Dosage & Administration
Prior to initiating ALYFTREK obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter. (
Prior to initiating ALYFTREK, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing elexacaftor, tezacaftor, and/or ivacaftor
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
| Age | Weight | Once Daily Oral Dosage |
|---|---|---|
| 6 to less than 12 years old | Less than 40 kg | Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg (total dose of vanzacaftor 12 mg/tezacaftor 60 mg/ deutivacaftor 150 mg) |
| Greater than or equal to 40 kg | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) | |
| 12 years and older | Any weight | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) |
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Alyftrek Prescribing Information
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Drug-Induced Liver Injury and Liver Failure[see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions, Including Anaphylaxis[see Warnings and Precautions (5.2)]
- Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions[see Warnings and Precautions (5.3)]
- Intracranial Hypertension[see Warnings and Precautions (5.4)]
- Cataracts[see Warnings and Precautions (5.7)]
Most common adverse reactions to ALYFTREK (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion.
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 adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive
The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one
In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively.
Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%).
| Adverse Reactions | ALYFTREK N=480 | ELX/TEZ/IVA N=491 |
|---|---|---|
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor | ||
| CoughCough is composed of several similar terms including productive cough. | 120 (25%) | 116 (24%) |
| Nasopharyngitis | 102 (21%) | 95 (19%) |
| Upper respiratory tract infectionUpper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection. | 101 (21%) | 97 (20%) |
| Headache | 76 (16%) | 63 (13%) |
| Oropharyngeal pain | 69 (14%) | 60 (12%) |
| Influenza | 52 (11%) | 26 (5%) |
| Fatigue | 51 (11%) | 46 (9%) |
| ALT increased | 38 (8%) | 29 (6%) |
| Rash | 37 (8%) | 22 (4%) |
| AST increased | 33 (7%) | 27 (5%) |
| Sinus congestion | 32 (7%) | 15 (3%) |
Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting.
The incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7.1% in ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2.
| Maximum ALT or AST Elevation | ALYFTREK N=480 | ELX/TEZ/IVATrials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information. N=491 |
|---|---|---|
| Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor. | ||
| >3× ULN | 29 (6%) | 15 (3.1%) |
| >5× ULN | 12 (2.5%) | 6 (1.2%) |
| >8× ULN | 6 (1.3%) | 1 (0.2%) |
In Trials 1 and 2, the incidence of rash (e.g., rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7.7% in ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was 9.4% in males and 13% in females with ALYFTREK treatment and 7.6% in males and 7.9% in females with ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded
In Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7.9% with ALYFTREK treatment and 6.5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was 0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).
Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was 3.5% in ALYFTREK-treated patients and 3.3% in ELX/TEZ/IVA-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and >5 mmHg increase from baseline on at least two occasions was 1.7% in ALYFTREK-treated patients and 1.8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms.
A 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3.8%, 1.3%, and 0%, respectively.
The following adverse reactions have been identified during post approval use of drugs containing the same or similar active ingredients as ALYFTREK. 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.
Prior to initiating ALYFTREK, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing elexacaftor, tezacaftor, and/or ivacaftor
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Drug-Induced Liver Injury and Liver Failure[see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions, Including Anaphylaxis[see Warnings and Precautions (5.2)]
- Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions[see Warnings and Precautions (5.3)]
- Intracranial Hypertension[see Warnings and Precautions (5.4)]
- Cataracts[see Warnings and Precautions (5.7)]
Most common adverse reactions to ALYFTREK (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion.
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 adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive
The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one
In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively.
Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%).
| Adverse Reactions | ALYFTREK N=480 | ELX/TEZ/IVA N=491 |
|---|---|---|
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor | ||
| CoughCough is composed of several similar terms including productive cough. | 120 (25%) | 116 (24%) |
| Nasopharyngitis | 102 (21%) | 95 (19%) |
| Upper respiratory tract infectionUpper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection. | 101 (21%) | 97 (20%) |
| Headache | 76 (16%) | 63 (13%) |
| Oropharyngeal pain | 69 (14%) | 60 (12%) |
| Influenza | 52 (11%) | 26 (5%) |
| Fatigue | 51 (11%) | 46 (9%) |
| ALT increased | 38 (8%) | 29 (6%) |
| Rash | 37 (8%) | 22 (4%) |
| AST increased | 33 (7%) | 27 (5%) |
| Sinus congestion | 32 (7%) | 15 (3%) |
Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting.
The incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7.1% in ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2.
| Maximum ALT or AST Elevation | ALYFTREK N=480 | ELX/TEZ/IVATrials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information. N=491 |
|---|---|---|
| Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor. | ||
| >3× ULN | 29 (6%) | 15 (3.1%) |
| >5× ULN | 12 (2.5%) | 6 (1.2%) |
| >8× ULN | 6 (1.3%) | 1 (0.2%) |
In Trials 1 and 2, the incidence of rash (e.g., rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7.7% in ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was 9.4% in males and 13% in females with ALYFTREK treatment and 7.6% in males and 7.9% in females with ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded
In Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7.9% with ALYFTREK treatment and 6.5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was 0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).
Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was 3.5% in ALYFTREK-treated patients and 3.3% in ELX/TEZ/IVA-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and >5 mmHg increase from baseline on at least two occasions was 1.7% in ALYFTREK-treated patients and 1.8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms.
A 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3.8%, 1.3%, and 0%, respectively.
The following adverse reactions have been identified during post approval use of drugs containing the same or similar active ingredients as ALYFTREK. 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.
ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK has not been studied in patients with CF with severe HI
The use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK should only be considered in patients with HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored
The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
- Severe Hepatic Impairment (Child-Pugh Class C): ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C).
- Moderate Hepatic Impairment (Child-Pugh Class B): The use of ALYFTREK in patients with moderate HI (Child-Pugh Class B) is not recommended. Use of ALYFTREK should only be considered in patients with moderate HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored[see Dosage and Administration (2.1, 2.2)].
- Mild Hepatic Impairment (Child-Pugh Class A): The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored[see Dosage and Administration (2.1, 2.2)].
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Drug-Induced Liver Injury and Liver Failure[see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions, Including Anaphylaxis[see Warnings and Precautions (5.2)]
- Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions[see Warnings and Precautions (5.3)]
- Intracranial Hypertension[see Warnings and Precautions (5.4)]
- Cataracts[see Warnings and Precautions (5.7)]
Most common adverse reactions to ALYFTREK (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion.
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 adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive
The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one
In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively.
Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%).
| Adverse Reactions | ALYFTREK N=480 | ELX/TEZ/IVA N=491 |
|---|---|---|
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor | ||
| CoughCough is composed of several similar terms including productive cough. | 120 (25%) | 116 (24%) |
| Nasopharyngitis | 102 (21%) | 95 (19%) |
| Upper respiratory tract infectionUpper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection. | 101 (21%) | 97 (20%) |
| Headache | 76 (16%) | 63 (13%) |
| Oropharyngeal pain | 69 (14%) | 60 (12%) |
| Influenza | 52 (11%) | 26 (5%) |
| Fatigue | 51 (11%) | 46 (9%) |
| ALT increased | 38 (8%) | 29 (6%) |
| Rash | 37 (8%) | 22 (4%) |
| AST increased | 33 (7%) | 27 (5%) |
| Sinus congestion | 32 (7%) | 15 (3%) |
Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting.
The incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7.1% in ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2.
| Maximum ALT or AST Elevation | ALYFTREK N=480 | ELX/TEZ/IVATrials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information. N=491 |
|---|---|---|
| Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor. | ||
| >3× ULN | 29 (6%) | 15 (3.1%) |
| >5× ULN | 12 (2.5%) | 6 (1.2%) |
| >8× ULN | 6 (1.3%) | 1 (0.2%) |
In Trials 1 and 2, the incidence of rash (e.g., rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7.7% in ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was 9.4% in males and 13% in females with ALYFTREK treatment and 7.6% in males and 7.9% in females with ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded
In Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7.9% with ALYFTREK treatment and 6.5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was 0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).
Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was 3.5% in ALYFTREK-treated patients and 3.3% in ELX/TEZ/IVA-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and >5 mmHg increase from baseline on at least two occasions was 1.7% in ALYFTREK-treated patients and 1.8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms.
A 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3.8%, 1.3%, and 0%, respectively.
The following adverse reactions have been identified during post approval use of drugs containing the same or similar active ingredients as ALYFTREK. 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.
ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK has not been studied in patients with CF with severe HI
The use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK should only be considered in patients with HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored
The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored
The pharmacokinetic parameters for vanzacaftor, tezacaftor, and deutivacaftor in patients with CF aged 12 years and older are provided in Table 6 as mean (SD) unless otherwise specified. No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, and deutivacaftor were observed between healthy adult subjects and patients with CF.
| Vanzacaftor | Tezacaftor | Deutivacaftor | |
|---|---|---|---|
Abbreviations: AUC: area under the concentration versus time curve; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of maximum concentration; ss: steady state | |||
Exposure | |||
| Cmax,ss(mcg/mL) | 0.812 (0.344) | 6.77 (1.24) | 2.33 (0.637) |
| AUC0-24h,ss(mcg ∙ h/mL) | 18.6 (8.08) | 89.5 (28.0) | 39.0 (15.3) |
| Time to steady state | within 20 days | within 8 days | within 8 days |
| AUC Accumulation Ratio | 6.09 (1.81) | 1.92 (0.337) | 1.74 (0.497) |
Absorption | |||
| TmaxMedian (range)(hours) | 7.80 (3.70, 11.9) | 1.60 (1.40, 1.70) | 3.7 (2.7, 11.4) |
Effect of food | |||
| AUCinfWhen administered with fat-containing meals relative to fasted conditions. Note: The high-fat meal was approximately 800-1000 calories with 50% fat. The low-fat meal was approximately 400-500 calories with 25% fat. | Increase 4- (low-fat meal) to 6- (high-fat meal) fold | No clinically significant change | Increase 3- (low-fat meal) to 4- (high-fat meal) fold |
Distribution Vanzacaftor, tezacaftor, deutivacaftor do not partition preferentially into human red blood cells. | |||
| Apparent (oral) volume of distribution (L) | 121 (28.6) | 73.1 (13.3) | 159 (26.1) |
| Protein BindingVanzacaftor and deutivacaftor bind primarily to albumin and alpha 1-acid glycoprotein. Tezacaftor binds primarily to albumin. | > 99% | Approximately 99% | > 99% |
Elimination | |||
| Effective Half-life (hours)The mean (SD) terminal half-lives of vanzacaftor, tezacaftor, and deutivacaftor are 54.0 (10.1) hours, 92.4 (23.1) hours and 17.3 (2.67) hours, respectively based on a single dose of vanzacaftor/tezacaftor/deutivacaftor tablets in healthy subjects in the fed state. | 92.8 (30.2) | 22.5 (5.85) | 19.2 (8.71) |
| Apparent (oral) Clearance (L/hours) | 1.34 (0.819) | 1.22 (0.390) | 7.29 (2.68) |
Metabolism | |||
| Primary Pathway | CYP3A4/5 | CYP3A4/5 | CYP3A4/5 |
| Active metabolites | None | M1-TEZ | M1-D-IVA |
| Metabolite potency (relative to parent) | Not applicable | Similar | Approximately 20% |
Excretion Following radiolabeled doses. | |||
| Feces | 91.6% (primarily metabolites) | 72% (unchanged or M2-TEZ) [0.79% as unchanged drug] | Not available |
| Urine | 0.50% | 13.7% | Not available |
No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed based on age, sex, race,
Weight was identified as the key covariate having a clinically meaningful impact on pharmacokinetics of vanzacaftor, tezacaftor, and deutivacaftor.
Vanzacaftor, tezacaftor and deutivacaftor exposures observed in clinical trials are presented by age group and dosage administered in Table 7. No clinically significant differences in vanzacaftor, tezacaftor, and deutivacaftor exposures were observed in patients with CF aged 6 to less than 18 years compared to adults following the recommended dosages.
| Age Group | Weight | Dosage (once daily) | AUC0-24h(mcg∙h/mL) | ||
|---|---|---|---|---|---|
| Vanzacaftor | Tezacaftor | Deutivacaftor | |||
Abbreviations : SD: Standard Deviation; AUC0-24h: Area Under the Concentration versus time curve at steady state | |||||
| 6 to <12 years | <40 kg (N = 70) | vanzacaftor 12 mg tezacaftor 60 mg deutivacaftor 150 mg | 13.0 (4.90) | 69.1 (20.7) | 30.2 (11.6) |
| ≥40 kg (N = 8) | vanzacaftor 20 mg tezacaftor 100 mg deutivacaftor 250 mg | 18.6 (7.49) | 101 (33.7) | 48.5 (18.7) | |
| 12 to <18 years | - (N = 66) | vanzacaftor 20 mg tezacaftor 100 mg deutivacaftor 250 mg | 15.8 (6.52) | 93.0 (32.5) | 37.1 (15.3) |
| ≥18 years | - (N = 414) | 19.0 (8.22) | 89.0 (27.2) | 39.3 (15.3) | |
Vanzacaftor AUC was approximately 30% lower, tezacaftor AUC was comparable, and deutivacaftor AUC was approximately 20% lower in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal liver function matched for demographics
The effect of mild hepatic impairment (Child-Pugh Class A) or severe hepatic impairment (Child-Pugh Class C) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown.
Exposure changes associated with concomitant use of vanzacaftor, tezacaftor, ivacaftor and/or deutivacaftor with other drugs are shown in Table 8.
| Dosage | Effected Drug | Geometric Mean Ratio (90% CI) No Effect = 1.0 | ||
|---|---|---|---|---|
| AUC | Cmax | |||
Abbreviations : CI = Confidence Interval; ELX = elexacaftor; VNZ = vanzacaftor; TEZ = tezacaftor; IVA = ivacaftor; D-IVA = deutivacaftor; PK = Pharmacokinetics; qd = once daily | ||||
| Itraconazole 200 mg q12h on Day 1, followed by 200 mg daily | TEZ 25 mg daily + IVA 50 mg daily | Tezacaftor | 4.02 (3.71, 4.63) | 2.83 (2.62, 3.07) |
| Itraconazole 200 mg daily | ELX 20 mg + TEZ 50 mg + D-IVA 50 mg single dose | Tezacaftor | 4.51 (3.85, 5.29) | 1.48 (1.33, 1.65) |
| Deutivacaftor | 11.1 (8.72, 14.1) | 1.96 (1.70, 2.26) | ||
| Itraconazole 200 mg dailyThe itraconazole dosing (200 mg qd for14 days) did not fully cover the elimination of vanzacaftor. A 10.5-fold increase in vanzacaftor AUC is predicted by physiologically based pharmacokinetic modeling and simulations when itraconazole fully covers the elimination. | VNZ 5 mg single dose | Vanzacaftor | 6.37 (5.53, 7.35) | 1.55 (1.41, 1.70) |
| CiprofloxacinEffect is not clinically significant [see Drug Interactions (7.3)] .750 mg twice daily | TEZ 50 mg q12h + IVA 150 mg q12h | Tezacaftor | 1.08 (1.03, 1.13) | 1.05 (0.99, 1.11) |
| Digoxin 0.5 mg single dose | TEZ 25 mg daily + IVA 50 mg daily | Digoxin | 1.3 (1.17, 1.45) | 1.32 (1.07, 1.64) |
| Fluconazole 200 mg daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 2.55 (2.12, 3.12)Predicted by physiologically based pharmacokinetic modeling and simulations. Data presented as geometric mean ratio and 5thto 95thpercentiles of individuals in the simulated population [see Drug Interactions (7.1)]. | 2.48 (2.04, 3.01) |
| Deutivacaftor | 3.13 (2.44, 3.95) | 2.27 (1.82, 2.93) | ||
| Erythromycin 500 mg four times daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 3.29 (1.62, 7.55) | 3.19 (1.60, 7.29) |
| Deutivacaftor | 4.13 (1.80, 9.73) | 2.89 (1.52, 6.97) | ||
| Verapamil 80 mg three times daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 3.93 (1.84, 8.75) | 3.80 (1.78, 8.33) |
| Deutivacaftor | 5.11 (2.06, 12.5) | 3.43 (1.64, 7.65) | ||
| Rifampin 600 mg daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 0.18 (0.10, 0.34) | 0.22 (0.12, 0.38) |
| Deutivacaftor | 0.10 (0.04, 0.26) | 0.20 (0.08, 0.44) | ||
| Carbamazepine 400 mg twice daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 0.44 (0.28, 0.61) | 0.46 (0.31, 0.64) |
| Deutivacaftor | 0.24 (0.11, 0.47) | 0.32 (0.17, 0.57) | ||
| Efavirenz 600 mg daily | VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd | Vanzacaftor | 0.31 (0.16, 0.57) | 0.35 (0.19, 0.59) |
| Deutivacaftor | 0.27 (0.11, 0.50) | 0.44 (0.23, 0.68) | ||
Warnings and Precautions, Intracranial Hypertension (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 ALYFTREK [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 ALYFTREK and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ALYFTREK. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk. | 09/2025 |
ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one
Based on Clinical DataClinical data is obtained from Trials 1 and 2. | ||||||
A455E | G551D | L1077PThis mutation is also predicted to be responsive by FRT assay with ALYFTREK. | R352Q | S549N | V754M | |
D1152H | G85E | L206W | R75Q | S549R | W1098C | |
F508del | H1054D | M1101K | S1159F | S945L | W1282R | |
G1244E | I336K | R1066H | S1251N | V562I | Y563N | |
Based on in vitro DataThe N1303K mutation is predicted to be responsive only by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay. | ||||||
1507_1515del9 | E116Q | G424S | I556V | P140S | R334L | T1053I |
2183A→G | E193K | G463V | I601F | P205S | R334Q | T1086I |
3141del9 | E292K | G480C | I618T | P499A | R347H | T1246I |
3195del6 | E403D | G480S | I807M | P5L | R347L | T1299I |
3199del6 | E474K | G551A | I980K | P574H | R347P | T338I |
546insCTA | E56K | G551S | K1060T | P67L | R352W | T351I |
A1006E | E588V | G576A | K162E | P750L | R516G | T604I |
A1067P | E60K | G576A;R668CComplex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. | K464E | P99L | R516S | V1153E |
A1067T | E822K | G622D | L1011S | Q1100P | R553Q | V1240G |
A107G | E92K | G628R | L102R | Q1291R | R555G | V1293G |
A120T | F1016S | G91R | L1065P | Q1313K | R560S | V201M |
A234D | F1052V | G970D | L1324P | Q237E | R560T | V232D |
A309D | F1074L | G970S | L1335P | Q237H | R668C | V392G |
A349V | F1099L | H1085P | L137P | Q359R | R709Q | V456A |
A46D | F1107L | H1085R | L1480P | Q372H | R74Q | V456F |
A554E | F191V | H1375P | L15P | Q452P | R74W | V520F |
A559T | F200I | H139R | L165S | Q493R | R74W;D1270N | V603F |
A559V | F311del | H199R | L320V | Q552P | R74W;V201M | W361R |
A561E | F311L | H199Y | L333F | Q98R | R74W;V201M;D1270N | Y1014C |
A613T | F508C | H609R | L333H | R1048G | R75L | Y1032C |
A62P | F508C;S1251N | H620P | L346P | R1066C | R751L | Y109N |
A72D | F575Y | H620Q | L441P | R1066L | R792G | Y161D |
C491R | F587I | H939R | L453S | R1066M | R933G | Y161S |
D110E | G1047R | H939R;H949L | L619S | R1070Q | S1045Y | Y301C |
D110H | G1061R | I1027T | L967S | R1070W | S108F | Y569C |
D1270N | G1069R | I105N | L997F | R1162L | S1118F | Y913C |
D1445N | G1123R | I1139V | M1101R | R117C | S1159P | |
D192G | G1247R | I1234Vdel6aa | M1137V | R117C;G576A;R668C | S1235R | |
D443Y | G1249R | I125T | M150K | R117G | S1255P | |
D443Y;G576A;R668C | G126D | I1269N | M152V | R117H | S13F | |
D513G | G1349D | I331N | M265R | R117L | S341P | |
D565G | G149R | I1366N | M952I | R117P | S364P | |
D579G | G178E | I1398S | M952T | R1283M | S492F | |
D614G | G178R | I148N | N1088D | R1283S | S549I | |
D836Y | G194R | I148T | N1303I | R170H | S589N | |
D924N | G194V | I175V | N1303K | R258G | S737F | |
D979V | G27E | I502T | N186K | R297Q | S912L | |
D993Y | G27R | I506L | N187K | R31C | S977F | |
E116K | G314E | I506T | N418S | R31L | T1036N | |
Based on ExtrapolationEfficacy is extrapolated to certain non-canonical splice mutations because clinical trials in all mutations in this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system. | ||||||
1341G→A | 2789+2insA | 3041-15T→G | 3849+10kbC→T | 3850-3T→G | 5T;TG13 | 711+3A→G |
1898+3A→G | 2789+5G→A | 3272-26A→G | 3849+4A→G | 4005+2T→C | 621+3A→G | E831X |
2752-26A→G | 296+28A→G | 3600G→A | 3849+40A→G | 5T;TG12 | ||
Vanzacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including
The combined effect of vanzacaftor, tezacaftor and deutivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR mediated chloride transport in vitro and by sweat chloride in patients with CF.
Effects of vanzacaftor/tezacaftor/deutivacaftor on chloride transport for mutant CFTR protein was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing CFTR protein from individual mutations. Vanzacaftor/tezacaftor/deutivacaftor increased chloride transport in FRT cells expressing select
The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline. This threshold was used because it is expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.
