Topium

White crystalline powder filled in light blue opaque cap and transparent colorless body hard gelatin size no. 3 capsules with 'ACME' and 'TOPIUM' printed on cap and body respectively with blank ink.
Each capsule contains: Tiotropium (as bromide monohydrate) BP 22.5 mcg is equivalent to Tiotropium 18 mcg.

Pharmacology: Pharmacodynamics: Mechanism of action: Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (broncho constrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has a similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, tiotropium bromide competitively and reversibly antagonizes the M3 receptors, resulting in relaxation. The effect was dose-dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M3 receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur.
Pharmacodynamic effects: The bronchodilation is primarily a local effect (on the airways), not a systemic one. Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M3 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
Pharmacokinetics: Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation. Generally, with the inhaled route of administration, the majority of the delivered dose is deposited in the gastrointestinal tract, and to a lesser extent in the intended organ of the lung.
Absorption: Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak tiotropium plasma levels in COPD patients were 12.9 pg/ml and decreased rapidly in a multi-compartmental manner. Steady-state trough plasma concentrations were 1.71 pg/ml.
Distribution: Tiotropium has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that Tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. The ester Tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on muscarinic receptors. In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (< 20% of dose after intravenous administration) is metabolised by cytochrome P450 (CYP) dependent oxidation and subsequent glutathione conjugation to a variety of Phase II-metabolites. In vitro studies in liver microsomes revealed that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole, and gestodene. Thus, CYP 2D6 and 3A4 are involved in metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in human liver microsomes.
Elimination: The effective half-life of tiotropium ranges between 27-45 h in COPD patients. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers. Intravenously administered Tiotropium is mainly excreted unchanged in urine (74%). After dry powder inhalation by COPD patients to steady-state, urinary excretion is 7% (1.3 μg) of the unchanged drug over 24 hours, the remainder being mainly non-absorbed drug in gut that is eliminated via the feces. The renal clearance of Tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Used in the maintenance treatment of reversible airways obstruction, as in Chronic Obstructive Pulmonary Disease.

The capsules are intended for use with a Rotahaler device. While using with the device, the capsule will be pierced and the powder will be released on the screen of the device that is to be inhaled by the patient. The contents of one capsule are inhaled daily, at the same time each day.
Adults: One Rotacap once daily.
Children: Safety and effectiveness of Tiotropium in patients under 18 years of age has not been established.
Or as directed by the Physician.

There were no systemic adverse effects following a single inhaled dose of up to 340 micrograms Tiotropium bromide in healthy volunteers. No relevant adverse effects, beyond dry mouth, were observed following a 7-day dosing of up to 170 micrograms Tiotropium bromide in healthy volunteers. However, high doses of Tiotropium bromide may lead to anticholinergic signs and symptoms, include fast heart rate, increased pressure in the eyes, unable to urinate, flushing, dry skin and mouth, altered mental status, dilated (widened) pupils, which are the dark center of the eyes. If an overdose is suspected, seek medical attention immediately.

Tiotropium is contraindicated in patients with hypersensitivity to Tiotropium bromide, Atropine or its derivatives e.g., Ipratropium, or to the excipient lactose.

Patients should be instructed about the proper use of Rotahaler to ensure that the drug reaches the target areas of the lungs. This drug should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction. Care should also be taken in patients with moderate to severe renal or hepatic impairment.

Administration of drugs during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. It is not known whether Tiotropium is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if this drug is administered to a nursing woman.

The side effects of Tiotropium include dry mouth, nausea, constipation, increased heart rate, blurred vision, glaucoma, urinary difficulty, and headache.

Other anticholinergic drugs.

Special Precautions for Disposal and other Handling: Keep this medication in the container it came in, if the patient accidentally opens the capsule that cannot be used immediately, discard that capsule. Never store capsules inside the inhaler. Unused and unneeded medications should be properly disposed in accordance with local requirements. Consult the pharmacist or local waste management center for more details about how to safely discard expired or unused medicines.

Store at temperatures not exceeding 30°C.

Antiasthmatic & COPD Preparations

R03BB04 - tiotropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.

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