Tobramycin: FDA label

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Indications

Tobramycin inhalation solution is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa . Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ]. Tobramycin is an aminoglycoside antibacterial indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa .

( 1 ) Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia. ( 1 )

Warnings and precautions

Bronchospasm: Can occur with inhalation of tobramycin. Treat as medically appropriate, if it occurs. ( 5.1 ) Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin. If noted, manage as medically appropriate, including potentially discontinuing tobramycin. ( 5.2 ) Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin.

( 5.3 ) Neuromuscular Disorders: Aminoglycosides may aggravate muscle weakness because of a potential curare‐like effect on neuromuscular function. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. ( 5.4 ) Embryo-fetal Toxicity: Aminoglycosides can cause fetal harm. ( 5.5 , 8.1 )

5.1

Pregnancy and breastfeeding

8.1Pregnancy 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 [see Warnings and Precautions (5.5) ]. Although there are no available data on tobramycin 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 [see Clinical Pharmacology (12.3) ] .

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 administered by inhalation. 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. 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.

Adverse reactions

The following serious adverse reactions are described below and elsewhere in the labeling: Bronchospasm [see Warnings and Precautions (5.1) ] Ototoxicity [see Warnings and Precautions (5.2) ] Nephrotoxicity [see Warnings and Precautions (5.3) ] Neuromuscular Disorders [see Warnings and Precautions (5.4) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.5) ] Concomitant Use of Systemic Aminoglycosides [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence > 5%) are increased cough, pharyngitis, increased sputum, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion and rash.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 was studied in two Phase 3 clinical studies involving 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin 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.

Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin patients during the two Phase 3 studies. Table 1: Percent of Patients With Selected Adverse Reactions Occurring in > 5% of Tobramycin Patients Adverse Reaction Tobramycin Inhalation Solution (n = 258) % Placebo (n = 262) % Cough Increased 46.1

47.3 Pharyngitis 38.0

39.3 Sputum Increased 37.6

39.7 Dyspnea 33.7

38.5 Hemoptysis 19.4

23.7 Lung Function Decreased 1 16.3

15.3 Voice Alteration 12.8

6.5 Taste Perversion 6.6

6.9Rash 5.4 6.1 1

Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. Selected adverse reactions that occurred in less than or equal to 5% of patients treated with tobramycin: Ear and Labyrinth Disorders: Tinnitus Musculoskeletal and Connective Tissue disorders: Myalgia Infections and Infestations: Laryngitis Voice Alteration and Tinnitus Voice alteration and tinnitus were the only adverse reactions reported by significantly more tobramycin-treated patients.

Thirty-three patients (13%) treated with tobramycin 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 group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin treatment regimen, and were not associated with loss of hearing in audiograms.

Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the tobramycin and placebo groups. Changes in Serum Creatinine Nine (3%) patients in the tobramycin group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline.

In all nine patients in the tobramycin group, creatinine decreased at the next visit.

6.2Post-marketing Experience

The following adverse reactions have been identified during post-approval use of tobramycin. 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 [see Warnings and Precautions (5.2) ]. Skin and Subcutaneous Tissue Disorders Hypersensitivity, pruritus, urticaria, rash Nervous System Disorders Aphonia, dysgeusia Respiratory, Thoracic, and Mediastinal Disorders Bronchospasm [see Warnings and Precautions (5.1) ], oropharyngeal pain Metabolism and Nutrition Disorders Decreased appetite

Tobramycin

Indications

Contraindications

Warnings and precautions

5.1

Two medicines in one question?

5.2Ototoxicity Ototoxicity

5.3Nephrotoxicity

5.4Neuromuscular Disorders

5.5Embryo-fetal Toxicity

5.6Concomitant Use of Systemic Aminoglycosides

Interactions

7.1Drugs with Neurotoxic, Nephrotoxic or Ototoxic Potential

7.2Diuretics

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.9Rash 5.4 6.1 1

6.2Post-marketing Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines