Seebri^® Breezhaler (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Siegfried Barbera, S.L. (Spain)

Or

Novartis Pharma Stein AG (Switzerland)

Primary Packaging

SIEGFRIED BARBERA, S.L. (Spain)

Secondary Packaging

SIEGFRIED BARBERA, S.L. (Spain)

Or

NOVARTIS PHARMA STEIN, AG (Switzerland)

Quality Control Release

NOVARTIS PHARMA STEIN, AG (Switzerland)

Or

NOVARTIS FARMACEUTICA, S.A. (Spain)

ATC Code

R03BB06 (Glycopyrronium bromide)

Active Substance

Glycopyrronium bromide (Rec.INN registered by WHO)

Dosage Form

Seebri® Breezhaler®

Powder for inhalation capsules 50 mcg: 6, 10, 12, 18, 20, 24, 30, 40 or 50 pcs. in a kit with an inhalation device (Breezhaler)

Dosage Form, Packaging, and Composition

Powder for inhalation capsules hard, size No. 3, transparent, with an orange cap and body, marked with a black logo under a black band on the cap and the inscription “GPL50” in black ink above a black band on the body; capsule contents – powder white or almost white in color.

Excipients : lactose monohydrate – 24.9 mg, magnesium stearate – 0.037 mg.

Capsule shell composition: hypromellose – 45.59 mg, water – 2.7 mg, carrageenan – 0.42 mg, sodium chloride – 0.18 mg, sunset yellow dye (E110) – 0.12 mg.

Ink composition: shellac, black iron oxide dye, propylene glycol, sodium hydroxide.

6 pcs. – blisters made of PA/Al/PVC and aluminum foil (1) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (2) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (3) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (4) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
6 pcs. – blisters made of PA/Al/PVC and aluminum foil (5) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
10 pcs. – blisters made of PA/Al/PVC and aluminum foil (1) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
10 pcs. – blisters made of PA/Al/PVC and aluminum foil (2) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
10 pcs. – blisters made of PA/Al/PVC and aluminum foil (3) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
10 pcs. – blisters made of PA/Al/PVC and aluminum foil (4) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.
10 pcs. – blisters made of PA/Al/PVC and aluminum foil (5) in a kit with an inhalation device (Breezhaler) – cardboard packs^x.

^x The presence of a first-opening control on the cardboard pack is allowed.

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, m-cholinolytic. The mechanism of action is based on blocking the action of acetylcholine on the smooth muscle cells of the airways, which leads to a bronchodilator effect.

Glycopyrronium bromide, being an m-cholinolytic, has a high affinity for m-cholinergic receptors of the M1-3 subtypes. At the same time, Glycopyrronium bromide has 4-5 times greater selectivity for the M1 and M3 receptor subtypes compared to the M2 receptor subtype.

The duration of action of glycopyrronium bromide after inhalation is due to the prolonged maintenance of its therapeutic concentration in the lungs, which is confirmed by a longer T_1/2 of the active substance after inhalation compared to intravenous administration. In numerous clinical studies, it has been shown that the use of glycopyrronium bromide in patients with COPD significantly improves lung function (assessed by changes in FEV1): the therapeutic effect occurs within the first 5 minutes after inhalation, with a significant increase in FEV1 from baseline values within the range of 0.091 L to 0.094 L, the bronchodilator effect of glycopyrronium bromide after inhalation lasts more than 24 hours.

Pharmacokinetics

After inhalation, Glycopyrronium bromide is rapidly absorbed into the systemic circulation and reaches C_max within 5 minutes.

The absolute bioavailability of glycopyrronium bromide after inhalation is approximately 40%. About 90% of the systemic exposure to glycopyrronium bromide is due to absorption in the lungs, and 10% is due to absorption from the gastrointestinal tract. The absolute bioavailability after oral administration of glycopyrronium bromide is estimated at 5%. With regular inhalations (once daily), the steady state of glycopyrronium bromide is reached within 1 week. The C_ss^max of glycopyrronium bromide (inhalation 50 mcg once daily) and the plasma concentration of glycopyrronium bromide immediately before the next dose are 166 pg/ml and 8 pg/ml, respectively.

After intravenous administration, the V_ss of glycopyrronium bromide was 83 L and the volume of distribution in the terminal phase (V_z) was 376 L. The apparent V_z after inhalation (V_z/F) was 7310 L, reflecting slower elimination of glycopyrronium bromide after inhalation.

The binding of glycopyrronium bromide to human plasma proteins in vitro was 38-41% at concentrations of 1-10 ng/ml. These concentrations are at least 6 times higher than the C_ss achieved in plasma when using the drug at a dose of 50 mcg once daily.

It was noted that hydroxylation of glycopyrronium bromide leads to the formation of various mono- and bis-hydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). In vitro studies have shown that CYP450 isoenzymes contribute to the oxidative biotransformation of glycopyrronium bromide. Hydrolysis to M9 appears to be catalyzed by cholinesterase enzymes. Since in vitro studies did not reveal metabolism of the active substance in the lungs, and M9 contributes insignificantly to circulation (4% of the C_max and AUC of glycopyrronium bromide) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance absorbed from the gastrointestinal tract (after inhalation) through presystemic hydrolysis and/or during the “first pass” through the liver. After inhalation or intravenous administration, only minimal amounts of M9 were detected in urine (<0.5% of the administered dose). Glucuronic acid conjugates and/or sulfates of glycopyrronium bromide were detected in human urine after repeated inhalations in amounts of approximately 3% of the dose. In vitro inhibition studies demonstrated that Glycopyrronium bromide did not cause significant inhibition of the CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 isoenzymes, the MDR1, MRP2 or MXR transporters, or the OAT1 or OAT2 transporters. In enzyme induction studies in vitro, no significant induction by glycopyrronium bromide of any of the tested cytochrome P450 isoenzymes, or of UGT1A1 and the MDR1 and MRP2 transporters, was detected.

