Dosing and uses of Orkambi (lumacaftor/ivacaftor)
Adult dosage forms and strengths
lumacaftor/ivacaftor
tablet
- 200mg/125mg
Cystic Fibrosis
Indicated for cystic fibrosis (CF) in patients who are homozygous for the F508del mutation in the CFTR gene
2 tablets PO q12hr (each tablet containing 200 mg/125 mg [ie, 400 mg/250 mg per dose]); take with fat-containing food
Dosage modifications
Hepatic impairment
- Mild (Child-Pugh A): Dosage adjustment not required
- Moderate (Child-Pugh B): Reduce dose to 2 tablets in the morning and 1 tablet in the evening (ie, lumacaftor 600 mg/ivacaftor 375 mg per day)
- Severe (Child-Pugh C)
- Not studied, but exposure is systemic and expected to be higher than moderate impairment
- Use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (ie, lumacaftor 400 mg/ivacaftor 250 mg per day), or less, after weighing the risks and benefits of treatment
Increased liver enzymes
- ALT or AST >5 x ULN (not associated with elevated bilirubin): Interrupt dosing
- ALT or AST >3 x ULN associated with elevated bilirubin >3 x ULN: Interrupt dosing
- Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing
Coadministration with CYP3A inhibitors
- Initiating CYP3A inhibitor in patients already taking lumacaftor/ivacaftor: No dosage adjustment required Initiating lumacaftor/ivacaftor in patients currently taking a strong
- CYP3A inhibitor: Reduce lumacaftor/ivacaftor dose to 1 tablet daily for the first week of treatment; following this period, continue with the recommended daily dose
- If lumacaftor/ivacaftor is interrupted for >1 week and then reinitiated while taking a strong CYP3A inhibitor, reduce lumacaftor/ivacaftor dose to 1 tablet daily for the first week of treatment; following this period, continue with the recommended daily dose
Dosing Considerations
Efficacy and safety have not been established in patients with CF other than those homozygous for the F508del mutation
If 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
Pediatric dosage forms and strengths
lumacaftor/ivacaftor
tablet
- 100mg/125mg
- 200mg/125mg
Cystic Fibrosis
Indicated for cystic fibrosis (CF) in patients aged ≥6 yr who are homozygous for the F508del mutation in the CFTR gene
<6 years: Safety and efficacy not established
6-11 years: 2 tablets PO q12hr (each tablet containing 100 mg/125 mg [ie, 200 mg/250 mg per dose])
≥12 years: 2 tablets PO q12hr (each tablet containing 200 mg/125 mg [ie, 400 mg/250 mg per dose])
Take doses with fat-containing food (see Administration)
Dosage modifications
Hepatic impairment
- Mild (Child-Pugh A): Dosage adjustment not required
- Moderate (Child-Pugh B): Reduce dose to 2 tablets in the morning and 1 tablet in the evening
- Severe (Child-Pugh C)
- Not studied, but exposure is systemic and expected to be higher than moderate impairment
- Use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening, or less, after weighing the risks and benefits of treatment
Increased liver enzymes
- ALT or AST >5 x ULN (not associated with elevated bilirubin): Interrupt dosing
- ALT or AST >3 x ULN associated with elevated bilirubin >3 x ULN: Interrupt dosing
- Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing
Coadministration with CYP3A inhibitors
- Initiating CYP3A inhibitor in patients already taking lumacaftor/ivacaftor: No dosage adjustment required Initiating lumacaftor/ivacaftor in patients currently taking a strong
- CYP3A inhibitor: Reduce lumacaftor/ivacaftor dose to 1 tablet daily for the first week of treatment; following this period, continue with the recommended daily dose
- If lumacaftor/ivacaftor is interrupted for >1 week and then reinitiated while taking a strong CYP3A inhibitor, reduce lumacaftor/ivacaftor dose to 1 tablet daily for the first week of treatment; following this period, continue with the recommended daily dose
Dosing Considerations
Efficacy and safety have not been established in patients with CF other than those homozygous for the F508del mutation
If 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
Orkambi (lumacaftor/ivacaftor) adverse (side) effects
>10%
Dyspnea (13%)
Nasopharyngitis (13%)
Nausea (13%)
Diarrhea (12%)
1-10%
