Bronpriva solopharm (Aerosol) Instructions for Use

Marketing Authorization Holder

Grotex, LLC (Russia)

ATC Code

R03BB04 (Tiotropium bromide)

Active Substance

Tiotropium bromide (Rec.INN registered by WHO)

Dosage Form

Bronpriva solopharm

Metered dose inhalation aerosol 9 mcg/dose

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol in the form of a white or almost white suspension, under pressure in an aluminum canister or a stainless steel canister, equipped with a metering valve.

(200 doses) – canisters – carton packs – By prescription

Clinical-Pharmacological Group

Bronchodilator drug – m-cholinergic receptor blocker

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other agents for inhalation administration used for the treatment of obstructive airway diseases; anticholinergic agents

Pharmacological Action

Bronchodilator agent – long-acting m-cholinergic receptor blocker.

It has the same affinity for various m-cholinergic receptor subtypes from M₁ to M₅. Inhibition of M₃ receptors in the airways leads to relaxation of smooth muscle. The bronchodilatory effect is dose-dependent and lasts for at least 24 hours. The significant duration of action is probably associated with a very slow dissociation from M₃ receptors, compared with ipratropium bromide. When administered by inhalation, Tiotropium bromide, as an anticholinergic agent of a quaternary N-structure, exerts a local selective action, and in therapeutic doses does not cause systemic anticholinergic side effects. The dissociation of tiotropium bromide from M₂ receptors occurs faster than from M₃ receptors. High receptor affinity and slow dissociation from them determine an intense and prolonged bronchodilatory effect in patients with COPD.

Bronchodilation after inhalation of tiotropium bromide is a consequence of local, not systemic action.

Clinical studies have shown that 30 minutes after a single dose, Tiotropium bromide significantly improves lung function (increase in FEV₁ and FVC) for 24 hours. Pharmacodynamic equilibrium was achieved within the 1st week, and a pronounced bronchodilatory effect was observed on the 3rd day. Tiotropium bromide significantly increases morning and evening peak expiratory flow rate measured by patients. No tolerance to the bronchodilatory effect was observed over the course of a year.

Tiotropium bromide significantly reduces the frequency of COPD exacerbations and increases the time to the first exacerbation compared with placebo. It significantly improves the quality of life, which is observed throughout the entire treatment period. Tiotropium bromide significantly reduces the number of hospitalizations associated with COPD exacerbation and increases the time to the first hospitalization.

Pharmacokinetics

Tiotropium bromide is a quaternary ammonium compound, moderately soluble in water.

Tiotropium bromide has linear pharmacokinetics within the therapeutic range after IV administration and inhalation of dry powder.

When administered by inhalation, the absolute bioavailability of tiotropium bromide is 19.5%, which indicates high bioavailability of the fraction of the drug reaching the lungs. C_max in blood plasma is reached 5 minutes after inhalation. Tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium. When taken orally as a solution, the absolute bioavailability of tiotropium bromide was 2-3%.

Plasma protein binding – 72%. V_d – 32 L/kg. At steady state, C_max in blood plasma in patients with COPD is 17-19 pg/mL 5 minutes after inhalation of the powder at a dose of 18 mcg and decreases rapidly. C_ss in blood plasma were 3-4 pg/mL.

Does not penetrate the blood-brain barrier.

The degree of biotransformation is insignificant. Tiotropium bromide is cleaved by a non-enzymatic pathway to the alcohol N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors.

Metabolism impairment is possible when using inhibitors of CYP2D6 and 3A4 isoenzymes (quinidine, ketoconazole, gestodene). Thus, CYP2D6 and 3A4 isoenzymes are involved in the metabolism of the drug. Tiotropium bromide, even at supratherapeutic concentrations, does not inhibit cytochrome P450 isoenzymes 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 in human liver microsomes.

After inhalation administration, the terminal T_1/2 is 5-6 days. Total clearance after IV administration to healthy young volunteers is 880 mL/min, with individual variability of 22%. Tiotropium bromide after IV administration is excreted mainly unchanged in the urine – 74%. After inhalation of the powder, renal excretion is 14%, the remainder, not absorbed in the intestine, is excreted in the feces. The renal clearance of tiotropium bromide exceeds the creatinine clearance, which indicates tubular secretion of the drug. After long-term use of the drug once daily in patients with COPD, the steady state of pharmacokinetic parameters is reached after 2-3 weeks, with no further accumulation observed.

