Tobramycin-vista

INSTRUCTIONS for medical use of the medicinal product TOBRAMYCIN-VISTA (TOBRAMYCIN-VISTA)

Composition:

Active substance: tobramycin;

1 ampoule (5 ml) contains 300 mg of tobramycin;

Excipients: sodium chloride, sodium hydroxide 1.0 N, sulfuric acid 2.0 N, water for injections.

Pharmaceutical form. Solution for inhalation.

Main physical and chemical characteristics: clear solution, free from particles.

Pharmacotherapeutic group. Antibacterial aminoglycosides. ATC code J01G B01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by inhibiting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell wall, and ultimately cell death. It is bactericidal at concentrations equal to or slightly above inhibitory concentrations.

Breakpoints.

Established susceptibility breakpoints for parenteral administration of tobramycin are not applicable when the drug is administered as an aerosol. Aminoglycosides have been shown to exert inhibitory effects on the biological activity of sputum in cystic fibrosis (CF). This necessitates that concentrations of aerosolized tobramycin and its bactericidal activity in sputum be approximately 10 to 25 times higher than the minimum inhibitory concentration (MIC) for inhibition of P. aeruginosa growth, respectively. In controlled clinical studies, 97% of patients receiving tobramycin achieved sputum concentrations 10 times higher than the MIC for P. aeruginosa isolated from the patient, and 95% of patients achieved concentrations 25 times higher than the MIC. Clinical benefit is still observed in most patients who harbor strains with MIC values above the parenteral breakpoints.

Susceptibility.

In the absence of established susceptibility breakpoints for the nebulized route of administration, caution should be exercised when classifying organisms as susceptible or resistant to nebulized tobramycin. However, clinical studies of tobramycin have shown that microbiological data indicating in vitro resistance do not necessarily preclude clinical benefit for the patient.

Most patients with P. aeruginosa isolates having a tobramycin MIC < 128 µg/mL at baseline demonstrated improvement in lung function following tobramycin treatment. Patients with P. aeruginosa isolates having an MIC ≥ 128 µg/mL at baseline are less likely to exhibit a clinical response. However, in placebo-controlled studies, 7 out of 13 patients (54%) receiving tobramycin with isolates exhibiting an MIC ≥ 128 µg/mL showed improvement in lung function.

Throughout the 96-week duration of long-term studies, the MIC₅₀ of tobramycin for P. aeruginosa increased from 1 to 2 µg/mL, and the MIC₉₀ increased from 8 to 32 µg/mL. Based on in vitro data and/or clinical trial experience, microorganisms associated with pulmonary infections in CF are expected to respond to tobramycin therapy as follows:

Treatment with tobramycin in clinical studies showed a small but clear increase in the minimum inhibitory concentrations of tobramycin, amikacin, and gentamicin for the investigated isolates of P. aeruginosa. Each additional 6 months of treatment led to an increase in magnitude similar to that observed over 6 months of controlled studies. The most common mechanism of resistance to aminoglycosides observed in P. aeruginosa isolated from chronically infected CF patients is impermeability, characterized by a general lack of sensitivity to all aminoglycosides. It has also been shown that P. aeruginosa isolated from CF patients demonstrates adaptive resistance to aminoglycosides, which is characterized by a return to sensitivity after discontinuation of the antibiotic.

Other information.

There is no evidence that patients who received tobramycin for 18 months had a higher risk of infection with B. cepacia, S. maltophilia, or A. xylosoxidans compared to patients who did not receive tobramycin. Aspergillus species were more frequently isolated from sputum of patients receiving tobramycin; however, clinical consequences such as allergic bronchopulmonary aspergillosis were rarely reported and with the same frequency as in the control group. There are insufficient clinical data on the safety and efficacy of use in children under 6 years of age.

In an open-label uncontrolled study, 88 CF patients (37 patients aged 6 months to 6 years, 41 patients aged 6 to 18 years, and 10 patients aged 18 years and older) with early (non-chronic) P. aeruginosa infection received tobramycin treatment for 28 days. After 28 days, patients were randomized in a 1:1 ratio to either discontinue (n=45) or continue treatment for another 28 days (n=43). The primary outcome was the median time to P. aeruginosa recurrence (any strain), which was 26.1 and 25.8 months for the 28-day and 56-day groups, respectively. It was established that 93% and 92% of patients were free of P. aeruginosa infection one month after the end of treatment in the 28-day and 56-day groups, respectively. The use of tobramycin with a dosing regimen of more than 28 days of continuous treatment has not been approved.

