ivacaftor (Rx)

Brand and Other Names:Kalydeco
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 150mg

oral granules

  • 25mg/unit dose packet
  • 50mg/unit dose packet
  • 75mg/unit dose packet

Cystic Fibrosis

Indicated for cystic fibrosis (CF) in patients who have 1 mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data

150 mg PO q12hr

Dosage Modification

Strong or moderate CYP3A4 inhibitors

  • Coadministration with strong CYP3A inhibitors: Reduce to 150 mg PO twice-a-week
  • Coadministration with moderate CYP3A inhibitors: Reduce to 150 mg PO qDay
  • Avoid foods containing grapefruit or Seville oranges

Renal impairment

  • Not studied in patients with renal impairment
  • Mild-to-moderate: No dosage adjustment required
  • Severe (CrCl <30 mL/min) or end stage renal disease: Caution advised

Hepatic impairment

  • Mild (Child-Pugh Class A): No dosage adjustment required
  • Moderate (Child-Pugh Class B): Reduce to 150 mg PO qDay
  • Severe (Child-Pugh Class C): Reduce to 150 mg PO qDay or less frequently

Dosing Considerations

Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene

If genotype is unknown, use a FDA-cleared CF mutation test to detect a CFTR mutation followed by verification with bi-directional sequencing when recommended by mutation test

Dosage Forms & Strengths

tablet

  • 150mg

oral granules

  • 25mg/unit dose packet
  • 50mg/unit dose packet
  • 75mg/unit dose packet

Cystic Fibrosis

Indicated for cystic fibrosis (CF) in patients aged ≥4 months who have 1 mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data

<4 months: Safety and efficacy not established

4 to <6 months

  • ≥5 kg: 25 mg granules PO q12hr

6 months to <6 years

  • 5 to <7 kg: 25 mg granules PO q12hr
  • 7 to <14 kg: 50 mg granules PO q12hr
  • ≥14 kg: 75 mg granules PO q12hr

≥6 years

  • 150 mg PO q12hr

Dosage Modifications

CYP3A inhibitors

  • Age >6 months
    • Coadministration with strong CYP3A inhibitors: Reduce to 1 tablet or 1 weight-based dose of oral granules PO twice-a-week
    • Coadministration with moderate CYP3A inhibitors: Reduce to 1 tablet or 1 weight-based dose of oral granules PO qDay
    • Avoid foods containing grapefruit or Seville oranges

Renal impairment

  • Not studied in patients with renal impairment
  • Mild-to-moderate: No dosage adjustment required
  • Severe (CrCl <30 mL/min) or end stage renal disease: Caution advised

Hepatic impairment

<6 months: Not recommended

≥6 months
  • Mild (Child-Pugh Class A): No dosage adjustment required
  • Moderate (Child-Pugh Class B): Reduce dose frequency from q12hr to qDay
  • Severe (Child-Pugh Class C): Reduce dosage frequency of qDay or less frequently

Dosing Considerations

Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene

If genotype is unknown, use a FDA-cleared CF mutation test to detect a CFTR mutation followed by verification with bi-directional sequencing when recommended by mutation test

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Interactions

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            Adverse Effects

            >10%

            Headache (24%)

            Oropharyngeal pain (22%)

            Upper respiratory tract injection (22%)

            Nasal congestion (20%)

            Abdominal pain (16%)

            Nasopharyngitis (15%)

            Rash (13%)

            Diarrhea (13%)

            Nausea (12%)

            1-10%

            Dizziness (9%)

            Rhinitis (6%)

            Arthralgia (5%)

            Bacteria in sputum (5%)

            4-7%

            • Rhinitis
            • Aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased
            • Arthralgia, musculoskeletal chest pain, myalgia
            • Sinus headache
            • Pharyngeal erythema, pleuritic pain, sinus congestion, wheezing
            • Acne
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            Warnings

            Contraindications

            None

            Cautions

            Noncongenital lens opacities/cataracts reported in pediatric patients; baseline and follow-up examinations recommended when initiating treatment

            Transaminase elevations

            • Elevated transaminases reported
            • Assess ALT and AST before initiating, every 3 months during first year of treatment, and annually thereafter
            • For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests
            • If AST or ALT levels increase, closely monitor until abnormalities resolve
            • Interrupt dosing in patients with ALT or AST >5x ULN; once resolved, consider benefits versus risks before resumption

