Tobi^® Podhaler (Capsules) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharmaceuticals, Corporation (USA)

Primary and Secondary Packaging

KONAPHARMA, AG (Switzerland)

Quality Control Release

NOVARTIS PHARMA, GmbH (Germany)

ATC Code

J01GB01 (Tobramycin)

Active Substance

Tobramycin (Rec.INN registered by WHO)

Dosage Form

Tobi® Podhaler®

Powder for inhalation capsules 28 mg: 56 or 224 pcs. incl. with inhaler

Dosage Form, Packaging, and Composition

Powder for inhalation capsules hard transparent size #2, with radially printed blue ink symbols “NVR AVCI” on the cap and the company symbol on the body or the company symbol on the cap and “NVC AVCI” on the body; capsule contents white or almost white powder.

Excipients: sulfuric acid – 9.8 mg, 1,2-distearoyl-sn-glycero-3-phosphocholine – 6.4 mg, calcium chloride – 0.4 mg.

Shell weight and composition: 61 mg (hypromellose – 93.8%, purified water – 5%, carrageenan (E407) – 0.8%, potassium chloride – 0.4%, blue printing ink (shellac, indigo carmine-based aluminum lake (E132), titanium dioxide, macrogol) – sufficient quantity, carnauba wax – sufficient quantity).

8 pcs. – double-sided aluminum blisters (7) with perforation (morning/evening) in a kit with an inhaler case – cardboard packs.
8 pcs. – double-sided aluminum blisters (7) with perforation (morning/evening) in a kit with an inhaler case – cardboard packs (4) – cardboard boxes.

Clinical-Pharmacological Group

Antibiotic of the aminoglycoside group

Pharmacotherapeutic Group

Antibiotic-aminoglycoside

Pharmacological Action

Aminoglycoside antibiotic, produced by the fungus Streptomyces tenebrarius. It inhibits protein synthesis in the microbial cell, which leads to disruption of the cell membrane permeability, its damage, and death of the bacterial cell.

Active against a wide range of gram-negative microorganisms, including Pseudomonas aeruginosa. Bactericidal concentrations of tobramycin are equal to or slightly exceed the minimum inhibitory concentrations for Pseudomonas aeruginosa (MIC).

During inhalation use of tobramycin in most patients with cystic fibrosis, the concentration of tobramycin in sputum was 25 times higher than the MIC for Pseudomonas aeruginosa.

The group of microorganisms sensitive to tobramycin includes: Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus.

Non-susceptible are: Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans.

Pharmacokinetics

Tobramycin does not actively penetrate epithelial cell membranes. The systemic bioavailability of tobramycin after inhalation depends only on the fraction of the active substance that reaches the airways, because Tobramycin is not absorbed when taken orally. The bioavailability of tobramycin is individual and depends on the anatomical and functional characteristics of the airways and the properties of the inhaler. Ten minutes after inhalation of 300 mg of tobramycin, the average concentration of tobramycin in sputum is 1237 mcg/g (35-7414 mcg/g). Tobramycin does not accumulate in sputum. After 20 weeks of use, the average concentration of the active substance in sputum 10 minutes after inhalation is 1154 mcg/g (39-7414 mcg/g). Two hours after inhalation, the tobramycin content in sputum is 14% of its concentration in sputum 10 minutes after inhalation.

The average concentration of tobramycin in plasma 1 hour after inhalation at a dose of 300 mg in patients with cystic fibrosis is 0.95 mcg/ml (maximum permissible tobramycin content in blood plasma is 3.62 mcg/ml). Twenty weeks after the start of treatment, the average concentration of tobramycin in blood plasma 1 hour after inhalation is 1.05 mcg/ml. After inhalation, Tobramycin is mainly concentrated in the airways. The binding of tobramycin to blood plasma proteins is insignificant.

Tobramycin is not metabolized and is excreted unchanged by the kidneys.

Tobramycin is excreted by the kidneys through glomerular filtration unchanged.

The T_1/2 of tobramycin from blood plasma after inhalation of 300 mg is 3 hours in patients with cystic fibrosis.

Indications

Long-term treatment of chronic pulmonary infection caused by Pseudomonas aeruginosa, in patients with cystic fibrosis aged 6 years and older.

ICD codes

Dosage Regimen

Administer only by inhalation using the Tobi Podhaler device. Do not swallow the capsules.

The dosage for adults and children over 6 years is 112 mg (four 28 mg capsules) taken twice daily. This constitutes a total daily dose of 224 mg.

Inhale the contents of the four capsules in a single session. Follow each administration with a subsequent session approximately 12 hours later.

Adhere to a 28-day treatment cycle, followed by a 28-day therapy-free period. Continue this alternating schedule for as long as clinically indicated.

Maintain a minimum interval of 6 hours between inhalation sessions. Do not reduce the dose or frequency.

Perform inhalations at approximately the same times each day, such as morning and evening. Always use a new set of four capsules for each administration.

This regimen is fixed and is not adjusted for body weight.

Adverse Reactions

From the digestive system rarely – nausea, loss of appetite, vomiting, mouth ulcers; very rarely – diarrhea, abdominal pain and oral candidiasis.

