Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Bronchospasm
(Additions
and/or revisions are underlined)
Bronchospasm can occur with inhalation of
TOBI. In clinical studies with TOBI, changes in FEV1 measured after the inhaled
dose were similar in tobramycin inhalation solution and placebo groups.
Bronchospasm that occurs during the use of TOBI should be treated as medically
appropriate.
5.2 Ototoxicity
(Additions
and/or revisions are underlined)
Ototoxicity, manifested as both auditory and
vestibular toxicity, has been reported with parenteral aminoglycosides.
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 further clinical investigation.
InOtotoxicity, as measured by complaints of
hearing loss or by audiometric evaluations, did not occur with TOBI therapy during clinical studies,
however in postmarketing experience, patients receiving TOBI have reported
hearing loss.
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 TOBI. 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 TOBI.
5.3 Nephrotoxicity
(Additions and/or revisions are
underlined)
Nephrotoxicity was not seen during clinical
studies with TOBI but has beenwith aminoglycosides as a class. Patients with
known or suspected renal dysfunction or taking concomitant nephrotoxic drugs
along with TOBI 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
TOBI.
5.4 Neuromuscular Disorders
(Additions
and/or revisions are underlined)
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 concomitant neuromuscular blocking
agents. If neuromuscular blockade occurs, it may be reversed by the
administration of calcium salts but mechanical assistance may be necessary.
5.5 Embryo-fetal Toxicity
(Additions and/or revisions are
underlined)
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 TOBI during
pregnancy or become pregnant
while taking TOBI should
be apprised of the potential hazard to the fetus.
5.6 Concomitant Use of Systemic Aminoglycosides
(Newly
added subsection)
Patients receiving concomitant TOBI and
parenteral aminoglycoside therapy should be monitored as clinically appropriate for
toxicities associated with aminoglycosides as a class. Serum tobramycin levels
should be monitored.
6
Adverse Reactions
6. ADVERSE REACTIONS
6.1 Clinical Trials Experience
(Additions
and/or revisions are underlined)
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.
TOBI was studied in two phase 3 clinical studies involving 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients
received TOBI 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 TOBI patients during the two Phase III studies.
Selected adverse reactions that occurred in
less than or equal to 5% of patients treated with TOBI:
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 TOBI-treated patients. Thirty- three patients (13%) treated
with TOBI complained of voice alteration compared to 17 (7%) placebo patients.
Voice alteration was more common in the on-drug periods.
Eight patients from the TOBI group (3%)
reported tinnitus compared to no placebo patients. All episodes were transient,
resolved without discontinuation of the TOBI 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
TOBI and placebo groups.
Changes in Serum Creatinine
Nine (3%) patients in the TOBI 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 TOBI group, creatinine
decreased at the next visit.
6.2 Postmarketing Experience
(Additions and/or revisions are
underlined)
The following adverse reactions have been
identified during post-approval use of TOBI. 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
Metabolism and Nutrition Disorders
Decreased appetite
7
Drug Interactions
7.1 Drugs with Neurotoxic, Nephrotoxic or Ototoxic Potential
(Newly
added subsection)
Concurrent and/or sequential use of TOBI with
other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be
avoided.
7.2 Diuretics
(Additions
and/or revisions are underlined)
Some diuretics can enhance aminoglycoside
toxicity by altering aminoglycoside concentrations in serum and tissue. TOBI should not be administered concomitantly
with ethacrynic acid, furosemide, urea, or intravenous mannitol. The
interaction between inhaled mannitol and TOBI has not been evaluated.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
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 TOBI 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. 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. 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 TOBI (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 greater than or equal
to 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.
8.2 Lactation
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
There are no data on the presence
of TOBI in either human or animal
milk, the effects on the breastfed
infant, or the effects on milk production. 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.
Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical
need for TOBI and any potential
adverse effects on the breastfed
infant from TOBI 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
(Pregnancy
and Lactation Labeling Rule (PLLR) Conversion)
The safety and efficacy of TOBI in
pediatric patients under 6 years of age has not been established. The use of
TOBI is not indicated in children <6 years of age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Newly added subsection)
Advise
the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use). Difficulty Breathing
Advise
patients to inform their physicians if they experience shortness of breath or
wheezing after administration of tobramycin inhalation solution. Tobramycin
inhalation solution can cause a narrowing of the airway.
Hearing
Loss:
Advise
patients to inform their physician if they experience ringing in the ears,
dizziness, or any changes in hearing because tobramycin inhalation solution has
been associated with hearing loss.
Kidney
Damage:
Advise
patients to inform their physician if they have any history of kidney problems
because tobramycin inhalation solution is in a class of drugs that have caused
kidney damage.
Embryofetal
Toxicity:
Advise
pregnant women that aminoglycosides can cause irreversible congenital deafness
when administered to a pregnant woman.
Lactation:
Advise
a woman to monitor their breastfed infants for diarrhea and/or bloody stools.
Other
PATIENT INFORMATION
(Patient
Information section has been added, please refer to the label)
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