Indian Pharmaceuticals Company in world Dezrol LA (Tolterodine Tartrate)

Dezrol LA (tolterodine tartrate) Extended Release Capsules

DRUG DESCRIPTION
DETROL LA Capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist.

DETROL LA for oral administration contains 2 mg or 4 mg of tolterodine tartrate. Both capsule strengths are imprinted with a pharmaceutical grade printing ink that contains shellac glaze, titanium dioxide, propylene glycol, and simethicone.

INDICATIONS
DETROL LA Capsules are once daily extended release capsules indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

USES
This medication is used to treat an overactive bladder. By relaxing the muscles in the bladder, tolterodine improves your ability to control your urination. It helps to reduce leaking of urine, feelings of needing to urinate right away, and frequent trips to the bathroom. This medication belongs to the class of drugs known as antispasmodics.

DOSAGE AND ADMINISTRATION
The recommended dose of DETROL LA Capsules are 4 mg daily. DETROL LA should be taken once daily with liquids and swallowed whole. The dose may be lowered to 2 mg daily based on individual response and tolerability, however, limited efficacy data is available for DETROL LA 2 mg (see Clinical Studies). For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4, the recommended dose of DETROL LA is 2 mg daily.

SIDE EFFECTS The Phase 2 and 3 clinical trial program for DETROL LA Capsules included 1073 patients who were treated with DETROL LA (n=537) or placebo (n=536). The patients were treated with 2, 4, 6, or 8 mg/day for up to 15 months. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. The data described below reflect exposure to DETROL LA 4 mg once daily every morning in 505 patients and to placebo in 507 patients exposed for 12 weeks in the Phase 3, controlled clinical study. Adverse events were reported in 52% (n=263) of patients receiving DETROL LA and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving DETROL LA were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with DETROL LA occurring in 23.4% of patients treated with DETROL LA and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic agents. A serious adverse event was reported by 1.4% (n=7) of patients receiving DETROL LA and by 3.6% (n=18) of patients receiving placebo. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with DETROL LA or placebo discontinued treatment due to adverse events. Treatment was discontinued due to adverse events and dry mouth was reported as an adverse event in 2.4% (n=12) of patients treated with DETROL LA and in 1.2% (n=6) of patients treated with placebo. Table 4 lists the adverse events reported in 1% or more of patients treated with DETROL LA 4 mg once daily in the 12-week study. The adverse events were reported regardless of causality. OVERDOSE A 27-month-old child who ingested 5 to 7 tolterodine immediate release tablets 2 mg was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered. CONTRAINDICATIONS DETROL LA Capsules are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL LA is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Do not take DETROL LA if * you have trouble emptying your bladder (also called "urinary retention") * your stomach empties slowly (also called "gastric retention") * you have an eye problem called "uncontrolled narrow-angle glaucoma" * you are allergic to DETROL LA or to any of its ingredients. See the end of this leaflet for a complete list of ingredients. STORAGE Store at room temperature (77 degrees F or 25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children Presentation Dezrol LA Capsules Blister of 10 Capsules

Note : This product information is intended only for residents of the India. Taj Pharmaceuticals Limited, medicines help to treat and prevent a range of conditions—from the most common to the most challenging—for people around the world.

DETROL LA Capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate

Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between n- octanol and water is 1.83 at pH 7.3.

What side effects may occur?

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Detrol.

· Side effects may include:

The most common side effects include, but are not limited to:

• dry mouth
• dyspepsia
• headache
• constipation
• xerophthalmia (eye disorder that results from a deficiency of vitamin A)
• abnormal vision

Many of these side effects are expected of antimuscarinic agents. Detrol is present in the breast milk of nursing mice. It is not known if it is present in the milk of nursing mothers. This drug also causes increased fetal abnormalities in mice. No studies have been done with pregnant mothers. Therefore the drug should only used by pregnant mothers if the benefit to the mother outweighs the potential risk to the fetus.

Detrol is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Detrol is also contraindicated in patients who have showed hypersensitivity to the drug or its ingredients.

