What Are the Different Types of COPD Inhalers?

Tiotropium bromide powder inhalation, indication is tiotropium bromide is a bronchodilator, suitable for maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, and maintenance of dyspnea Treatment and prevention of acute attacks.

Tiotropium bromide powder inhalation, indication is tiotropium bromide is a bronchodilator, suitable for maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, and maintenance of dyspnea Treatment and prevention of acute attacks.

Drug Name

Tiotropium bromide powder inhaler

Drug type

Prescription drugs, medicines for medical workers' injuries

Tiotropium bromide powder inhaler ingredients

Chemical Name of Tiotropium Bromide: (1, 2, 4, 5, 7) 3-oxa-9-azepine tricyclo [3.3.1.02,4] nonane, 7-[(hydroxy-di-2-thiopheneacetyl ) Oxy] -9.9-dimethyl, bromo,-hydrate chemical structural formula:

Molecular formula: C ₁₉ H ₂₂ NO ₄ S ₂ Br · H ₂ O
Molecular weight: 490.4 (hydrate)

Tiotropium bromide powder inhalant properties

This product is a hard capsule with a white powder content.

Tiotropium bromide powder inhaler specifications

18 micrograms (based on tiotropium, equivalent to 22.5 micrograms of tiotropium bromide-hydrate)

Tiotropium bromide powder inhaler usage dosage

The recommended dose of tiotropium bromide is once a day, and one capsule is inhaled with each HandiHaler® inhalation device. This product can only be inhaled with the HandiHaler® inhalation device. It should not be used in excess of the recommended dose. Tiotropium bromide should not be swallowed.
Elderly patients in special populations can use tiotropium at the recommended dose.
Patients with renal insufficiency can use tiotropium at the recommended dose. However, for patients with moderate to severe renal insufficiency (creatinine clearance 50ml / min), the application of tiotropium bromide should be closely monitored like other drugs excreted mainly through the kidney (see [Precautions]).
Patients with liver dysfunction can use tiotropium at the recommended dose (see [Pharmacokinetics]).
Pediatric patients: There is no experience with tiotropium in pediatric patients, so patients less than 18 years of age are not recommended to use this product.
Instructions for use The following methods are used to instruct patients to use the HandiHaler® (Powder Inhaler) inhalation device to inhale the required medication from the tiotropium bromide capsules.
Remember to use tiotropium exactly as directed by your doctor. The HandiHaler® inhaler is designed for tiotropium bromide capsules and should not be used for any other medicine. Your HandiHaler® inhaler can be used continuously for one year.

HandiHaler® inhalation devices include:
1) dust cap 2) suction nozzle 3) base 4) puncture button 5) central chamber

1. Pull up to open the dust cap. Then open the nozzle.

2. Take a capsule out of the blister pack (just remove it immediately before use) and place it in the central chamber, as shown in the figure, no matter how the capsule is placed.

3. Close the nozzle firmly until you hear a click, and keep the dust cap open.

4. Hold the HandiHaler® (powder inhaler) device so that the nozzle is up, press the green puncture button completely once, and then release it. This will pierce many small holes in the capsule and the drug will be released when you inhale.

5. Exhale completely (take a deep breath first).
Note: Avoid exhaling into the mouthpiece at all times.

6. Lift the HandiHaler® (medicine powder inhaler) device to your mouth, hold the mouthpiece tightly with your lips, keep your head vertical, and inhale slowly and slowly, at a rate sufficient to hear the capsule vibrate. When inhaling until the lungs are full, hold your breath for as long as possible while removing the HandiHaler® device from the mouth. Resume normal breathing. Repeat steps 5 and 6 once, the drug in the capsule is completely aspirated.

7. Open the nozzle again, pour out the used capsules and discard. Close the suction nozzle and dust cap and store the HandiHaler® device.