Menstrual abnormalities (10%)
Upper respiratory tract infection (10%)
Fatigue (9%)
Abnormal respiration (9%)
Increased blood CPK (7%)
Rash (7%)
Flatulence (7%)
Rhinorrhea (6%)
<1%
Increased ALT or ASt
Increased bilirubin
Hepatic encephalopathy
Warnings
Contraindications
None
Cautions
Worsening liver function, including hepatic encephalopathy, in patients with advanced liver disease reported
Elevated transaminases associated with elevated bilirubin in some patients; measure transaminases and bilirubin before initiating therapy, every 3 months during first year of treatment, and annually thereafter; elevated transaminases may require therapy interruption (see Dosage modifications)
Chest discomfort, including dyspnea, and abnormal respiration reported during initiation; clinical experience in patients with percent predicted FEV1 <40 is limited; additional monitoring recommended during initiation of therapy
Increase in blood pressure reported in some patients; monitor blood pressure periodically
Cases of noncongenital lens opacities have been reported in pediatric patients treated with ivacaftor
Lumacaftor is a strong inducer of CYP3A; coadministration with sensitive CYP3A substrates or those with a narrow therapeutic index is not recommended
Ivacaftor is a substrate of CYP3A4 and CYP3A5; coadministration with strong inducers is not recommended because of significantly reduced systemic exposure of ivacaftor
Use in transplanted patients not recommended due to potential drug-drug interactions
Safety and efficacy in patients < 12 years, with cystic fibrosis, not established; cases of non-congenital lens opacities reported in pediatric patients treated with ivacaftor; although other risk factors present, direct cause cannot be excluded
Pregnancy
Pregnancy
Pregnancy category: B
There are no adequate and well-controlled trials in pregnant women; use only if clearly needed during pregnancy
Embryofetal development studies in rats and rabbits were conducted with the individual components
Lactation
Excretion of lumacaftor or ivacaftor into human milk is probable; caution advised
Both lumacaftor and ivacaftor are excreted into the milk of lactating female rats
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Orkambi (lumacaftor/ivacaftor)
Mechanism of action
Lumacaftor
- CFTR corrector
- Corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein
Ivacaftor
- CFTR potentiator
- The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs; ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of mutated CFTR proteins
- Indicated for R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations in the CFTR gene
Absorption
Fat-containing food: When lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was ~2 times higher and ivacaftor exposure was ~3 times higher than when taken in a fasting state
Peak plasma concentration
- Lumacaftor: 25 mcg/mL
- Ivacaftor: 0.502 mcg/mL
AUC
- Lumacaftor: 198 mcg·hr/mL
- Ivacaftor: 3.66 mcg·hr/mL
Distribution
Vd: 86 L (lumacaftor)
Protein bound
- Lumacaftor: 99%; primarily to albumin
- Ivacaftor: 99%; primarily to alpha 1-acid glycoprotein and albumin
Metabolism
Lumacaftor: Not extensively metabolized
Ivacaftor: Extensively metabolized, primarily by CYP3A to M1 and M6 (major metabolites)
Elimination
Half-life
- Lumacaftor: 25.2 hr
- Ivacaftor: 9.34 hr
Clearance
- Lumacaftor: 2.38 L/hr
- Ivacaftor: 25.1 L/hr
Excretion
- Lumacaftor: 51% (unchanged) in feces; 8.6% urine
- Ivacaftor: 87.8% (as metabolites) in feces; 6.6% urine
Pharmacogenomics
Indicated specifically for individuals who are homozygous for the F508del mutation in the 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
Administration
Oral Administration
Take with fat containing food (eg, eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products [eg, whole milk, cheese, yogurt])
Missed doses
- Within 6 hr: Take the dose with fat-containing food
- >6 hr elapsed: Skip that dose and resume the normal schedule for the following dose
- Do not double the dose to make up for the forgotten dose
Storage
Store at controlled room temperature (20-25°C [68-77°F]); excursions permitted to 15-30°C (59-86°F)
