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.

TEFLARO (NDA-200327)

(CEFTAROLINE FOSAMIL)

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

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11/27/2020 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Neurological Adverse Reactions

New subsection added

Neurological adverse reactions have been reported during postmarketing surveillance in patients treated with cephalosporins, including Teflaro. These reactions include encephalopathy and seizures [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. The neurological adverse reactions were reversible and resolved after discontinuation of Teflaro or after hemodialysis. If neurological adverse reactions associated with Teflaro therapy occur, consider discontinuing Teflaro or making appropriate dosage adjustments in patients with renal impairment [see Dosage and Administration (2.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Neurological Adverse Reactions [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Additions underlined

…

Nervous system disorders: Encephalopathy, seizures [see Warnings and Precautions (5.3)]

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Advise patients that neurological adverse reactions could occur with Teflaro use. Instruct patients or their caregivers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including somnolence, lethargy, confusion, and slow thinking), and seizures for immediate treatment, dosage adjustment, or discontinuation of Teflaro.

…

09/13/2019 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

Pediatric Patients

Additions underlined:

A single study enrolled 11 pediatric patients with a gestational age of ?34 weeks and a postnatal age of 12

days to less than 2 months of age. The safety findings were similar to those observed in adult and pediatric

patients 2 months of age and older.

Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of Teflaro in adult patients.

Because these adverse 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.

Blood and lymphatic system disorders: Agranulocytosis, leukopenia, eosinophilic pneumonia.

8 Use in Specific Populations

Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of Teflaro in the treatment of ABSSSI have been established in pediatric patients at least 34 weeks gestational age and 12 days postnatal age.

The safety and effectiveness of Teflaro in the treatment of CABP have been established in the age groups 2 months to less than 18 years old.

Use of Teflaro in these age groups is supported by evidence from adequate and well controlled studies of Teflaro in adults with additional pharmacokinetic and safety data in pediatric patients 2 months of age and older with ABSSSI or CABP. Use of Teflaro in pediatric patients less than 2 months of age was supported by pharmacokinetic and safety data in 11 infants at least 34 weeks gestational age and 12 days postnatal age. In these infants, concentrations of Teflaro in the cerebrospinal fluid were not evaluated.

Results from the clinical studies in pediatric patients show that Teflaro demonstrated a safety profile that was comparable with treatment of ABSSSI and CABP in adults at the clinical dosages studied.

Safety and effectiveness of Teflaro in pediatric patients less than 34 weeks gestational age and less than days postnatal age for the treatment of ABSSSI have not been established.

Safety and effectiveness of Teflaro in pediatric patients below the age of 2 months for the treatment of CABP have not been established as no data are available.

05/27/2016 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Direct Coombs’ Test Seroconversion

Seroconversion from a negative to a positive direct Coombs’ test result occurred in 42/234 (17.9%) of children receiving Teflaro and 3/93 (3.2%) of patients receiving comparator drugs in the three pooled pediatric trials. No adverse reactions representing hemolytic anemia were reported in any treatment group (added paragraph).

6 Adverse Reactions

Clinical Trials Experience

Adult Patients (add this subheading)
Teflaro was evaluated in four controlled ….

Most Common Adverse Reactions

Rename Table 4 as Table 5 (Adverse Reactions Occurring in = 2% of Patients Receiving Teflaro in the Pooled Adult Phase 3 Clinical Trials
Pediatric Patients (add this subheading and following information)
Teflaro was evaluated in three clinical trials (one in ABSSSI and two in CABP) which included 257 pediatric patients 2 months to < 18 years of age treated with Teflaro, and 102 patients treated with comparator agents for a treatment period up to 21 days. In two trials, one in ABSSSI and one in CABP, the dose was selected to result in exposures comparable to adult exposure with 600 mg administered by IV infusion every 12h. In an additional pediatric trial in complicated CABP the dose was higher. The median age of pediatric patients treated with Teflaro was 5 years, ranging from 2 months to < 18 years of age. Patients treated with Teflaro were predominantly male (55%) and Caucasian (92%). A similar safety profile was seen in clinical trials of pediatric patients.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In the three pooled pediatric clinical trials, SARs occurred in 10/257 (4%) of patients receiving Teflaro and 3/102 (3%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 10/257 (3.9%) of patients receiving Teflaro and 2/102 (2%) of patients receiving comparator drugs with the most common adverse reaction leading to discontinuation being rash in 2/257 (0.8%) of patients treated with Teflaro.

Most Common Adverse Reactions

No adverse reactions occurred in greater than 8% of pediatric patients receiving Teflaro. The most common adverse reactions occurring in = 3% of patients receiving Teflaro in the pooled pediatric clinical trials were diarrhea, nausea, vomiting, pyrexia and rash.
Table 6 lists adverse reactions occurring in = 3% of patients receiving Teflaro in the pooled pediatric clinical trials. Table 6 is new. Please refer to new label for full information.
Following is a list of additional adverse reactions reported by the 257 patients who received Teflaro in the pediatric clinical trials with incidences less than 3%.
- Investigations – Alanine aminotransferase increased, Aspartate aminotransferase increased
- Nervous system disorders – Headache
- Skin and subcutaneous tissue disorders- Pruritus

8 Use in Specific Populations

Lactation (PLLR Conversion)

No data is available regarding the presence of ceftaroline in human milk, the effects of ceftaroline on breastfed infants, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Teflaro and any potential adverse effects on the breastfed child from Teflaro or from the underlying maternal condition.

Patients with Renal Impairment

Add: There is insufficient information to recommend a dosage regimen for pediatric patients with CrCl < 50 ml/min.

Pediatric Use

The safety and effectiveness of Teflaro in the treatment of ABSSI and CABP have been established in the age groups 2 months to less than 18 years. Use of Teflaro in these age groups is supported by evidence from adequate and well-controlled studies of Teflaro in adults with additional pharmacokinetic and safety data from pediatric trials. The clinical cure rates in the Teflaro group (Modified Intent To Treat [MITT] Population) were similar in patients = 18 years of age compared with patients 2 months to < 18 years of age in both the ABSSSI and CABP trials.
Results from the clinical studies in pediatric patients show that Teflaro demonstrated a safety profile that was compatible with treatment of ABSSSI and CABP at the clinical dosages studied. In summary, the safety findings were similar to those seen in the adult studies, and no safety concerns were identified beyond those already known to be cephalosporin class effects.
Safety and effectiveness in pediatric patients below the age of 2 months have not been established as no data are available.

Pregnancy (PLLR Conversion)

There are no adequate studies with Teflaro in pregnant women that informed any drug associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population.
In developmental toxicity studies conducted in animals, no malformations or other adverse developmental effects were observed in offspring of rats exposed to Teflaro at up to 4 times the maximum recommended human dose (MRHD) during the period of organogenesis through lactation. In rabbits exposed to Teflaro during organogenesis at levels approximately equal to the MRHD, no drug-induced fetal malformations were observed despite maternal toxicity.

Data

Animal Data

Replace 8 times with 4 times
Replace 0.8 with 0.4 times

05/27/2016 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

Blood and lymphatic system disorders: add leukopenia