In a double-blind, randomized, placebo-controlled study, 51 patients aged 3 months to 7 years with a confirmed diagnosis of CF and early P. aeruginosa colonization (defined as: first positive culture overall or first positive culture after at least one year of negative cultures) received tobramycin 300 mg/5 mL or placebo, both administered via nebulizer (PARI LC Plus®) twice daily for 28 days. Patients who had received anti-pseudomonal therapy in the previous year were excluded. A total of 26 patients were randomized to receive tobramycin and 25 to receive placebo. The primary outcome was based on the proportion of patients free from P. aeruginosa colonization, assessed by sputum/throat swab culture after completion of the 28-day treatment period, which was 84.6% (22 out of 26 patients) in the tobramycin group and 24% (6 out of 25 patients) in the placebo group (p < 0.001). The frequency, type, and severity of adverse events observed in children < 7 years of age were consistent with the known safety profile of tobramycin.

Tobramycin use is not indicated in children under 6 years of age.

Clinical efficacy.

Two identically designed double-blind, randomized, placebo-controlled, 24-week parallel-group clinical studies (Study 1 and Study 2) were conducted in patients with cystic fibrosis and P. aeruginosa to confirm the initial registration of tobramycin, which occurred in 1999. The studies included 520 subjects with a baseline FEV₁ of 25% to 75% of the predicted normal value. Patients under 6 years of age, those with a baseline serum creatinine > 2 mg/dL, or those with Burkholderia cepacia isolated from sputum were excluded. In these clinical studies, 258 patients received tobramycin therapy on an outpatient basis using the PARI LC PLUS™ reusable multiple-dose nebulizer with the DeVilbiss® Pulmo-Aide® compressor. In each study, patients receiving tobramycin showed significant improvement in lung function and a significant reduction in P. aeruginosa colony-forming units in sputum during the treatment periods. Mean FEV₁ remained above baseline levels during the 28-day drug-free period, although it declined somewhat in most cases. Sputum bacterial density returned to baseline levels during the drug-free periods. Additionally, the reduction in sputum bacterial density was smaller in each subsequent cycle.

Patients receiving tobramycin had fewer days of hospitalization and required fewer days of parenteral administration of anti-pseudomonal antibiotics on average compared to patients receiving placebo.

In open-label studies 1 and 2, 396 patients were included from the 464 who completed either of the two 24-week double-blind studies. Overall, 313, 264, and 120 patients completed tobramycin treatment for 48, 72, and 96 weeks, respectively. The rate of decline in lung function was significantly lower after initiation of tobramycin therapy compared to patients who received placebo during the double-blind randomized treatment period. The estimated slope in the regression model of lung function decline was ‑6.52% during the blinded placebo treatment and ‑2.53% during tobramycin treatment (p=0.0001).

Pharmacokinetics.

Absorption.

Tobramycin is a cationic, polar molecule that does not easily penetrate epithelial membranes. Systemic effects of tobramycin after inhalation are expected to result from absorption in the lungs of the fraction of the dose deposited in the lungs, as tobramycin is not significantly absorbed following oral administration. Bioavailability of tobramycin may vary due to individual differences in nebulizer performance and respiratory tract pathology.

Concentration in sputum.

Ten minutes after inhalation of the first 300 mg dose, the mean concentration of tobramycin in sputum was 1237 µg/g (range: 35 to 7414 µg/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy, the mean concentration of tobramycin in sputum 10 minutes after inhalation was 1154 µg/g (range: 39 to 8085 µg/g). High variability in sputum tobramycin concentrations was observed. Two hours after inhalation, sputum tobramycin concentration decreased to approximately 14% of the level measured 10 minutes after inhalation.

Serum concentrations.

The mean serum concentration of tobramycin one hour after inhalation of a single 300 mg dose in CF patients was 0.95 µg/mL (range: below the lower limit of quantification BLQ – 3.62 µg/mL). After 20 weeks of therapy, the mean serum concentration of tobramycin one hour after dosing was 1.05 µg/mL (range: BLQ – 3.41 µg/mL). For comparison, peak concentrations after intravenous or intramuscular administration of a single dose of tobramycin at 1.5 to 2 mg/kg typically range from 4 to 12 µg/mL.

Distribution.

After administration, tobramycin remains predominantly concentrated in the respiratory tract. Less than 10% of tobramycin binds to plasma proteins.

Biotransformation.

Tobramycin is not metabolized and is primarily excreted unchanged in urine.

Elimination.

Elimination of tobramycin after inhalation has not been studied. After intravenous administration, tobramycin is primarily eliminated via glomerular filtration in unchanged form. The terminal half-life of tobramycin after inhalation of a single 300 mg dose was 3 hours in cystic fibrosis patients. Renal function affects tobramycin elimination; however, data are lacking, as the use of tobramycin in patients with serum creatinine ≥2 mg/dL (176.8 µmol/L) or blood urea nitrogen ≥40 mg/dL has not been studied in clinical trials. Unabsorbed tobramycin is likely excreted primarily in expectorated sputum.

Clinical characteristics.

Indications.

Treatment of chronic pulmonary infection caused by Pseudomonas aeruginosa in patients with cystic fibrosis.

Contraindications.

Use is contraindicated in patients with hypersensitivity to tobramycin, other aminoglycosides, or any component of the medicinal product.

Concomitant use with potent diuretics such as furosemide or ethacrynic acid, which have ototoxic effects, is contraindicated.

Special precautions.

General warnings.

Tobramycin should be used with caution in patients with known or suspected renal impairment, vestibular or auditory function disorders, neuromuscular dysfunction, or active haemoptysis. Continuous monitoring of renal function and the eighth cranial nerve is necessary in patients with established or suspected renal insufficiency, as well as in patients with baseline normal renal function but who develop signs of renal dysfunction during treatment. If signs of renal, vestibular, and/or auditory impairment occur, the drug should be discontinued or the dosage adjusted. For monitoring serum tobramycin concentrations, blood sampling should be performed via venipuncture rather than fingerstick, as the latter method is not validated. Skin contamination of fingers from preparation and nebulization of tobramycin may lead to falsely elevated serum drug levels. Washing hands immediately before blood sampling does not completely eliminate residual drug.

Bronchospasm.

Bronchospasm may occur during inhalation of tobramycin, as with other inhaled medicinal products. The first dose should be administered under medical supervision and preceded by a bronchodilator if already part of the patient’s treatment regimen. Forced expiratory volume in 1 second (FEV₁) should be measured before and after inhalation. If bronchospasm occurs in a patient not receiving a bronchodilator, the drug should be re-administered with a bronchodilator. Development of bronchospasm despite bronchodilator therapy may indicate an allergic reaction. If an allergic reaction is suspected, the drug should be discontinued. Appropriate therapy should be initiated to manage bronchospasm.

Neuromuscular disorders.

Tobramycin should be used with caution in patients with neuromuscular disorders such as Parkinson’s disease or other conditions characterized by myasthenia, including myasthenia gravis, as aminoglycosides may exacerbate muscle weakness due to their potential curare-like effect on neuromuscular function.

Nephrotoxicity.

Although nephrotoxicity is primarily associated with parenteral administration of aminoglycosides, nephrotoxicity has not been observed during clinical studies of inhaled tobramycin. The drug should be used with caution in patients with established or suspected renal dysfunction, and serum tobramycin concentrations should be monitored. Quantitative serum level determinations should be performed after two or three doses, at intervals of 3–4 days during treatment, to allow dose adjustments if necessary. If renal function changes are detected, serum tobramycin levels should be monitored more frequently, and dosage or dosing intervals should be adjusted accordingly. Patients with acute renal failure (serum creatinine > 2 mg/dL [176.8 µmol/L]) were excluded from clinical studies.

Current clinical practice recommends initial assessment of renal function. Additionally, periodic reassessment of renal function through regular monitoring of blood urea nitrogen and creatinine levels is necessary, at least every 6 full treatment cycles of tobramycin (180 days of inhaled tobramycin therapy).

If signs of nephrotoxicity occur, tobramycin therapy should be discontinued until serum drug concentrations fall below 2 µg/mL. Thereafter, treatment with tobramycin may be resumed based on clinical judgment. Patients receiving concomitant parenteral therapy with other aminoglycosides should be closely monitored due to the potential for cumulative toxicity. Monitoring of renal function is particularly important in elderly patients, who may have reduced renal function not detected by routine screening tests such as serum urea or creatinine. Measurement of creatinine clearance is preferable. Urinalysis should be performed to detect increased protein excretion, cells, and casts. Periodic quantitative determination of serum creatinine or creatinine clearance (preferable over blood urea nitrogen) is required.

