Lumacaftor and Ivacaftor

Name: Lumacaftor and Ivacaftor

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

Introduction

Fixed combination containing lumacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] corrector) and ivacaftor (CFTR potentiator).1 4 5 6 7 8

Lumacaftor and Ivacaftor Dosage and Administration

Administration

Oral Administration

Administer orally every 12 hours with fat-containing food (e.g., eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole milk dairy products) to increase systemic absorption of the drug.1 (See Food under Pharmacokinetics.) Typical diet recommended for patients with cystic fibrosis satisfies requirement for fat-containing food.1

Dosage

Available as fixed-combination tablets containing 200 mg of lumacaftor and 125 mg of ivacaftor.1

Pediatric Patients

Cystic Fibrosis Oral

Children ≥12 years of age: Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.1

Dosage adjustment necessary when used concomitantly with potent inhibitors of CYP3A.1 (See Interactions.)

Adults

Cystic Fibrosis Oral

Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.1

Dosage adjustment necessary when used concomitantly with potent inhibitors of CYP3A.1 (See Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.1

Moderate hepatic impairment (Child-Pugh class B): Lumacaftor 400 mg/ivacaftor 250 mg in the morning and lumacaftor 200 mg/ivacaftor 125 mg in the evening.1

Severe hepatic impairment (Child-Pugh class C): Use with caution and at a dosage of lumacaftor 200 mg/ivacaftor 125 mg twice daily (morning and evening), or less, after weighing risks and benefits of therapy.1

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Interactions for Lumacaftor and Ivacaftor

Lumacaftor is a potent inducer of CYP3A;1 has potential to induce CYP2B6, 2C8, 2C9, and 2C19; and may inhibit CYP2C8 and 2C9.1 Has potential to inhibit and induce P-glycoprotein (P-gp).1

Ivacaftor is a CYP3A4 and 3A5 substrate, may inhibit CYP2C9, and is a weak inhibitor of P-gp.1

Net effect of lumacaftor/ivacaftor in fixed combination is potent CYP3A induction.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A substrate: Possible pharmacokinetic interaction (decreased exposure and efficacy of substrate drug).1 Concomitant use with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index not recommended.1

Potent CYP3A inhibitors: Pharmacokinetic interaction (possible increased ivacaftor exposure).1 Because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation.1 Concomitant use not recommended; consider alternative therapy.1 If concomitant use required, dosage adjustment not necessary if potent CYP3A inhibitor initiated in patient already receiving lumacaftor/ivacaftor.1 However, if lumacaftor/ivacaftor initiated in patient already receiving a potent CYP3A inhibitor or if lumacaftor/ivacaftor interrupted for >1 week and then reinitiated in patient receiving a potent CYP3A inhibitor, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours1

Potent CYP3A inducers: Pharmacokinetic interaction (decreased ivacaftor exposure; may reduce efficacy of lumacaftor/ivacaftor).1 Concomitant use not recommended.1

Moderate or weak CYP3A inducers: Dosage adjustment not necessary.1

CYP2B6, 2C8, 2C9, and 2C19 substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).1

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased AUC of ivacaftor and reduced efficacy of lumacaftor/ivacaftor1

Concomitant use not recommended1

Antifungals, azoles (itraconazole, ketoconazole, posaconazole, voriconazole)

Itraconazole: Possible decreased exposure and efficacy of itraconazole;1 ivacaftor exposure increased by 4.3-fold;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Ketoconazole, posaconazole, voriconazole: Possible decreased exposure and efficacy of such azole antifungals;1 possible increased ivacaftor exposure;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Itraconazole, ketoconazole, posaconazole, voriconazole: Concomitant use not recommended;1 consider alternative azole antifungal (e.g., fluconazole);1 if concomitant use required, monitor for breakthrough fungal infections1

Dosage adjustment not necessary if such azole antifungals initiated in patient already receiving lumacaftor/ivacaftor1

If lumacaftor/ivacaftor initiated in patients already receiving such azole antifungals, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours1

If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in patient receiving such azole antifungals, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours1

Antimuscarinics (ipratropium, tiotropium)

Dosage adjustment not necessary1

Antimycobacterials (rifabutin, rifampin)

Rifabutin, rifampin: Possible decreased ivacaftor exposure and reduced efficacy of lumacaftor/ivacaftor1

Rifampin decreased ivacaftor exposure by 57%; minimal effect on lumacaftor exposure1

Concomitant use not recommended1

Azithromycin

Dosage adjustment not necessary1

Aztreonam

Dosage adjustment not necessary1

Benzodiazepines (midazolam, triazolam)

