ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Cardiovascular: rapid heartbeat, flushingCentral Nervous System: blurred vision, dizziness, drowsinessGenitourinary: difficult micturition, acute urinary retentionGastrointestinal: dry mouth, nausea and vomitingRespiratory: shortness of breath or trouble breathingSerious allergic reactions to this drug are rare. Seek immediate medical attention if you notice symptoms of serious allergic reaction, including itching, rash, severe dizziness, swelling or trouble breathing.This medication can cause urine and sometimes stools to turn blue to blue-green. This effect is harmless and will subside after medication is stopped.Call your doctor or physician for medical advice about side effects. To report SUSPECTED ADVERSE REACTIONS, contact A.G. Marin Pharmaceuticals at 305-593-5333 or FDA at 1-800-FDA-1088, www.fda.gov/medwatch.. Drug interactions. As result of hyoscyamines effects on gastrointestinal motility and gastric emptying, absorption of other oral medications may be decreased during concurrent use with this combination medication. Methylene blue inhibits range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. This interaction could be more pronounced with narrow therapeutic index drugs that are metabolized by one of these enzymes (e.g., digoxin, warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). However, the clinical relevance of these in vitro interactions is unknown. Urinary alkalizers and thiazide diuretics: May cause the urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Antimuscarinics: Concurrent use may intensify antimuscarinic effects of hyoscyamine because of secondary antimuscarinic activities of these medications. Antacids/antidiarrheals: Concurrent use may reduce absorption of hyoscyamine resulting in decreased therapeutic effectiveness. Concurrent use with antacids may cause urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Doses of these medications should be spaced hour apart from doses of hyoscyamine. Antimyasthenics: Concurrent use with hyoscyamine may further reduce intestinal motility, therefore, caution is recommended. Ketoconazole and hyoscyamine may cause increased gastrointestinal pH. Concurrent administration with hyoscyamine may result in marked reduction in the absorption of ketoconazole. Patients should be advised to take this combination at least hours after ketoconazole. Monoamine oxidase (MAO) inhibitors: Concurrent use with hyoscyamine may intensify antimuscarinic side effects. Opioid (narcotic) analgesics may result in increased risk of severe constipation. Sulfonamides: These drugs may precipitate with formaldehyde in the urine increasing the danger of crystalluria. Patients should be advised that the urine and/or stools may become blue to blue-green as result of the excretion of methylene blue.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. HYOSCYAMINE SULFATE is parasympatholytic which relaxes smooth muscles and thus produces an antispasmodic effect. It is well absorbed from the gastrointestinal tract and is rapidly distributed throughout the body tissues. Most is excreted in the urine within 12 hours, 13% to 50% being unchanged. Its biotransformation is hepatic. Its protein binding is moderate.METHENAMINE degrades in an acidic urine environment releasing formaldehyde which provides bactericidal or bacteriostatic action. It is well absorbed from the gastrointestinal tract. 70%-90% reaches the urine unchanged at which point it is hydrolyzed if the urine is acidic. Within 24 hours it is almost completely (90%) excreted; of this at pH of 5, approximately 20% is formaldehyde. Protein binding some formaldehyde is bound to substances in the urine and surrounding tissues. Methenamine is freely distributed to body tissue and fluids but is not clinically significant as it does not hydrolyze at pH greater than 6.8.METHYLENE BLUE possesses weak antiseptic properties. It is well absorbed by the gastrointestinal tract and rapidly reduced to leukomethylene blue which is stabilizied in some combination form in the urine. 75% is excreted unchanged.PHENYL SALICYLATE releases salicylate, mild analgesic for pain.SODIUM PHOSPHATE MONOBASIC an acidifier, helps to maintain an acid pH in the urine necessary for the degradation of methenamine.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Hypersensitivity to any of the ingredients is possible. Risk benefits should be carefully considered when the following medical problems exist: cardiac disease (especially cardiac arrhythmias, congestive heart failure, coronary heart disease, and mitral stenosis); gastrointestinal tract obstructive disease; glaucoma; myasthenia gravis, acute urinary retention may be precipitated in obstructive uropathy (such as bladder neck obstruction due to prostatic hypertrophy).

DESCRIPTION SECTION.

