Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

KITABIS PAK (NDA-205433)

(TOBRAMYCIN)

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

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04/10/2023 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Embryo-Fetal Toxicity

Additions and revisions 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 KITABIS PAK during pregnancy, or become pregnant while taking tobramycin inhalation solution should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes to table; please refer to label

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

PATIENT COUNSELING INFORMATION

Newly added information:

Embryo-Fetal Toxicity:

Advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to a pregnant woman [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Lactation:

Advise a woman to monitor their breastfed infants for diarrhea and/or bloody stools [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Additions and revisions underlined:

Before using KITABIS PAK, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had breathing problems such as wheezing, coughing, or chest tightness.

• 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.

• have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from

your mother.

• have dizziness.

• have or have had kidney problems.

• have or have had problems with muscle weakness such as myasthenia gravis or Parkinson’s disease.

• are pregnant or plan to become pregnant. KITABIS PAK contains a medicine that may cause harm to your unborn

baby.

02/10/2023 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 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 COUNSELING INFORMATION

Additions and/or revisions underlined

…

Pregnancy

Advise patients to talk with their physician if they want to become pregnant while on tobramycin inhalation solution because tobramycin inhalation solution is in a class of antibacterial drugs that have caused harm to the fetus[see Warnings and Precautions (5.5)].

Nursing Mothers

Advise patients to talk with their physician before using tobramycin inhalation solution while nursing a baby [see Use in Specific Populations (8.3)].

PATIENT INFORMATION

Additions and/or revisions underlined

…

What should I tell my healthcare provider before using KITABIS PAK? Before you use KITABIS PAK, tell your healthcare provider 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.
have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from your mother.
…
have had an organ transplant
…

12/06/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Embryo-Fetal Toxicity

(additions 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 KITABIS PAK during pregnancy, or become pregnant while taking tobramycin inhalation solution should be apprised of the potential hazard to the fetus.

8 Use in Specific Populations

8.1 Pregnancy

(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 [Warnings and Precautions (5.5)]. Although there are no available data on KITABIS PAK 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 (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 reproductive toxicity studies have been conducted with tobramycin inhalation solution. 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 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

(PLLR conversion)

Risk Summary

There are no data on the presence of tobramycin inhalation solution 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 (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KITABIS PAK and any potential adverse effects on the breastfed infant from KITABIS PAK 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 underlined)

…

Embryo-Fetal 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.

PATIENT INFORMATION

(additions underlined)

…

What should I tell my healthcare provider before using KITABIS PAK?

Before using KITABIS PAK, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. KITABIS PAK contains a medicine that may cause harm to your unborn baby. See “What are the possible side effects of KITABIS PAK?” below for more information.

…

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

Using KITABIS PAK with certain other medicines can cause serious side effects. Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

…