Cleaning your HandiHaler® inhaler: Clean the HandiHaler® inhaler once a month. Open the dust cap and nozzle, then push up the piercing button to open the base. Thoroughly rinse the inhaler with warm water to remove the powder. Place the HandiHaler® (medicine powder inhaler) device on a paper towel to absorb moisture, and then keep it dust-proof The cap, nozzle and base are left open and allowed to air dry for 24 hours. Therefore, it should be cleaned immediately after use. This will ensure the next use. If necessary, the outside of the nozzle can be cleaned with a damp tissue.

Method for removing capsules A. Divide the blister strip into two plates along the perforations on the blister pack.

B. Remove the aluminum foil on the back of the blister (only immediately before use). Make one capsule fully exposed.

C. Remove the capsule

Adverse reactions of Tiotropium bromide powder inhaler

a) Overview In a total of 906 patients who received tiotropium in a one-year clinical trial, the most common adverse reaction was dry mouth. Dry mouth occurs in about 14% of patients. The dry mouth response is usually mild and will disappear with continued treatment.
b) The following table lists the reported rates of this adverse reaction. These data are from a 1-year clinical trial of patients receiving tiotropium bromide (based on WHO organ system classification):

All adverse events listed as common refer to a reported frequency of more than 1% to 2% compared to the placebo group.
Post-marketing experience: reports of spontaneous adverse reactions to nausea, hoarseness, and dizziness have been received.
c) With regard to individual severe and / or frequent adverse reactions, the most common adverse reaction of anticholinergic therapy in COPD patients is dry mouth. The symptoms of dry mouth are mild in most cases. In general, dry mouth occurs from 3 to 5 weeks after treatment. The symptoms of dry mouth usually disappear after continuous treatment. In a 906-year clinical trial of 906 patients taking the drug, 3 patients terminated the trial due to dry mouth adverse reactions (0.3% of the total number of patients treated).
In the one-year clinical trial of the drug, serious and persistent adverse reactions reported in individual cases were constipation and urinary retention. Urinary retention is only seen in older men with predisposing factors (such as enlarged prostate).
Ventricular tachycardia and atrial fibrillation have occurred in a few cases after application of tiotropium. Usually seen in susceptible patients.
As with all inhalation treatments, tiotropium can cause bronchospasm caused by inhalation irritation.
Allergic reactions reported as spontaneous adverse reactions include angioedema, rash, rubella, and itching of the skin.
d) Pharmacological classification of adverse reactions. Many organ systems and functions are controlled by the parasympathetic nervous system and are therefore susceptible to anticholinergic agents. Adverse reactions that may be related to systemic anticholinergic effects include dry mouth, dry throat, increased heart rate, blurred vision, glaucoma, dysuria, urinary retention, and constipation. In addition, patients with inhaled tiotropium can experience upper respiratory tract irritation. The incidence of dry mouth and constipation increases with age.

Tiotropium bromide powder inhalation contraindications

Tiotropium bromide inhalable powder is contraindicated in patients who have an allergic reaction to tiotropium bromide, atropine or its derivatives, such as ipratropium bromide or oxtropium bromide or the excipient lactose of this product.

Precautions for Tiotropium Bromide Powder Inhaler

Tiotropium bromide as a bronchodilator for once-a-day maintenance therapy should not be used as the initial treatment for acute exacerbations of bronchospasm, that is, as a rescue medication.
An allergic reaction may occur immediately after inhaling tiotropium bromide powder.
As with other anticholinergic drugs, caution should be used in patients with narrow-angle glaucoma, prostate hyperplasia, or bladder neck obstruction.
Inhaling medication may cause inhaled bronchospasm.
As with all drugs that are mainly excreted by the kidney, for patients with moderate to severe renal insufficiency (creatinine clearance 50ml / min). Use tiotropium bromide only when the expected benefits outweigh the potential harm. There is no long-term experience with tiotropium in patients with severe renal insufficiency (see [Pharmacokinetics]).
Patients must be careful not to get the powder into their eyes. Patients must be informed that the accidental injection of powder into the eye may cause or exacerbate narrow-angle glaucoma, pain or discomfort in the eyes, transient blurred vision, visual halo or color images with red eyes and corneal edema caused by conjunctival hyperemia. If you have signs of narrow-angle glaucoma, you should stop using tiotropium bromide and see your doctor immediately.
Dry mouth is caused by anticholinergic treatment and can cause dental caries in the long term.
Tiotropium bromide should not be used more than once a day (see [Overdose]).
[Impact on the ability to drive and operate machines]
No studies have been conducted on the impact on the ability to drive and operate machines. Based on the pharmacological and adverse reaction characteristics obtained at the recommended doses, there is no evidence to influence the ability to drive and operate machines.

