Drug Safety-related Labeling Changes (SrLC)

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BETHKIS (NDA-201820)

(TOBRAMYCIN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/10/2023 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ototoxicity

Additions and/or revisions underlined

…

Risk of Ototoxicity Due to Mitochondrial DNA Variants

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined

….

Before you take BETHKIS, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had hearing problems (including noises in your ears such as ringing or hissing), hearing loss, or your mother has had hearing problems after taking an aminoglycoside.

  …

12/09/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ototoxicity

Newly added information underlined:

… Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. 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 BETHKIS. Monitoring may include obtaining audiometric evaluations and serum tobramycin levels. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing BETHKIS.

5.2 Nephrotoxicity

Newly added information underlined:

Nephrotoxicity was not seen during BETHKIS clinical studies but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with BETHKIS 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 BETHKIS until serum concentrations fall below 2 mcg/mL.

5.3 Neuromuscular Disorders

Newly added information underlined:

BETHKIS should be used cautiously in patients with muscular disorders.

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.

5.6 Embryo-Fetal Toxicity

Newly added information 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 [see Clinical Pharmacology (12.3)]. Patients who use BETHKIS during pregnancy, or become pregnant while taking BETHKIS should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Newly added subsection follows:

5.7 Concomitant Use of Systematic Aminoglycosides

Patients receiving concomitant BETHKIS and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

7 Drug Interactions

7.2 Diuretics (replaces Ethacrynic Acid, Furosemide, Urea, or Mannitol)

Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue …

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, additions and/or revisions underlined:

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 BETHKIS 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

PLLR conversion, as below:

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 BETHKIS. 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 BETHKIS and any potential adverse effects on the breastfed child from BETHKIS 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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

17.5 Embryo-Fetal Toxicity (replaces Pregnancy)

Inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman …

Newly added subsection:

17.6 Administration

Patients should be informed about what to do in the event they miss a dose of BETHKIS:

• In case a dose of BETHKIS is missed and there are at least 6 hours until the next dose, patients should be instructed to take the prescribed dose of BETHKIS as soon as possible. Otherwise, the missed dose should not be taken and the patient should resume the usual dosing schedule.

• Patients should be advised to contact their healthcare provider if they have questions.

PATIENT INFORMATION

Additions and/or revisions underlined:

What is BETHKIS?

It is not known if BETHKIS is safe and effective:

• in people who have decreased lung volume or a forced expiratory volume in one second (FEV1) less than 40% or greater than 80% predicted

Do not take BETHKIS if you are allergic to tobramycin, any of the ingredients in BETHKIS, or to any other aminoglycoside antibacterial.

See the end of this Patient Information for a complete list of ingredients in BETHKIS.

Before you take BETHKIS, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had hearing problems (including noises in your ears such as ringing or hissing)

• are pregnant or plan to become pregnant. BETHKIS is in a class of medicines that can harm your unborn baby and may be connected with complete deafness in babies at birth. The deafness affects both ears and cannot be changed.

• are breastfeeding or plan to breastfeed. It is not known if BETHKIS passes into your breast milk. Tobramycin, the medicine in BETHKIS may cause the following symptoms in your breastfed baby:

• loose or bloody stools

• yeast infection in the mouth or throat (thrush)

• diaper rash

Call your baby’s healthcare provider if your breastfed baby has any of these problems. Talk to your healthcare provider about the best way to feed your baby during treatment with BETHKIS.

• are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking BETHKIS. Your blood levels of tobramycin will be checked.

Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements.

How should I take BETHKIS?

Take BETHKIS exactly as your healthcare provider tells you to. Do not change your dose or stop taking BETHKIS unless your healthcare provider tells you to.

The usual dose of BETHKIS for adults and children over 6 years of age is:

• 1 single-use ampule of BETHKIS inhaled 2 times each day using your hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios air compressor.

• BETHKIS is taken as a breathing treatment (inhalation) with a hand-held PARI LC Reusable Nebulizer with a PARIVios air compressor. Do not use any other nebulizer for your BETHKIS treatment.

• BETHKIS should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth.

• If you forget to take BETHKIS and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose.

• After taking BETHKIS for 28 days, you should stop taking it and wait 28 days. After you have stopped taking BETHKIS for 28 days, you should start taking BETHKIS again for 28 days. Complete the full 28-day course even if you are feeling better. It is important that you keep to the 28-day on, 28-day off cycle.

• If you are taking several other medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling BETHKIS or as directed by your healthcare provider.

• If you take too much BETHKIS, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of BETHKIS? BETHKIS can cause serious side effects, including:

• hearing loss or ringing in the ears (ototoxicity). Some people who were treated with tobramycin, the medicine in BETHKIS had hearing loss or ringing in the ears. Tell your healthcare provider right away if you have hearing loss or hear noises in your ears (such as ringing or hissing), or if you develop vertigo, dizziness, or difficulty with balance.

• worsening muscle weakness (neuromuscular disorder). BETHKIS can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson’s disease).

05/29/2017 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Bronchospasm

(additions underlined)

Bronchospasm has been reported with inhalation of tobramycin. In clinical studies with BETHKIS, bronchospasm was observed in one (0.5%) BETHKIS-treated patient and in no placebo-treated patients. Wheezing occurred in ten (5%) BETHKIS-treated patients and four (4%) placebo- treated patients. Bronchospasm and wheezing should be treated as medically appropriate.

5.5 Laboratory Tests

(additions underlined)

Audiograms

 Clinical studies of inhaled tobramycin solutions 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.

Serum Concentrations

In patients with normal renal function treated with BETHKIS, serum tobramycin concentrations range from approximately 0.06-1.89 mcg/mL one 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.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during postapproval use of tobramycin inhalation solution. 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, 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

(addition underlined)

Concurrent and/or sequential use of BETHKIS with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided.

7.2 Ethacrynic Acid, Furosemide, Urea, or Mannitol

(additions underlined)

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

8 Use in Specific Populations

8.5 Geriatric Use

(subsection revised, additions underlined)

Clinical studies of BETHKIS 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(additions underlined)

…

What is BETHKIS?

BETHKIS is a prescription medicine used to treat people with cystic fibrosis who have a bacterial infection called

Pseudomonas aeruginosa. BETHKIS contains an antibacterial medicine called tobramycin (an aminoglycoside). It is not known if BETHKIS is safe and effective:

• in children under 6 years of age

• in people who have decreased lung volume or an FEV1 less than 40% of predicted

• in people who are colonized with a bacterium called Burkholderia cepacia

• when used for more than 3 cycles

  …

  Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

  Taking BETHKIS with certain other medicines can cause serious side effects.

  If you are taking BETHKIS, you should discuss with your healthcare provider if you should take:

• other medicines that may harm your nervous system, kidneys, or hearing

• “water pills” (diuretics) such as Edecrin (ethacrynic acid), Lasix (furosemide), or intravenous mannitol

• urea

  …