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Drug Interactions With ORKAMBI® (lumacaftor/ivacaftor)

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Drug-Drug Interactions Tool

The Drug-Drug Interactions (DDI) Tool provides the established or predicted effect of ORKAMBI on other medicinal products or effect of other medicinal products on ORKAMBI1-3

  • The clinical comments are based on drug interaction studies, clinical relevance, or predicted interactions due to elimination pathways
  • Drugs shown within a therapeutic class do not represent all possible drugs within the class. Drugs within a therapeutic class may have different metabolic profiles and, therefore, clinical recommendations apply only to the indicated drugs and not the class. The table does not represent all possible drugs or drug classes that a patient could be receiving. For further information, contact your clinical pharmacist

Choose or Begin Typing the Brand or Generic Drug Name or Drug Class to Learn More About Potential DDIs

Drug Name Potential Effect on Exposure of Concomitant Drug Clinical Considerations

Aripiprazole
(Abilify®)2

 Decreased ↓
  • A higher dose of this antipsychotic may be required to obtain the desired clinical effect

Ethinyl estradiol/
Levonorgestrel
(Afirmelle®, Altavera®,
Aviane®, Ayuna®,
Enpresse®, Falmina®,
Kurvelo®, Lessina®,
Levora®, Marlissa®,
Myzilra®, Nordette®,
Portia-28®, Trivora-28®,
Vienva®)1,2

 Decreased ↓
  • Do not rely on hormonal contraceptives, including oral, injectable, transdermal, and implantable, as an effective method of contraception
  • Concomitant use of ORKAMBI with hormonal contraceptives increased menstrual abnormality events
  • Avoid concomitant use unless the benefits outweigh the risks

Fexofenadine
(Allegra®)2

 Increased ↑ or
decreased ↓
  • Use with caution and appropriate monitoring

Alprazolam
(Xanax®)2

 Decreased ↓
  • ORKAMBI may reduce the exposure of this benzodiazepine and may reduce its efficacy

Glimepiride
(Amaryl®)2

 Increased ↑ or
decreased ↓
  • A dose adjustment may be recommended to obtain the desired clinical effect
  • Use with caution and appropriate monitoring

Antacids1

 Increased ↑ or
decreased ↓
  • A dose adjustment may be required to obtain the desired clinical effect, no dose adjustment is recommended for calcium carbonate antacid

Atorvastatin
(Lipitor®)2

 Decreased ↓
  • Use with caution and appropriate monitoring

Azithromycin
(Zithromax®)1,2

 No effect predicted
  • No effect predicted

Clarithromycin
(Biaxin®)1

 Decreased ↓
  • Consider an alternative, such as ciprofloxacin, azithromycin, and levofloxacin
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antibiotic, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

Carbamazepine
(Tegretol®, Equetro®, Carbatrol®)1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

Citalopram
(Celexa®)1

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Ciprofloxacin
(Cipro®)1,2

 No effect predicted
  • No effect predicted

Clonazepam
(Klonopin®)2

 Decreased ↓
  • ORKAMBI may reduce the exposure of this benzodiazepine and may reduce its efficacy

Clozapine
(Clozaril®)2

 Decreased ↓
  • A higher dose of this antipsychotic may be required to obtain the desired clinical effect

Cyclosporine
(Sandimmune®)1

 Decreased ↓
  • Concomitant use not recommended
  • Avoid the use of ORKAMBI

Duloxetine
(Cymbalta®)2

 No effect predicted
  • No effect predicted

Dexamethasone2

 Decreased ↓
  • A higher dose of this systemic corticosteroid may be required to obtain the desired clinical effect

Diazepam
(Valium®)2

 Decreased ↓
  • ORKAMBI may reduce the exposure of this benzodiazepine and may reduce its efficacy

Fluconazole
(Diflucan®)1,2

 Increased ↑
  • A higher dose of fluconazole may be required to obtain desired clinical effect
  • No dose adjustment of ORKAMBI is recommended

Digoxin
(Lanoxin®)1

 Increased ↑ or
decreased ↓
  • Monitor the serum concentration and titrate the dose to obtain the desired clinical effect

Erythromycin
(Ery-Tab®)1,2

 Decreased ↓
  • Consider an alternative, such as azithromycin
  • No dose adjustment recommended

