trospium chloride 20 MG Oral Tablet
Generic Name: TROSPIUM CHLORIDE
Brand Name: TROSPIUM CHLORIDE
- Substance Name(s):
- TROSPIUM CHLORIDE
DRUG INTERACTIONS
7 Concomitant use with digoxin did not affect the pharmacokinetics of either drug. (7.1) Some drugs which are actively secreted by the kidney may interact with trospium chloride tablets by competing for renal tubular secretion. (7.2) Concomitant use with metformin immediate release tablets reduced exposure and peak concentration of trospium. (7.4) 7.1 Digoxin Concomitant use of trospium chloride tablets and digoxin did not affect the pharmacokinetics of either drug [see Clinical Pharmacology (12.3)]. 7.2 Drugs Eliminated by Active Tubular Secretion Although demonstrated in a drug-drug interaction study not to affect the pharmacokinetics of digoxin, trospium chloride tablets have 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 trospium chloride tablets with these drugs may increase the serum concentration of trospium chloride tablets 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 (12.3)]. 7.3 Antimuscarinic Agents The concomitant use of trospium chloride tablets with other antimuscarinic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Trospium chloride tablets may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. 7.4 Metformin Co-administration of 500 mg metformin immediate release tablets twice daily with trospium chloride 60 mg extended release tablets reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax [see Clinical Pharmacology (12.3)].
OVERDOSAGE
10 Overdosage with antimuscarinic agents, including trospium chloride tablets, can result in severe antimuscarinic effects. Supportive treatment should be provided according to symptoms. In the event of overdosage, electrocardiographic 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.
DESCRIPTION
11 Trospium chloride tablets are a quaternary ammonium compound with the chemical name of (1α,3β,5α)-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]octane-8,1’-pyrrolidinium] chloride. The molecular formula of trospium chloride is C25H30ClNO3 and its molecular weight is 427.96. The structural formula of trospium chloride is represented below: Trospium chloride is a white to off-white powder. Very soluble in water. Each trospium chloride tablet contains 20 mg of trospium chloride and is to be given orally. Each tablet also contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycol, titanium dioxide and yellow iron oxide. Chemical Structure-Trospium chloride
CLINICAL STUDIES
14 Trospium chloride tablets were 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 trospium chloride 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 trospium chloride tablets treatment groups are summarized in Table 3 and Figures 2 and 3. 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 1. Efficacy endpoint Placebo N=256 Trospium chloride N=253 P-value Urinary frequency/24hoursa,* Mean baseline 12.9 12.7 <0.001 Mean change from baseline -1.3 (0.2) -2.4 (0.2) Urge incontinence episodes/weekb,* Mean baseline 30.1 27.3 0.012 Mean change from baseline -13.9 (1.2) -15.4 (1.1) Urinary void volume/toilet void (mL) a,c Mean baseline 156.6 155.1 <0.001 Mean change from baseline 7.7 (3.1) 32.1 (3.1) 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. cPlacebo N=253, Trospium chloride N=248 *Denotes co-primary endpoint ITT= intent to treat, LOCF=last observation carried forward Study 2 was nearly identical in design to Study 1. A total of 329 patients received trospium chloride 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 trospium chloride treatment groups are summarized in Table 4 and Figures 4 and 5. Table 4. 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. Efficacy endpoint Placebo N=325 Trospium chloride N=323 P-value Urinary frequency/24hoursa,* Mean baseline 13.2 12.9 Mean change from baseline -1.8 (0.2) -2.7 (0.2) <0.001 Urge incontinence episodes/weekb 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 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. cPlacebo N=320, Trospium chloride N=319 *Denotes co-primary endpoint ITT= intent to treat, LOCF=last observation carried forward Figure 2 Figure 3 Figure 4 Figure 5
HOW SUPPLIED
16 /STORAGE AND HANDLING Trospium chloride tablets 20 mg (brownish-yellow, round, biconvex, film-coated tablets, engraved “APO” on one side and “TR” over “20” on the other side) are supplied as follows: Bottles of 60 NDC 60429-103-60 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Warnings and Precautions, Central Nervous System Effects (5.5) 07/2012
GERIATRIC USE
8.5 Geriatric Use Of the 591 patients with overactive bladder who received treatment with trospium chloride in the two U.S., placebo-controlled, efficacy and safety studies, 249 patients (42%) were 65 years of age and older. Eighty-eight trospium chloride tablets treated patients (15%) were greater than or equal to 75 years of age. In these 2 studies, the incidence of commonly reported anticholinergic adverse reactions in patients treated with trospium chloride tablets (including dry mouth, constipation, dyspepsia, urinary tract infection, 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 (12.3)]. Therefore, based upon tolerability, the dose frequency of trospium chloride tablets may be reduced to 20 mg once daily in patients 75 years of age and older.
