Serobid®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEROBID® (SEROBID)

Composition:

Active substance: salmeterol;

1 dose of the medicinal product contains 25 mcg of salmeterol (as salmeterol xinafoate);

Excipients: lecithin, anhydrous ethanol, propellant HFA-134a (tetrafluoroethane).

Pharmaceutical form. Pressurized inhalation, suspension.

Main physicochemical properties: white, homogeneous suspended aerosol for inhalation, contained in a pressurized container.

Pharmacotherapeutic group.

Antiasthmatic agents. Adrenergic drugs for inhalation. Selective β2-adrenoreceptor agonists. ATC code: R03AC12.

Pharmacological properties.

Pharmacodynamics.

Salmeterol is a selective long-acting β2-adrenergic receptor agonist (duration of action 12 hours), whose molecule has a long side chain that binds to the outer site of the receptor. Due to this, salmeterol is a more effective agent for preventing histamine-induced bronchospasm and produces a longer-lasting (at least 12 hours) bronchodilation compared to short-acting β2-adrenergic receptor agonists. In vitro experiments have shown that salmeterol is a potent and long-lasting inhibitor of the release from mast cells of mediators such as histamine, leukotrienes, and prostaglandin D2. Salmeter policrom suppresses both the early and late phases of the allergic reaction; after a single dose, suppression of the late phase lasts up to 30 hours, while the bronchodilatory effect has already subsided. A single administration of salmeterol reduces bronchial hyperreactivity. These properties indicate that salmeterol has additional, non-bronchodilatory activity; however, the full clinical significance of this is not completely understood. The mechanism of this activity differs from the anti-inflammatory effect of corticosteroids, and therefore corticosteroid therapy should not be discontinued or its dose reduced when using salmeterol.

The use of salmeterol has been studied in the treatment of chronic obstructive pulmonary diseases, where it has been demonstrated that the drug improves symptoms, lung function, and patients' quality of life.

Pharmacokinetics.

Salmeterol acts locally in the lungs; therefore, its plasma concentration does not influence the therapeutic effect. Additional data on the pharmacokinetics of salmeterol are limited due to technical difficulties in measuring this active substance in plasma, owing to the very low concentration of salmeterol (approximately 200 picograms/mL or less) in blood plasma when therapeutic inhaled doses are administered.

Clinical characteristics.

Indications.

Regular symptomatic add-on treatment of reversible airway obstruction in bronchial asthma, including patients with nocturnal asthma attacks, whose disease symptoms are not adequately controlled by inhaled corticosteroids.

Treatment of chronic obstructive pulmonary disease (COPD).

Prevention of exercise-induced asthma attacks.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of both non-selective and selective β-blockers should be avoided in the treatment of reversible broncho-obstructive syndrome, except in cases of acute necessity.

Administration of β2-agonists may lead to potentially serious hypokalaemia. Particular attention should be paid to this effect during treatment of severe asthma, as hypokalaemia may be potentiated by concomitant use of xanthine derivatives, steroids, and diuretics.

Concomitant use of ketoconazole and salmeterol results in a significant increase in salmeterol plasma concentrations (1.4-fold for Cmax and 15-fold for AUC), which may lead to QT interval prolongation and increased heart rate. No significant clinical effects on blood pressure, heart rate, blood glucose, or serum potassium levels have been observed. Therefore, concomitant use with ketoconazole should be avoided unless the benefit outweighs the potentially increased risk of adverse effects associated with salmeterol use. A similar interaction risk is likely with other potent CYP3A4 inhibitors (e.g., itraconazole, telithromycin, ritonavir).

Concomitant use with erythromycin may cause a slight, but statistically non-significant, increase in the effect of salmeterol. Concomitant use with erythromycin is not associated with any serious adverse effects.

Special precautions for use

Asthma treatment should generally follow a stepwise programme, with the patient's response to treatment assessed clinically and by lung function tests.

Salmeterol should not be used as initial asthma treatment. Salmeterol does not replace oral or inhaled corticosteroids; it should be used as an add-on therapy to them. Patients must not discontinue or reduce corticosteroid therapy, even if their condition improves during salmeterol treatment, without prior consultation with a physician.

The product must not be used for the treatment of acute asthma attacks; for this purpose, short-acting inhaled bronchodilators should be used. Patients should be advised to always carry such medications for symptom relief.

An increased use of bronchodilators, particularly short-acting inhaled β2-agonists, indicates worsening asthma control. In such cases, the treatment plan should be reviewed and a decision made to intensify anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids).

Although Serobid® may be used as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, treatment with Serobid® should not be initiated during significant worsening or severe exacerbation of asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Serobid®. Therefore, patients should be warned about the need to continue treatment, but should consult a physician if asthma symptoms are poorly controlled during therapy.

Sudden and progressive asthma exacerbation is a potentially life-threatening condition requiring prompt decisions regarding increased corticosteroid dosing. Daily peak flow monitoring may be beneficial for patients at risk of such events.

Serobid® should be used as maintenance therapy for asthma in combination with inhaled or oral corticosteroids. Long-acting bronchodilators cannot be the sole or primary component of asthma maintenance therapy.