Tiotropium bromide powder inhaler for pregnant and lactating women

For tiotropium bromide, there is no clinical data on medications in pregnancy. Animal studies have shown maternal-related reproductive toxicity. See toxicological information.
There is no information on the use of tiotropium in lactating women. According to studies on lactating rodents, small amounts of tiotropium bromide can be secreted into milk.
Therefore, tiotropium bromide should not be used in pregnant or lactating women unless the expected benefits outweigh the risks that may be brought to the unborn fetus or infant.

Tiotropium bromide powder inhaler for children

There is no experience with tiotropium bromide in pediatric patients, so this product is not recommended for patients younger than 18 years old. See [Dosage and Administration].

Tiotropium bromide powder inhaler for the elderly

Elderly patients can use tiotropium at the recommended dose. See [Dosage and Administration].

Tiotropium bromide powder inhaler drug interactions

Although no formal drug interaction studies have been conducted, no adverse effects have been found when tiotropium bromide inhaled powder is used with other drugs, including sympathetic bronchodilators, methylxanthine, oral or inhaled steroid Drugs and the like are drugs commonly used to treat chronic obstructive pulmonary disease (COPD).
Tiotropium bromide has not been studied in combination with other anticholinergics, so it is not recommended to be combined with other anticholinergics.

Tiotropium bromide powder inhaler overdose

High doses of tiotropium bromide may cause anticholinergic symptoms and signs.
however. Healthy volunteers did not develop systemic anticholinergic effects after a single inhalation of 340 micrograms of tiotropium bromide. In addition, healthy volunteers inhaled 170 micrograms of tiotropium bromide once a day for 7 days, except for dry mouth. No other adverse reactions were seen. In a multi-dose study of patients with chronic obstructive pulmonary disease (COPD), no significant adverse effects were observed after 4 weeks of treatment with a maximum daily dose of 43 micrograms of tiotropium bromide.
Acute poisoning caused by inadvertent administration of tiotropium bromide capsules is unlikely due to its low oral bioavailability.