            Drug interaction overview

            • Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; caution when coadministration with CYP3A and/or P-gp substrates
            • CYP3A4 inhibitors
              • Ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure by 8.5-fold
              • Fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold
              • Avoid eating grapefruit juice, grapefruit, or Seville oranges during treatment with ivacaftor; these fruits contain 1 or more components that moderately inhibit CYP3A
            • Strong CYP3A4 inducers
              • Not recommended
              • Strong CYP3A4 inducers may substantially decreased (~9-fold) systemic exposure of ivacaftor, which may reduce therapeutic effect
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            Pregnancy & Lactation

            Pregnancy

            There are limited and incomplete human data from clinical trials and postmarketing reports on use in pregnant females

            Animal data

            • Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to ~5x (rats) and 11x (rabbits) the exposure at the maximum recommended human dose (MRHD)
            • No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures ~3x the exposures at the MRHD

            Lactation

            No information available regarding presence in human milk, effects on breastfed infants, or effects on milk production

            Excreted into milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk

            Consider developmental and health benefits of breastfeeding along with the mother’s clinical need, and any potential adverse effects on the breastfed child or from the underlying maternal condition

            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

            Potentiates the cystic fibrosis transmembrane conductance regulator (CFTR)

            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 the G551D-CFTR protein

            CFTR gene mutations that produce CFTR protein and are responsive to ivacaftor

            • A455E, A1067T
            • D110E, D110H, D579G, D1152H, D1270N
            • E56K, E831X, E193K
            • F1052V, F1074L
            • G178R, G551D, G551S, G1069R, G1244E, G1349D
            • K1060T
            • L206W
            • P67L
            • R74W, R117C, R117H, R347H, R352Q, R1070Q, R1070W
            • S549N, S549R, S945L, S977F, S1251N, S1255P
            • 711+3A→G, 2789+5G→A, 3272-26A→G, 3849+10κβC→T

            Absorption

            Peak Plasma Time: 4 hr (with high fat food)

            Peak Plasma Concentration: 768 ng/mL

            AUC

            • 6 to <12 months, 5 to <7 kg (25 mg PO q12hr): 5790 ng•hr/mL
            • 6 to <12 months, 7 to <14 kg (50 mg PO q12hr): 9250 ng•hr/mL
            • 12 to <24 months, 7 to <14 kg (50 mg PO q12hr): 9050 ng•hr/mL
            • 12 to <24 months, ≥14 to <25 kg (75 mg PO q12hr): 9600 ng•hr/mL
            • 2 to <6 years, <14 kg (50 mg PO q12hr): 10,500 ng•hr/mL
            • 2 to <6 years, ≥14 to <25 kg (75 mg PO q12hr): 11,300 ng•hr/mL
            • 6 to <12 years (150 mg PO q12hr): 20,000 ng•hr/mL
            • 12 to <18 years (150 mg PO q12hr): 9240 ng•hr/mL
            • ≥18 years (150 mg PO q12hr): 10,700 ng•hr/mL

            Distribution

            Protein Bound: 99% (primarily albumin and alpha 1-acid glycoprotein)

            Does not bind to red blood cells

            Vd: 353 L

            Metabolism

            Metabolized by CYP3A

            Metabolites: M1 and M6 are the 2 major metabolites; M1 has 1/6 the potency of ivacaftor and is considered pharmacologically active; whereas, M6 has <1/50 the potency of ivacaftor and is not considered pharmacologically active

            Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp

            Elimination

            Half-life: 12 hr

            Total body clearance: 17.3 L/hr

            Excretion: feces 87.8% (M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6); urine (negligible)

            Pharmacogenomics

            G551D mutation in the CFTR gene

            • In 2 studies of patients with the G551D mutation, treatment with ivacaftor resulted in a significant improvement in FEV1
            • The treatment difference between ivacaftor and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2
            • These changes persisted through 48 weeks

            Homozygous for the F508del mutation in the CFTR gene

            • Should not be used in patients homozygous for the F508del mutation in the CFTR gene
            • Efficacy results from a double-blind, placebo-controlled trial in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of ivacaftor treatment compared to placebo
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            Administration

            Oral Administration

            Tablets

            • Take with fat-containing food (eg, eggs, butter, peanut butter, cheese pizza)

            Oral granules

            • Mix entire contents of each packet of oral granules with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed; food or liquid should be at or below room temperature
            • Once mixed, administer within 1 hr
            • Some examples of soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, milk, or juice
            • Administer each dose just before or just after eating fat-containing food (eg, eggs, butter, peanut butter, cheese pizza)

            Storage

            Capsules or granules: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Mixed granules: Stable for 1 hr after mixed with soft foods or liquid

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            Formulary

            FormularyPatient Discounts

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            • Compare formulary status to other drugs in the same class.
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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
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            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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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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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.