For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

GENERIC NAME

Tiotropium Bromide Powder for Inhalation

BRAND NAME

TIOVA Rotacaps

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each rotacap contains:

Tiotropium (as Tiotropium Bromide Monohydrate) …… 18 mcg

Excipient……………..q.s.

DOSAGE FORM(S) AND STRENGTH(S)

Dry powder for inhalation

Tiotropium (as Tiotropium Bromide Monohydrate) …… 18 mcg

CLINICAL PARTICULARS

Therapeutic Indications

TIOVA Rotacaps is indicated in the maintenance treatment of chronic obstructive pulmonary disorder (COPD).

Posology and Method of Administration

The recommended dosage of TIOVA Rotacaps is one rotacap inhaled once daily, using the Cipla Rotahaler/ Revolizer.

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment, who are being treated with TIOVA Rotacaps, should be monitored closely.

TIOVA Rotacaps are for inhalation only and must not be swallowed.

Contraindications

TIOVA Rotacaps are contraindicated in patients with a history of hypersensitivity to tiotropium, atropine or its derivatives, including ipratropium, or to any component of this product.

Special Warnings and Precautions for Use

TIOVA Rotacaps are intended as a once-daily maintenance treatment for COPD and are not indicated for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy. In the event of an acute attack, a rapid-acting beta2-agonist should be used.

If such a reaction occurs, therapy with TIOVA Rotacaps should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to TIOVA Rotacaps. In addition, TIOVA Rotacaps should be used with caution in patients with severe hypersensitivity to milk proteins.

Inhaled medicines, including TIOVA Rotacaps, may cause paradoxical bronchospasm. If this occurs, treatment with TIOVA Rotacaps should be stopped and other treatments considered.

Tiotropium should be used with caution in patients with known cardiac rhythm disorders. Tiotropium should be used with caution in patients with recent myocardial infarction < 6 months; any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy in the past year; hospitalisation of heart failure (NYHA Class III or IV) within the past year. These patients were excluded from the clinical trials and these conditions may be affected by the anticholinergic mechanism of action.

TIOVA Rotacaps should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. Also in general, patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in the precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema. In such a case, patients should stop using TIOVA Rotacaps and consult a specialist immediately.

Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Patients should consult a physician immediately should any of these signs or symptoms develop.

As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) TIOVA Rotacaps should be used only if the expected benefit outweighs the potential risk. There is no long term experience in patients with severe renal impairment. Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.

Tiotropium bromide should not be used more frequently than once daily.

Drug Interactions

Although no formal drug interaction studies have been performed, tiotropium bromide has been used concomitantly with other drugs commonly used in COPD and asthma without clinical evidences of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE treatment. Use of LABA or ICS was not found to alter the exposure to tiotropium.

The co-administration of tiotropium bromide with other anticholinergic containing drugs has not been studied and therefore is not recommended.

Renal impairment

Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with TIOVA Rotacaps should be monitored closely for anticholinergic side effects.

Hepatic impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses.

As a precautionary measure, it is preferable to avoid the use of TIOVA Rotacaps during pregnancy.

Lactation

Clinical data from nursing mothers exposed to tiotropium are not available. Based on studies in lactating rodents, tiotropium is excreted into breast milk only in small amounts. It is not known whether tiotropium is excreted into human milk, but because many drugs are excreted into human milk and given the findings in rats, caution should be exercised if tiotropium bromide is administered to a nursing mother.

Paediatric Use

TIOVA Rotacaps are approved for use in the maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema. This disease does not normally occur in children. The safety and effectiveness of tiotropium bromide in paediatric patients have not been established. The efficacy and safety of Tiotropium in children and adolescents has not yet been established.

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 tiotropium bromide dosage in geriatric patients is warranted.

Undesirable Effects

Many of the listed undesirable effects can be assigned to the anticholinergic properties of tiotropium. In COPD, the frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,647 patients) from 28 pooled placebo-controlled clinical trials in COPD with treatment periods ranging from four weeks to four years.