Renal excretion of glycopyrronium bromide reaches 60-70% of the total plasma clearance, 30-40% is excreted by other routes – with bile or through metabolism. After single and repeated inhalations of glycopyrronium bromide in the range from 50 to 200 mcg once daily in healthy volunteers and patients with COPD, the mean renal clearance was in the range of 17.4-24.4 L/h. Active tubular secretion contributes to the renal excretion of glycopyrronium bromide. Up to 20% of the administered dose is found in the urine unchanged. The plasma concentration of glycopyrronium bromide decreases in a multiphasic manner. The mean terminal T_1/2 is longer after inhalation (33-57 h) than after intravenous administration (6.2 h) and oral administration (2.8 h). The nature of the elimination suggests prolonged absorption in the lungs and/or penetration of glycopyrronium bromide into the systemic circulation during and after 24 hours after inhalation.

In patients with COPD, systemic exposure, as well as total urinary excretion of glycopyrronium bromide at steady state, increased proportionally to the dose in the range from 50 mcg to 200 mcg.

Indications

Maintenance therapy of bronchial obstruction disorders in patients with COPD.

ICD codes

Dosage Regimen

Administer Seebri Breezhaler by oral inhalation only. Do not swallow the capsules.

The recommended dose for the maintenance treatment of COPD is one 50 mcg capsule inhaled once daily.

Use the Breezhaler inhalation device provided. Always use a new capsule immediately before each dose. Do not use a capsule that has been previously pierced or is loose in the packaging.

Inspect the capsule before use. Use only capsules that are intact and contain a white or almost white powder.

Prepare the dose immediately before use. Open the blister pack only at the time of inhalation to prevent moisture degradation.

If a dose is missed, administer it as soon as remembered on the same day. Do not double the dose to make up for a forgotten one.

Do not exceed the prescribed once-daily dosage. More frequent administration is not recommended and will not provide additional benefit.

This product is not indicated for the relief of acute bronchospasm. Have a separate, fast-acting bronchodilator available for rescue therapy.

Rinse your mouth with water after each inhalation to help reduce the risk of oropharyngeal side effects such as dry mouth.

Regularly clean the Breezhaler device as described in the patient instructions to ensure proper drug delivery.

Adverse Reactions

Respiratory system disorders common – nasopharyngitis; uncommon – rhinitis, sinus congestion, productive cough, pharyngeal irritation, epistaxis.

Digestive system disorders common – dry mouth, gastroenteritis, vomiting; uncommon – dyspepsia, dental caries.

Nervous system disorders common – headache, insomnia; uncommon – hypoesthesia.

Metabolism disorders uncommon – hyperglycemia, diabetes mellitus.

Cardiovascular system disorders uncommon – atrial fibrillation, palpitations.

Skin and subcutaneous tissue disorders uncommon – skin rash.

Musculoskeletal system disorders common – muscle pain; uncommon – limb pain, skeletal muscle pain in the chest.

Urinary system disorders common – urinary tract infection; uncommon – cystitis, dysuria, urinary retention.

General disorders common – neck pain; uncommon – fatigue, asthenia.

Contraindications

Concomitant use with inhaled medicinal products containing other m-cholinolytics; children and adolescents under 18 years of age; hypersensitivity to glycopyrronium bromide.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus or breastfed infant.

There are no clinical data on the use of glycopyrronium bromide during pregnancy. It is not known whether Glycopyrronium bromide is excreted in human breast milk.

Preclinical studies have shown no teratogenic effect of the drug after inhalation. Neither reproductive toxicity studies nor other animal studies provide any reason to believe that Glycopyrronium bromide may affect fertility in men or women.

Special Precautions

Use with caution in angle-closure glaucoma, conditions accompanied by urinary retention, severe renal failure (GFR below 30 ml/min/1.73 m²), including the terminal stage requiring hemodialysis, in unstable coronary artery disease, history of myocardial infarction, cardiac arrhythmias, QT_c prolongation (corrected QT >0.44 s). If use in such cases is necessary, medical supervision is required.

Glycopyrronium bromide is not recommended for the relief of acute episodes of bronchospasm.

In the general COPD population, patients over 40 years of age significantly predominate, so if use in patients under 40 years of age is necessary, spirometric confirmation of the COPD diagnosis is required.

Drug Interactions

In clinical studies in healthy volunteers, cimetidine, an inhibitor of organic cation transporters affecting the renal clearance of glycopyrronium bromide, increased the AUC of glycopyrronium bromide by 22% and decreased renal clearance by 23%. Based on these indicators, no clinically significant interaction is expected with the concomitant use of glycopyrronium bromide with cimetidine or other cation transporter inhibitors.

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.