In elderly patients, a decrease in the renal clearance of tiotropium bromide is observed (326 mL/min in COPD patients under 58 years old, to 163 mL/min in COPD patients over 70 years old), which is apparently due to an age-related decrease in renal function. After inhalation, the urinary excretion of tiotropium bromide decreases from 14% (young healthy volunteers) to 7% (COPD patients), however, in elderly COPD patients, no significant changes in plasma concentration were observed, taking into account inter- and intra-individual variability (after inhalation of the powder, an increase in AUC_0-4 by 43%).

In case of impaired renal function, after inhalation and IV administration, the plasma concentration of the drug increases and renal clearance decreases. In mild renal impairment (creatinine clearance 50-80 mL/min), often observed in elderly patients, the increase in plasma concentration of tiotropium bromide is insignificant (after IV administration, an increase in AUC_0-4 by 39%). In COPD patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) after IV administration of ipratropium bromide, a twofold increase in its plasma concentration was observed (82% increase in AUC_0-4), compared with plasma concentrations determined after inhalation of dry powder.

Indications

As maintenance therapy in patients with COPD, including chronic bronchitis and emphysema (maintenance therapy for persistent dyspnea and for the prevention of exacerbations).

ICD codes

Dosage Regimen

Administer by oral inhalation once daily for the maintenance treatment of COPD.

Inhale the contents of one puff, delivering 9 mcg of tiotropium.

Ensure the canister is at room temperature before use. Shake the inhaler well immediately before each inhalation.

Exhale fully. Place the mouthpiece between your lips and close them tightly.

Begin to inhale slowly and deeply through your mouth. Simultaneously, press down firmly on the canister to release the dose.

Continue to inhale as deeply as possible. Hold your breath for 10 seconds, or for as long as is comfortable.

Exhale slowly. If an additional dose is prescribed, wait approximately one minute and repeat the sequence.

Do not exceed the prescribed once-daily dosage. This product is not indicated for the relief of acute bronchospasm.

Rinse your mouth with water after each use to reduce the risk of oral candidiasis and dry mouth.

Clean the mouthpiece regularly with a damp cloth to prevent blockage.

Monitor the number of doses used. Discard the canister after 200 doses, or if it is past the expiration date, even if it is not completely empty.

Adverse Reactions

From the digestive system: mild dry mouth, often disappearing with continued treatment (≥ 1% and < 10%); oral candidiasis (≥ 0.1% and < 1%); constipation, gastroesophageal reflux (≥ 0.01% and < 1%); in isolated cases – intestinal obstruction (including paralytic ileus), dysphagia.

From the respiratory system: dysphonia, bronchospasm, cough and local pharyngeal irritation (≥ 0.1% and < 1%); epistaxis (≥ 0.01% and < 1%).

From the cardiovascular system: tachycardia, palpitations (≥ 0.01% and < 1%); in isolated cases – supraventricular tachycardia, atrial fibrillation.

From the CNS: dizziness (≥ 0.1% and < 1%).

From the urinary system: difficult urination and urinary retention in men with predisposing factors, urinary tract infections (≥ 0.01% and < 1%).

Allergic reactions: rash, urticaria, itching, hypersensitivity reactions, including immediate-type reactions (≥ 0.01% and < 1%); in isolated cases – angioedema.

Other: in isolated cases – blurred vision, increased intraocular pressure (≥ 0.01% and < 1%); glaucoma.

Most of the above adverse reactions may be associated with the anticholinergic action of tiotropium bromide.

Contraindications

First trimester of pregnancy; children and adolescents under 18 years of age; hypersensitivity to tiotropium bromide; hypersensitivity to atropine or its derivatives (including ipratropium and oxitropium).

Use in Pregnancy and Lactation

Use is contraindicated in the first trimester of pregnancy.

In the second and third trimesters of pregnancy and during lactation, Tiotropium bromide should be used only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus or breastfed infant.

Special Precautions

Use with caution in angle-closure glaucoma, prostatic hyperplasia, bladder neck obstruction.

Not intended for the relief of acute bronchospasm attacks.

After inhalation, immediate-type hypersensitivity reactions may develop.

The inhalation process itself may cause bronchospasm.

During treatment, the condition of patients with renal failure (creatinine clearance ≤ 50 mL/min) should be carefully monitored.

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate machinery. Cases of dizziness and blurred vision when using the drug may have a negative impact on the aforementioned ability.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.