In patients with COPD, the common (≥1/100 to <1/10) adverse reaction includes dry mouth; the uncommon (≥1/1,000 to <1/100) adverse reactions include dizziness, headache, taste disorders, blurred vision, atrial fibrillation, cough, pharyngitis, dysphonia, constipation, gastroesophageal reflux disease, oropharyngeal candidiasis, rash, dysuria and urinary retention; rare (≥1/10,000 to <1/1,000) adverse reactions include insomnia, glaucoma, increased intraocular pressure, supraventricular tachycardia, tachycardia, palpitations, bronchospasm, epistaxis, laryngitis, sinusitis, intestinal obstruction, including ileus paralytic, gingivitis, glossitis, dysphagia, stomatitis, nausea, urticaria, pruritus, hypersensitivity (including immediate reactions), angioedema and urinary tract infection; not known (cannot be estimated from the available data) adverse reactions include: dehydration, dental caries, anaphylactic reaction, skin infection, skin ulcer, dry skin, joint swelling.

In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients.

In 28 clinical trials, dry mouth led to discontinuation in 18 of 9,647 tiotropium treated patients (0.2%).

Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.

An increase in anticholinergic effects may occur with increasing age.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared with the incidence observed in the clinical trials of another drug and may not reflect the incidence observed in practice. 

6-Month to 1-Year Trials

The data described below reflect exposure to tiotropium dry powder inhaler in 2,663 patients.  Tiotropium was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1,308 patients were treated with tiotropium at the recommended dose of 18 mcg once a day.  The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in 1 second (FEV₁) percent predicted of 39% to 43%.  Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only data on serious adverse events were collected. 

The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention. 

Four multicentre, 1-year, placebo-controlled and active-controlled trials evaluated tiotropium in patients with COPD. The table below shows all adverse reactions that occurred with a frequency of ³3% in the tiotropium group in the 1-year placebo-controlled trials where the rates in the tiotropium group exceeded placebo by ³1%.  The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.  

Adverse Reactions (% Patients) in 1-Year COPD Clinical Trials

Body System (Event)	Placebo-controlled Trials		Ipratropium-controlled Trials
	Tiotropium (n = 550)	Placebo (n = 371)	Tiotropium (n = 356)	Ipratropium (n = 179)
Body as a Whole Chest pain (non-specific)	7	5	5	2
Oedema, dependent	5	4	3	5
Gastrointestinal System Disorders Dry mouth	16	3	12	6
Dyspepsia	6	5	1	1
Abdominal pain	5	3	6	6
Constipation	4	2	1	1
Vomiting	4	2	1	2
Musculoskeletal System Myalgia	4	3	4	3
Resistance Mechanism Disorders Infection	4	3	1	3
Moniliasis	4	2	3	2
Respiratory System (Upper) Upper respiratory tract infection	41	37	43	35
Sinusitis	11	9	3	2
Pharyngitis	9	7	7	3
Rhinitis	6	5	3	2
Epistaxis	4	2	1	1
Skin and Appendage Disorders Rash	4	2	2	2
Urinary System Urinary tract infection	7	5	4	2

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the tiotropium treatment group, but were <1% in excess of the placebo group. 

Other reactions that occurred in the tiotropium group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group included the following:

Body as a Whole: allergic reaction, leg pain

Central and Peripheral Nervous System: dysphonia, paraesthesia

Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastro-oesophageal reflux, stomatitis (including ulcerative stomatitis)

Metabolic and Nutritional Disorders: hypercholesterolaemia, hyperglycaemia Musculoskeletal System Disorders: skeletal pain

Cardiac Events: angina pectoris (including aggravated angina pectoris)

Psychiatric Disorder: depression

Infections: herpes zoster

Respiratory System Disorder (Upper): laryngitis

Vision Disorder: cataract 

In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angio-oedema, and urinary retention. 

In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age.

Two multicentre, 6-month, controlled studies evaluated tiotropium in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials. 

4-Year Trial

The data described below reflect exposure to tiotropium in 5,992 COPD patients in a 4-year placebo-controlled trial.  In this trial, 2,986 patients were treated with tiotropium at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV₁ percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.  When the adverse reactions were analysed with a frequency of ≥3% in the tiotropium group where the rates in the tiotropium group exceeded placebo by ≥1%, adverse reactions included the following (tiotropium, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%). 

Additional Adverse Reactions

Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with tiotropium than placebo include  dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling. 

Postmarketing Experience

Adverse reactions have been identified during worldwide post-approval use of tiotropium dry powder inhaler. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions included application-site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction, including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria. 

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg of tiotropium in 6 healthy volunteers.

In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. 

