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.

ORKAMBI (NDA-211358)

(IVACAFTOR; LUMACAFTOR)

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

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03/17/2026 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors

Newly added subsection:

Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking ORKAMBI or drugs containing the same or similar active ingredients [see Adverse Reactions (6.2)]. The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation.

Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with ORKAMBI should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.5)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following adverse reactions have been identified during postapproval use of ORKAMBI or drugs containing the same or similar active ingredients as ORKAMBI. 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.
…
Psychiatric Disorders: anxiety, depression, suicidal ideation and behavior, insomnia

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors

Inform patients that neuropsychiatric symptoms, including anxiety, depression, suicidal thoughts and behaviors, and sleep disturbances (e.g., insomnia), have been reported with the use of ORKAMBI or drugs containing the same or similar active ingredients as ORKAMBI. The symptoms have been observed in patients with and without a history of similar symptoms and may occur within three months of ORKAMBI initiation. Instruct patients to contact their healthcare provider

immediately if changes in behavior or thinking that are not typical for the patient occur, or if the patient develops suicidal ideation or behavior [see Warnings and Precautions (5.5)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking ORKAMBI, tell your doctor about all of your medical conditions, including if you:

…

have or have had mental health problems.
…

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

Serious mental health problems such as anxiety, depression, suicidal thoughts and behaviors, and trouble sleeping have happened in people treated with ORKAMBI or medicines containing the same or similar ingredients
…

09/25/2025 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Intracranial Hypertension

Newly added subsection:

Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of ORKAMBI [see Adverse Reactions (6.2)]. Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt ORKAMBI and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Intracranial Hypertension [see Warnings and Precautions (5.4)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Nervous System Disorders: intracranial hypertension

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Intracranial Hypertension

Inform patients that intracranial hypertension has occurred with the use of ORKAMBI. Instruct patients to notify their healthcare provider right away if they experience signs and symptoms of intracranial hypertension, including headache, blurred vision, diplopia, and vision loss [see Warnings and Precautions (5.4)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

What are the possible side effects of ORKAMBI?

ORKAMBI can cause serious side effects, including:

…

Increased pressure around the brain (intracranial hypertension) has happened in people treated with ORKAMBI. If you experience an unusual headache, blurred vision, double vision, or vision loss, call your doctor right away.
…

12/13/2024 (SUPPL-6)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and revisions underlined:

. . .

Data

Animal Data

Lumacaftor

In an embryo-fetal development (EFD) study, pregnant rats were administered lumacaftor at oral doses of 500, 1000, or 2000 mg/kg/day during the period of organogenesis from gestation days 7-17. Lumacaftor did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). In an EFD study, pregnant rabbits were administered lumacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-19. Lumacaftor did not affect fetal development or survival at exposures up to 5 times the MRHD (on an AUC basis at maternal oral doses up to 200 mg/kg/day). Maternal toxicity as evidenced by decreased body weight, decreased food consumption, and clinical signs was observed at 100 and 200 mg/kg/day without any adverse fetal effects. In a pre- and post-natal development study in pregnant female rats administered lumacaftor at 250, 500, or

1000 mg/kg/day from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits.

Ivacaftor

In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to

200 mg/kg/day). Maternal toxicity (i.e., decreased mean body weight and body weight gain) was observed at 100 and 200 mg/kg/day (5 and 7 times the exposure at the MRHD, respectively) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (7 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 15 times the MRHD). In a pre- and post-natal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20

. . .

8.4 Pediatric Use

Newly added information:

Safety was evaluated in a 96-week open-label clinical trial (Trial 8) in 52 patients (39 rolled over from Trial 7 and 13 ORKAMBI naïve) aged 1 to 2 years. Adverse reactions from trial 8 were generally similar to those reported in Trial 7.

08/03/2023 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Hypersensitivity Reactions, Including Anaphylaxis

New subsection added:

Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3)]
Cataracts [see Warnings and Precautions (5.7)]
6.2 Postmarketing Experience
Addition and/or revisions underlined:
The following adverse reactions have been identified during post approval use of ORKAMBI. 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.
Hepatobiliary: liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension [see Warnings and Precautions (5.1)].
Immune System Disorders: anaphylaxis, angioedema

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions including angioedema and anaphylaxis are possible with use of ORKAMBI. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of ORKAMBI immediately and contact their physician or go to the emergency department if these symptoms occur.

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking ORKAMBI, tell your doctor about all of your medical conditions, including if you:

…

are allergic to ORKAMBI or any ingredients in ORKAMBI. See the end of this patient information leaflet for a complete list of ingredients in ORKAMBI.
…
What are the possible side effects of ORKAMBI?
ORKAMBI can cause serious side effects, including:
…

Serious Allergic Reactions can happen to people who are treated with ORKAMBI. Call your doctor or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include:

rash or hives
swelling of the face, lips, and/or tongue,
tightness of the chest or throat or difficulty breathing difficulty swallowing

light-headedness or dizziness

…

09/02/2022 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and revisions underlined:

In addition, the following clinical trials have been conducted:

A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del-CFTR mutation.

In a 24-week, open-label, multicenter study in 46 patients aged 1 through 2 years with CF who are homozygous for the F508del-CFTR mutation (Trial 7) the safety profile was similar to that observed in studies in patients aged 2 years and older [see Clinical Pharmacology (12.2)].

During the 24-week, open-label, clinical trial in 46 patients aged 1 through 2 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46), respectively. No patients had total bilirubin levels >2 x ULN. One patient discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations.

7 Drug Interactions

7.1 Inhibitors of CYP3A

Additions and revisions underlined:

However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dosage as recommended for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose [see Dosage and Administration (2.3)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of ORKAMBI in pediatric patients one year of age and older have been established. Use of ORKAMBI in these age groups is supported by evidence from adequate and well-controlled studies of ORKAMBI in patients 12 years of age and older [see Clinical Studies (14) and Adverse Reactions (6.1)] with additional data as follows:

extrapolation of efficacy in patients aged 12 years and older homozygous for the F508del mutation in the CFTR gene to pediatric patients aged 1 through 11 years with support from population pharmacokinetic analyses showing similar drug exposure levels in patients aged 12 years and older and in patients aged 1 through 11 years [see Clinical Pharmacology (12.3)].
Safety data were obtained from a 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years, mean age 9 years (Trial 3) and a 24-week, placebo- controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4). Trial 3 evaluated subjects with a screening ppFEV1 greater than or equal to 40 [mean ppFEV1 91.4 at baseline (range: 55 to 122.7)]. Trial 4 evaluated subjects with a screening ppFEV1 greater than or equal to 70 (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]). The safety profile of ORKAMBI in pediatric patients 6 through 11 years of age was similar to that in patients 12 years and older [see Adverse Reactions (6.1)]. In Trial 3, spirometry (ppFEV1) was assessed as a planned safety endpoint. The within-group LS mean absolute change from baseline in ppFEV1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV1 was also assessed. The within-group LS mean absolute change in ppFEV1 from Week 24 at Week 26 was -3.2 percentage points.
Additional safety data were obtained from Trial 6, a 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years at screening (mean age at baseline 3.7 years). The safety profile in Trial 6 was similar to that in patients aged 6 years and older [see Adverse Reactions (6.1)].
Additional safety data were obtained from Trial 7, a 24-week, open-label, clinical trial in 46 patients aged 1 to 2 years at screening (mean age at baseline 18.1 months). The safety profile in Trial 7 was similar to that in patients aged 2 years and older [see Adverse Reactions (6.1)].

The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established.

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

Patient Counseling Information

Extensive changes; please refer to label

Patient Information

Extensive changes; please refer to label