lumacaftor/ivacaftor (Rx)

Brand and Other Names:Orkambi
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Dosing & Uses

AdultPediatric

Dosage Forms & 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

Dosage Forms & Strengths

lumacaftor/ivacaftor

tablet

  • 100mg/125mg
  • 200mg/125mg

oral granules

  • (100mg/125mg)/packe
  • (150mg/188mg)/packet

Cystic Fibrosis

Indicated for cystic fibrosis (CF) in patients aged ≥2 yr who are homozygous for the F508del mutation in the CFTR gene

<2 years: Safety and efficacy not established

2-5 years

  • Weight <14 kg: 100 mg/125 mg oral granule packet PO q12hr
  • Weight ≥14 kg: 150 mg/188 mg oral granule packet PO q12hr

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) aged 2-5 years
    • Oral granules
    • <14 kg: 100 mg/125 mg-packet in the morning and 100 mg/125 mg-packet every other evening
    • ≥14 kg: 150 mg/188 mg-packet in the morning and 150 mg/188 mg-packet every other evening
  • Moderate (Child-Pugh B) aged ≥6 years
    • 100 mg/125 mg-tablet: Reduce dose to 2 tablets in the morning and 1 tablet in the evening
  • Severe (Child-Pugh C) aged 2-5 years
    • Oral granules
    • <14 kg: 100 mg/125 mg-packet in the morning and no dose in the evening
    • ≥14 kg: 150 mg/188 mg-packet in the morning and no dose in the evening
  • Severe (Child-Pugh C) aged ≥6 years
    • 100 mg/125 mg-tablet: 1 tablet PO q12hr (or less frequently)

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 or 1 oral granule packet every other day 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 or 1 oral granule packet every other day 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

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Interactions

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            Adverse 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

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            Warnings

            Contraindications

            None

            Cautions

            Worsening liver function, including hepatic encephalopathy, in patients with advanced liver disease reported

            Liver function decompensation, including liver failure leading to death, has been reported in cystic fibrosis patients with pre-existing cirrhosis with portal hypertension

            Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of therapy compared to those who received placebo; these events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40); clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended

            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

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            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.

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            Pharmacology

            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

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            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])

            Oral granules

            • The entire content of each packet of oral granules should be mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed
            • Soft foods examples include puréed fruits, flavored yogurt or pudding, and milk or juice
            • Food should be at or below room temperature or below
            • Each packet is for single use only
            • Once mixed, consume within 1 hr; mixture is stable for up to 1 hr

            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

            Tablets or oral granule packets: Store at controlled room temperature (20-25°C [68-77°F]); excursions permitted to 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.