administration and the vascularity of the tissue locally. Bupivacaine is about 95% bound to plasma proteins, mainly to alpha-1-acid glycoprotein at low concentrations and to albumin at high concentrations.

In adults, the terminal half-life of Bupivacaine is 2.7 hours. The maximum blood concentration varies with the site of injection. Foetal concentrations are lower than maternal concentrations because only the free, unbound drug is available for placental transfer.

Local anaesthetics are distributed to some extent to all body tissues, with higher concentrations found in highly perfused organs such as liver, heart and brain. Bupivacaine is metabolised in the liver and is excreted in the urine mainly as metabolites, with only 5 to 6% as unchanged drug.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Water for Injections

6.2 Incompatibilities

Bupivacaine Hydrochloride Infusion Solution 0.125% w/v should not be mixed with other drugs unless compatibility is known. The pH range is 4.0 to 6.5.

The solution must not be stored in contact with metal e.g. needles or metal parts of syringes as dissolved metal ions may cause swelling at site of the injection.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

100ml or 250ml polypropylene infusion bags in packs of 10, 20 or 50.

6.6 Special Precautions For Disposal And Other Handling

The infusion is for single patient use and should be used immediately after opening. Any unused portion should be discarded.

Bupivacaine Hydrochloride Infusion Solution has been demonstrated to be compatible with fentanyl 2 micrograms/ml, 5 micrograms/ml and 10 micrograms/ml for 48 hours at 25°C and 2 – 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Administrative Data

7. Marketing Authorisation Holder

Antigen International Limited

Roscrea

Co. Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 02848/0198

9. Date Of First Authorisation/Renewal Of The Authorisation

30/09/2005

10. Date Of Revision Of The Text

21/10/2010