Homozygous and heterozygous
Select patients 6 years of age and older for treatment of CF with ALYFTREK based on the presence of at least one
Table 5 lists
Based on Clinical DataClinical data is obtained from Trials 1 and 2. | ||||||
A455E | G551D | L1077PThis mutation is also predicted to be responsive by FRT assay with ALYFTREK. | R352Q | S549N | V754M | |
D1152H | G85E | L206W | R75Q | S549R | W1098C | |
F508del | H1054D | M1101K | S1159F | S945L | W1282R | |
G1244E | I336K | R1066H | S1251N | V562I | Y563N | |
Based on in vitro DataThe N1303K mutation is predicted to be responsive only by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay. | ||||||
1507_1515del9 | E116Q | G424S | I556V | P140S | R334L | T1053I |
2183A→G | E193K | G463V | I601F | P205S | R334Q | T1086I |
3141del9 | E292K | G480C | I618T | P499A | R347H | T1246I |
3195del6 | E403D | G480S | I807M | P5L | R347L | T1299I |
3199del6 | E474K | G551A | I980K | P574H | R347P | T338I |
546insCTA | E56K | G551S | K1060T | P67L | R352W | T351I |
A1006E | E588V | G576A | K162E | P750L | R516G | T604I |
A1067P | E60K | G576A;R668CComplex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. | K464E | P99L | R516S | V1153E |
A1067T | E822K | G622D | L1011S | Q1100P | R553Q | V1240G |
A107G | E92K | G628R | L102R | Q1291R | R555G | V1293G |
A120T | F1016S | G91R | L1065P | Q1313K | R560S | V201M |
A234D | F1052V | G970D | L1324P | Q237E | R560T | V232D |
A309D | F1074L | G970S | L1335P | Q237H | R668C | V392G |
A349V | F1099L | H1085P | L137P | Q359R | R709Q | V456A |
A46D | F1107L | H1085R | L1480P | Q372H | R74Q | V456F |
A554E | F191V | H1375P | L15P | Q452P | R74W | V520F |
A559T | F200I | H139R | L165S | Q493R | R74W;D1270N | V603F |
A559V | F311del | H199R | L320V | Q552P | R74W;V201M | W361R |
A561E | F311L | H199Y | L333F | Q98R | R74W;V201M;D1270N | Y1014C |
A613T | F508C | H609R | L333H | R1048G | R75L | Y1032C |
A62P | F508C;S1251N | H620P | L346P | R1066C | R751L | Y109N |
A72D | F575Y | H620Q | L441P | R1066L | R792G | Y161D |
C491R | F587I | H939R | L453S | R1066M | R933G | Y161S |
D110E | G1047R | H939R;H949L | L619S | R1070Q | S1045Y | Y301C |
D110H | G1061R | I1027T | L967S | R1070W | S108F | Y569C |
D1270N | G1069R | I105N | L997F | R1162L | S1118F | Y913C |
D1445N | G1123R | I1139V | M1101R | R117C | S1159P | |
D192G | G1247R | I1234Vdel6aa | M1137V | R117C;G576A;R668C | S1235R | |
D443Y | G1249R | I125T | M150K | R117G | S1255P | |
D443Y;G576A;R668C | G126D | I1269N | M152V | R117H | S13F | |
D513G | G1349D | I331N | M265R | R117L | S341P | |
D565G | G149R | I1366N | M952I | R117P | S364P | |
D579G | G178E | I1398S | M952T | R1283M | S492F | |
D614G | G178R | I148N | N1088D | R1283S | S549I | |
D836Y | G194R | I148T | N1303I | R170H | S589N | |
D924N | G194V | I175V | N1303K | R258G | S737F | |
D979V | G27E | I502T | N186K | R297Q | S912L | |
D993Y | G27R | I506L | N187K | R31C | S977F | |
E116K | G314E | I506T | N418S | R31L | T1036N | |
Based on ExtrapolationEfficacy is extrapolated to certain non-canonical splice mutations because clinical trials in all mutations in this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system. | ||||||
1341G→A | 2789+2insA | 3041-15T→G | 3849+10kbC→T | 3850-3T→G | 5T;TG13 | 711+3A→G |
1898+3A→G | 2789+5G→A | 3272-26A→G | 3849+4A→G | 4005+2T→C | 621+3A→G | E831X |
2752-26A→G | 296+28A→G | 3600G→A | 3849+40A→G | 5T;TG12 | ||
If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.
Prior to initiating ALYFTREK obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter. (
Prior to initiating ALYFTREK, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing elexacaftor, tezacaftor, and/or ivacaftor
Elevated transaminases have been observed in patients treated with ALYFTREK
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
| Age | Weight | Once Daily Oral Dosage |
|---|---|---|
| 6 to less than 12 years old | Less than 40 kg | Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg (total dose of vanzacaftor 12 mg/tezacaftor 60 mg/ deutivacaftor 150 mg) |
| Greater than or equal to 40 kg | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) | |
| 12 years and older | Any weight | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) |
- Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. If used, no dose adjustment is recommended. Liver function tests should be closely monitored. (,
2.4 Recommended Dosage for Patients with Hepatic Impairment- Severe Hepatic Impairment (Child-Pugh Class C): ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C).
- Moderate Hepatic Impairment (Child-Pugh Class B): The use of ALYFTREK in patients with moderate HI (Child-Pugh Class B) is not recommended. Use of ALYFTREK should only be considered in patients with moderate HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored[see Dosage and Administration (2.1, 2.2)].