Ototoxicity.

Ototoxicity, affecting both auditory and vestibular functions, has been reported with parenteral administration of aminoglycosides. Vestibular toxicity may manifest as vertigo, ataxia, or dizziness. Controlled clinical studies of tobramycin have reported cases of mild hearing loss and vertigo, whereas controlled clinical studies of other inhaled tobramycin-containing products have not shown evidence of auditory toxicity based on patient reports of hearing loss or audiometric evaluations. Open-label studies and post-marketing experience indicate that some patients with a history of prolonged prior or concomitant intravenous aminoglycoside therapy have experienced hearing loss.

The physician should be aware that aminoglycosides may cause vestibular and auditory toxicity, and hearing function should be evaluated during treatment with Tobramycin-Vista. Patients with risk factors due to prior prolonged systemic aminoglycoside use are recommended to undergo audiometric testing before initiating tobramycin therapy. Tinnitus should be considered as a potential sign of ototoxicity. If a patient reports tinnitus or hearing loss during aminoglycoside therapy, audiologic evaluation should be considered. Periodic audiograms are recommended, if possible, in patients undergoing long-term treatment, as this increases the risk of ototoxicity. Patients receiving concomitant parenteral aminoglycoside therapy should be under appropriate clinical surveillance due to the risk of cumulative toxicity.

Haemoptysis.

Inhalation of nebulized solutions may trigger a cough reflex. Administration of inhaled tobramycin in patients with acute active haemoptysis should only be considered if the benefit of treatment outweighs the risk of further bleeding.

Microbial resistance.

Clinical studies have shown increased minimum inhibitory concentrations of aminoglycosides against isolated strains of P. aeruginosa in some patients receiving tobramycin inhalations. There is a theoretical risk that patients receiving inhaled tobramycin may develop resistance of P. aeruginosa strains to intravenous tobramycin (see section "Pharmacological properties", "Pharmacodynamics"). Clinical trial data are not available for patients with cystic fibrosis.

Interaction with other medicinal products and other forms of interaction.

Concomitant and/or sequential use of tobramycin with other potentially nephrotoxic or ototoxic medicinal products should be avoided. Some diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissues. Tobramycin should not be administered concurrently with furosemide, ethacrynic acid, urea, or intravenous or oral mannitol.

Other agents that may increase the potential toxicity of aminoglycosides when administered parenterally: amphotericin B, cephalothin, cyclosporine, tacrolimus, polymyxins (risk of increased nephrotoxicity), platinum-containing agents (risk of increased nephrotoxicity and ototoxicity). Concomitant use of tobramycin with anticholinesterases and botulinum toxin should be avoided due to their neuromuscular effects.

Others: Clinical studies have shown that patients receiving inhaled tobramycin concomitantly with dornase alfa, mucolytics, beta-agonists, inhaled corticosteroids, and other oral or parenteral anti-pseudomonal antibiotics experienced adverse reactions similar to those in the control group.

Special precautions for use.

Patients with mitochondrial DNA mutations, particularly the A to G substitution at nucleotide 1555 in the 12S rRNA gene, may have an increased risk of developing ototoxicity, even if serum aminoglycoside levels remain within recommended ranges. If there is a family history of aminoglycoside-induced deafness or known mitochondrial DNA mutations in the 12S rRNA gene, alternative treatment options should be considered.

Use during pregnancy or breastfeeding.

Tobramycin may be used during pregnancy or breastfeeding only if the potential benefit to the mother outweighs the potential risks to the fetus or infant. Pregnancy. Adequate data on the use of inhaled tobramycin in pregnant women are not available. Animal studies have not revealed teratogenic effects of tobramycin. However, aminoglycosides may pose a risk to the fetus (e.g., congenital deafness) when high systemic concentrations are achieved in pregnant women. If Tobramycin-Vista is used during pregnancy or if pregnancy occurs during treatment with tobramycin, the patient should be informed about the potential risks to the fetus. Breastfeeding period. Following systemic administration, tobramycin is excreted into breast milk. It has not been established whether inhaled tobramycin reaches sufficiently high serum concentrations to be detected in breast milk. Due to the potential risk of ototoxicity and nephrotoxicity in neonates associated with tobramycin, a decision should be made whether to discontinue breastfeeding or to discontinue tobramycin therapy.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of tobramycin on the ability to drive or operate machinery have not been conducted. Based on reported adverse reactions of the medicinal product, tobramycin is unlikely to affect the ability to drive or operate machinery. However, patients intending to drive or operate machinery should exercise caution due to the potential occurrence of dizziness and/or vertigo.