Treatment of overdosage consists of discontinuation of tiotropium together with institution of appropriate symptomatic and/or supportive therapy. 

Accidental Ingestion

Acute intoxication by inadvertent oral ingestion of tiotropium is unlikely since it is not well absorbed systemically. 

A case of overdose has been reported from postmarketing experience of tiotropium dry powder inhaler. A female patient was reported to have inhaled 30 capsules over a 2.5-day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalised, tiotropium was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day. 

PHARMACOLOGICAL PROPERTIES

Mechanism of Action

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, M₁ to M₅.  In the airways, it exhibits pharmacological effects through inhibition of M3-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 preclinical 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.

Pharmacodynamic Properties

Cardiac Electrophysiology

In a multicentre, randomised, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the tiotropium group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs 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 did not detect an effect of the drug on QTc intervals.  

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomised, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium dry powder for inhalation 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.

Pharmacokinetic Properties

Absorption

Following inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lungs is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2 to 3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma concentrations were observed 7 minutes after inhalation

Distribution

Tiotropium shows a volume of distribution of 32 L/kg and is bound by 72% to plasma proteins after intravenous administration to young healthy volunteers. 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.

Elimination

The terminal half-life of tiotropium in COPD patients following once-daily inhalation of 5 mcg tiotropium was approximately 25 hours.  Total clearance was 880 mL/min after intravenous administration in young healthy volunteers.  After chronic once-daily dry powder inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Metabolism

The extent of metabolism 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 metabolised 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 CYP1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation in COPD patients at the steady state, urinary excretion was 7% (1.3 mcg) of the unchanged dose over 24 hours. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.

Special Populations

Geriatric Patients

As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients <65 years of age to 271 mL/min in COPD patients ≥65 years of age. This did not result in a corresponding increase in AUC_0-6,ss or C_max,_ss values following administration via a device.

Renal Impairment

Following 4-week once daily tiotropium dosing in patients with COPD, mild renal impairment (creatinine clearance 60 to <90 mL/min) resulted in 6 to 23% higher AUC_0-6,_ss and 6 to 17% higher C_max,_ss values; moderate renal impairment (creatinine clearance 30 to <60 mL/min) resulted in 54 to 57% higher AUC_0-6,_ss and 15 to 31% higher C_max,ss values compared with COPD patients with normal renal function (creatinine clearance ≥90 mL/min).

There is insufficient data for tiotropium exposure in patients with severe renal impairment (creatinine clearance <30 mL/min) following inhalation of tiotropium. However, AUC_0-4 and C_max were 94% and 52% higher, respectively, in patients with severe renal impairment following intravenous infusion of tiotropium bromide. 

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

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 urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. 

Common concomitant medications [long-acting beta₂-adrenergic agonists (LABA), inhaled corticosteroids (ICS)] used by patients with COPD were not found to alter the exposure to tiotropium. 

NONCLINICAL PROPERTIES

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5 times the recommended human daily inhalation dose MRHDID on an mcg/m² basis, respectively.  

Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay. 

In rats, decrease in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 40 times the MRHDID on an mcg/m² basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on an mcg/m² basis). The fertility index, however, was not affected at inhalation doses up to 1,689 mcg/kg/day (approximately 910 times the MRHDID on an mcg/m² basis).  

CLINICAL STUDIES

The tiotropium bromide inhalation powder clinical development program consisted of six Phase 3 studies in 2663 patients with COPD (1308 receiving tiotropium bromide inhalation powder): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7. In these studies, tiotropium bromide inhalation powder, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose. Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebocontrolled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial.

6-Month to 1-Year Effects on Lung Function

In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance. In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with tiotropium bromide inhalation powder, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period.

Figure 1: Mean FEV1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*

*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the tiotropium bromide inhalation powder and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward. Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2.

Figure 2: Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies*

*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the tiotropium bromide inhalation powder and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward. A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether tiotropium bromide inhalation powder was administered in the morning or in the evening. Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking tiotropium bromide inhalation powder had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6- month studies.

4-Year Effects on Lung Function

A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of tiotropium bromide inhalation powder on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long- acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3). Tiotropium bromide inhalation powder maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3).

Figure 3: Trough (pre-dose) FEV1 Mean Values at Each Time Point

Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis.

Exacerbations

The effect of tiotropium bromide inhalation powder on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre- bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium bromide inhalation powder significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs. 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used tiotropium bromide inhalation powder compared to placebo was 7.0% vs. 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056.

Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium bromide inhalation powder significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p <0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p <0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the tiotropium bromide inhalation powder group. All-Cause Mortality In the 4-year placebo-controlled lung-function trial described above, all-cause mortality compared to placebo was assessed. There were no significant differences in all- cause mortality rates between tiotropium bromide inhalation powder and placebo.

DESCRIPTION

TIOVA Rotacaps is a dry powder for oral inhalation  that   contains  tiotropium bromide monohydrate.

The active component of TIOVA Rotacaps is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1_α, 2_β, 4_β, 5_α, 7_β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish-white powder. It is sparingly soluble in water and soluble in methanol. 

The structural formula is as below:

Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C₁₉H₂₂NO₄S₂Br • H₂O. 

PHARMACEUTICAL PARTICULARS

Incompatibilities

Not applicable.

Shelf-Life

As on the pack.

Packaging Information

TIOVA Rotacaps:   Each bottle contains 30 Rotacaps.

Storage and Handling Instructions

• Store below 30°C. Do not freeze.
• Keep the container tightly closed.
• Keep away from contact with the eyes.
• Keep out of the reach of children.

PATIENT COUNSELLING INFORMATION

Read the information that comes with your TIOVA Rotacaps before you start using it and each time you refill your prescription. 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 is COPD (chronic obstructive pulmonary disease)? 

COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking. When you have COPD, your airways become narrow.  So, air moves out of your lungs more slowly. This makes it hard to breathe.

What is TIOVA Rotacaps?

• TIOVA Rotacaps is a prescription medicine used each day (a maintenance medicine) to control symptoms of chronic obstructive pulmonary disease (COPD).
• TIOVA Rotacaps helps make your lungs work better for 24 hours. TIOVA Rotacaps relaxes your airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take longer for you to feel the full effects of the medicine. TIOVA Rotacaps works best and may help make it easier to breathe when you use it every day.
• TIOVA Rotacaps reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.

TIOVA Rotacaps is not a rescue medicine and should not be used for treating sudden breathing problems. Your doctor may give you other medicine to use for sudden breathing problems.

It is not known if TIOVA Rotacaps is safe and effective in children. 

Who should not use TIOVA Rotacaps?

Do not use TIOVA Rotacaps if you

• are allergic to tiotropium, ipratropium, or any of the ingredients in TIOVA Rotacaps

Symptoms of a serious allergic reaction to TIOVA Rotacaps may include the following:

• raised red patches on your skin (hives)
• itching
• rash
• swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing

If you have these symptoms of an allergic reaction, stop using TIOVA Rotacaps and call your doctor right away or go to the nearest hospital emergency room.

What should I tell my doctor before using TIOVA Rotacaps?

Before using TIOVA Rotacaps, tell your doctor about all your medical conditions, including any of the following:

• Kidney problems.
• TIOVA Rotacaps may make your glaucoma worse.
• Enlarged prostate, problems passing urine, or a blockage in your bladder. TIOVA Rotacaps may make these problems worse.
• Are pregnant or plan to become pregnant. It is not known if TIOVA Rotacaps could harm your unborn baby.
• Are breastfeeding or plan to breastfeed. It is not known if TIOVA Rotacaps passes into breast milk. You and your doctor will decide if TIOVA Rotacaps is right for you while you breastfeed.
• Have a severe allergy to milk proteins. Ask your doctor if you are not sure.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye drops, vitamins, and herbal supplements.  Some of your other medicines or supplements may affect the way TIOVA Rotacaps works.  TIOVA Rotacaps is an anticholinergic medicine. You should not take other anticholinergic medicines while using TIOVA Rotacaps, including ipratropium. Ask your doctor or pharmacist if you are not sure if one of your medicines is an anticholinergic.

Know the medicines you take.  Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.  

How should I use TIOVA Rotacaps?

