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.

KALYDECO (NDA-207925)

(IVACAFTOR)

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

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03/17/2026 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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 KALYDECO or drugs containing the same or similar active ingredient [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 KALYDECO 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 (5.4)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following adverse reactions have been identified during postapproval use of KALYDECO or drugs containing the same or similar active ingredient as KALYDECO. 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 KALYDECO or drugs containing the same or similar active ingredient as KALYDECO. The symptoms have been observed in patients with and without a history of similar symptoms and may occur within three months of KALYDECO 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 (5.4)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking KALYDECO, 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 KALYDECO?
KALYDECO 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 KALYDECO or medicines containing the same or similar ingredient as KALYDECO. If you experience new or worsening mental health problems, call your doctor right away.
…

09/25/2025 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Intracranial Hypertension

Newly added subsection:

Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients as KALYDECO [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 KALYDECO and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO. 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 (5.3)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Postmarketing Adverse Reactions with Other Drugs Containing the Same or Similar Active Ingredients as KALYDECO
The following adverse reactions have been identified during post approval use of drugs containing the same or similar active ingredients as KALYDECO. 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.
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 in patients who received drugs containing the same or similar active ingredients as KALYDECO. 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 (5.3)].

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PATIENT INFORMATION

Additions and/or revisions underlined:

…

What are the possible side effects of KALYDECO?

KALYDECO can cause serious side effects, including:

…

Increased pressure around the brain (intracranial hypertension) has happened in people treated with medicines containing the same or similar ingredients as KALYDECO. If you experience an unusual headache, blurred vision, double vision, or vision loss, call your doctor right away.

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05/22/2025 (SUPPL-19)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Data

Animal Data

In an embryo-fetal development 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 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 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 11 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 5 times the MRHD). In a pre- and post-natal development study, pregnant female rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

8.4 Pediatric Use

Additions and/or revisions underlined:

…

Safety of KALYDECO in patients aged 1 month and older was evaluated in a 96-week, open-label study (Trial 9) in 86 patients (38 rolled over from Trial 8, and 48 KALYDECO-naïve). Adverse reactions from Trial 9 were generally similar to those reported in Trial 8.

…

08/03/2023 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypersensitivity Reactions, Including Anaphylaxis

New subsection added:

Hypersensitivity reactions, including cases of 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 KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2)]
6.2 Postmarketing Experience
New subsection Added:
The following adverse reactions have been identified during post approval use of KALYDECO. 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.
Immune System Disorders: anaphylaxis

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 anaphylaxis are possible with use of KALYDECO. 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 KALYDECO immediately and contact their physician …

or go to the emergency department if these symptoms occur.

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

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

…

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

Serious Allergic Reactions can happen to people who are treated with KALYDECO. Call your healthcare provider 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
- tightness of the chest or throat or difficulty breathing
- light-headedness or dizziness
  …

05/03/2023 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

A 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8) including a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, a cohort of 6 patients aged 4 months to less than 6 months, and a cohort of 7 patients aged 1 month to less than 4 months. Patients with a gating mutation or R117H mutation were eligible for the first three cohorts of this study. Patients with any ivacaftor-responsive mutation were eligible for the cohort aged 1 to less than 4 months.

Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo for 16 to 48 weeks.

…

During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 x ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ?5 x ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (>3x ULN). In the cohort of patients aged 1 month to less than 4 months (N=7), 1 patient (14.3%) had maximum ALT or AST >3 x ULN (ALT >8 x ULN and AST of >3 to less than or equal to 5 x ULN); the patient discontinued ivacaftor treatment. [see Warnings and Precautions (5.1)].

7 Drug Interactions

Additions and/or revisions underlined:

Potential for other drugs to affect ivacaftor

7.1 Inhibitors of CYP3A

Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food or drink containing grapefruit during treatment with KALYDECO [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.1 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of KALYDECO for the treatment of CF have been established in pediatric patients 1 month to 17 years of age who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data [see Clinical Pharmacology (12.1) and Clinical Studies (14)].

The use of KALYDECO for this indication is supported by evidence from placebo-controlled clinical trials in the following pediatric patients with CF:

6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation in the CFTR gene [see Adverse Reactions (6) and Clinical Studies (14)].

12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].

The effectiveness of KALYDECO in patients aged 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric patients 2 to less than 6 years of age [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a 24-week, open-label clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). The type and frequency of adverse reactions in this trial were similar to those in patients 6 years and older.

Transaminase elevations were more common in patients who had abnormal transaminases at baseline [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

The effectiveness of KALYDECO in patients aged 1 month to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing that the exposure of ivacaftor in pediatric patients 1 month to less than 24 months of age is within the range of exposure in adults and pediatric patients 6 years of age and older [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a cohort of 7 patients aged 1 month to less than 4 months (mean age 1.9 months at baseline), a cohort of 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline), a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical trial, administered 5.8 mg, 11.4 mg, 17.1 mg, 22.8 mg, 25 mg, 50 mg, or 75 mg (11.4 mg, 17.1 mg, and 22.8 mg are not recommended dosages) of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial was similar to that observed in patients 2 years and older.

The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established.

Juvenile Animal Toxicity Data

In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.1 to 0.8 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is necessary for patients aged 6 months or older [see Clinical Pharmacology (12.3)].

Moderate Hepatic Impairment (Child-Pugh Class B): A reduced dose is recommended in patients aged 6 months or older [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Severe Hepatic Impairment (Child-Pugh Class C): Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dose, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any level of hepatic impairment [see Dosage and Administration (2.3)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John’s wort) is not recommended, as they may reduce the therapeutic effectiveness of KALYDECO. Dose reduction is recommended when patients aged 6 months and older are taking concomitant strong CYP3A inhibitors, such as ketoconazole, or moderate CYP3A inhibitors, such as fluconazole [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months who are taking concomitant moderate or strong CYP3A inhibitors. Food or drink containing grapefruit should be avoided [see Drug Interactions (7.1, 7.2) and Clinical Pharmacology (12.3)].

Use in Patients with Hepatic Impairment

Inquire and/or assess whether patients have liver impairment. Reduce the dose of KALYDECO in patients aged 6 months and older with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) to one tablet or one packet of granules once daily. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15); however, exposure is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients aged 6 months and older with severe hepatic impairment at a reduced dose [see Dosage and Administration (2.3)]. Treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any signs of hepatic impairment. No dose adjustment is recommended for patients 6 months and older with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Use in Specific Populations (8.6)].

Driving and Operating Machinery

Dizziness has been reported in patients receiving KALYDECO, which could influence the ability to drive or operate machines [see Adverse Reactions (6.1)]. Advise patients not to drive or operate machines if they experience dizziness until symptoms abate.

Administration

KALYDECO (ivacaftor) tablets 150 mg

Inform patients that KALYDECO tablet is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.

KALYDECO (ivacaftor) oral granules 5.8 mg, 13.4 mg, 25 mg, 50 mg, or 75 mg

Inform patients and caregivers that KALYDECO oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.

Inform patients and caregivers that KALYDECO is best absorbed by the body when taken with food that contains fat; therefore, KALYDECO oral granules should be taken just before or just after consuming food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, and infant formula), etc.

…

PATIENT INFORMATION

Additions and/or revisions underlined:

What is KALYDECO?

KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 1 month and older who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR gene) that is responsive to KALYDECO.
Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if KALYDECO is safe and effective in children under 1 month of age.

…

How should I take KALYDECO?

…

• Always take KALYDECO tablets or oral granules with food that contains fat. Examples of fat-containing foods include eggs, butter, peanut butter, cheese pizza, and whole-milk dairy products such as whole milk, cheese, yogurt, breast milk, or infant formula.

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KALYDECO Tablets (ages 6 years and older):

…

Swallow the KALYDECO tablets whole.

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KALYDECO Oral Granules (ages 1 month to under 6 years old):

…

For people who have had high liver enzymes in the past, your doctor may do blood tests to check the liver more often. Call your doctor right away if you have any of the following symptoms of liver problems:

…

09/24/2020 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Transaminase (ALT or AST) Elevations

(Additions and/or revisions underlined)

Elevated transaminases have been reported in patients with CF receiving KALYDECO. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO [see Adverse Reactions (6) and Use in Specific Populations (8.6)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Transaminase Elevations [see Warnings and Precautions (5.1)]
Cataracts [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

(Additions and/or revisions 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 clinical practice.

The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted [see Clinical Pharmacology (12) and Clinical Studies (14)]:

An 8-week, crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene.
A 24-week, placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene.
A 24-week, open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.
An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor. A total of 156 patients were randomized to and received KALYDECO.

A cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, and a cohort of 6 patients aged 4 months to less than 6 months in a 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8).

…

During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3 , >5 , and >8 x ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ?5 x ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (> 3x ULN). No patients had elevations in total bilirubin, or discontinued ivacaftor treatment due to transaminase elevations in any cohort [see Warnings and Precautions (5.1)].

7 Drug Interactions

7.1 Inhibitors of CYP3A

(Additions and/or revisions underlined)

Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food containing grapefruit during treatment with KALYDECO [see Clinical Pharmacology (12.3)].

7.4 CYP2C9 Substrates

(Subsection title revised; Additions and/or revisions underlined)

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co administration of KALYDECO with warfarin is recommended. Other therapeutic products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these therapeutic products should be used with caution [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of KALYDECO for the treatment of CF have been established in pediatric patients 4 months to 17 years of age who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data [see Clinical Pharmacology (12.1) and Clinical Studies (14)].

The use of KALYDECO for this indication is supported by evidence from placebo-controlled clinical trials in the following pediatric patients with CF:

6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation in the CFTR gene [see Adverse Reactions (6) and Clinical Studies (14)].

12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].

The effectiveness of KALYDECO in patients aged 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 2 to less than 6 years of age [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a 24-week, open label, clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). The type and frequency of adverse reactions in this trial were similar to those in patients 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

The effectiveness of KALYDECO in patients aged 4 months to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 4 months to less than 24 months of age [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a cohort of 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline), a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical study, administered either 25 mg, 50 mg or 75 mg of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial is similar to that observed in patients 2 years and older.

The safety and effectiveness of KALYDECO in patients with CF younger than 4 months of age have not been established. The use of KALYDECO in children under the age of 4 months is not recommended.

Juvenile Animal Toxicity Data

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

No dose adjustment is necessary for patients aged 6 months or older with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].

A reduced dose is recommended in patients aged 6 months or older with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dose, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with KALYDECO is not recommended in patients aged 4 months to less than 6 months with hepatic impairment [see Dosage and Administration (2.3)].

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Transaminase (ALT or AST) Elevations and Monitoring

Inform patients that elevation in liver tests have occurred in patients treated with KALYDECO. Liver function tests will be performed prior to initiating KALYDECO, every 3 months during the first year of treatment and annually thereafter. More frequent monitoring of liver function tests should be considered in patients with a history of transaminase elevations [see Warnings and Precautions (5.1)].

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John’s wort) is not recommended, as they may reduce the therapeutic effectiveness of KALYDECO. Dose reduction is recommended when patients aged 6 months and older are taking concomitant strong CYP3A inhibitors, such as ketoconazole, or moderate CYP3A inhibitors, such as fluconazole [see Dosage and Administration (2.5), Drug Interactions (7.1)]. Treatment with KALYDECO is not recommended in patients aged 4 months to less than 6 months who are taking concomitant moderate or strong CYP3A inhibitors. Food containing grapefruit should be avoided [see Drug Interactions (7.1, 7.2) and Clinical Pharmacology (12.3)].

Use in Patients with Hepatic Impairment

Inquire and/or assess whether patients have liver impairment. Reduce the dose of KALYDECO in patients aged 6 months and older with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) to one tablet or one packet of granules once daily. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15); however, exposure is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients aged 6 months and older with severe hepatic impairment at a reduced dose [see Dosage and Administration (2.4)]. Treatment with KALYDECO is not recommended in patients aged 4 months to less than 6 months with any signs of hepatic impairment. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Use in Specific Populations (8.6)].

Administration

KALYDECO® (ivacaftor) tablets 150 mg

KALYDECO® (ivacaftor) oral granules 25 mg, 50 mg or 75 mg

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

In case a dose of KALYDECO is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of KALYDECO with fat-containing food as soon as possible.
If more than 6 hours have passed since KALYDECO is usually taken, 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.

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving KALYDECO. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating KALYDECO treatment [see Warnings and Precautions (5.3)].

PATIENT INFORMATION

(Additions and/or revisions underlined)

Read this Patient Information before you start taking KALYDECO and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is KALYDECO?

KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 4 months and older who have at least one mutation in their CF gene that is responsive to KALYDECO.

Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if KALYDECO is safe and effective in children under 4 months of age.