DESCRIPTION. Uretron (TM) D/S tablets for oral administration Each tablet contains:Methenamine81.6 mgSodium Phosphate Monobasic40.8 mgPhenyl Salicylate36.2 mgMethylene Blue10.8 mgHyoscyamine Sulfate0.12 mgHYOSCYAMINE SULFATE. [620-61-1][3(S)-endo]--(Hydroxymethyl)-benzeneacetic acid 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester sulfate(2:1)(salt); 1H,5H-tropan-3-ol(-)-tropate(ester) sulfate(2:1)(salt);3-tropanyl S-(-)-tropate; l-tropic acid ester with tropine; l-tropine tropate. 34H 48N 2O 10S. Hyoscyamine Sulfate is an alkaloid of belladonna. Exists as white crystalline powder. Its solutions are alkaline to litmus. Affected by light, it is slightly soluble in water; freely soluble in alcohol; sparingly soluble in ether. METHENAMINE. [100-97-0] 1,3,5,7-Tetraazatricyclo [3.3.1.-1 3,7] decane; hexamethylenetetramine; HMT; HMTA; hexamine; 1,3,5,7-tetraazaadamantane hexamethylenemine; Uritone; Urotropin. 6H 12N 4; mol wt 140.19; 51.40%, 8.63%, 39.96%. Methenamine (hexamethylenetetramine) exists as colorless, lustrous crystals or white crystalline powder. Its solutions are alkaline to litmus. Freely soluble in water, soluble in alcohol and in chloroform. METHYLENE BLUE. [61-73-4] 3,7-Bis(dimethylamino) phenothiazin-5-ium chloride; C.I. Basic Blue 9; methylthioninium chloride; tetramethylthionine chloride; 3,7-bis(dimethylamino) phenazathionium chloride. 16H 18ClN 3S; mol wt 319.85, 60.08%, 5.67%, Cl 11.08%, 13.14%, 10.03%. Methylene Blue (Methylthionine chloride) exists as dark green crystals. It is soluble in water and in chloroform; sparingly soluble in alcohol. PHENYL SALICYLATE. [118-55-8] 2-Hydroxybenzoic acid phenyl ester; Salol. 13H 10O 3; mol wt 214.22, 72.89%, 4.71%, 22.41%. Made by the action of phosphorus oxy-chloride on mixture of phenol and salicylic acid. Phenyl Salicylate exists as white crystals with melting point of 41-43 C. It is very slightly soluble in water and freely soluble in alcohol. SODIUM PHOSPHATE MONOBASIC. [7558-80-7] Phosphoric acid sodium salt (1:1); Sodium biphosphate; sodium dihydrogen phosphate; acid sodium phosphate; monosodium orthophosphate; primary sodium phosphate; 2NaO 4P; mol wt 119.98, 1.68%, Na 19.16%, 53.34%, 25.82%. Monohydrate, white, odorless slightly deliquesce crystals or granules. At 100 loses all its water; when ignited it converts to metaphosphate. It is freely soluble in water and practically insoluble in alcohol. The aqueous solution is acid. pH of 0.1 molar aqueous solution at 25 C: 4.5. Uretron D/S tablets contain inactive ingredients: Crospovidone, Dicalcium Phosphate, FD&C Blue Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Stearic Acid, Talc, and Titanium Dioxide.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Adults One tablet orally times per day followed by liberal fluid intake. Older Children Dosage must be individualized by physician. Not recommended for use in children six years of age or younger.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. dependence on the use of Uretron D/S tablets has not been reported and due to the nature of its ingredients, abuse of Uretron D/S tablets is not expected.

DRUG INTERACTIONS SECTION.

Drug interactions. As result of hyoscyamines effects on gastrointestinal motility and gastric emptying, absorption of other oral medications may be decreased during concurrent use with this combination medication. Methylene blue inhibits range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. This interaction could be more pronounced with narrow therapeutic index drugs that are metabolized by one of these enzymes (e.g., digoxin, warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). However, the clinical relevance of these in vitro interactions is unknown. Urinary alkalizers and thiazide diuretics: May cause the urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Antimuscarinics: Concurrent use may intensify antimuscarinic effects of hyoscyamine because of secondary antimuscarinic activities of these medications. Antacids/antidiarrheals: Concurrent use may reduce absorption of hyoscyamine resulting in decreased therapeutic effectiveness. Concurrent use with antacids may cause urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde. Doses of these medications should be spaced hour apart from doses of hyoscyamine. Antimyasthenics: Concurrent use with hyoscyamine may further reduce intestinal motility, therefore, caution is recommended. Ketoconazole and hyoscyamine may cause increased gastrointestinal pH. Concurrent administration with hyoscyamine may result in marked reduction in the absorption of ketoconazole. Patients should be advised to take this combination at least hours after ketoconazole. Monoamine oxidase (MAO) inhibitors: Concurrent use with hyoscyamine may intensify antimuscarinic side effects. Opioid (narcotic) analgesics may result in increased risk of severe constipation. Sulfonamides: These drugs may precipitate with formaldehyde in the urine increasing the danger of crystalluria. Patients should be advised that the urine and/or stools may become blue to blue-green as result of the excretion of methylene blue.