Drug Interactions:

Pharmokinetic studies with patients concomitantly receiving cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin) or antifungal agents (ketoconazole, itraconazole, and miconazole) have not been performed. Patients receiving cytochrome P450 3A4 inhibitors should not receive doses of Detrol greater than 1 mg twice daily. (From FDA Label)

Abdominal pain, blurred vision, constipation, diarrhea, dizziness, drowsiness, dry eyes, dry mouth, fatigue, flu-like symptoms, headache, indigestion, vertigo.

Possible food and drug interactions when taking Tolterodine tartrate

If you take Detrol with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Detrol with any of the following:

Clarithromycin

Cyclosporine

Erythromycin antibiotics

Ketoconazole

Itraconazole

Miconazole

Vinblastine

Special information if you are pregnant or breastfeeding

The use of Detrol during pregnancy has not been adequately studied. If you are pregnant or plan to become pregnant while taking Detrol, tell your doctor immediately.

Researchers are not sure whether Detrol appears in breast milk. Use of the drug is not recommended while breastfeeding.

Recommended dosage for Tolterodine tartrate

ADULTS

The usual starting dosage is 2 milligrams twice a day. Your doctor may decrease the dose to 1 milligram twice a day if the higher dose causes problems. The 1-milligram dose is also recommended if you have liver problems or must take any of the drugs listed in the "Possible food and drug interactions" section above.

Detrol LA

The usual starting dosage is 4 milligrams taken once a day. Your doctor may cut the dose in half if it causes problems. A dose of 2 milligrams once daily is recommended for people with liver problems and those taking drugs that might interact.

indications It is used to treat overactive bladder (frequency and urgency). It controls bladder incontinence by controlling contractions.

contraindications Factors that prohibit its use include known hypersensitivity, uncontrolled narrow-angle glaucoma, urinary retention, and gastric retention.

adverse effects Adverse effects include paresthesia, fatigue, headache, chest pain, hypertension, vision abnormalities, xerophthalmia, abdominal pain, constipation, dry mouth, dyspepsia, dysuria, urinary retention, urinary frequency, urinary tract infection, rash, pruritus, bronchitis, cough, pharyngitis, and upper respiratory infection. Common side effects include anxiety, dizziness, nausea, vomiting, and anorexia.

Detrol LA (tolterodine tartrate) is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. It is available by prescription only in a 2 and 4 mg extended release capsule formulation.

Three placebo-controlled, 12 week studies were held involving a total of 339 patients who received Detrol 2 mg twice daily and 177 patients who received the placebo. The majority of patients were Caucasian (95%) and female (75%), with the mean age being 60 years of age (range 19-91). At their entrance into the study almost all patients perceived symptoms of urgency (98%) and increased frequency of micturitions (89%) and urge incontinence (83%). These characteristics were balanced across treatment groups for all three studies.

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. In the anesthetized cat, tolterodine shows a selectivity for the urinary bladder over salivary glands; however, the clinical relevance of this finding has not been established.

After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for the muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.

Tolterodine has a pronounced effect on bladder function in healthy volunteers. The main effects following a 6.4-mg single dose of tolterodine were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with a potent antimuscarinic action on the lower urninary tract. (From FDA Label)

Absorption: In a study with 14C-tolterodine solution in healthy volunteers who received

a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Tolterodine

immediate release is rapidly absorbed, and maximum serum concentrations (Cmax)

typically occur within 1 to 2 hours after dose administration. Cmax and area under the

concentration-time curve (AUC) determined after dosage of tolterodine immediate

release are dose-proportional over the range of 1 to 4 mg.

Effect of Food: Food intake increases the bioavailability of tolterodine (average

increase 53%), but does not affect the levels of the 5-hydroxymethyl metabolite in

extensive metabolizers. This change is not expected to be a safety concern and

adjustment of dose is not needed.

Distribution: Tolterodine is highly bound to plasma proteins, primarily α1-acid

glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the

concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not

extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%.

The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6

and 0.8, respectively, indicating that these compounds do not distribute extensively into

erythrocytes. The volume of distribution of tolterodine following administration of a

1.28-mg intravenous dose is 113 ± 26.7 L.

Metabolism: Tolterodine is extensively metabolized by the liver following oral dosing.

The primary metabolic route involves the oxidation of the 5-methyl group and is

mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a

pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to

formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites,

which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine,

respectively.