…

KALYDECO Oral Granules (ages 4 months to under 6 years old):

Hold the packet with cut line on top.
Shake the packet gently to settle the KALYDECO granules.
Tear or cut packet open along cut line.
Carefully pour all of the KALYDECO granules in the packet into 1 teaspoon of soft food or liquid. Food or liquid should be at or below room temperature. Some examples of soft foods or liquids include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.
Mix the KALYDECO granules with food or liquid.
After mixing, give KALYDECO within 1 hour. Make sure all medicine is taken.
Give a child fat-containing food just before or just after the KALYDECO granules dose. Examples of fat- containing foods include eggs, butter, peanut butter, cheese pizza, and whole-milk dairy products such as whole milk, cheese, yogurt, breast milk and infant formula.

04/29/2019 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

A cohort of 19 patients aged 12 months to less than 24 months, and a cohort of 11 patients aged 6 months to less than 12 months in a 24-week, open-label clinical trial in patients with CF aged less than 24 months (Trial 8).
...

Laboratory Abnormalities
…
During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3 , >5 , and >8 x ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to less than or equal to 5 x ULN. No patients had elevations in total bilirubin, or discontinued ivacaftor treatment due to transaminase elevations in either cohort.

7 Drug Interactions

7.1 Inhibitors of CYP3A

(additions and revisions underlined)

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet twice a week; in patients 6 months to less than 6 years with body weight 5 kg to less than 7 kg, reduce dose to one 25 mg packet of granules twice a week; in patients 6 months to less than 6 years with body weight 7 kg to less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients 6 months to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week.

Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet once daily; in patients 6 months to less than 6 years with body weight 5 kg to less than 7 kg, reduce dose to one 25 mg packet of granules once daily; in patients 6 months to less than 6 years with body weight 7 kg to less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients 6 months to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily.

…

8 Use in Specific Populations

8.4 Pediatric Use

(additions and revisions underlined)

The efficacy of KALYDECO in patients aged 6 months to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 6 months to less than 24 months of age. Safety of KALYDECO in this population was derived from a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical study, administered either 25 mg, 50 mg or 75 mg of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial is similar to that observed in patients 2 years and older.

The safety and efficacy of KALYDECO in patients with CF younger than 6 months of age have not been established. The use of KALYDECO in children under the age of 6 months is not recommended.

…

8.6 Hepatic Impairment

(additions and revisions underlined)

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of KALYDECO is recommended in patients with moderate hepatic impairment (Child-Pugh Class B), as follows: in patients 6 years and older, one 150 mg tablet once daily; in patients 6 months to less than 6 years with body weight 5 kg to less than 7 kg, one 25 mg packet of granules once daily; in patients 6 months to less than 6 years with body weight 7 kg to less than 14 kg, one 50 mg packet of granules once daily; and in patients 6 months to less than 6 years with body weight 14 kg or greater, one 75 mg packet of granules once daily. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a dose of one tablet or one packet of granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

KALYDECO® (ivacaftor) oral granules 25 mg, 50 mg or 75 mg

... Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.

…

PATIENT INFORMATION

(additions and revisions underlined)

…

What is KALYDECO?

KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 6 months and older who have at least one mutation in their CF gene that is responsive to KALYDECO.

Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if KALYDECO is safe and effective in children under 6 months of age.

…

KALYDECO Oral Granules (ages 6 months to under 6 years old):

…

Carefully pour all of the KALYDECO granules in the packet into 1 teaspoon of soft food or liquid. Food or liquid should be at or below room temperature. Some examples of soft foods or liquids include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.
…

08/15/2018 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

A cohort of 19 patients aged 12 months to less than 24 months in a 24-week, open-label clinical trial in patients with CF aged less than 24 months (Trial 8).
…
During the 24-week, open-label, clinical trial in 19 patients aged 12 months to less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3 , >5 , and >8 x ULN was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. No patients had elevations in total bilirubin. No subjects discontinued ivacaftor treatment due to transaminase elevations.

7 Drug Interactions

7.1 Inhibitors of CYP3A

(additions and revisions underlined)

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet twice a week; in patients 12 months to less than 6 years with body weight 7 kg to less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients 12 months to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week.

Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet once daily; in patients 12 months to less than 6 years with body weight 7 kg to less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients 12 months to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily.

…

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

KALYDECO is indicated for the treatment of CF in pediatric patients 12 months to 17 years of age who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data [see Clinical Pharmacology (12.1) and Clinical Studies (14)].