Due to the risk of asthma exacerbation, salmeterol treatment should not be abruptly discontinued once asthma control is achieved. The dose of Serobid® may be gradually reduced under medical supervision to the minimum effective dose. In patients with chronic obstructive pulmonary disease (COPD), discontinuation of therapy may also lead to symptom decompensation and should be performed under medical supervision.

The dose should be gradually reduced under medical supervision.

As with other inhaled therapies, paradoxical bronchospasm with immediate wheezing and deterioration in expiratory spirometry parameters may occur during Serobid® use. In such cases, immediate treatment with a rapid-acting inhaled bronchodilator is required. Salmeterol should be discontinued immediately, the patient evaluated, and alternative therapy initiated if necessary.

There have been reports of pharmacological side effects associated with β2-agonist therapy, such as tremor, tachycardia, and headache, although these tend to be transient and diminish with regular use (see section "Adverse reactions").

Serobid® should be prescribed with caution in patients with thyrotoxicosis.

There are isolated reports of increased blood glucose levels with salmeterol use; therefore, this should be considered when treating patients with diabetes mellitus.

Cardiovascular effects such as elevated systolic blood pressure and increased heart rate may occasionally occur with sympathomimetics, particularly at doses exceeding therapeutic levels. Therefore, Serobid® should be used with caution in patients with pre-existing cardiovascular disorders.

β2-agonist therapy may cause potentially severe hypokalaemia. Particular caution is required during severe asthma exacerbation, as this effect may be potentiated by hypoxia and concomitant use of xanthine derivatives, corticosteroids, and diuretics. In such situations, serum potassium levels should be monitored.

Data from a large U.S. clinical trial (the Salmeterol Multicenter Asthma Research Trial - SMART), which compared the safety of Serobid® versus placebo as add-on therapy to standard asthma treatment, showed an increased risk of asthma-related deaths in patients treated with Serobid®. These data suggested that African-American patients may have a higher risk of serious respiratory complications or death when treated with salmeterol compared to placebo. It is unknown whether this is related to pharmacogenetic or other factors. Therefore, patients of African or Afro-Caribbean origin should be warned to consult a physician if their condition worsens or asthma symptoms are not controlled during salmeterol therapy.

Data from drug interaction studies indicate that concomitant use with systemic ketoconazole increases the effects of salmeterol. This may lead to QT interval prolongation and enhanced tachycardia. Therefore, concomitant use with ketoconazole should be avoided unless the potential benefit outweighs the increased risk of adverse effects associated with salmeterol.

Patients should be instructed in the correct use of the inhaler, and their inhaler technique should be checked regularly to ensure optimal delivery of the inhaled medication to the lungs.

Since systemic absorption primarily occurs through the lungs, using a spacer (a device to facilitate inhalation of inhaled medications) in combination with the inhaler may alter the amount of drug reaching the lungs. This may potentially increase the risk of systemic adverse reactions; therefore, dosage selection should be carefully considered.

Use during pregnancy or breastfeeding

Moderate clinical data on the use of the drug in pregnant women indicate no evidence of developmental malformations or fetal/neonatal toxicity with salmeterol.

As a precautionary measure, it is advisable to avoid using Serobid® during pregnancy.

Available pharmacodynamic/toxicological data in animals show excretion of salmeterol into milk. A risk to breastfed infants cannot be excluded.

The decision to discontinue breastfeeding or to discontinue/abstain from Serobid® therapy should be made by weighing the benefits of breastfeeding for the child against the benefits of therapy for the woman.

Effect on ability to drive vehicles or operate machinery

There are no data on the effect of this drug on driving ability. However, if adverse reactions affecting the nervous system (e.g. tremor, dizziness) occur, driving vehicles or operating machinery should be avoided.

Method of Administration and Dosage

The product is intended exclusively for inhalation use.

The medication should be used regularly. Full therapeutic effect is achieved after several doses of the product. Since there is a possibility of adverse effects occurring with overdosing of drugs of this class, the dosage and frequency of administration may be increased only under medical supervision.

Recommended Dosages

Asthma

Adults and children aged 12 years and older: 2 inhalations (2 × 25 mcg salmeterol) twice daily. In cases of severe airway obstruction, the dose may be increased to 4 inhalations (4 × 25 mcg salmeterol) twice daily.

Children aged 4 years and older: 2 inhalations (2 × 25 mcg salmeterol) twice daily.

Insufficient clinical data on the use of salmeterol for the treatment of children under 4 years of age preclude administration of the product to patients in this age group.

Chronic Obstructive Pulmonary Disease (COPD)

Adults: 2 inhalations (2 × 25 mcg salmeterol) twice daily.

Children: the product is not indicated for use in children for this condition.

Special Patient Groups

Dosage adjustment is not required when treating elderly patients or patients with renal impairment. There are no clinical data on the use of salmeterol in patients with hepatic impairment.

Instructions for Using the Inhaler

Checking the Inhaler

Before first use of the inhaler or after a break in use of more than 1 week, remove the mouthpiece cap by gently pressing its sides, shake the inhaler well, and release 1 spray into the air to ensure proper functioning.

