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

            • 711+3A→G, 2789+5G→A, 3272-26A→G, 3849+10κβC→T
            • A120T, A234D, A349V, A455E, A1067T
            • D110E, D110H, D192G, D579G, D924N, D1152H, D1270N
            • E56K, E193K, E822K, E831X
            • F311del, F311L, F508C, F508C;S1251N, F1052V, F1074L
            • G178E, G178R, G194R, G314E, G551D, G551S, G576A, G970D, G1069R, G1244E, G1249R, G1349D
            • H939R, H1375P
            • I148T, I175V, I807M, I1027T, I1139V
            • K1060T
            • L206W, L320V, L967S, L997F, L1480P
            • M152V, M952I, M952T
            • P67L
            • Q237E, Q237H, Q359R, Q1291R
            • R74W, R75Q, R117C, R117G, R117H, R117L, R117P, R170H, R347H, R347L, R352Q, R553Q, R668C, R792G, R933G, R1070Q, R1070W, R1162L, R1283M
            • S549N, S549R, S589N, S737F, S945L, S977F, S1159F, S1159P, S1251N, S1255P
            • T338I, T1053I
            • V232D, V562I, V754M, V1293G
            • W1282R
            • Y1014C, Y1032C

            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

            G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R Mutation in the CFTR gene

            • Efficacy and safety in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a double-blind, placebo-controlled, crossover design clinical trial
            • For the 9 mutations studied, ivacaftor compared to placebo resulted in significant improvement in percent predicted FEV1 through Week 8
            • High degree of variability of efficacy responses among the 9 mutations

            R117H mutation in the CFTR gene

            • CF patients who have an R117H mutation in the CFTR gene were evaluated in a clinical trial
            • Primary efficacy endpoint was improvement in lung function by percent predicted FEV1 baseline through 24 weeks of treatment: did not reach statistical significance

            Heterozygous for the F508del mutation and a second mutation

            • Ivacaftor compared to placebo resulted in significant improvement in ppFEV1 [4.7 percent points from study baseline to average of Week 4 and Week 8 and CFQ-R respiratory domain score (9.7 points from study baseline to average of Week 4 and Week 8)
            • Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutation

            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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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            Kalydeco oral
            -
            150 mg tablet
            Kalydeco oral
            -
            25 mg package

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            ivacaftor oral

            IVACAFTOR - ORAL

            (EYE-va-KAF-tor)

            COMMON BRAND NAME(S): Kalydeco

            USES: This medication is used to treat cystic fibrosis in certain people (those with an abnormal "CFTR" gene). It may help to improve breathing, reduce the risk of lung infections, and improve weight gain.

            HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start taking ivacaftor and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth as directed by your doctor, usually twice daily (every 12 hours).If you are taking the tablet form of this medication, take this medication with fat-containing foods (such as eggs, butter, peanut butter, cheese).If you are taking the granules form of this medication, gently shake the packet before use. Empty the packet into a small cup with 1 teaspoonful (5 milliliters) of soft food (such as yogurt, applesauce) or liquid (such as water, milk, infant formula). The soft food or liquid should be at or below room temperature. Mix the granules with the soft food or liquid and take the entire mixture within 1 hour of mixing. Eat a fat-containing food either right before or just after taking the mixture.The dosage is based on your medical condition, age, weight, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day.Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Also avoid eating Seville oranges (often found in marmalade). Grapefruit and Seville oranges can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.Tell your doctor if your condition does not improve or if it worsens.

            SIDE EFFECTS: Dizziness, headache, and nausea may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: vision changes.Ivacaftor may rarely cause serious liver disease. Get medical help right away if you have any symptoms of liver damage, including: nausea/vomiting that doesn't stop, loss of appetite, dark urine, stomach/abdominal pain, yellowing eyes/skin.Ivacaftor can commonly cause a rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe reaction. Tell your doctor right away if you develop any rash.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Before taking ivacaftor, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease.This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: See also How To Use section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Other medications can affect the removal of ivacaftor from your body, which may affect how ivacaftor works. Examples include rifamycins (such as rifabutin), drugs for seizures (such as carbamazepine, phenytoin), St. John's wort, among others.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

            NOTES: Do not share this medication with others.Lab and/or medical tests (such as CFTR gene testing, liver/lung function, eye exams) will be done before you start taking this medication and while you are taking it. Keep all medical and lab appointments. Consult your doctor for more details.

            MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is less than 6 hours until the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            Information last revised December 2022. Copyright(c) 2022 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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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.
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            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.
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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.