Placebo-controlled clinical trials established efficacy and safety in the following pediatric patients with CF:

6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation in the CFTR gene.
12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor.
…
The efficacy of KALYDECO in patients 12 months to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 12 months to less than 24 months of age.Safety of KALYDECO in this population was derived from a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open label clinical study, administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial is similar to that observed in patients 2 years and older.
The safety and efficacy of KALYDECO in patients with CF younger than 12 months of age have not been established. The use of KALYDECO in children under the age of 12 months is not recommended.

8.6 Hepatic Impairment

(additions underlined)

...

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

PATIENT INFORMATION

(additions underlined)

…

What is KALYDECO?

KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have at least one mutation in their CF gene that is responsive to KALYDECO.

Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if KALYDECO is safe and effective in children under 12 months of age.

…

KALYDECO Oral Granules (ages 12 months to under 6 years old):

Hold the packet with cut line on top.
Shake the packet gently to settle the KALYDECO granules.
…

07/31/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

The overall safety profile of KALYDECO is based on pooled data … In addition, the following clinical trials have also been conducted.

Addition of the following:

An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor. A total of 156 patients were randomized to and received KALYDECO.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

KALYDECO is indicated for the treatment CF in pediatric patients age 2-17 years of age who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

Clinical trials included the following CF patients:

6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, 49Rr or R117H mutation in the CFTR gene.
12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor.
The efficacy of KALYDECO in patients 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 2 to less than 6 years of age. Safety of KALYDECO in this population was derived from a 24 week, open label, clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules …

02/08/2017 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Transaminase (ALT or AST) Elevations

(additions underlined)

Elevated transaminases have been reported in patients with CF receiving KALYDECO. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

In addition, the following clinical trials have also been conducted:

• An 8-week crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, ,S1255P, S549N, or S549R mutation in the CFTR gene.

• A 24-week placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene.

• A 24-week open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.

…

The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-6) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2).

Laboratory Abnormalities

Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 x ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations.

During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 x ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 x ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient.

7 Drug Interactions

7.1 Inhibitors of CYP3A

(additions underlined)

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet twice a week; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week.

Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO doseis recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet once daily; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily.

Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are limited and incomplete human data from clinical trials and postmarketing reports on use of KALYDECO in pregnant women. In animal reproduction studies, oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 5 (rats) and 11 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 3 times the exposures at the MRHD, respectively (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% in clinically recognized pregnancies.

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 11 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Ivacaftor is excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KALYDECO, and any potential adverse effects on the breastfed child from KALYDECO or from the underlying maternal condition.

Data

Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels.

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and efficacy of KALYDECO in patients 6 to 17 years of age with CF who have a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene have been demonstrated.

The safety and efficacy of KALYDECO in patients 6 to 17 years of age with CF who have an R117H mutation in the CFTR gene have been demonstrated.

The efficacy of KALYDECO in children 2 to less than 6 years of age is extrapolated from efficacy in patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and children 2 to less than 6 years of age.

The safety of KALYDECO in children 2 to less than 6 years of age (mean age 3 years) is derived from a 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). Eligible patients were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.

The type and frequency of adverse reactions in this trial were similar to those in patients 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered.

The safety and efficacy of KALYDECO in patients with CF younger than 2 years of age have not been studied. The use of KALYDECO in children under the age of 2 years is not recommended.

Juvenile Animal Toxicity Data

8.5 Hepatic Impairment

(additions underlined)

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of is recommended in patients with moderate hepatic impairment (Child-Pugh Class B), as follows: in patients 6 years and older, one 150 mg tablet once daily; in patients 2 to less than 6 years with body weight less than 14 kg, one 50 mg packet of granules once daily; and in patients 2 to less than 6 years with body weight 14 kg or greater, one 75 mg packet of granules once daily. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a dose of one tablet or one packet of granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment.

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

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Administration

KALYDECO® (ivacaftor) tablets 150 mg

KALYDECO® (ivacaftor) oral granules 50 mg or 75 mg

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

• In case a dose of KALYDECO is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of KALYDECO with fat-containing food as soon as possible.

• If more than 6 hours have passed since KALYDECO is usually taken, the missed dose should NOT be taken and the patient should resume the usual dosing schedule.

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

Cataracts

PATIENT INFORMATION

(extensive additions, please refer to label)