Possible decreased exposure and efficacy of the benzodiazepine1

Concomitant use not recommended; consider alternatives to midazolam and triazolam1

Calcium carbonate

Dosage adjustment not necessary1

Ceftazidime

Dosage adjustment not necessary1

Cetirizine

Dosage adjustment not necessary1

Colistin (commercially available in US as colistimethate sodium)

Dosage adjustment not necessary1

Corticosteroids (budesonide, fluticasone, methylprednisolone, prednisone)

Methylprednisolone, prednisone: Possible decreased exposure and efficacy of the corticosteroid1

Methylprednisolone, prednisone: Increased dosage of corticosteroid may be needed to obtain desired clinical effect1

Budesonide, fluticasone: Dosage adjustment not necessary1

Co-trimoxazole

Dosage adjustment not necessary1

Digestive enzymes (pancreatin, pancrelipase)

Dosage adjustment not necessary1

Digoxin

Possible altered digoxin concentrations1

Monitor serum digoxin concentrations and titrate digoxin dosage to obtain desired clinical effect1

Dornase alfa

Dosage adjustment not necessary1

Estrogens and progestins (oral, injectable, transdermal, implantable contraceptives)

Possible decreased exposure and efficacy of the contraceptive1

Avoid concomitant use;1 not considered reliable method of contraception when used concomitantly1

Fluoroquinolones (ciprofloxacin, levofloxacin)

Dosage adjustment not necessary1

Ibuprofen

Possible decreased exposure and efficacy of ibuprofen1

Increased dosage of ibuprofen may be required to obtain desired therapeutic effect1

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)

Possible decreased exposure and efficacy of the immunosuppressant1

Data not available in patients with cystic fibrosis and organ transplants, but potential for drug interaction exists1

Concomitant use not recommended1

Avoid concomitant use in patients with cystic fibrosis and organ transplants1

Macrolides (clarithromycin, erythromycin, telithromycin)

Clarithromycin, erythromycin, telithromycin: Possible decreased exposure and efficacy of such macrolide antibiotics1

Clarithromycin, telithromycin: Possible increased ivacaftor exposure;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Clarithromycin, erythromycin, telithromycin: Consider alternative antibiotic (e.g., azithromycin, ciprofloxacin, levofloxacin)1

Clarithromycin, telithromycin: If concomitant use with such macrolides required, dosage adjustment not needed if macrolide initiated in patients already receiving lumacaftor/ivacaftor1

Clarithromycin, telithromycin: If lumacaftor/ivacaftor initiated in patients already receiving such macrolides, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours1

Clarithromycin, telithromycin: If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in patients already receiving such macrolides, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours1

Metformin

Dosage adjustment not necessary1

Montelukast

Possible decreased exposure and efficacy of montelukast1

Dosage adjustment not necessary; clinically monitor patient1

Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole)

Possible decreased exposure and efficacy of the proton-pump inhibitor1

Dosage adjustment of the proton-pump inhibitor may be required to obtain desired therapeutic effect1

Ranitidine

Possible decreased ranitidine exposure and efficacy1

Ranitidine dosage adjustment may be required to obtain desired therapeutic effect1

Repaglinide

Possible decreased repaglinide exposure and efficacy1

Repaglinide dosage adjustment may be required to obtain desired therapeutic effect1

Selective β2-adrenergic agonists (albuterol, salmeterol)

Dosage adjustment not necessary1

SSRIs (citalopram, escitalopram, sertraline)

Possible decreased exposure and efficacy of the SSRI1

Increased SSRI dosage may be required to obtain desired therapeutic effect1

St. John’s wort (Hypericum perforatum)

Possible decreased AUC of ivacaftor and reduced efficacy of lumacaftor/ivacaftor1

Concomitant use not recommended1

Tobramycin

Dosage adjustment not necessary1

Warfarin

Possible altered warfarin exposure1

Monitor INR1

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
  • Chest pain or pressure.
  • Shortness of breath.
  • Breathing that is not normal.
  • Feeling confused.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take lumacaftor and ivacaftor or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to lumacaftor and ivacaftor. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Brand Names U.S.

  • Orkambi

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies when testing the individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis, rhinitis, rhinorrhea, diarrhea, nausea, loss of strength and energy, flatulence, flu-like symptoms, signs of common cold, or menstrual irregularities. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe headache, severe dizziness, passing out, vision changes, angina, shortness of breath, abnormal breathing, or confusion (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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