- Mild Hepatic Impairment (Child-Pugh Class A): The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored[see Dosage and Administration (2.1, 2.2)].
,5.1 Drug-Induced Liver Injury and Liver FailureElevated transaminases have been observed in patients treated with ALYFTREK
[Adverse Reactions (6.1)]. Cases of serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without a history of liver disease who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA.Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.
[see Dosage and Administration (2.4)and Use in Specific Populations (8.7)].Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
- Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit of normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
- Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely
[see Dosage and Administration (2.4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].,6.1 Clinical Trials ExperienceBecause 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 adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive
CFTRmutation who were able to tolerate ELX/TEZ/IVA. Adverse reactions data in patients who previously discontinued or interrupted ELX/TEZ/IVA due to adverse reactions are not available.Adverse Reactions in Patients Aged 12 Years and Older with CFThe safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one
F508delmutation or another responsive mutation in theCFTRgene in two, 52-week, active-controlled trials (Trials 1 and 2)[see Clinical Studies (14)].In both trials, patients received a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA) in a 4-week run-in period and then were subsequently randomized to continue ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) or receive ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg) once daily. Patients with a history of prior intolerance to ELX/TEZ/IVA (i.e., patients who discontinued or interrupted treatment due to adverse reactions) were excluded. Trials 1 and 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA adverse reactions, refer to ELX/TEZ/IVA Prescribing Information.In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively.
Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%).
Table 3: Adverse Reactions Occurring in ≥5% of ALYFTREK-Treated Patients and ≥1% Higher than ELX/TEZ/IVA-Treated Patients Aged 12 Years and Older with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Adverse Reactions ALYFTREK
N=480ELX/TEZ/IVA
N=491Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor CoughCough is composed of several similar terms including productive cough. 120 (25%) 116 (24%) Nasopharyngitis 102 (21%) 95 (19%) Upper respiratory tract infectionUpper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection. 101 (21%) 97 (20%) Headache 76 (16%) 63 (13%) Oropharyngeal pain 69 (14%) 60 (12%) Influenza 52 (11%) 26 (5%) Fatigue 51 (11%) 46 (9%) ALT increased 38 (8%) 29 (6%) Rash 37 (8%) 22 (4%) AST increased 33 (7%) 27 (5%) Sinus congestion 32 (7%) 15 (3%) Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting.
Liver Function Test ElevationsThe incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7.1% in ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2.
Table 4: Number and Incidence of Maximum Transaminase Elevation in Patients Aged 12 Years and Older with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Maximum ALT or AST Elevation ALYFTREK
N=480ELX/TEZ/IVATrials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information.
N=491Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor. >3× ULN 29 (6%) 15 (3.1%) >5× ULN 12 (2.5%) 6 (1.2%) >8× ULN 6 (1.3%) 1 (0.2%) RashIn Trials 1 and 2, the incidence of rash (e.g., rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7.7% in ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was 9.4% in males and 13% in females with ALYFTREK treatment and 7.6% in males and 7.9% in females with ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded
[see Drug Interactions (7.3)].Increased Creatine PhosphokinaseIn Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7.9% with ALYFTREK treatment and 6.5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was 0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).
Increased Blood PressureElevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was 3.5% in ALYFTREK-treated patients and 3.3% in ELX/TEZ/IVA-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and >5 mmHg increase from baseline on at least two occasions was 1.7% in ALYFTREK-treated patients and 1.8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms.
Adverse Reactions in Pediatric Patients Aged 6 to Less Than 12 Years with CFA 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3.8%, 1.3%, and 0%, respectively.
)8.7 Hepatic ImpairmentSevere Hepatic ImpairmentALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK has not been studied in patients with CF with severe HI
[see Warnings and Precautions (5.1)and Adverse Reactions (6.1)].Moderate Hepatic ImpairmentThe use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK should only be considered in patients with HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored
[see Dosage and Administration (2.2), Warnings and Precautions (5.1)and Adverse Reactions (6.1)].Mild Hepatic ImpairmentThe recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored
[see Warnings and Precautions (5.1)and Adverse Reactions (6.1)]. - See full prescribing information for dosage modifications for concomitant use of ALYFTREK with strong or moderate CYP3A inhibitors. (,
2.3 Dosage Modification for Strong or Moderate CYP3A InhibitorsTable 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or moderate CYP3A inhibitors
[see Warnings and Precautions (5.6)]. Administer ALYFTREK orally (swallow the tablets whole) with fat-containing food, once daily, at approximately the same time each day[see Clinical Pharmacology (12.3)].Table 2: Dosage Modification for Concomitant Use of ALYFTREK with Strong or Moderate CYP3A Inhibitors in Adult and Pediatric Patients Aged 6 Years and Older Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors 6 to less than 12 years old Less than 40 kg Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) Greater than or equal to 40 kg One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week 12 years and older Any weight One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week ,5.6 Adverse Reactions with Concomitant Use with CYP3A InhibitorsFollowing concomitant use of strong or moderate CYP3A inhibitors with ALYFTREK, exposures of vanzacaftor, tezacaftor, and deutivacaftor were increased, which may increase the risk of ALYFTREK-associated adverse reactions. Reduce the ALYFTREK dosage with concomitant use of strong or moderate CYP3A inhibitors
[see Dosage and Administration (2.3)and Drug Interactions (7.1)].)7.1 Effect of Other Drugs and Grapefruit on ALYFTREKStrong or Moderate CYP3A InducersConcomitant use of ALYFTREK with strong or moderate CYP3A inducers is not recommended.
