Dosage and Administration

Recommended Dose and Dosage Adjustments for ORKAMBI Tablets1
Clinical Situations Dose Administration Frequency Total Daily Dose
Recommended Doses
For patients age 6-11 years, taken with fat-containing food 2 tablets of ORKAMBI (each containing lumacaftor 100 mg/ivacaftor 125 mg) Every 12 hours lumacaftor 400 mg/ivacaftor 500 mg
For patients age 12 years and older, taken with fat-containing food 2 tablets of ORKAMBI (each containing lumacaftor 200 mg/ivacaftor 125 mg) Every 12 hours lumacaftor 800 mg/ivacaftor 500 mg
Dosage Adjustments for Patients With Hepatic Impairment Patients
6-11 years
Patients
12 years and older
Severe impairment
(Child-Pugh Class C)a
1 tablet of ORKAMBI Every 12 hours or less frequently lumacaftor 200 mg/ivacaftor 250 mg lumacaftor 400 mg/ivacaftor 250 mg
Moderate impairment
(Child-Pugh Class B)
2 tablets of ORKAMBI Morning lumacaftor 300 mg/ivacaftor 375 mg lumacaftor 600 mg/ivacaftor 375 mg
1 tablet of ORKAMBI Evening
(12 hours later)
Mild impairment
(Child-Pugh Class A)
No adjustment required, see Recommended Doses above
Dosage Adjustment for CYP3A Inhibitors Patients
6-11 years
Patients
12 years and older
Initiating ORKAMBI in patients already taking a strong CYP3A inhibitor (e.g., itraconazole)b First week:
1 tablet of ORKAMBI
Once daily lumacaftor 100 mg/ivacaftor 125 mg lumacaftor 200 mg/ivacaftor 125 mg
After first week:
Continue with the full recommended daily doses as prescribed
Initiating CYP3A inhibitors in patients already taking ORKAMBIc No dose adjustment required, see Recommended Doses above
Dose interruptions of ORKAMBI while taking strong CYP3A inhibitors If ORKAMBI is interrupted for more than 1 week, and then reinitiated while taking strong CYP3A inhibitors, reduce dose to 1 tablet daily for the first week of treatment reinitiation. Following this period, continue with the full recommended daily dose as prescribed
a Use with caution after weighing the risks and benefits of treatment.1
b Additional examples include ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin.1
c No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors.1
Examples of Fat-Containing Foods1
Fat-containing foods help the body absorb ORKAMBI better. A typical CF diet will satisfy this requirement. When counseling patients, the list provides examples of a variety of fat-containing foods to take with ORKAMBI
  • Almonds
  • Avocado
  • Cheese pizza
  • Deli ham
  • Eggs
  • Granola
  • Hummus
  • Nuts
  • Peanut butter
  • Roasted peanuts
  • Salmon
  • Trail mix with nuts
  • Tuna
  • Whole milk
  • Whole-milk cheese
  • Whole-milk yogurt

Missed dose1

  • If a patient misses a dose and remembers the missed dose within 6 hours, the patient should take the dose with fat-containing food
  • If more than 6 hours elapse after the usual dosing time, the patient should skip that dose and resume the normal schedule for the following dose
  • A double dose should not be taken to make up for the forgotten dose

Child-Pugh classification system2

  • The Child-Pugh classification system is used to assess the severity of liver disease. According to this system, there are 3 levels of hepatic impairment—mild (Class A), moderate (Class B), and severe (Class C). The Child-Pugh Class is calculated by adding the scores of the 5 factors listed below. The patient receives a score of 1, 2, or 3 for each factor, which are added together to get the total Child-Pugh score to determine the Child-Pugh Class
  • Child-Pugh Classes of A (5-6 points), B (7-9 points), and C (10-15 points) correlate to increasing disease severity
Scoring System for Child-Pugh Classification of Liver Disease2
Factor Units 1 Point 2 Points 3 Points
Serum bilirubin µmol/L
mg/dL
<34
<2.0
34-51
2.0-3.0
>51
>3.0
Serum albumin g/L >35 30-35 <30
Prothrombin time Seconds prolonged
INR
0-4
<1.7
4-6
1.7-2.3
>6
>2.3
Ascites n/a None Easily controlled Poorly controlled
Hepatic
encephalopathy
n/a None Minimal Advanced

INR, international normalized ratio; n/a, not applicable.

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ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.


Limitations of Use

The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF while receiving ORKAMBI
  • Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered
  • Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN
  • Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.

×
+

ORKAMBI® (lumacaftor/ivacaftor) INDICATIONS AND USAGE

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.


Limitations of Use

The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

IMPORTANT SAFETY INFORMATION

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF while receiving ORKAMBI
  • Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered
  • Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN
  • Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

Substrates of CYP3A

  • Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
  • ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI

Strong CYP3A Inducers

  • Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile for patients age 6 through 11 years in an open-label Phase 3 trial (Trial 3; N=58) was similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information.