Method of Administration and Dosage

Tobramycin-Vista is intended for inhalation use only and must not be used parenterally. Appropriate official recommendations regarding the proper use of antibacterial agents should be followed.

Treatment must be supervised by a physician experienced in managing patients with cystic fibrosis.

Recommended dose for adults and children aged 6 years and older: one single-dose ampoule (300 mg) twice daily (morning and evening) for 28 days. The dosing interval should be maintained at approximately 12 hours. After 28 days of treatment with Tobramycin-Vista, a 28-day treatment break should follow. Treatment should follow alternating 28-day on-treatment cycles followed by 28-day off-treatment periods (a 28-day treatment cycle followed by a 28-day break from tobramycin).

Children under 6 years of age.

The efficacy and safety of tobramycin in patients under 6 years of age have not been established.

Elderly patients.

Tobramycin should be used with caution in elderly patients, who may have reduced renal function (see section "Special Warnings").

Patients with renal impairment.

Tobramycin should be used with caution in patients with known or suspected renal dysfunction. If signs of nephrotoxicity occur, treatment with Tobramycin-Vista should be suspended until serum tobramycin concentrations fall below 2 µg/mL (see section "Special Warnings").

Patients with hepatic impairment.

No dosage adjustment of tobramycin is required for patients with hepatic impairment.

The dosing regimen does not vary according to body weight. All patients should receive one single-dose ampoule of Tobramycin-Vista (300 mg tobramycin) twice daily. Tobramycin treatment should continue on a cyclical basis, and the duration of treatment should be determined by the physician based on the patient's clinical response to tobramycin as part of the treatment regimen. In case of evident clinical worsening of pulmonary status, additional antibacterial therapy should be considered.

Method of Administration.

The single-dose ampoule should be opened immediately before use. Any unused portion of the solution after administration must be discarded and not stored for subsequent use.

Administration of tobramycin should follow general hygiene standards. The device used must be clean and in proper working condition. The nebulizer, intended for personal use only, must be kept clean and disinfected regularly (refer to the nebulizer instructions for cleaning and disinfection procedures).

Maximum recommended daily dose.

The maximum recommended daily dose of Tobramycin-Vista has not been established.

Instructions for opening the ampoule:

• Bend the single-dose ampoule in both directions;
• Separate the ampoule from the strip, starting with the top part, then the middle;
• Open the ampoule by twisting the top part in the direction indicated by the arrow;
• Gently squeeze the ampoule walls to pour the medication into the nebulizer glass chamber.

The contents of one single-dose ampoule (300 mg), transferred into the nebulizer, should be administered by inhalation over approximately 15 minutes using the reusable PARI LC PLUS nebulizer with the PARI TURBO BOY compressor (drug delivery rate 6.2 mg/min, total delivered dose 92.8 mg, mean aerodynamic particle size: D10 0.65 µm, D50 3.15 µm, D90 8.99 µm) or the PARI LC SPRINT nebulizer with the PARI BOY Sx compressor (drug delivery rate 6.7 mg/min, total delivered dose 99.8 mg, mean aerodynamic particle size: D10 0.70 µm, D50 3.36 µm, D90 9.41 µm). Tobramycin inhalations should be performed while the patient is sitting or standing, breathing normally through the mouthpiece of the nebulizer. Nasal clips may help the patient breathe through the mouth. The patient should continue their standard chest physiotherapy regimen. The use of appropriate bronchodilators should be continued if clinically necessary. When multiple respiratory therapies are used, the following sequence is recommended: bronchodilator, chest physiotherapy, other inhaled medications, and finally Tobramycin-Vista. Tobramycin-Vista must not be mixed with other inhaled medications.

Children.

The medication may be used in children aged 6 years and older.

Overdose.

