"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
Caution should be exercised when prescribing TOBI® to patients with known or suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate.
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. Patients who use TOBI® during pregnancy, or become pregnant while taking TOBI® should be apprised of the potential hazard to the fetus.
Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with TOBI® therapy during clinical studies. However, transient tinnitus occurred in eight TOBI®-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 caution (see ADVERSE REACTIONS). Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.
In postmarketing experience, patients receiving TOBI® have reported hearing loss. Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus.
Nephrotoxicity was not seen during TOBI® clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving TOBI®, tobramycin therapy should be discontinued until serum concentrations fall below 2 mg/mL.
TOBI® should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson's disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.
Bronchospasm can occur with inhalation of TOBI®. In clinical studies of TOBI®, changes in FEV1 measured after the inhaled dose were similar in the TOBI® and placebo groups. Bronchospasm should be treated as medically appropriate.
Clinical studies of TOBI® did not identify hearing loss using audiometric tests which evaluated hearing up to 8000 Hz. Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.
In patients with normal renal function treated with TOBI®, serum tobramycin concentrations are approximately 1 μg/mL 1 hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.
The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.
The clinical studies of TOBI® did not reveal any imbalance in the percentage of patients in the TOBI® and placebo groups who experienced at least a 50% rise in serum creatinine from baseline (see ADVERSE REACTIONS). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI® has been completed. Rats were exposed to TOBI® for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of tobramycin of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumor.
Additionally, TOBI® has been evaluated for genotoxicity in a battery of in-vitro and in-vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.
Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.
Pregnancy Category D (See WARNINGS.)
No reproduction toxicology studies have been conducted with TOBI®. However, subcutaneous administration of tobramycin at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of tobramycin ≥ 40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of teratogenicity. Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin. If TOBI®is used during pregnancy, or if the patient becomes pregnant while taking TOBI®, the patient should be apprised of the potential hazard to the fetus.
It is not known if TOBI® will reach sufficient concentrations after administration by inhalation to be excreted in human breast milk. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue TOBI® .
The safety and efficacy of TOBI® have not been studied in pediatric patients under 6 years of age.
Clinical studies of TOBI® did not include patients aged 65 years and over. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see WARNINGS – Nephrotoxicity; PRECAUTIONS – Serum Concentrations).
Last reviewed on RxList: 5/8/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Tobi Information
Tobi - User Reviews
Tobi User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.