From the blood and lymphatic system rarely – lymphadenopathy.

From the nervous system rarely – dizziness, taste disturbances, very rarely – drowsiness.

From the respiratory system infrequently – voice changes (including hoarseness), aphonia, shortness of breath, increased cough, pharyngitis; rarely – bronchospasm, chest tightness, cough, breath holding, pulmonary disorders, increased sputum production, hemoptysis, decreased lung function, laryngitis, nosebleeds, rhinitis, exacerbation of bronchial asthma; very rarely – hyperventilation, hypoxia, sinusitis; frequency not known – oropharyngeal pain.

From the hearing organ and labyrinthine disorders rarely – tinnitus, hearing loss/loss; very rarely – ear pain.

From the skin and subcutaneous tissues rarely – rash; frequency not known – hypersensitivity, itching, urticaria.

General reactions rarely – chest pain, asthenia, fever, headache; very rarely – allergic reactions, including urticaria and skin itching, fungal infection, general malaise, back pain.

Contraindications

Hypersensitivity to tobramycin and other aminoglycosides; pregnancy, breastfeeding period; children under 6 years of age.

With caution

In case of impaired function of the auditory or vestibular apparatus, in established or suspected kidney disease, in patients with neuromuscular disorders such as parkinsonism or other diseases accompanied by muscle weakness, including severe pseudoparalytic myasthenia gravis.

Since activation of the cough reflex is possible during inhalation using a nebulizer, in patients with hemoptysis, it is used only in cases where the expected benefit of therapy outweighs the potential risk of pulmonary bleeding.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Tobramycin is not metabolized by liver enzymes, therefore, changes in the systemic bioavailability of tobramycin in patients with hepatic insufficiency are unlikely.

Use in Renal Impairment

The drug should be prescribed with caution to patients with established or suspected kidney diseases,

Pediatric Use

Contraindicated for use in children under 6 years of age.

Geriatric Use

The dosage regimen in patients over 65 years of age is established individually, taking into account the state of renal function.

Special Precautions

Drug therapy should be carried out only under the supervision of a physician experienced in the treatment of cystic fibrosis.

Treatment with alternating courses of therapy with breaks is carried out as long as the clinical effect persists. If the disease worsens during treatment, the appointment of additional antimicrobial therapy active against Pseudomonas aeruginosa should be considered.

Before and after inhalation, it is necessary to determine the function of external respiration – FEV1. If bronchospasm develops in patients not receiving bronchodilator therapy, FEV1 determination should be repeated, in some cases using bronchodilators. If bronchospasm is not relieved after the use of bronchodilators, then the cause of its development may be hypersensitivity to tobramycin. If an allergic reaction is suspected, tobramycin inhalation should be discontinued and appropriate bronchodilator therapy initiated.

Given the potential nephrotoxicity of aminoglycosides with parenteral use, renal function should be assessed before starting therapy.

After every 6 full cycles of therapy, the plasma urea and creatinine levels are re-determined.

Given the potential ototoxicity of aminoglycosides, during treatment it is necessary to determine hearing acuity in patients with any hearing impairments (tinnitus, hearing loss), as well as at risk of such complications (especially with previous long-term systemic therapy with aminoglycosides or with concomitant parenteral therapy with aminoglycoside antibiotics).

In patients who have previously received long-term systemic treatment with aminoglycosides, hearing acuity should be determined before using tobramycin by inhalation.

If signs of nephrotoxicity or ototoxicity are present, treatment should be discontinued until the tobramycin level in the blood plasma falls below 2 mcg/ml. After that, at the discretion of the doctor, treatment can be resumed. In patients with normal renal function, 1 hour after inhalation of tobramycin, the serum concentration of the drug is approximately 1 mcg/ml.

In patients with hearing impairment and/or renal impairment, as well as those receiving concomitant parenteral therapy with aminoglycosides, it is necessary to regularly determine the concentration of tobramycin in the blood plasma.

Given the risk of cumulative toxicity, it is necessary to ensure monitoring of patients receiving concomitant parenteral therapy with other aminoglycoside antibiotics.

Aminoglycosides can have a curare-like effect on neuromuscular transmission and increase muscle weakness.

There is a theoretically possible risk that in patients treated with inhaled tobramycin, resistance of Pseudomonas aeruginosa to intravenous tobramycin may develop.

Effect on ability to drive vehicles and mechanisms

Due to the possible occurrence of dizziness or drowsiness, patients should exercise caution when driving vehicles or operating machinery.

Drug Interactions

Simultaneous and/or sequential use of tobramycin by inhalation with drugs that have nephrotoxicity or ototoxicity should be avoided.

Some diuretics may enhance the toxicity of aminoglycosides by changing the concentration of the antibiotic in plasma and tissues. Tobramycin for inhalation should not be used together with ethacrynic acid, furosemide, urea or mannitol.

The following drugs may also increase the potential toxicity of parenterally administered aminoglycosides: amphotericin B, cephalothin, cyclosporine, polymyxins (possible enhancement of nephrotoxic effect); platinum compounds (possible enhancement of nephrotoxic and ototoxic effects); anticholinesterase drugs, botulinum toxin (effect on the neuromuscular system).

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.