GERIATRIC USE SECTION.

Geriatric Use. Use with caution in elderly patients as they may respond to usual doses of hyoscyamine with exctextent, agitation, drowsiness or confusion.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Uretron D/S tablets are blue tablets imprinted with SAT on one side and 902 on opposite side. NDC 12539-144-01, Bottle of 100 Tablets. STORAGE. Dispense in tight, light-resistant container as defined in the USP/NF with child resistant closure.Store at controlled room temperature 20-25C (68-77F).Keep in cool, dry place. Keep container tightly closed.. Keep this and all drugs out of reach of children.Rx OnlyManufactured for: A.G. MARIN PHARMACEUTICALS P.O. BOX 174 MIAMI, FL 33144.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Uretron D/S tablets are indicated for the treatment of symptoms of irritative voiding. Indicated for the relief of local symptoms, such as inflammation, hypermotility, and pain, which accompany lower urinary tract infections. Indicated for the relief of urinary tract symptoms caused by diagnostic procedures.

NURSING MOTHERS SECTION.

Breast feeding. Problems in humans have not been documented; however, methenamine and traces of hyoscyamine are excreted in breast milk. Accordingly, Uretron D/S tablets should be given to nursing mother with caution and only if clearly needed.

OVERDOSAGE SECTION.

OVERDOSAGE. Emesis or gastric lavage. Slow intravenous administration of physostigmine in doses of to mg (0.5 to mg in children), repeated as needed in one to two hours to reverse severe antimuscarinic symptoms.Administration of small doses of diazepam to control exctextent and seizures. Artificial respiration with oxygen if needed for respiratory depression. Adequate hydration. Symptomatic treatment as necessary.If overdose is suspected, contact your local poison center or emergency room immediately. US residents can contact the US National Poison Hotline at 1-800-222-1222.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Uretron D/S Bottle Label. Uretron.

PEDIATRIC USE SECTION.

Pediatric. Infants and young children are especially susceptible to the toxic effect of the belladonna alkaloids.

PRECAUTIONS SECTION.

PRECAUTIONS. Cross sensitivity and/or related problems. Patients intolerant of belladonna alkaloids or salicylates may be intolerant of this medication also. Delay in gastric emptying could complicate the management of gastric ulcers.. Pregnancy/Reproduction. FDA Pregnancy Category C. Hyoscyamine and methenamine cross the placenta. Studies concerning the effect of hyoscyamine and methenamine on pregnancy and reproduction have not been done in animals or humans. Thus it is not known whether Uretron D/S tablets cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Uretron D/S should be given to pregnant woman only if clearly needed. Breast feeding. Problems in humans have not been documented; however, methenamine and traces of hyoscyamine are excreted in breast milk. Accordingly, Uretron D/S tablets should be given to nursing mother with caution and only if clearly needed. Prolonged use. There have been no studies to establish the safety of prolonged use in humans. No known long-term animal studies have been performed to valuate carcinogenic potential.. Pediatric. Infants and young children are especially susceptible to the toxic effect of the belladonna alkaloids.. Geriatric Use. Use with caution in elderly patients as they may respond to usual doses of hyoscyamine with exctextent, agitation, drowsiness or confusion.

PREGNANCY SECTION.

Pregnancy/Reproduction. FDA Pregnancy Category C. Hyoscyamine and methenamine cross the placenta. Studies concerning the effect of hyoscyamine and methenamine on pregnancy and reproduction have not been done in animals or humans. Thus it is not known whether Uretron D/S tablets cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Uretron D/S should be given to pregnant woman only if clearly needed.

SPL UNCLASSIFIED SECTION.

Rx Only100 Tablets.

STORAGE AND HANDLING SECTION.

STORAGE. Dispense in tight, light-resistant container as defined in the USP/NF with child resistant closure.Store at controlled room temperature 20-25C (68-77F).Keep in cool, dry place. Keep container tightly closed.

TERATOGENIC EFFECTS SECTION.

FDA Pregnancy Category C. Hyoscyamine and methenamine cross the placenta. Studies concerning the effect of hyoscyamine and methenamine on pregnancy and reproduction have not been done in animals or humans. Thus it is not known whether Uretron D/S tablets cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Uretron D/S should be given to pregnant woman only if clearly needed.

WARNINGS SECTION.

WARNINGS. Do not exceed recommended dosage. If rapid pulse, dizziness or blurring of vision occurs discontinue use immediately.