Recommendations for Using the Inhaler

1. Remove the mouthpiece cap by gently pressing its sides.
2. Ensure that there are no foreign objects inside or outside the inhaler, including the mouthpiece.
3. Shake the inhaler thoroughly to remove any foreign objects and to ensure uniform mixing of its contents.
4. Hold the inhaler vertically in the hand between the thumb and other fingers, with the thumb placed on the body of the inhaler below the mouthpiece.
5. Breathe out as deeply as possible, then place the mouthpiece in the mouth between the teeth and close the lips around it without biting.
6. While inhaling slowly and deeply through the mouth, press down on the top of the inhaler to release the salmeterol spray, continuing to inhale slowly and deeply. One press of the inhaler top delivers one dose.
7. Hold your breath, remove the inhaler from the mouth, and remove your finger from the top of the inhaler. Continue holding your breath for as long as possible.
8. If additional sprays are needed, wait approximately 30 seconds, keeping the inhaler in a vertical position. Then repeat steps 3–7.
9. Replace the mouthpiece cap by pressing it into place in the correct direction until a click is heard.

Children. It may be necessary for adults to administer inhalations to children. Ask the child to breathe out and then immediately administer the spray as the child begins to inhale. It is recommended to practice the inhalation technique together. Older children or weakened adults may hold the inhaler with both hands. Place both index fingers on top of the inhaler and both thumbs on the base below the mouthpiece.

Recommendations for Cleaning the Inhaler

The inhaler should be cleaned at least once a week.

1. Remove the mouthpiece cap.
2. Do not remove the metal canister from the plastic holder.
3. Wipe the inside and outside surfaces of the mouthpiece cap and the plastic holder with a dry cloth.
4. Replace the mouthpiece cap.

Important Notes!

Steps 5, 6, and 7 should be performed without rushing.

Inhale as slowly as possible just before actuating the spray. For the first few times, practice in front of a mirror.

If a "mist" appears around the top of the inhaler or around the mouth, restart the procedure from step 2.

Immediately after use, close the mouthpiece with the cap, pressing gently until a click is heard.

As with other inhaled medications, therapeutic effectiveness may decrease if the canister becomes cold.

Do not place the metal canister in water.

Do not disassemble, puncture, or burn the canister, even after complete use.

Children.

Insufficient clinical data on the use of salmeterol for the treatment of children under 4 years of age preclude administration of the product to patients in this age group.

Overdose.

Signs and symptoms expected in salmeterol overdose are those typical of excessive stimulation of β2-adrenergic receptors, including tremor, headache, dizziness, tachycardia, increased systolic blood pressure, and hypokalemia.

In case of overdose, the patient should be treated symptomatically with appropriate monitoring as necessary.

Adverse Reactions

The adverse reactions listed below are classified by organ systems and frequency of occurrence. Frequency is defined as follows: very common ≥ 1/10; common ≥ 1/100, < 1/10; uncommon ≥ 1/1000, < 1/100; rare ≥ 1/10,000, < 1/1000; very rare < 1/10,000.

Immune System

Hypersensitivity reactions, including those listed below.

Uncommon: rash.

Very rare: anaphylactic reaction, including swelling and angioneurotic edema, bronchospasm, and anaphylactic shock.

Metabolism and Nutrition

Rare: hypokalemia.

Very rare: hyperglycemia.

Psychiatric Disorders

Uncommon: nervousness.

Rare: insomnia.

Nervous System

Common: tremor and headache.

Adverse reactions typical for all β2-agonists such as tremor and headache have been reported, but these were reversible and diminished with regular use of the drug. Tremor occurred when doses exceeding 50 mcg twice daily were used.

Cardiovascular System

Common: palpitations.

Palpitations, a known adverse reaction associated with all β2-agonists, have been reported; however, this effect was reversible and decreased with regular use of the medication.

Uncommon: tachycardia.

Tachycardia occurs more frequently when doses exceeding 50 mcg twice daily are administered.

Very rare: cardiac arrhythmias, including atrial fibrillation, supraventricular tachycardia, and extrasystoles.

Respiratory System

Very rare: oropharyngeal irritation and paradoxical bronchospasm.

As with other inhaled medications, paradoxical bronchospasm may occur, requiring immediate discontinuation of the drug, administration of fast-acting bronchodilators, and, if necessary, initiation of alternative therapy.

Gastrointestinal System

Very rare: nausea.

Musculoskeletal System

Common: muscle cramps.

Very rare: arthralgia.

General Disorders

Very rare: non-specific chest pain.

Shelf Life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage Conditions.

Store below 30 °C. Keep out of reach of children. Protect from direct sunlight. Do not freeze.

Packaging.

120 doses in an aluminum pressurized container with a metering valve. Each container is equipped with a polypropylene actuator with a protective cap. One container per cardboard box, enclosed in a transparent plastic pack with a tear-off strip for tamper-evident sealing.

Prescription Category. Prescription only.

Manufacturer.

Cipla Ltd. (Unit II).

Manufacturer's Address and Place of Business.

Plot No. L-139, S-103 and M-62, Verna Industrial Estate, IN – 403 722 Verna, Goa, India.