Escitalopram
(Lexapro®)1

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Esomeprazole
(Nexium®)1

 Decreased ↓
  • A dose adjustment may be required to obtain the desired clinical effect

Ethinyl
estradiol/Norethindrone
(Loestrin®)1,2

 Decreased ↓
  • Do not rely on hormonal contraceptives, including oral, injectable, transdermal, and implantable, as an effective method of contraception
  • Concomitant use of ORKAMBI with hormonal contraceptives increased menstrual abnormality events
  • Avoid concomitant use unless the benefits outweigh the risks

Fluoxetine
(Prozac®)2

 No effect predicted
  • No effect predicted

Glipizide
(Glucotrol®)2

 Increased ↑ or
decreased ↓
  • A dose adjustment may be recommended to obtain the desired clinical effect
  • Use with caution and appropriate monitoring

Metformin
(Glumetza®, Riomet®)1,2

 No effect predicted
  • No effect predicted

St. John’s wort
(Hypericum perforatum)1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

Ibuprofen
(Advil®, Motrin IB®)1

 Decreased ↓
  • A higher dose of ibuprofen may be required to obtain the desired clinical effect

Itraconazole*
(Sporanox®)1

 Decreased ↓
  • Concomitant use not recommended
  • Monitor closely for breakthrough fungal infections if use is necessary
  • Consider an alternative, such as fluconazole
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antifungal, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

*Based on clinical drug-drug interaction studies. All other drug interactions shown are predicted based on elimination pathways. Co-administration with itraconazole did not impact the exposure of lumacaftor but increased ivacaftor exposure by 4.3-fold.

Warfarin
(Jantoven®)1

 Exposure may be altered
  • Monitor international normalized ratio when co-administration with ORKAMBI is required

Ketoconazole
(Nizoral®)1

 Decreased ↓
  • Concomitant use not recommended
  • Monitor closely for breakthrough fungal infections if use is necessary
  • Consider an alternative, such as fluconazole
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antifungal, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

Lansoprazole
(Prevacid®)1

 Decreased ↓
  • A dose adjustment may be required to obtain the desired clinical effect

Pitavastatin
(Livalo®, Zypitamag®)2

 Decreased ↓
  • Use with caution and appropriate monitoring

Methylprednisolone
(Medrol®)1

 Decreased ↓
  • A higher dose of this systemic corticosteroid may be required to obtain the desired clinical effect

Midazolam1

 Decreased ↓
  • Concomitant use not recommended
  • Consider an alternative to this benzodiazepine

Mirtazapine
(Remeron®)

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Montelukast
(Singulair®)1

 Decreased ↓
  • No dose adjustment recommended
  • Appropriate clinical monitoring, as is reasonable

Rifabutin
(Mycobutin®)1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

Nateglinide2

 May alter exposure and effectiveness
  • A dose adjustment may be recommended to obtain the desired clinical effect
  • Use with caution and appropriate monitoring

Posaconazole
(Noxafil®)1

 Decreased ↓
  • Concomitant use not recommended
  • Monitor closely for breakthrough fungal infections if use is necessary
  • Consider an alternative, such as fluconazole
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antifungal, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

Omeprazole
(Prilosec®)1

 Decreased ↓
  • A dose adjustment may be required to obtain the desired clinical effect

Paroxetine
(Paxil®)2

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Risperidone
(Perseris®, Risperdal®)2

 Decreased ↓
  • A higher dose of this antipsychotic may be required to obtain the desired clinical effect

Phenobarbital1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

Pravastatin2

 Decreased ↓
  • Use with caution and appropriate monitoring

Prednisone
(Prednisone Intensol®, Rayos®)1

 Decreased ↓
  • A higher dose of this systemic corticosteroid may be required to obtain the desired clinical effect

Quetiapine
(Seroquel®)2

 Decreased ↓
  • A higher dose of this antipsychotic may be required to obtain the desired clinical effect

Ranitidine1

 Increased ↑ or
decreased ↓
  • A dose adjustment may be required to obtain the desired clinical effect

Repaglinide1,2

 Decreased ↓
  • A dose adjustment may be recommended to obtain the desired clinical effect
  • Use with caution and appropriate monitoring

Rifampin*
(Rifadin®)1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

*Based on clinical drug-drug interaction studies. All other drug interactions shown are predicted based on elimination pathways. Co-administration with rifampin had minimal effect on the exposure of lumacaftor but decreased ivacaftor exposure (AUC) by 57%.

Sertraline
(Zoloft®)1,2

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Telithromycin1

 Decreased ↓
  • Consider an alternative, such as ciprofloxacin, azithromycin, and levofloxacin
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antibiotic, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

Trazodone2

 Decreased ↓
  • A higher dose of this antidepressant may be required to obtain the desired clinical effect

Voriconazole
(Vfend®)1

 Decreased ↓
  • Concomitant use not recommended
  • Monitor closely for breakthrough fungal infections if use is necessary
  • Consider an alternative, such as fluconazole
  • If patient already on ORKAMBI, no dose adjustment recommended
  • When initiating ORKAMBI in patients taking this antifungal, reduce the ORKAMBI dose to 1 tablet daily (patients age 6 years and older) or 1 packet of oral granules every other day (patients age 1 through 5 years) for the first week, then 2 tablets (patients age 6 and older) or 1 packet of oral granules (patients age 1 through 5 years) every 12 hours

Everolimus
(Zortress®, Afinitor®)1

 Decreased ↓
  • Concomitant use not recommended
  • Avoid the use of ORKAMBI

Mycophenolate mofetil2

 No effect predicted
  • No effect predicted

Phenytoin
(Dilantin®)1

 Decreased ↓
  • Concomitant use not recommended
  • Decreased ivacaftor exposure; may reduce the effectiveness of ORKAMBI

Rifapentine
(Priftin®)2

 ORKAMBI exposure decreased ↓
  • ORKAMBI exposures may be decreased, resulting in reduced ORKAMBI effectiveness. However, no dose adjustment of ORKAMBI is recommended

Rosuvastatin
(Crestor®, Ezallor®)2

 Decreased ↓
  • Use with caution and appropriate monitoring

Simvastatin
(Zocor®, Flolipid®)2

 Decreased ↓
  • Use with caution and appropriate monitoring

Sirolimus
(Rapamune®)1

 Decreased ↓
  • Concomitant use not recommended
  • Avoid the use of ORKAMBI

Tacrolimus
(Prograf®)1

 Decreased ↓
  • Concomitant use not recommended
  • Avoid the use of ORKAMBI

Triazolam
(Halcion®)1

 Decreased ↓
  • Concomitant use not recommended
  • Consider an alternative to this benzodiazepine

Drug names in the table that are BOLD are listed in the full Prescribing Information for ORKAMBI.

POTENTIAL FOR OTHER DRUGS TO AFFECT ORKAMBI

Inhibitors of CYP3A1

  • Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours (the approved dose of ivacaftor monotherapy). Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI
  • However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dose to 1 tablet daily or 1 packet every other day (patients age 1 through 5 years) for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose. Examples of strong CYP3A inhibitors include
    • Ketoconazole, itraconazole, posaconazole, and voriconazole
    • Telithromycin, clarithromycin
  • No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors

Inducers of CYP3A1

  • Co-administration of lumacaftor/ivacaftor with rifampin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) is not recommended
  • No dose adjustment is recommended when used with moderate or weak CYP3A inducers

POTENTIAL FOR ORKAMBI TO AFFECT OTHER DRUGS

CYP3A Substrates1

  • Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%. Administration of ORKAMBI may decrease systemic exposure of medicinal products which are substrates of CYP3A, thereby decreasing the therapeutic effect of the medicinal product
  • Co-administration of ORKAMBI is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index such as
    • Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines)
    • Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI)

CYP2B6 and CYP2C Substrates1

  • In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates

Digoxin and Other P-gp Substrates1

  • Based on in vitro results, which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates
  • Monitor the serum concentration of digoxin and titrate the digoxin dose to obtain the desired clinical effect

Anti-allergics and Systemic Corticosteroids

  • ORKAMBI may decrease the exposure of montelukast, which may reduce its efficacy. No dose adjustment for montelukast is recommended. Employ appropriate clinical monitoring, as is reasonable, when co-administered with ORKAMBI
  • Concomitant use of ORKAMBI may reduce the exposure and effectiveness of prednisone and methylprednisolone. A higher dose of these systemic corticosteroids may be required to obtain the desired clinical effect

Antibiotics1

  • Concomitant use of ORKAMBI may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics. Consider an alternative to these antibiotics, such as ciprofloxacin, azithromycin, and levofloxacin