Symptoms. Inhalation of tobramycin results in low systemic bioavailability. Symptoms of overdose may include severe hoarseness. Accidental oral ingestion is unlikely to lead to toxic effects, as tobramycin is poorly absorbed from the healthy gastrointestinal tract. In case of accidental intravenous administration, signs and symptoms of parenteral tobramycin overdose may occur, such as dizziness, tinnitus, vertigo, hearing loss, respiratory distress and/or neuromuscular blockade, and renal impairment.

Treatment. In case of acute toxicity, Tobramycin-Vista should be discontinued immediately, and baseline assessment of renal function parameters should be performed. Serum tobramycin concentration monitoring may be helpful in managing overdose. In any case of overdose, potential drug interactions should be considered, and tobramycin or other medications should be withdrawn sequentially as appropriate.

Adverse Reactions

Summary of safety profile

Two parallel 24-week randomized, double-blind, placebo-controlled clinical trials were conducted with tobramycin involving 520 patients with cystic fibrosis aged 6 to 63 years.

The most common (≥ 10%) adverse events reported in the studies during tobramycin treatment were cough, pharyngitis, productive cough, asthenia, rhinitis, dyspnea, pyrexia, impaired lung function, headache, chest pain, change in sputum color, hemoptysis, anorexia, asthma, vomiting, abdominal pain, dysphonia, nausea, and weight loss. Most of these reactions were reported with similar or higher frequency in patients receiving placebo.

Dysphonia and tinnitus were the only adverse reactions reported in significantly more patients receiving tobramycin: (12.8% tobramycin vs. 6.5% placebo) and (3.1% tobramycin vs. 0% placebo), respectively. These cases of tinnitus were transient, resolved without discontinuation of tobramycin, and were not associated with permanent hearing loss. The risk of developing tinnitus does not increase with repeated courses of tobramycin treatment.

Summary of adverse reactions

In the 24-week placebo-controlled trials and open-label active treatment data, a total of 313, 264, and 120 patients completed tobramycin treatment at 48, 72, and 96 weeks, respectively.

Table 1 lists the frequency of treatment-emergent adverse reactions meeting the following criteria: reported at a frequency ≥ 2% in patients receiving tobramycin, occurring more frequently in the tobramycin group compared to placebo, and considered drug-related in ≥ 1% of patients.

Adverse reactions observed during clinical trials are listed by MedDRA system organ class. Within each system organ class, adverse reactions are ranked by frequency, with the most frequent reactions listed first. Within each frequency grouping, adverse reactions are presented in order of decreasing severity.

All adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Adverse reactions observed in clinical trials

Table 1

As the duration of tobramycin exposure increased during two open-label extension studies, the frequency of productive cough and decline in lung function test increased; however, the frequency of dysphonia was found to decrease. Overall, the frequency of adverse events decreased with increased tobramycin exposure: respiratory, thoracic and mediastinal disorders, gastrointestinal disorders, and general disorders and administration site reactions.

Adverse reactions reported from spontaneous reports.

The adverse reactions listed below, reported spontaneously, do not always have a reliably established frequency or causal relationship to the drug exposure.

Nervous system disorders: aphonia, dysgeusia.

Ear and labyrinth disorders: hearing loss.

Respiratory, thoracic and mediastinal disorders: bronchospasm, oropharyngeal pain.

Skin and subcutaneous tissue disorders: hypersensitivity, pruritus, urticaria, rash.

In open-label studies and post-marketing experience, some patients with prolonged prior or concomitant intravenous aminoglycoside use had a history of hearing loss. Hypersensitivity, ototoxicity, and nephrotoxicity have been associated with parenteral administration of aminoglycosides.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging in a refrigerator (2–8 °C).

Keep out of the reach of children.

After removal from the refrigerator or if refrigeration is not available, strips (intact or opened) may be stored at temperatures up to 25 °C for up to 28 days.

Packaging.

5 ml in vials, 7 vials in a hermetically sealed strip, 8 strips in a carton.

Prescription category. Prescription only.

Manufacturer.

MÉDICHEM, S.A./MEDICHEM, S.A.

Manufacturer's address and place of business.

Narcis Monturiol, 41 A, Sant Joan Despí, Barcelona, 08970, Spain /
Narcis Monturiol, 41 A, Sant Joan Despi, Barcelona, 08970, Spain.