Tiotropium bromide powder inhaler pharmacology and toxicology

Pharmacological properties Tiotropium bromide is a long-acting, specific anti-muscarinic drug, which is commonly called clinically as an anticholinergic drug. By binding to muscarinic receptors on the bronchial smooth muscle, tiotropium bromide can inhibit the cholinergic (bronchial contraction) effect of acetylcholine released from the parasympathetic nerve ends. It has similar affinity for muscarinic receptor subtypes M1 to M5. In the respiratory tract, tiotropium inhibits M3 receptors competitively and reversibly, causing smooth muscle relaxation. This effect is dose-dependent and can last more than 24 hours. The long duration of action may be due to its very slow dissociation from the M3 receptor. Its dissociation half-life is significantly longer than ipratropium bromide. As a tetravalent ammonium anticholinergic drug, tiotropium bromide is locally (bronchial) selective when administered by inhalation, thereby achieving a therapeutic effect without causing systemic anticholinergic effects. Its bronchiectasis is basically a local (airway) effect, not a systemic effect.
Tiotropium dissociates faster from the M2 receptor than from the M3 receptor. In in vitro studies. Its selectivity for M3 receptor subtype is higher than M2. Efficient and slow dissociation from the receptor makes tiotropium bromide clinically a significant and long-acting bronchodilator in patients with chronic obstructive pulmonary disease (COPD).
Clinical studies included four randomized, double-blind studies of a total of 2,663 patients for one year and two six-month studies (of which 1,308 patients were treated with tiotropium bromide). The one-year study consisted of two placebo-controlled trials and two ipratropium bromide-controlled trials; two six-month trials used salmeterol and placebo as controls. These studies include measurements of lung function and dyspnea, exacerbations, and health-related quality of life.
In the above study, tiotropium bromide was administered once a day, and pulmonary function (forced expiratory volume (FEV1) and forced vital capacity (FVC)) was significantly improved within 30 minutes after the first administration, and For 24 hours. On the third day of medication. The bronchodilation effect basically reached steady state, and the pharmacodynamic steady state reached within one week. According to the results of daily measurement by patients, it was shown that tiotropium bromide (Spiriva) significantly improved PEFR (peak expiratory flow rate) in the morning and evening. Tiotropium bromide maintained its bronchiectasis effect during the one-year administration period without tolerance. A randomized, placebo-controlled clinical study of 96 patients with chronic obstructive pulmonary disease (COPD) demonstrated that compared with placebo, the bronchial tubes remained dilated during the 24-hour interval of administration. Whether tiotropium is administered in the morning or evening. Long-term clinical trials (6 months and 1 year) have proven the following results:
Tiotropium bromide significantly improved dyspnea (evaluated by the Mahalana dyspnea index) and this improvement was maintained throughout the treatment period.
Preclinical Safety Information (Toxicology)
The results observed in conventional safety pharmacology (general pharmacology) tests, long-term toxicity tests, and reproductive toxicity tests can be explained by the anticholinergic properties of tiotropium bromide, especially such as reduced animal food intake and weight gain Suppression, dry mouth and dry nose, reduced tear and saliva secretion, dilated pupils, and increased heart rate. Other relevant effects observed in the long-term toxicity test are: mild respiratory irritation response in rats and mice manifests as rhinitis and epithelial changes in the nasal cavity and nasopharynx. Prostatitis in rats is accompanied by bladder protein deposition and stones.
Harmful effects on pregnancy, embryo / fetal development, childbirth, or perinatal development can only be observed at dose levels that produce maternal toxicity. Tiotropium bromide has no teratogenic effect on rats and rabbits. The effects on the respiratory tract (irritant) and urethra (prostatitis) and reproductive toxicity are only observed when the local or systemic dose exceeds 5 times the therapeutic dose. Genotoxicity and carcinogenicity studies have not observed harm to humans.