• Do not use TIOVA Rotacaps unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly.
• Use TIOVA Rotacaps exactly as your healthcare provider tells you to use it (the recommended dosage is to use TIOVA Rotacaps one time every day).
• Do not use TIOVA Rotacaps more often than prescribed.
• Take a complete dose of the medicine in TIOVA Rotacaps
• If you miss a dose, take it as soon as you remember. Do not use TIOVA Rotacaps more than one time every 24 hours.
• If you use more than your prescribed dose of TIOVA Rotacaps, call your doctor.  
• Place the Tiova Rotacaps in the Revolizer or Rotahaler device and breathe out fullybefore placing the mouthpiece inside your mouth. Do not blow into the mouthpiece.
• To breathe the medicine deeply into the airways, place the mouthpiece in your mouth and close the lips firmly around it, followed by rapid and steady deep breathing.
• Hold breath for at least 5-10 seconds or as long as comfortably possible after inhalation, while taking the inhaler out of the mouth.
• Open the inhaler and check if any powder is remaining after the inhalation, If there is powder left in the capsule, close the inhaler and repeat the inhalation procedure.
• After finishing inhalation of TIOVA Rotacaps, open the mouthpiece and remove the empty capsule by tipping it out of the capsule chamber and dispose the empty capsule in the household waste.
• If you miss a dose of TIOVA Rotacaps, take your next dose at the same time you normally do. Do not take more than your prescribed dose of TIOVA Rotacaps.
• If you use too much TIOVA Rotacaps, call your healthcare provider or go to the nearest hospital emergency room right away if you have unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.
• Do not stop using TIOVA Rotacaps unless told to do so by your healthcare provider because your symptoms might come back. Your healthcare provider will change your medicines as needed.
• TIOVA Rotacaps does not relieve sudden symptoms of COPD. Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.
• Call your healthcare provider or get medical care right away if:

• your breathing problems get worse.
• you need to use your rescue inhaler more often than usual.
• your rescue inhaler does not work as well to relieve your symptoms.

What should I avoid while using TIOVA Rotacaps?

• Do not let the contents from TIOVA Rotacaps get into your eyes. Your vision may get blurry and the pupil in your eye may get larger (dilate). If this happens, call your doctor.
• TIOVA Rotacaps can cause dizziness and blurred vision. Should you experience these symptoms, you should use caution when engaging in activities such as driving a car or operating appliances or other machines. 

What are the possible side effects of TIOVA Rotacaps?

TIOVA Rotacaps can cause serious side effects, including the following: 

• Allergic reaction. Symptoms may include
• raised red patches on your skin (hives);
• itching;
• rash; and,
• swelling of the lips, tongue or throat that may cause difficulty in breathing or swallowing.

If you have these symptoms of an allergic reaction, stop using TIOVA Rotacaps and call your doctor right away or go to the nearest hospital emergency room.  

• Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets worse.  If you have these symptoms of bronchospasm, stop using TIOVA Rotacaps and call your doctor right away or go to the nearest hospital emergency room. 
• New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-angle glaucoma may include 
  • eye pain;
  • blurred vision; and,
  • seeing halos (visual halos) or coloured images along with reddened eyes

Using only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking TIOVA Rotacaps and call your doctor right away. 

• New onset of or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include difficulty passing urine, painful urination.

If you have these symptoms of urinary retention, stop taking TIOVA ROTACAPS and call your doctor right away. 

Other side effects with TIOVA Rotacaps include the following:

• upper respiratory tract infection
• dry mouth
• sinus infection
• sore throat
• non-specific chest pain
• urinary tract infection
• indigestion
• runny nose
• constipation
• increased heart rate
• blurred vision

These are not all the possible side effects with TIOVA Rotacaps.  Tell your doctor if you have any side effect that bothers you or that does not go away.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side effects, you can help provide more information on the safety of this product. 

How do I store TIOVA Rotacaps?

• Store TIOVA Rotacaps below 30°C.  Do not freeze.
• Keep the bottle tightly closed
• Keep away from contact with the eyes.
• Ask your doctor or pharmacist if you have any questions about storing your TIOVA Rotacaps. 

• Keep TIOVA Rotacaps and all medicines out of the reach of children.

General information about TIOVA Rotacaps

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets.  Do not use TIOVA Rotacaps for a purpose for which it has not been prescribed.  Do not give TIOVA Rotacaps to other people even if they have the same symptoms that you have.  It may harm them.

For more information about TIOVA Rotacaps, talk with your doctor.

DETAILS OF THE MANUFACTURER

Mfd. by: Cipla Ltd

Regd. Office: Peninsula Business Park, Ganapatrao Kadam Marg,

Lower Parel (West), Mumbai – 400013, India

DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

M.L. MNB/05/109

DATE OF REVISION

12/04/2024