DOSAGE FORMS AND STRENGTHS
3 Trospium chloride tablets are supplied as 20 mg (brownish-yellow, round, biconvex, film-coated tablets, engraved “APO” on one side and “TR” over “20” on the other side). 20 mg tablets. (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Trospium chloride tablets are 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.
INDICATIONS AND USAGE
1 Trospium chloride tablets are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Trospium chloride tablets are a muscarinic antagonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. (1)
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of trospium chloride tablets in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies of trospium chloride tablets in pregnant women. Trospium chloride tablets 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 trospium chloride treatment are encouraged to contact their physician. Risk Summary Based on animal data, trospium chloride tablets are predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk. Adverse developmental findings were not observed to correlate with dose in rats or in rabbits. No increased risk above background was observed in rats and rabbits treated at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg. Animal Data In a rat embryo/fetal development study, pregnant rats received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate, with maternal systemic exposures corresponding to approximately nine times the exposure of women treated at the MRHD of 40 mg, based on AUC. No malformations or fetal toxicity were observed. The offspring of female rats exposed orally, pre- and post-natally, to trospium chloride up to 200 mg/kg/day showed no increased developmental toxicity over background in surviving pups. However, maternal toxicity (death, irregular breathing, increased excitability) was observed at 200 mg/kg/day. A no-effect level for maternal and pup toxicity (survival to Day 4) was 20 mg/kg/day, an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg. In a rabbit embryo/fetal development study, pregnant rabbits received doses of trospium chloride up to 200 mg/kg/day, from implantation to closure of the fetal hard palate. At 200 mg/kg/day, maternal systemic exposures corresponded to approximately 16 times the exposure of women treated at the MRHD of 40 mg, based on AUC. However, one fetus in each of the three treated dose groups (0.3 to 16 times exposures at the MRHD) demonstrated multiple malformations, including umbilical hernia and skeletal malformations. A maternal no-effect level was set at 20 mg/kg/day, at an exposure approximately equivalent to the maximal recommended human dose (MRHD) of 40 mg, due to clinical signs (reduced feces, hunched posture, diarrhea) observed in a pharmacokinetic study at 200 mg/kg/day.
NUSRING MOTHERS
8.3 Nursing Mothers Trospium chloride (2 mg/kg orally and 50 mcg/kg intravenously) was excreted, to a limited extent (less than 1%), into the milk of lactating rats (primarily as parent compound). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, trospium chloride tablets should be used during lactation only if the potential benefit justifies the potential risk to the newborn.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Trospium chloride tablets should be administered with caution to patients with clinically significant bladder outflow obstruction or gastrointestinal obstructive disorders due to risk of urinary or gastric retention. (5.1,5.3) Angioedema of the face, lips, tongue and/or larynx has been reported with trospium chloride. (5.2) In patients with controlled narrow angle glaucoma trospium chloride tablets should be used only with careful monitoring. (5.4) Central Nervous System Effects: Somnolence has been reported with trospium chloride tablets. Advise patients not to drive or operate heavy machinery until they know how trospium chloride tablets affect them. (5.5) Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known but systemic exposure is likely increased. Therefore, the risk of anticholinergic adverse reactions is expected to be greater in patients with moderate renal impairment. (5.6) 5.1 Risk of Urinary Retention Trospium chloride tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)]. 5.2 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride tablets should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. 5.3 Decreased Gastrointestinal Motility Trospium chloride tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)]. Trospium chloride tablets, like other antimuscarinic agents, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, intestinal atony and myasthenia gravis. 5.4 Controlled Narrow-angle Glaucoma In patients being treated for narrow-angle glaucoma, trospium chloride tablets should only be used if the potential benefits outweigh the risks and in that circumstance only with careful monitoring [see Contraindications (4)]. 5.5 Central Nervous System Effects Trospium chloride tablets are associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. A variety of CNS anticholinergic effects have been reported, including dizziness, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how trospium chloride tablets affect them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 5.6 Anticholinergic Adverse Reactions in Patients with Moderate Renal Impairment Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on systemic exposure are not known but systemic exposure is likely increased. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate renal impairment [see Dosage and Administration (2), and Use in Specific Populations (8.6)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION “See FDA-approved Patient Labeling (Patient Information)” 17.1 Angioedema Patients should be informed that trospium chloride, the active ingredient in trospium chloride tablets, may produce angioedema which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue trospium chloride tablets and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing. 17.2 When Not to Use Prior to treatment, patients should fully understand the risks and benefits of trospium chloride tablets. In particular, patients should be informed not to take trospium chloride tablets if they: have urinary retention; gastric retention; uncontrolled narrow-angle glaucoma; are allergic to any component of trospium chloride tablets. 