SAFETY PROFILE

Safety data from 510 patients with CF in 2 double‑blind, controlled, Phase 3 trials of 24 weeks (Trial 1) and 4 weeks (Trial 2) treatment duration1 

  • A total of 257 patients with CF aged 12 years and older received at least one dose of TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
  • Except where otherwise noted, the safety data provided below are from Trial 1, the placebo-controlled 24-week trial with patients heterozygous for F508del and another specific mutation. The safety profiles for the patients with CF enrolled in Trials 2 and 3 were similar to that observed in Trial 1
  • With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients regardless of age, sex, baseline ppFEV₁, and geographic region

Adverse event-related discontinuations1,2

1% OF PATIENTS
TREATED WITH TRIKAFTA (n=2)

0% OF PATIENTS
TREATED WITH PLACEBO (n=0)

Serious adverse reactions1

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

Most common adverse reactions in Trial 11

Incidence of adverse drug reactions in 5% of patients treated with TRIKAFTA and higher than placebo by 1%

TRIKAFTA n (%) (N=202)

Placebo n (%) (N=201)

Headache

35 (17)

30 (15)

Upper respiratory tract infectiona

32 (16)

25 (12)

Abdominal painb

29 (14)

18 (9)

Diarrhea

26 (13)

14 (7)

Rashc

21 (10)

10 (5)

ALT increased

20 (10)

7 (3)

Nasal congestion

19 (9)

15 (7)

Blood CPK increased

19 (9)

9 (4)

AST increased

19 (9)

4 (2)

Rhinorrhea

17 (8)

6 (3)

Rhinitis

15 (7)

11 (5)

Influenza

14 (7)

3 (1)

Sinusitis

11 (5)

8 (4)

Blood bilirubin increased

10 (5)

2 (1)

TRIKAFTA n (%) (N=202)

Headache

35 (17)

Upper respiratory tract infectiona

32 (16)

Abdominal painb

29 (14)

Diarrhea

26 (13)

Rashc

21 (10)

ALT increased

20 (10)

Nasal congestion

19 (9)

Blood CPK increased

19 (9)

AST increased

19 (9)

Rhinorrhea

17 (8)

Rhinitis

15 (7)

Influenza

14 (7)

Sinusitis

11 (5)

Blood bilirubin increased

10 (5)

Placebo n (%) (N=201)

Headache

30 (15)

Upper respiratory tract infectiona

25 (12)

Abdominal painb

18 (9)

Diarrhea

14 (7)

Rashc

10 (5)

ALT increased

7 (3)

Nasal congestion

15 (7)

Blood CPK increased

9 (4)

AST increased

4 (2)

Rhinorrhea

6 (3)

Rhinitis

11 (5)

Influenza

3 (1)

Sinusitis

8 (4)

Blood bilirubin increased

2 (1)

aIncludes upper respiratory tract infection and viral upper respiratory tract infection.
bIncludes abdominal pain, abdominal pain upper, and abdominal pain lower.
cIncludes rash, rash generalized, rash erythematous, rash macular, and rash pruritic.

  • Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2 to <5% and higher than placebo ≥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.

Rash events1

  • The overall incidence of rash events was 10% in patients treated with TRIKAFTA and 5% in placebo-treated patients
  • The incidence of rash events was higher in female patients treated with TRIKAFTA (16%) than in male patients treated with TRIKAFTA (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

Additional information on rash3

  • The median time to onset of first rash event was 12 days (range 5-157 days) in patients treated with TRIKAFTA and 23 days (range 1-157 days) in placebo-treated patients. The median duration of rash events was 8 days (range 1-92 days) in patients treated with TRIKAFTA and 9 days (range 3-61 days) in placebo-treated patients
  • The rash events were exanthematous—consistent with a typical drug eruption

Laboratory and vital sign abnormalities
Liver function test elevations1,4

Incidence of maximum transaminases and maximum total bilirubin elevations in Trial 1
 TRIKAFTA
(N=202)
Placebo
(N=201)
Elevated ALT or AST, n (%)>3x ULN16 (8)11 (5)
>5x ULN5 (2)3 (1)
>8x ULN3 (1)2 (1)
Total bilirubin elevation >2x ULN, %4<1

 

Incidence of maximum transaminases and maximum total bilirubin elevations in Trial 1
TRIKAFTA (N=202)
Elevated ALT or AST, n (%) >3x ULN 16 (8)
>5x ULN 5 (2)
>8x ULN 3 (1)
Total bilirubin elevation >2x ULN, % 4
Placebo (N=201)
Elevated ALT or AST, n (%) >3x ULN 11 (5)
>5x ULN 3 (1)
>8x ULN 2 (1)
Total bilirubin elevation >2x ULN, % <1
  • The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in patients treated with TRIKAFTA and 4% in placebo-treated patients1
  • No patients treated with TRIKAFTA discontinued due to transaminase elevations2
  • Maximum indirect bilirubin elevations >1.5x ULN occurred in 11% of patients treated with TRIKAFTA. Maximum direct bilirubin elevations >1.5x ULN occurred in 3% of patients treated with TRIKAFTA1
  • No patients treated with TRIKAFTA developed maximum direct bilirubin elevation >2x ULN1

Increased CPK1

  • The incidence of maximum CPK >5x ULN was 10% in patients treated with TRIKAFTA and 5% in placebo-treated patients
  • Among the patients treated with TRIKAFTA with CPK elevation >5x ULN, 14% (3/21) required treatment interruption and none discontinued treatment

 

Increased blood pressure1

Maximum increase from baseline in mean blood pressure
 TRIKAFTA
(N=202)
Placebo
(N=201)
Mean systolic blood pressure, mmHgBaseline113114
Maximum increase from baseline3.50.9
Mean diastolic blood pressure, mmHgBaseline6970
Maximum increase from baseline1.90.5
Maximum increase from baseline in mean blood pressure
Mean systolic blood pressure (mmHg)
TRIKAFTA (N=202)

Baseline

113

Maximum increase from baseline

3.5

Placebo (N=201)

Baseline

114

Maximum increase from baseline

0.9

Mean diastolic blood pressure (mmHg)
TRIKAFTA (N=202)

Baseline

69

Maximum increase from baseline

1.9

Placebo (N=201)

Baseline

70

Maximum increase from baseline

0.5

  • The proportion of patients who had an increase in systolic blood pressure of >140 mmHg and 10 mmHg from baseline on at least two occasions:
  • 4% of patients treated with TRIKAFTA and 1% of placebo-treated patients
  • The proportion of patients who had an increase in diastolic blood pressure of >90 mmHg and 5 mmHg from baseline on at least two occasions:
  • 1% of patients treated with TRIKAFTA and 2% of placebo-treated patients

Safety Data from Post-marketing Experience1

Adverse reactions have been identified during post approval use of TRIKAFTA and include liver failure leading to transplantation in a patient with pre-existing cirrhosis and portal hypertension, and liver injury characterized by concomitant transaminase (ALT and AST) and total bilirubin elevationsd

dBecause 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.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; ULN, upper limit of normal.

Important Safety Information

Elevated Transaminases and Hepatic Injury

  • 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
  • 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
  • Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
  • In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
  • For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered

Indications and Usage

TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

Concomitant Use With CYP3A Inducers

  • Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended

Concomitant Use With CYP3A Inhibitors

  • Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA

Pediatric Use

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

Serious Adverse Reactions

  • Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0)

Most Common Adverse Reactions

  • The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 1) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, and blood bilirubin increased
     
  • The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
     
  • The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=66) was similar to that observed in trials of patients age 12 years and older

Click here to access full Prescribing Information for TRIKAFTA.

References:

1. TRIKAFTA [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; October 2021. 2. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809-1819. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3535 (v1.0); 2019. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3493 (v1.0); 2019.