Drug Safety-related Labeling Changes (SrLC)

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TRIKAFTA (COPACKAGED) (NDA-212273)

(ELEXACAFTOR, IVACAFTOR, TEZACAFTOR; IVACAFTOR)

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

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10/04/2021 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Elevated Transaminases and Hepatic Injury

Additions and/or revisions underlined

Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment [see Dosage and Administration (2.3), Adverse Reactions (6), Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease.

6 Adverse Reactions

Additions underlined

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

  • Elevated Transaminases and Hepatic Injury [see Warnings and Precautions (5.1)]

  • Cataracts [see Warnings and Precautions (5.4)]

    6.2 Postmarketing Experience

    New subsection added

    The following adverse reactions have been identified during post approval use of TRIKAFTA. 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.

    Liver failure leading to transplantation in a patient with pre-existing cirrhosis and portal hypertension. Liver injury characterized by concomitant transaminase (ALT and AST) and total bilirubin elevations [see Warnings and Precautions (5.1)].

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

PATIENT COUNSELING INFORMATION

Additions underlined

Elevated Transaminases and Hepatic Injury

Inform the patients that liver failure leading to transplantation has been reported in a patient with cirrhosis with portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

Inform patients that isolated elevation of transaminases or bilirubin have occurred in patients treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or INR and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease. Liver function tests (ALT, AST and bilirubin) should be assessed prior to initiating TRIKAFTA, every

3 months during the first year of treatment, and annually thereafter. More frequent monitoring should be considered in patients with a history of hepatobiliary disease or liver function test elevations [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Population (8.7) and Clinical Pharmacology (12.3)].

PATIENT INFORMATION

Additions underlined

What are the possible side effects of TRIKAFTA?

TRIKAFTA can cause serious side effects, including:

  • Liver damage and worsening liver function in people with severe liver disease that can be serious and may require transplantation. Liver damage has also happened in people without liver disease.

     …

06/08/2021 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

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

  • Liver Function Test Elevations [see Warnings and Precautions (5.1)]

  • Cataracts [see Warnings and Precautions (5.4)]

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 safety profile of TRIKAFTA is based on data from 510 CF patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA.

In addition, the following clinical trials have also been conducted [see Use in Specific Population (8.4) and Clinical Pharmacology (12.3)]:

  • a 24-week open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3)

In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0). There were no deaths in Trials 1, 2 and 3.

Table 4 shows adverse reactions occurring in greater than or equal to 5% of TRIKAFTA-treated patients and higher than placebo by greater than or equal to 1% in the 24-week placebo-controlled, parallel-group trial (Trial 1).

Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2 to <5% and higher than placebo by greater than or equal to 1% include the following: Flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, c-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus.

The safety profile for the CF patients enrolled in Trial 2 and Trial 3 was similar to that observed in Trial 1.

Rash Events

In Trial 1, the overall incidence of rash events was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4). The incidence of rash events was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%).

Hormonal contraceptives may play a role in the occurrence of rash. For patients taking hormonal contraceptives who develop rash, consider interrupting TRIKAFTA and hormonal contraceptives. Following the resolution of rash, consider resuming TRIKAFTA without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

Laboratory and Vital Sign Abnormalities

Liver Function Test Elevations

In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x ULN was 1%, 2%, and 8% in TRIKAFTA-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients.

In Trial 1, the incidence of maximum total bilirubin elevation >2 x ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 x ULN occurred in 11% and 3% of TRIKAFTA-treated patients, respectively. No TRIKAFTA-treated patients developed maximum direct bilirubin elevation >2 x ULN.

During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued treatment due to transaminase elevations.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of TRIKAFTA for the treatment of CF in patients aged 6 to less than 18 years who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data has been established. Use of TRIKAFTA for this indication was supported by evidence from two adequate and well-controlled studies in CF patients aged 12 years and older (Trial 1 and Trial 2) and one open-label study in CF patients aged 6 to less than 12 years (Trial 3). In these trials, a total of 138 patients (aged 6 to less than 18 years) received TRIKAFTA, including:

  • In Trial 1, 56 adolescents aged 12 to less than 18 years who had an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].

  • In Trial 2, 16 adolescents aged 12 to less than 18 years who were homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14)].

  • In Trial 3, 66 children aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation with a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].

The effectiveness of TRIKAFTA in patients aged 6 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing elexacaftor, tezacaftor and ivacaftor exposure levels in patients aged 6 to less than 12 years within the range of exposures observed in patients aged 12 years and older [see Clinical Pharmacology (12.3)]. Safety of TRIKAFTA in this population was derived from a 24-week, open-label, clinical trial in 66 patients aged 6 to less than 12 years (mean age at baseline 9.3 years) administered either a total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg in the morning and ivacaftor 75 mg in the evening (for patients weighing less than30 kgs) or a total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening (for patients weighing 30 kgs or more) (Trial 3). The safety profile of patients in this trial was similar to that observed in Trial 1 [see Adverse Reactions (6)].

The safety and effectiveness of TRIKAFTA in patients with CF younger than 6 years of age have not been established.

Juvenile Animal Toxicity Data

Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.21 time the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals [see Warnings and Precautions (5.4) and Patient Counseling Information (17)].

Studies were conducted with tezacaftor in juvenile rats starting at postnatal day (PND) 21 and ranging up to PNDs 35 to 49. Findings of convulsions and death were observed in juvenile rats that received a tezacaftor dose level of 100 mg/kg/day (approximately equivalent to 1.9 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). A no effect dose level was identified at 30 mg/kg/day (approximately equivalent to 0.8 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period (PND 7, which would be approximately equivalent to a human neonate). Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are not relevant for the indicated pediatric population 6 to 11 years of age, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults.

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

No dose modification is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B). In a clinical study of 11 subjects with moderate hepatic impairment, one subject developed total and direct bilirubin elevations >2 x ULN, and a second subject developed direct bilirubin elevation >4.5 x ULN. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution at a reduced dose (see Table 2). Liver function tests should be closely monitored in patients with mild and moderate hepatic impairment. TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. TRIKAFTA should not be used in patients with severe hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3) and Patient Counseling Information (17)].

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Use in Patients with Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6). See Table 2. Liver function tests should be closely monitored.

Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B, score 7-9). Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution at a reduced dose (see Table 2). Liver function tests should be closely monitored.

TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15), but the exposure is expected to be higher than in patients with moderate hepatic impairment. TRIKAFTA should not be used in patients with severe hepatic impairment. Inquire and/or assess whether patients have liver impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

PATIENT INFORMATION

(Extensive changes; please refer to label)

11/18/2020 (SUPPL-1)

Approved Drug Label (PDF)

6 Adverse Reactions

Addition of Cataracts to the bulleted line listing

8 Use in Specific Populations

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dose modification is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B). In a clinical study of 11 subjects with moderate hepatic impairment, one subject developed total and direct bilirubin elevations >2 x ULN, and a second subject developed direct bilirubin elevation >4.5 x ULN. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution at a reduced dose (see Table 1). Liver function tests should be closely monitored in patients with mild and moderate hepatic impairment. TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. TRIKAFTA should not be used in patients with severe hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Use in Patients with Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6). See Table 1. Liver function tests should be closely monitored.

Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B, score 7-9). Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution at a reduced dose (see Table 1). Liver function tests should be closely monitored.

TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15), but the exposure is expected to be higher than in patients with moderate hepatic impairment. TRIKAFTA should not be used in patients with severe hepatic impairment. Inquire and/or assess whether patients have liver impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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