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Product
Anti-asthmatic Products (Theoday)
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Anti-asthmatic Products (Theoday)
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Tiova Inhaler
Tiotropium Bromide
COMPOSITION
TIOVA Inhaler
Each actuation delivers:
Tiotropium (as Tiotropium Bromide Monohydrate) …...... 9 mcg
DOSAGE FORM
Inhalation aerosol .
PHARMACOLOGY
Pharmacodynamics
Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M 1 to M 5 . In the airways, it exhibits pharmacological effects through inhibition of M 3 -receptors at the smooth muscle, leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In pre-clinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.
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Pharmacokinetics
Tiotropium in common with other inhaled drugs, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lungs, the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Absorption
Following inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lungs is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium is poorly absorbed from the gastrointestinal tract. Food is not expected to influence the absorption of tiotropium for the same reason. Oral solutions of tiotropium have an absolute bioavailability of 2–3%. Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation.
Distribution
Tiotropium shows a volume of distribution of 32 L/kg, indicating that the drug binds extensively to tissues. The drug is bound by 72% to plasma proteins. At steady state, peak tiotropium plasma levels in chronic obstructive pulmonary disease (COPD) patients were 17–19 pg/mL when measured 5 minutes after inhalation of an 18 mcg dose, and decreased rapidly in a multi-compartmental manner. Steady-state trough plasma concentrations were 3–4 pg/mL. Local concentrations in the lungs are not known, but the mode of administration suggests substantially higher concentrations in the lungs. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier.
Biotransformation
The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is non-enzymatically cleaved to the alcohol; N -methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
Elimination
The terminal elimination half-life of tiotropium is between 5–6 days, following inhalation. After an intravenous dose in young healthy volunteers, total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered tiotropium is mainly excreted unchanged in the urine (74%). After inhalation, urinary excretion is 14% of the dose, the remainder being mainly non-absorbed drug in the gut, which is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance (CrCl), indicating active secretion into the urine. After continual once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2–3 weeks with no accumulation thereafter.
Drug Interactions
An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily, or ranitidine 300 mg once daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC 0-–4h , a 28% decrease in the renal clearance of tiotropium, and no significant change in the C max and amount excreted in the urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. Therefore, no clinically significant interaction occurred between tiotropium and cimetidine or ranitidine.
Electrophysiology
In a multicentre, randomized, double-blind trial that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30–60 msec was higher in the tiotropium bromide group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients versus 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients versus 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with tiotropium bromide did not detect an effect of the drug on QTc intervals.
Special Populations
Elderly Patients
As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients >70 years), which may be explained by decreased renal function. Tiotropium excretion in the urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma concentrations were numerically increased with advancing age within COPD patients (43% increase in AUC 0-4h after inhalation), which was not significant when considered in relation to inter- and intra-individual variability.
Hepatically-impaired Patients
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. However, hepatic insufficiency is not expected to have relevant influence on tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and by simple non-enzymatic ester cleavage to products that do not bind to muscarinic receptors
Renally-impaired Patients
Since tiotropium is predominantly renally excreted, renal impairment was associated with increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and inhalation. Mild renal impairment (CrCl of 50–80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations (39% increase in AUC 0–4h after intravenous infusion). In COPD patients with moderate to severe renal impairment (CrCl ≤ 50 mL/min), the intravenous administration of tiotropium resulted in the doubling of plasma concentrations (82% increase in AUC 0–4h) , which was confirmed by plasma concentrations after inhalation.
INDICATIONS
TIOVA Inhaler is indicated in the maintenance treatment of COPD.
DOSAGE AND ADMINISTRATION
The recommended dosage of tiotropium bromide is 2 puffs of TIOVA Inhaler once daily, inhaled via a Cipla Zerostat spacer device.
The recommended dose should not be exceeded.
CONTRAINDICATIONS
TIOVA Inhaler is contraindicated in patients with hypersensitivity to tiotropium bromide, atropine or its derivatives.
WARNINGS AND PRECAUTIONS
TIOVA Inhaler is a once-daily maintenance bronchodilator and should not be used for the initial treatment of acute episodes of bronchospasm, i.e., rescue therapy.
Immediate hypersensitivity reactions may occur after administration of TIOVA Inhaler . As with other anticholinergic drugs, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction.
Inhaled medicines may cause inhalation-induced bronchospasm.
Patients should be cautioned to avoid getting the drug into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, and visual halos or coloured images in association with red eyes from conjunctival and corneal congestion. Patients should stop using tiotropium bromide and consult a physician immediately when signs and symptoms of narrow-angle glaucoma appear.
Dry mouth, which has been observed with anti-cholinergic treatment, may, in the long- term, be associated with dental caries.
Drug Interactions
The co-administration of tiotropium bromide with other anticholinergic-containing drugs (e.g., ipratropium) has not been studied and is, therefore, not recommended.
Pregnancy
Pregnancy category C . TIOVA Inhaler should not be used in pregnant women unless the expected benefit outweighs any possible risk to the unborn child.
Lactation
TIOVA Inhaler should not be used in lactating women unless the expected benefit outweighs any possible risk to the infant.
Geriatric Use
Instances of dry mouth increased with age in patients receiving tiotropium bromide. A higher frequency of constipation and urinary tract infections with increasing age was observed in the tiotropium bromide group in the placebo-controlled studies. No overall differences in effectiveness were observed among various age groups. Based on available data, no adjustment of TIOVA Inhaler dosage in geriatric patients is warranted.
UNDESIRABLE EFFECTS
Several organ systems and functions are under the control of the parasympathetic nervous system and, therefore, can be affected by anticholinergic agents. Possible adverse events attributable to systemic anticholinergic effects include dry mouth, dry throat, increased heart rate, blurred vision, glaucoma, urinary difficulty, urinary retention, and constipation.
The most common anticholinergic adverse reaction reported by COPD patients was dry mouth, which was mild in the majority of cases. In general, dry mouth had an onset of 3 and 5 weeks, which resolved while patients continued to receive tiotropium bromide.
OVERDOSAGE
High doses of TIOVA Inhaler may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 mcg of tiotropium bromide in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following a 7-day dosing of up to 170 mcg of tiotropium bromide in healthy volunteers. In a multiple-dose study in COPD patients with a maximum daily dose of 43 mcg of tiotropium bromide over 4 weeks, no significant undesirable effect has been observed.
PACKAGING INFORMATION
TIOVA INHALER
Sales pack is available in a canister containing 120 metered doses.
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