17.3 Administration Patients should be instructed regarding the recommended dosing and administration of trospium chloride tablets: Take one trospium chloride tablet twice daily with water. Take trospium chloride tablets on an empty stomach or at least 1 hour before a meal. 17.4 Adverse Reactions Patients should be informed that the most common side effects with trospium chloride tablets are dry mouth and constipation and that other less common side effects include trouble emptying the bladder, blurred vision, and heat prostration. Because anticholinergics, such as trospium chloride, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effects have been determined. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents. Manufactured by: Manufactured for: Marketed/Packaged by: Apotex Inc. Apotex Corp. GSMS, Inc. Toronto, Ontario Weston, Florida, Camarillo, CA Canada, M9L 1T9 33326 USA 93012 Revision: 5 Revised: November 2012 PATIENT INFORMATION Trospium Chloride Tablets Read the Patient Information that comes with trospium chloride tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What are trospium chloride tablets? Trospium chloride tablets are a prescription medicine used to treat adults with overactive bladder who have the following symptoms: a strong need to urinate right away; leaking or wetting accidents due to a strong need to urinate right away; a need to urinate often. Who should not take trospium chloride tablets? Do not take trospium chloride tablets if you: have trouble emptying your bladder; have delayed or slow emptying of your stomach; have an eye problem called “uncontrolled narrow-angle glaucoma”; are allergic to trospium chloride tablets or any of its ingredients. See the end of this leaflet for a complete list of ingredients. Trospium chloride tablets have not been studied in children under the age of 18 years. What should I tell my doctor before starting trospium chloride tablets? Tell your doctor about all of your medical conditions including if you: have any stomach or intestinal problems or problems with constipation; have trouble emptying your bladder or have a weak urine stream; have an eye problem called narrow-angle glaucoma; have kidney problems; have liver problems; are pregnant or planning to become pregnant. It is not known if trospium chloride can harm your unborn baby. are breastfeeding. It is not known if trospium chloride passes into breast milk and if it can harm your baby. You should talk to your doctor about the best way to feed your baby if you are taking trospium chloride tablets. Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Trospium chloride tablets and certain other medicines can interact and make some side effects worse. Trospium chloride tablets can affect how other medicines are handled by the body. Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine. How should I take trospium chloride tablet? Take trospium chloride tablets exactly as prescribed. Take one trospium chloride tablet twice daily with water. Take trospium chloride tablets on an empty stomach or at least 1 hour before a meal. If you take too much trospium chloride, call your local Poison Control Center or go to an emergency room right away. What are the possible side effects of trospium chloride? Trospium chloride may cause allergic reactions that may be serious. Symptoms of a serious allergic reaction may include swelling of the face, lips, throat or tongue. If you experience these symptoms, you should stop taking trospium chloride tablets and get emergency medical help right away. The most common side effects with trospium chloride tablets are: drymouth; constipation; headache. Trospium chloride tablets may cause other less common side effects, including: trouble emptying the bladder; blurred vision; and drowsiness. Do not drive or operate heavy machinery until you know how trospium chloride tablets affect you. Alcohol can worsen the drowsiness caused by drugs such as trospium chloride tablets. heat prostration. Due to decreased sweating, heat prostration can occur when drugs such as trospium chloride tablets are used in a hot environment. Tell your doctor if you have any side effects that bother you or that do not go away. These are not all possible side effects of trospium chloride tablets. For more information, ask your doctor, healthcare professional or pharmacist. How should I store trospium chloride tablets? Keep trospium chloride tablets and all other medicines out of the reach of children. Store trospium chloride tablets at room temperature, 68° to 77°F (20° to 25°C). Safely dispose of trospium chloride tablets that are out of date or that you no longer need. General information about trospium chloride tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use trospium chloride tablets for a condition for which it was not prescribed. Do not give trospium chloride tablets to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about trospium chloride tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about trospium chloride tablets that is written for health professionals. What are the ingredients in trospium chloride tablets? Each tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycol, titanium dioxide and yellow iron oxide. Manufactured by: Manufactured for: Marketed/Packaged by: Apotex Inc. Apotex Corp. GSMS, Inc. Toronto, Ontario Weston, Florida, Camarillo, CA Canada, M9L 1T9 33326 USA 93012 Revision: 0 Revised: November 2012
DOSAGE AND ADMINISTRATION
2 The recommended dose is 20 mg twice daily. Trospium chloride tablets 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 Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 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 Use in Specific Populations (8.5)]. The recommended dose of trospium chloride is one 20 mg tablets twice daily. Trospium chloride tablets should be dosed with water on an empty stomach, at least one hour before a meal. (2) For patients with severe renal impairment (creatinine clearance less than 30mL/min),the recommended dose is 20 mg once daily at bed time. (2) 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. (2)