Tobramycin Inhalation (Page 3 of 7)

7 DRUG INTERACTIONS

7.1 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.

7.2 Diuretics

Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Therefore, Tobramycin Inhalation Solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and Tobramycin Inhalation Solution has not been evaluated.

8 USE IN SPECIFIC POPULATIONS

8.1 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 [Warnings and Precautions (5.6)]. Although there are no available data on use of Tobramycin Inhalation Solution in pregnant women to be able 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 reproduction toxicology studies have been conducted with inhaled tobramycin. 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 ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin.

8.2 Lactation

Risk Summary

There are no data on the presence of tobramycin in either human or animal milk, the effects on the breastfed infant, or the effects on milk production following oral inhalation of Tobramycin Inhalation Solution. Limited published data on other formulations of tobramycin in lactating women indicate that tobramycin is present in human milk. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3)]. Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tobramycin Inhalation Solution and any potential adverse effects on the breastfed child from Tobramycin Inhalation Solution or from the underlying maternal condition.

Clinical Considerations

Tobramycin may cause intestinal flora alteration. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash).

8.4 Pediatric Use

The safety and efficacy of Tobramycin Inhalation Solution have not been studied in pediatric cystic fibrosis patients under six years of age.

8.5 Geriatric Use

Clinical studies of Tobramycin Inhalation Solution 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 and Precautions (5.2, 5.5)].

8.6 Renal Impairment

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure of tobramycin. The risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with serum creatinine > 2mg/dL and blood urea nitrogen (BUN) > 40mg/dL have not been included in clinical studies and there are no data in this population to support a recommendation for or against dose adjustment [see Warnings and Precautions (5.2, 5.5)].

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.

10 OVERDOSAGE

No overdoses have been reported with Tobramycin Inhalation Solution in clinical trials. Signs and symptoms of acute toxicity from overdosage of intravenous tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. 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.

In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.

11 DESCRIPTION

Tobramycin Inhalation Solution is a sterile, clear, colorless to pale yellow, non-pyrogenic, aqueous solution with pH and salinity adjusted. Tobramycin Inhalation Solution is administered by a compressed air driven reusable nebulizer. The chemical formula for tobramycin is C18 H37 N5 O9 and the molecular weight is 467.52. Tobramycin is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino- 2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L‑streptamine.

The structural formula for tobramycin is:

Tobramycin structural formula

Each single-use 4 mL ampule of Tobramycin Inhalation Solution contains one 300 mg dose of tobramycin, with sodium chloride and sulfuric acid in water for injection. Sulfuric acid and sodium hydroxide are used, as needed, to adjust the pH to 5.0. Nitrogen is used for sparging, filling and pouching. The formulation contains no preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tobramycin Inhalation Solution is an aminoglycoside antibacterial [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Tobramycin Inhalation Solution contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes.1 The bioavailability of Tobramycin Inhalation Solution may vary because of individual differences in nebulizer performance and airway pathology.2

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