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TOBI Podhaler

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TOBI Podhaler

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ototoxicity

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory or vestibular dysfunction.

Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI Podhaler clinical studies [see ADVERSE REACTIONS]. Tinnitus may be a sentinel symptom of ototoxicity, and ther efor e the onset of this symptom warrants caution. Ototoxicity, manifested as both auditory (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

Nephrotoxicity

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction.

Nephrotoxicity was not observed during TOBI Podhaler clinical studies but has been associated with aminoglycosides as a class.

Neuromuscular Disorders

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected neuromuscular dysfunction.

TOBI Podhaler 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

Bronchospasm can occur with inhalation of TOBI Podhaler [see ADVERSE REACTIONS]. Bronchospasm should be treated as medically appropriate.

Laboratory Tests

Audiograms

Physicians should consider an audiogram at baseline, particularly for patients at incr eased risk of auditory dysfunction.

If a patient reports tinnitus or hearing loss during TOBI Podhaler therapy, the physician should refer that patient for audiological assessment.

Serum Concentrations

In patients treated with TOBI Podhaler, serum tobramycin concentrations are approximately 1 to 2 μg/mL one hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with known or suspected auditory or renal dysfunction or patients treated with a concomitant parenteral aminoglycoside (or other nephrotoxic or ototoxic medications) should be monitored at the discretion of the treating physician. If ototoxicity or nephrotoxicity occurs in a patient receiving TOBI Podhaler, tobramycin therapy should be discontinued until serum concentrations fall below 2 μg/mL.

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.

Renal Function

Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.

Use In Pregnancy

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 Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Patient Counseling Information

See FDA-Approved Patient Labeling

Information for Patients

Information on the long term efficacy and safety of TOBI Podhaler is limited. There is no information in patients with limited pulmonary reserve (FEV1 < 25% predicted). Decreased susceptibility of Pseudomonas aeruginosa to tobramycin has been seen with use of TOBI Podhaler. The relationship between in vitro susceptibility test results and clinical outcome with TOBI Podhaler therapy is not clear. Occurrence of decreased susceptibility on treatment should be monitored, and treatment with an alternative therapy should be considered if clinical worsening is observed.

TOBI Podhaler may not be tolerated by all patients. Patients should be instructed to consider alternative therapy if they are unable to tolerate TOBI Podhaler. Patients should be advised to complete a full 28-day course of TOBI Podhaler, even if they are feeling better. After 28 days of therapy, patients should stop TOBI Podhaler therapy for the next 28 days, and then resume therapy for the next 28 day on and 28 day off cycle.

It is important for patients to understand how to correctly administer TOBI Podhaler capsules using the Podhaler device. It is recommended that caregivers and patients be adequately trained in the proper use of the TOBI Podhaler prior to use. [See Instructions for Use at the end of the PATIENT INFORMATION leaflet.] Caregivers should provide assistance to children using TOBI Podhaler (including preparing the dose for inhalation) particularly for those aged 10 years or younger, and should continue to supervise them until they are able to use the Podhaler device properly without help.

For patients taking several different inhaled medications and/or performing chest physiotherapy, advise the patient regarding the order they should take the therapies. It is recommended that TOBI Podhaler be taken last.

Ototoxicity

Inform patients that ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI Podhaler clinical studies. Physicians should consider an audiogram at baseline, particularly for patients at increased risk of auditory dysfunction. If a patient reports tinnitus or hearing loss during TOBI Podhaler therapy, the physician should refer that patient for audiological assessment.

Patients should be reminded that vestibular toxicity may manifest as vertigo, ataxia, or dizziness.

Bronchospasm

Inform patients that bronchospasm can occur with inhalation of TOBI Podhaler.

Risks Associated With Aminoglycosides

Inform patients of adverse reactions associated with aminoglycosides such as nephrotoxicity and neuromuscular disorders.

Laboratory Tests

Inform patients of the need to monitor hearing, serum concentrations of tobramycin, or renal function as necessary during treatment with TOBI Podhaler.

Pregnancy

Inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman. Advise them to inform their doctor if they are pregnant, become pregnant, or plan to become pregnant.

Cough

Inform patients that cough was reported with the use of TOBI Podhaler in clinical trials. If coughing that may be experienced with TOBI Podhaler becomes bothersome or cannot be tolerated, advise patients that tobramycin inhalation solution or alternative therapeutic options may be considered.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies were not conducted with TOBI Podhaler. A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI (tobramycin inhalation solution, USP) has been completed. Rats were exposed to TOBI for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin of up to 35 μg/mL were measured in rats, in contrast to the maximum 1.99 ± 0.59 μg/mL level observed in cystic fibrosis patients in TOBI Podhaler clinical trials. There was no drug-related increase in the incidence of any variety of tumor.

Additionally, tobramycin 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.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

No reproduction toxicology studies have been conducted with TOBI Podhaler. 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. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin.

Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. No adequate and well-controlled studies of TOBI Podhaler in pregnant women ha ve been conducted. If TOBI Podhaler is used during pregnancy, or if the patient becomes pregnant while taking TOBI Podhaler, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

The amount of tobramycin excreted in human breast milk after administration by inhalation is not known. Because of the potential for ototoxicity and nephr otoxicity in infants, a decision should be made whether to terminate nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Patients 6 years and older were included in the Phase 3 studies with TOBI Podhaler; 206 patients below 20 years of age received TOBI Podhaler. No dosage adjustments are needed based on age. The overall pattern of adverse events in pediatric patients was similar to the adults. Dysgeusia (taste disturbance) was more commonly reported in younger patients six to 19 years of age than in patients 20 years and older, 7.4% vs 2.7%, respectively. Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

Geriatric Use

Clinical studies of TOBI Podhaler did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be gr eater 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 Nephrotoxicity and Laboratory Tests].

Renal Impairment

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure to tobramycin. The risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with serum creatinine > 2 mg/dL and blood urea nitrogen (BUN) > 40 mg/dL have not been included in clinical studies and there are no data in this population to support a recommendation regarding dose adjustment with TOBI Podhaler [see Nephrotoxicityand Laboratory Tests].

Hepatic Impairment

No studies have been performed in patients with hepatic impairment. As tobramycin is not metabolized, an effect of hepatic impairment on the exposure to tobramycin is not expected.

Organ Transplantation

Adequate data do not exist for the use of TOBI Podhaler in patients after organ transplantation.

Last reviewed on RxList: 5/8/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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