Tevacomb (Aerosol) Instructions for Use

Marketing Authorization Holder

Cipla Ltd. (India)

ATC Code

R03AK06 (Salmeterol and Fluticasone)

Active Substances

Fluticasone (Rec.INN registered by WHO)

Salmeterol (Rec.INN registered by WHO)

Dosage Forms

	Tevacomb	Metered dose inhalation aerosol 25 mcg+50 mcg/1 dose: aerosol cans 120 doses
		Metered dose inhalation aerosol 25 mcg+125 mcg/1 dose: aerosol cans 120 doses
		Metered dose inhalation aerosol 25 mcg+250 mcg/1 dose: aerosol cans 120 doses

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol in the form of a homogeneous white suspension.

Excipients: ethanol – 1.56 mg, lecithin – 0.00001725 mg, tetrafluoroethane – 76.354 mg.

120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a protective cap (1) – cardboard packs.
120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a dose counter and a protective cap (1) – cardboard packs.

Metered dose inhalation aerosol in the form of a homogeneous white suspension.

Excipients: ethanol – 1.56 mg, lecithin – 0.000032 mg, tetrafluoroethane – 76.279 mg.

120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a protective cap (1) – cardboard packs.
120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a dose counter and a protective cap (1) – cardboard packs.

Metered dose inhalation aerosol in the form of a homogeneous white suspension.

Excipients: ethanol – 1.56 mg, lecithin – 0.00005726 mg, tetrafluoroethane – 76.154 mg.

120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a protective cap (1) – cardboard packs.
120 doses – aluminum aerosol cans with a metering valve, supplied with an inhalation device with a dose counter and a protective cap (1) – cardboard packs.

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Combined bronchodilator agent (selective beta₂-adrenomimetic + topical glucocorticosteroid)

Pharmacological Action

Combined bronchodilator drug containing two active components: Fluticasone (a synthetic fluorinated glucocorticosteroid) and Salmeterol (a long-acting selective beta₂-adrenergic receptor agonist), which have different mechanisms of action.

Fluticasone has pronounced anti-inflammatory and anti-allergic activity. The pharmacological action of fluticasone is due to its ability to bind to glucocorticoid receptors of target cells, including airway epithelial cells. In terms of receptor binding affinity, Fluticasone is 18 times more potent than dexamethasone, almost 2 times more potent than beclomethasone-17-monopropionate, the active metabolite of beclomethasone dipropionate, and almost 3 times more potent than budesonide. Fluticasone inhibits the influx of mast cells, eosinophils, lymphocytes, macrophages, neutrophils, and reduces the production and release of inflammatory mediators and other biologically active substances (including histamine, prostaglandins, leukotrienes, and cytokines) involved in the formation of allergen-specific sensitization. As a result, capillary permeability decreases, exudation disappears, mucus secretion by mucous glands decreases, and bronchial patency is restored.

Salmeterol increases the intracellular content of cyclic 3,5-adenosine monophosphate (cAMP), which leads to relaxation of the smooth muscles of the bronchial wall.

The salmeterol molecule has a long side chain that binds to the external domain of the receptor, which allows Salmeterol to provide protection against histamine-induced bronchoconstriction and longer bronchodilation (lasting at least 12 hours) compared to short-acting beta₂-adrenergic receptor agonists. Salmeterol is at least 50 times more selective for beta₂-adrenergic receptors than salbutamol.

It suppresses the early and late stages of an allergic reaction; after a single dose administration, bronchial hyperreactivity decreases, and the suppression of the late phase lasts for 30 hours, when the bronchodilating effect is no longer present.

The described properties indicate that Salmeterol, in addition to its bronchodilatory effect, has an additional action, the clinical significance of which has not been definitively established.

Salmeterol prevents the occurrence of bronchospasm, reduces airway resistance, and increases vital lung capacity. In therapeutic doses, it does not affect the cardiovascular system.

Pharmacokinetics

When administered together by inhalation, Fluticasone and Salmeterol do not affect each other’s pharmacokinetics.

Salmeterol is absorbed by lung tissues and, without undergoing metabolism in the lungs, enters the systemic circulation. The C_max of salmeterol in plasma is extremely low (about 200 pg/ml), reached within 5-10 minutes after drug administration. The plasma concentration of salmeterol correlates with the dose of the inhaled drug. Systemic absorption of fluticasone occurs primarily through the lungs, with absorption initially more intense but then slowing down. Part of the inhalation dose may be swallowed; due to the low solubility of the drug in water and due to its presystemic metabolism, bioavailability from the gastrointestinal tract is less than 1%.

Fluticasone

Absorption and Distribution

The absolute bioavailability of fluticasone when using salmeterol/fluticasone is 5.3% of the nominal dose. C_max in blood plasma is reached in approximately 0.33-1.5 hours. There is a direct relationship between the inhaled dose and the plasma concentration of fluticasone.

The distribution of fluticasone is characterized by rapid clearance from plasma, a large V_d at steady state (300 L), and a terminal T_1/2 of approximately 5.9 hours. Plasma protein binding is approximately 91%.

Metabolism and Excretion

Fluticasone undergoes biotransformation in the liver with the participation of the cytochrome P450 system isoenzyme 3A4 to form an inactive carboxyl metabolite.

It is excreted by the intestines and in the urine, mainly as a hydroxylated metabolite. Renal clearance of unchanged fluticasone is less than 0.2%, renal clearance of the metabolite containing a carboxyl group is less than 5% of the dose.

Indications

• As basic therapy for bronchial asthma, when the use of a combination of a long-acting selective beta₂-adrenergic agonist with an inhaled glucocorticosteroid is appropriate;
• As maintenance therapy for COPD.

ICD codes

Dosage Regimen

Intended for inhalation use.

For bronchial asthma, adults and adolescents over 12 years are prescribed Tevacomb 25 mcg/50 mcg or 25 mcg/125 mcg or 25 mcg/250 mcg, 2 inhalation doses 2 times/day. Children from 4 to 12 years are prescribed Tevacomb 25 mcg/50 mcg, 2 inhalation doses 2 times/day.

For COPD, adults are prescribed Tevacomb 25 mcg/125 mcg or 25 mcg/250 mcg, 2 inhalation doses 2 times/day.

The drug is prescribed at the minimum effective dose that provides control of disease symptoms. When the effect is achieved by using the drug 2 times/day, it is advisable to reduce the dose to the minimum effective or switch to a lower dose, with a frequency of application of 1 time/day. The amount of fluticasone in the selected form should correspond to the severity of the disease.

To achieve the optimal effect, the drug should be used regularly, even in the absence of symptoms of bronchial asthma and COPD. The course of treatment and the dose of the drug are determined individually by the doctor.

In elderly patients and in patients with liver or kidney pathology, dose adjustment is not required.

Instructions for using the inhaler

The Tevacomb drug is placed in an aluminum can with a metering valve, supplied with an inhalation device with a protective cap.

The inhalation device may contain a dose counter.

1. Remove the protective cap from the inhalation device and make sure that the outlet tube of the inhalation device is clean. Hold the inhalation device between the index finger and thumb in a vertical position, with the thumb placed on the bottom of the inhalation device and the index finger on the bottom of the aluminum can.
2. Shake the aluminum can up and down.

If the inhalation device contains a dose counter, then before using it for the first time, position the inhaler away from the face and press twice into the air to release 2 doses. The dose counter will show the number “120”: the number of doses in the can. Now the inhaler is ready for further use.

1. Take a deep breath out through the mouth and firmly grasp the outlet tube of the inhalation device with the lips.
2. Take a slow and deep breath. At the moment of inhalation, press the index finger on the bottom of the aluminum can, releasing a dose of Tevacomb, and continue to inhale slowly.
3. Then remove the inhalation device from the mouth and hold the breath for 10 seconds or for a time that does not cause discomfort. Exhale slowly.
4. After inhalation, rinse the mouth with water, trying not to swallow the aerosol that got on the oral mucosa during inhalation.
5. If more than one dose of the drug is required, wait 1 minute and repeat all actions, starting from step 2 and ending with step 6.
6. Then close the inhalation device with the protective cap.

When performing steps 3 and 4, do not rush. It is important to inhale as slowly as possible at the moment of releasing the dose of medicine. You can practice in front of a mirror before use. If “steam” was noticed coming out of the top of the can or from the corners of the mouth, then you need to start again from step 2.

Cleaning the inhaler

The inhalation device should be cleaned at least once a week.

Inhalation device without a dose counter. Remove the aluminum can from the inhalation device. Gently rinse the inhalation device and the protective cap with warm water. Do not use hot water! Shake the inhalation device and the protective cap to remove residual water and dry them without using heating devices. Do not immerse the aluminum can in water!

Inhalation device with a dose counter. Remove the protective cap from the inhalation device, but do not remove the aluminum can from it. Wipe the inside and outside of the inhalation device and its outlet tube with a clean, dry cloth. Replace the protective cap.

Warning: do not wash or rinse any part of the inhaler in water!

Information about the dose counter

The dose counter shows the number of doses in the can. As the inhaler is used, the numbers on the counter decrease, and the counter shows the remaining number of doses in the can. When 40 doses remain in the can, the color on the counter changes from green to red. This shows that there are not many doses left in the can and you need to think about a new inhaler.

When the dose counter shows the number “0”, it means that there is no more drug in the can and a new inhaler is needed. It may seem that the can is not completely empty, but with further use, the patient will not receive the correct amount of the drug.

Adverse Reactions

Since Tevacomb contains Salmeterol and Fluticasone, the development of adverse reactions characteristic of each component separately should be expected. No additional side effects with the simultaneous use of the two components of the drug have been noted.

Cardiovascular system: tachycardia, palpitations, cardiac arrhythmias, myocardial ischemia.

Nervous system: headaches, including migraines, sleep disorders, tremor, behavioral disorders, including hyperactivity and irritability, anxiety.

Allergic reactions: rash and angioedema; in isolated cases – angioedema of the face and oropharynx, development of respiratory symptoms – shortness of breath and bronchospasm and, extremely rarely, anaphylactic reactions, allergic rhinitis and conjunctivitis.

Respiratory system: nosebleeds, nasal congestion, dryness of the nasal mucosa, laryngitis, hoarseness.

Digestive system: irritation of the oropharyngeal mucosa, change in taste sensations, hyposalivation, gastrointestinal infections, damage to hard dental tissues, abdominal pain, increased gas formation, constipation, hemorrhoids.

Dermatological reactions: hemorrhages, eczema, dermatitis and dermatoses.

Musculoskeletal system: muscle cramps, bone and joint pain.

Infections and infestations: candidiasis of the oral mucosa and pharynx, urinary tract infections, respiratory infections, other bacterial and viral infections.

As with the use of other inhalation drugs, the development of paradoxical bronchospasm is possible while using Tevacomb. In this case, the use of the drug should be stopped immediately, the patient’s condition should be assessed, and, if necessary, alternative therapy should be prescribed.

Theoretically, the development of systemic reactions is possible, including Cushing’s syndrome, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma, hyperglycemia.

Contraindications

• Children under 4 years of age;
• Hypersensitivity to salmeterol, fluticasone and other components of the drug.

With caution, the drug should be prescribed for tuberculosis, fungal, viral or bacterial infections, pheochromocytoma, thyrotoxicosis, hypothyroidism, diabetes mellitus, uncontrolled hypokalemia, uncontrolled arterial hypertension, arrhythmia, coronary artery disease, QT interval prolongation on ECG, idiopathic hypertrophic subaortic stenosis, cataracts, glaucoma, osteoporosis, during pregnancy and lactation.

Use in Pregnancy and Lactation

The drug can be prescribed to pregnant and breastfeeding women only if the intended benefit to the mother outweighs the potential risk to the fetus or child.

Use in Hepatic Impairment

No dose adjustment is required in patients with liver pathology.

Use in Renal Impairment

No dose adjustment is required in patients with kidney pathology.

Pediatric Use

Contraindicated: children under 4 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Patients should be informed that for the best effect, Tevacomb must be used daily even in the absence of symptoms.

Tevacomb is not a drug for relieving attacks of bronchial asthma. Short-acting bronchodilators are used to relieve attacks. The patient should be advised to always carry a drug for relieving bronchospasm with them. An increased need for the use of short-acting bronchodilators indicates a worsening of the disease. Sudden and increasing deterioration in the control of bronchospastic syndrome is a potential life-threatening condition. In such a situation, it is necessary to consult a doctor, as the dose of Tevacomb used provides adequate control of the disease.

Like other inhalation drugs containing glucocorticosteroids, Tevacomb should be used with caution in patients with active or latent pulmonary tuberculosis, severe cardiovascular diseases, including cardiac arrhythmias, hypokalemia, thyrotoxicosis.

Any inhaled glucocorticosteroid can cause systemic effects, especially with long-term use in high doses; it should be noted, however, that the likelihood of such symptoms is much lower than with treatment with oral glucocorticosteroids. Possible systemic effects include suppression of adrenal function, growth retardation in children and adolescents, decreased bone mineral density, cataracts and glaucoma. In view of the above, the dose of the inhaled glucocorticosteroid should be titrated to the minimum that maintains effective control.

Effect on ability to drive vehicles and operate machinery

No special precautions are required for persons driving a car or operating complex machinery.

Overdose

Symptoms: tremor, headache, tachycardia.

Treatment: cardioselective beta-adrenergic receptor blockers are used as optimal antidotes, which should be used with caution when treating patients with a history of bronchospasm. If it is necessary to discontinue Tevacomb due to an overdose of the beta₂-agonist included in the drug, the patient should be prescribed appropriate glucocorticosteroid replacement therapy.

With long-term use of the drug in doses exceeding the recommended ones, some suppression of adrenal cortex function is possible. Given the possible complications, it is recommended to monitor the reserve function of the adrenal cortex.

Drug Interactions

Under normal conditions, low plasma concentrations of salmeterol and fluticasone are achieved after inhalation administration of the drug; however, potential interaction with other substrates or inhibitors of the CYP3A4 isoenzyme cannot be excluded.

The use of non-selective and selective beta-blockers in patients with bronchial asthma should be avoided due to the risk of bronchospasm. The use of the drug Tevacomb in combination with β-blockers is permissible only in the presence of strict indications.

Concomitant use with other agents containing beta₂-adrenoreceptor agonists may lead to an enhancement of effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F). Do not freeze.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.