Pharmacokinetics of Tiotropium Bromide Powder Inhaler

a) Overview Tiotropium bromide is an achiral tetravalent ammonium compound. Dissolved in small amounts in water. Tiotropium is administered as a dry powder by inhalation. When generally administered by inhalation, most of the drug is deposited in the gastrointestinal tract, and only a small amount of the drug reaches the target organ lung. Many of the pharmacokinetic data described below are obtained at higher doses than recommended treatments.
b) Specific absorption of active ingredients: After inhaling dry powder to young healthy volunteers. The measured absolute bioavailability was 19.5%, suggesting that the bioavailability of parts reaching the lungs is high. According to the chemical structure of the drug (tetravalent ammonium compound) and in vitro test results, it can be speculated that the absorption of tiotropium in the gastrointestinal tract is poor (10-15%). The absolute bioavailability of an oral solution of tiotropium bromide is only 2 to 3%. Tiotropium bromide reached its maximum plasma concentration 5 minutes after inhalation. Due to the characteristics of its tetravalent ammonium compound, food does not affect its absorption.
Distribution: The drug has a plasma protein binding rate of 72% and a distribution volume of 32L / kg. At steady state. The peak plasma concentration of COPD patients measured 5 minutes after inhaling 18 micrograms of dry powder was 17-19 pg / ml, and then decreased rapidly in a multi-chamber model. The steady state plasma concentration is 3 to 4 pg / ml. The local concentration of the lung is unknown, but the actual drug concentration in the lung can be seen from the mode of administration. Studies in rats have shown that tiotropium cannot pass the blood-brain barrier.
Biotransformation: The extent of biotransformation is very small, as evidenced by the fact that 74% of the dose of young healthy volunteers was excreted from the kidneys as a prototype after intravenous injection of the drug. Tiotropium bromide is an ester, which is non-enzymatically decomposed into an alcohol (N-methylscopolamine) and an acid (dithiophene glycolic acid), neither of which can bind to a muscarinic receptor.
In vitro experiments with human liver microsomes and human hepatocytes have shown that some drugs (less than 20% of the intravenous dose) rely on cytochrome P450 oxidation and subsequent binding to glutathione to form various phase II metabolites. In vitro liver microsomal tests show that this enzymatic pathway can be inhibited by CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole, and gestodene. Therefore, CYP 2D6 and 3A4 are included in the metabolic pathways and are involved in the elimination of a small number of drugs. Tiotropium bromide does not inhibit cytochromes CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in liver microsomes even at higher concentrations.
Elimination: The terminal elimination half-life of tiotropium is between 5 and 6 days after inhalation. The total clearance rate of young healthy volunteers after intravenous injection was 880ml / min, and the individual variability was 22%. After intravenous administration of tiotropium bromide, it was mainly excreted in the form of the original drug (74%). After inhaling the dry powder, 14% of the dose is excreted through the urine. The remaining drugs are mainly drugs that are not absorbed in the intestine and are excreted in the feces. Tiotropium's renal clearance exceeds creatinine clearance, indicating that the drug is secreted into the urine. COPD patients inhaled once a day continuously and reached a pharmacokinetic steady state after 2-3 weeks without further drug accumulation thereafter.
Linear / Non-linear: The pharmacokinetics of tiotropium bromide within the therapeutic range after intravenous and dry powder inhalation proves to be linear pharmacokinetics.
c) Patient-specific elderly patients: As with all drugs that are mainly excreted by the kidneys, the renal clearance of tiotropium in elderly patients is reduced (COPD patients younger than 58 years of age have a clearance rate of 326 ml / min; those older than 70 years of age In COPD patients, the clearance rate is 163 ml / min). This may be related to decreased kidney function. Urinary excretion after inhalation of tiotropium bromide decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however, variability between patients and within individuals (AUC0-4 increased after dry powder inhalation) (43%), compared with patients with COPD, plasma concentrations did not change significantly with age.
Patients with renal insufficiency: Like all other drugs that are mainly excreted by the kidneys, intravenous infusion or dry powder inhalation during renal insufficiency increases and the renal clearance of the drug decreases. Mild renal insufficiency (CLCR 50-80ml / min), which is more common in the elderly, can slightly increase the plasma concentration of tiotropium (39% increase in AUC0-4 after intravenous injection). In patients with COPD with moderate to severe renal insufficiency (CLCR <50ml / min). After intravenous administration of tiotropium bromide, the blood drug concentration doubled (82% increase in AUC0-4), and the blood drug concentration after dry powder inhalation also increased.
Patients with hepatic insufficiency: Hepatic insufficiency has no effect on the pharmacokinetics of tiotropium. Tiotropium is mainly excreted by the kidneys (74% of young healthy volunteers), and a small amount is decomposed into non-pharmacologically active products by non-enzymatic esters.
Pediatric patients: see [Dosage and Administration].
d) Correlation between pharmacokinetics and pharmacological properties There is no direct correlation between pharmacokinetics and pharmacological properties.

Tiotropium bromide powder inhalant storage

Store below 25 ° C and do not freeze.
Keep it out of the reach of children!

Tiotropium bromide powder inhaler packaging

Packed in aluminum foil. 10 capsules / box, 30 capsules / box,
10 capsules + 1 HandiHaler® (medicinal powder inhaler) inhalation device / box,
30 capsules + 1 HandiHaler® inhaler / box.

Tiotropium bromide powder inhalation expiration date

24 months (effective for 9 days after peeling off the aluminum foil package).

Standard for Tiotropium Bromide Powder Inhaler

Import drug registration standard JX20080017 ^[1]