Vanzacaftor, tezacaftor, and deutivacaftor are substrates of CYP3A. Concomitant use of ALYFTREK with a strong or moderate CYP3A inducer decreases vanzacaftor, tezacaftor, and deutivacaftor exposure
[see Clinical Pharmacology (12.3)]which may reduce ALYFTREK effectiveness[see Warnings and Precautions (5.5)].Strong or Moderate CYP3A InhibitorsReduce the ALYFTREK dosage when used concomitantly with a strong or moderate CYP3A inhibitor
[see Dosage and Administration (2.3)].Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Concomitant use with a strong CYP3A inhibitor increases vanzacaftor, tezacaftor, and deutivacaftor exposure
[see Clinical Pharmacology (12.3)], which may increase the risk of ALYFTREK adverse reactions[see Warnings and Precautions (5.6)].Concomitant use with a moderate CYP3A inhibitor is predicted to increase vanzacaftor, tezacaftor, and deutivacaftor exposure[see Clinical Pharmacology (12.3)], which may increase the risk of ALYFTREK adverse reactions[see Warnings and Precautions (5.6)].GrapefruitFood or drink containing grapefruit should be avoided during treatment with ALYFTREK. Concomitant use of ALYFTREK with grapefruit juice which contains one or more components that moderately inhibit CYP3A may increase exposure of vanzacaftor, tezacaftor and deutivacaftor.
Tablets:
- Fixed-dose combination containing vanzacaftor 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg. ()
3 DOSAGE FORMS AND STRENGTHSTablets:
- Fixed-dose combination containing vanzacaftor 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg.
- Fixed-dose combination containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg.
Tablets:
- Fixed-dose combination containing vanzacaftor 4 mg (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), tezacaftor 20 mg, and deutivacaftor 50 mg. Each tablet is purple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other.
- Fixed-dose combination containing vanzacaftor 10 mg (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), tezacaftor 50 mg, and deutivacaftor 125 mg. Each tablet is purple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other.
- Fixed-dose combination containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg. ()
3 DOSAGE FORMS AND STRENGTHSTablets:
- Fixed-dose combination containing vanzacaftor 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg.
- Fixed-dose combination containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg.
Tablets:
- Fixed-dose combination containing vanzacaftor 4 mg (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), tezacaftor 20 mg, and deutivacaftor 50 mg. Each tablet is purple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other.
- Fixed-dose combination containing vanzacaftor 10 mg (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), tezacaftor 50 mg, and deutivacaftor 125 mg. Each tablet is purple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other.
There are no available data on ALYFTREK use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no animal reproduction studies with the concomitant administration of vanzacaftor, tezacaftor, and deutivacaftor, separate reproductive and developmental studies were conducted with vanzacaftor and tezacaftor in pregnant rats and rabbits. Deutivacaftor is a deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor. Reproductive and development studies were conducted with ivacaftor in pregnant rats and rabbits.
In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the MRHD in rabbits. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and the metabolite M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 8 and 9 times the exposure at the MRHD, respectively (based on AUC of ivacaftor for rats and rabbits). No adverse developmental effects were observed after oral administration of vanzacaftor, tezacaftor, or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 18 times, 1 time, and 8 times the exposures at the MRHD, respectively (based on AUCs of vanzacaftor, tezacaftor and M1-TEZ, and ivacaftor) (
In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day during the period of organogenesis from gestation Days 7-17. Ivacaftor did not cause adverse effects to the fetus at exposures up to 8 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies up to 200 mg/kg/day). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of organogenesis from gestation Days 7-19. Ivacaftor did not cause adverse effects to the fetus at exposures up to 9 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies). 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 3 times the MRHD). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 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 8 times the MRHD (based on AUC for ivacaftor at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose (200 mg/kg/day, 13 times the exposure at MHRD). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.