Antifungals1

  • Concomitant use of ORKAMBI may reduce the exposure and effectiveness of itraconazole, ketoconazole, posaconazole, and voriconazole. Concomitant use of ORKAMBI with these antifungals is not recommended. Monitor patients closely for breakthrough fungal infections if such drugs are necessary. Consider an alternative such as fluconazole

Anti-inflammatories1

  • Concomitant use of ORKAMBI may reduce the exposure and effectiveness of ibuprofen. A higher dose of ibuprofen may be required to obtain the desired clinical effect

Antidepressants1

  • Concomitant use of ORKAMBI may reduce the exposure and effectiveness of citalopram, escitalopram, and sertraline. A higher dose of these antidepressants may be required to obtain the desired clinical effect

Hormonal Contraceptives1

  • ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
  • Concomitant use of ORKAMBI with hormonal contraceptives increased the menstrual abnormality events. Avoid concomitant use unless the benefit outweighs the risks

Oral Hypoglycemics1

  • Concomitant use of ORKAMBI may reduce the exposure and effectiveness of repaglinide and may alter the exposure of sulfonylurea. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for metformin

Proton Pump Inhibitors, H2 Blockers, Antacids1

  • ORKAMBI may reduce the exposure and effectiveness of proton pump inhibitors such as omeprazole, esomeprazole, and lansoprazole, and may alter the exposure of ranitidine. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for calcium carbonate antacid

Warfarin1

  • ORKAMBI may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with ORKAMBI is required

Concomitant Drugs That Do Not Need Dose Adjustment1

  • No dosage adjustment of ORKAMBI or concomitant drug is recommended when ORKAMBI is given with the following: azithromycin, aztreonam, budesonide, ceftazidime, cetirizine, ciprofloxacin, colistimethate, colistin, dornase alfa, fluticasone, ipratropium, levofloxacin, pancreatin, pancrelipase, salbutamol, salmeterol, sulfamethoxazole and trimethoprim, tiotropium, and tobramycin. Based on the metabolism and route of elimination, ORKAMBI is not expected to impact the exposure of these drugs

AUC, area under the curve.

AUC, area under the curve.

Resources
Clinical Trial for Age 1 to <2 Years

Important Safety Information

Warnings and Precautions

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Indication and Usage

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older 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.

Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Hypersensitivity Reactions, Including Anaphylaxis

  • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI 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 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

  • Substrates of CYP3A
    Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
  • Strong CYP3A Inducers
    Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

ADVERSE REACTIONS

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients

Most Common Adverse Reactions

  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased
  • The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older

USE IN SPECIFIC POPULATIONS

Pediatric Use

  • The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established

Click here to access full Prescribing Information for ORKAMBI.

References:

1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-10745 (v2.0); 2021. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 1, 2024.

Important Safety Information and Indication

EXPAND

COLLAPSE

Indication and Usage

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older 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.

Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

Important Safety Information

Warnings and Precautions

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Indication and Usage

ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older 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.

Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.

Important Safety Information

Warnings and Precautions

Use in Patients With Advanced Liver Disease

  • Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Hypersensitivity Reactions, Including Anaphylaxis

  • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI 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 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

  • Substrates of CYP3A
    Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
  • Strong CYP3A Inducers
    Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

ADVERSE REACTIONS

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients

Most Common Adverse Reactions

  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased
  • The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older

USE IN SPECIFIC POPULATIONS

Pediatric Use

  • The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established

Click here to access full Prescribing Information for ORKAMBI.

References:

1. ORKAMBI [prescribing information]. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-10745 (v2.0); 2021. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 1, 2024.

Liver-related Events

  • Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
  • It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
  • Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing

Hypersensitivity Reactions, Including Anaphylaxis

  • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI

Respiratory Events

  • Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI 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 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy

Effect on Blood Pressure

  • Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI

Drug Interactions

  • Substrates of CYP3A
    Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
  • Strong CYP3A Inducers
    Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers is not recommended

Cataracts

  • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI

ADVERSE REACTIONS

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients

Most Common Adverse Reactions

  • The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
  • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased
  • The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older

USE IN SPECIFIC POPULATIONS

Pediatric Use

  • The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established

Click here to access full Prescribing Information for ORKAMBI.

References:

1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-10745 (v2.0); 2021. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 1, 2024.