Kitabis Drug Information
Generic name: TOBRAMYCIN
Aminoglycoside Antibacterial [EPC]
Uses of Kitabis
(co-packaging of tobramycin inhalation solution and PARI LC PLUS Reusable Nebulizer) is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with P. aeruginosa. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV 1 < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia. KITABIS PAK contains tobramycin, an aminoglycoside antibacterial drug indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa.
Dosage & Administration of Kitabis
Dosing Information
KITABIS PAK is a co-packaging of tobramycin inhalation solution ampules with a PARI LC PLUS Reusable Nebulizer. Administer as follows: One single-use ampule (300 mg/5 mL) of tobramycin inhalation solution twice a day by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. The 300 mg/5 mL dose of tobramycin inhalation solution is the same for all patients regardless of age or weight.
The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.
Administration of Tobramycin Inhalation Solution Each dose of tobramycin inhalation solution is
administered by oral inhalation using only the co-packaged PARI LC PLUS Reusable Nebulizer (Model No. 022B81-T) included in the KITABIS PAK, along with a DeVilbiss Pulmo-Aide air compressor (Model No. 5650D). Tobramycin inhalation solution is not for subcutaneous, intravenous or intrathecal administration. Prior to administration, read the Patient Information / Instructions for Use for KITABIS PAK for detailed information on how to use KITABIS PAK and follow the manufacturer's instructions for use and care of the DeVilbiss Pulmo-Aide air compressor. The entire tobramycin inhalation solution treatment should take approximately 15 minutes to complete.
Continue treatment until all the tobramycin inhalation solution has been delivered, and there is no longer any mist being produced. Tobramycin inhalation solution should not be diluted or mixed with other drugs including dornase alfa in the nebulizer. Instruct patients on multiple therapies to take their medications prior to inhaling the tobramycin inhalation solution, or as directed by their physician.
Tobramycin inhalation solution should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days.
Side Effects of Kitabis
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tobramycin inhalation solution was studied in two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin inhalation solution in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks.
Adverse reactions reported in these studies are described below: The most frequent adverse reactions in the tobramycin inhalation arm were cough, pharyngitis, and increased sputum (see Table 1 ). Thirty-three patients (13%) treated with tobramycin inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods. Eight patients from the tobramycin inhalation solution group (3%) reported tinnitus compared to no placebo patients.
All episodes were transient, resolved without discontinuation of the tobramycin inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms. Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin inhalation solution patients during the two Phase III studies. Table 1: Percent of Patients with Selected Adverse Reactions Occurring in > 5% of Tobramycin Inhalation Solution Patients 1 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration.
Adverse Reaction Tobramycin Inhalation Solution (n=258) % Placebo (n=262) % Cough Increased 46.1
Lung Function Decrease 1 16.3 15.3 Voice Alteration 12.8 6.5 Taste Perversion
6.6
Rash 5.4 6.1 Selected adverse reactions that occurred in less than or
equal to 5% of patients treated with tobramycin inhalation solution: Ear and labyrinth disorders Tinnitus Musculoskeletal and connective tissue disorders Myalgia Infections and infestations Laryngitis
Postmarketing Experience
The following adverse reactions have been identified during post approval use of tobramycin inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ear and labyrinth disorders Hearing loss: Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides.
Patients with hearing loss frequently reported tinnitus. Skin and subcutaneous tissue disorders Hypersensitivity, pruritus, urticaria, rash Nervous system disorders Aphonia, dysgeusia Respiratory, thoracic, and mediastinal disorders Bronchospasm , oropharyngeal pain
Warnings & Cautions for Kitabis
Bronchospasm Bronchospasm can occur with inhalation of tobramycin inhalation solution.
In clinical studies with tobramycin inhalation solution, changes in FEV1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of tobramycin inhalation solution should be treated as medically appropriate.
Ototoxicity Ototoxicity with use of Tobramycin Inhalation Solution Transient tinnitus occurred in
eight tobramycin inhalation solution treated patients versus no placebo patients in the clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants further clinical investigation. In postmarketing experience, patients receiving tobramycin inhalation solution have reported hearing loss.
Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking tobramycin inhalation solution.
Monitoring might include obtaining audiometric evaluations and serum tobramycin levels. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution . Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range.
Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.
Nephrotoxicity Nephrotoxicity was not seen during clinical studies with tobramycin inhalation solution
but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with tobramycin inhalation solution should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician. If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution.
Neuromuscular Disorders Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a
potential curare-like effect on neuromuscular function. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson's disease. Prolonged respiratory paralysis may also occur in patients receiving neuromuscular blocking agents.
If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.
Embryo-Fetal Toxicity Aminoglycosides can cause fetal harm when administered to a pregnant
woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal.
Patients who use KITABIS PAK during pregnancy, or become pregnant while taking tobramycin inhalation solution should be apprised of the potential hazard to the fetus .
Concomitant Use of Systemic Aminoglycosides Patients receiving concomitant tobramycin inhalation solution and
parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.
Drug Interactions with Kitabis
Drugs with Neurotoxic, Nephrotoxic or Ototoxic Potential Concurrent and/or sequential use of
tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided if possible.
Diuretics Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in
serum and tissue. Tobramycin inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol.
Pregnancy Safety for Kitabis
Pregnancy Risk Summary Aminoglycosides can cause fetal harm. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman . Although there are no available data on KITABIS PAK use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal . There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies ( see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery.
Data Animal Data No reproductive toxicity studies have been conducted with tobramycin inhalation solution. However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes. Subcutaneous doses of tobramycin ≥40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes.
Ototoxicity was not evaluated in offspring during non-clinical reproductive toxicity studies with tobramycin.
Pediatric Use of Kitabis
Pediatric Use The safety and efficacy of tobramycin inhalation solution have not been studied in pediatric patients under 6 years of age.
Contraindications for Kitabis
Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside.
Overdosage Information for Kitabis
Signs and symptoms of acute toxicity from overdosage of IV tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. Administration by inhalation results in low systemic bioavailability of tobramycin. Tobramycin is not significantly absorbed following oral administration.
Tobramycin serum concentrations may be helpful in monitoring overdosage.
Clinical Studies of Kitabis
Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa with tobramycin inhalation solution. Subjects who were less than 6 years of age, had a baseline creatinine of > 2 mg/dL, or had B. cepacia isolated from sputum were excluded. All subjects had baseline FEV 1 % predicted between 25% and 75%. In these clinical studies, 258 patients received tobramycin inhalation solution therapy on an outpatient basis (see Table 2 ) using a PARI LC PLUS nebulizer along with a DeVilbiss Pulmo-Aide compressor.
Table 2: Dosing Regimens in Clinical Studies Cycle 1 Cycle 2 Cycle 3 28 days 28 days 28 days 28 days 28 days 28 days TOBRAMYCIN Inhalation Solution regimen n=258 TOBRAMYCIN Inhalation Solution 300 mg twice daily No drug TOBRAMYCIN Inhalation Solution 300 mg twice daily No drug TOBRAMYCIN Inhalation Solution 300 mg twice daily No drug Placebo regimen n=262 Placebo twice daily Placebo twice daily Placebo twice daily All patients received either tobramycin inhalation solution or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral anti-pseudomonal therapy, Beta 2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa. In each study, tobramycin inhalation solution-treated patients experienced significant improvement in pulmonary function.
Improvement was demonstrated in the tobramycin inhalation solution group in Study 1 by an average increase in FEV 1 % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, tobramycin inhalation solution-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV 1 % predicted over 24 weeks for both studies.
Figure 1: Relative Change From Baseline in FEV 1 % Predicted In each study, tobramycin inhalation solution therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle. (see Figure 2 ). Figure 2: Absolute Change From Baseline in Log 10 CFUs Patients treated with tobramycin inhalation solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients.
Patients treated with tobramycin inhalation solution required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of tobramycin inhalation solution patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics. The relationship between in vitro susceptibility test results and clinical outcome with tobramycin inhalation solution therapy is not clear.
However, 4 tobramycin inhalation solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 μg/mL did not experience an improvement in FEV 1 or a decrease in sputum bacterial density. Figure 1 Figure 2
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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