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Pediatric Pulmonology 51:S61–S70 (2016)

Therapeutic Challenges Posed by Critical Drug–Drug Interactions in Cystic Fibrosis

1 2 Cameron L. Jordan, PharmD, BCPS, CPP, * Terry L. Noah, MD, and 2 Marianna M. Henry, MD, MPH

Summary. This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug–drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmem- brane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications. The complexities of these interactions provide a strong rationale for case management by pharmacists and pharmacologists as a routine part of CF care. Pediatr Pulmonol. 2016;51:S61–S70. ß 2016 Wiley Periodicals, Inc.

Key words: cystic fibrosis (CF); pharmacology.

Funding source: none reported.

INTRODUCTION The prevalence and implications of multiple over- lapping drug exposures, so-called “polypharmacy,” Utilization of combination medical therapies for have been studied primarily in elderly patients.5–7 cystic fibrosis (CF), involving an expanding array of Polypharmacy is defined most commonly as concurrent therapeutic agents,1 has been met with optimism for use of five or more drugs.8 In general, risk of adverse drug further substantial improvements in survival and quality reactions increases with total number of daily medica- of life accompanied by challenges in design of regimens tions.8,9 Prevalence and characteristics of potential drug– for individual patients. As drug development has drug interactions in children have been highlighted proceeded in the last two decades, first-in-class medi- recently by a retrospective cohort study of drug use in cations have typically been evaluated in the context of hospitalized children using a large administrative data- continued use of existing therapies yielding potential for base.10–12 In analyses of nearly 500,000 hospitalizations greater treatment complexity.2,3 In a sample of CF adults in 43 U.S. children’s hospitals, 49% of children were queried in 2006, median number of daily medications exposed to at least one potential drug–drug interaction. reported was seven (range 0–20), including two nebulized medications, and time to completion of daily treatment including airway clearance was 2–3 hr.2 Treatment complexity scores of children were nearly as high as of 1Department of Pharmacy, University of North Carolina Medical Center, adults in a large observational study using data from a Chapel Hill, North Carolina. 4 similar time frame. Indeed, the emerging understanding 2Division of Pulmonology, Department of Pediatrics, University of North of the contribution of early airway infection and Carolina School of Medicine, Chapel Hill, North Carolina. inflammation to the pathogenesis of CF lung disease motivates greater intensity of therapy beginning in early Conflict of interest: None. childhood. This is not a new concept—but one with new ÃCorrespondence to: Marianna M. Henry, MD, MPH, Division of twists given anticipated frequency of overlapping short- Pulmonology, Department of Pediatrics, University of North Carolina term and cumulative exposures to medications over a School of Medicine, 450 MacNider Building, Campus Box 7217, Chapel lifetime, particularly in the context of availability of new Hill, NC 27599-7217. E-mail: [email protected] agents, like cystic fibrosis transmembrane conductance regulator (CFTR) modulators, and more widespread use Received 21 April 2016; Revised 28 May 2016; Accepted 2 June 2016. of antifungal and antimycobacterial agents recognized to DOI 10.1002/ppul.23505 have potential for significant adverse drug reactions, Published online in Wiley Online Library including drug-drug interactions. (wileyonlinelibrary.com). ß 2016 Wiley Periodicals, Inc. S62 Jordan et al. Five percent of hospitalizations included a potential drug– P-450 (CYP450) enzymes. The CYP450 enzymes are drug interaction categorized as “contraindicated,” and found in many cells, but are most highly concentrated in 41% had an exposure of potential “moderate” severity.11 hepatocytes.16 Activity of CYP450 enzymes tends to Older age, longer hospitalization, and having a complex increase with age, though most reach similar activity to chronic condition increased the likelihood of potential that of adults by age 2 years.17 The CYP450 enzymes are drug–drug interaction.11 These data offer new perspective grouped into families (1–3), subfamilies (A–E), and on the frequency of potential drug–drug interactions individual gene number. More than 90% of drug oxidation among hospitalized children and adolescents that is can be attributed to six enzymes: CYP1A2, 2C9, 2C19, relevant to CF patients who have high daily medication 2D6, 2E1, and 3A4.16 For the purposes of this article, requirements, even as outpatients. CYP3A4, CYP2C9, and 2C19 will be the primary While few relevant data exist, studies suggest that focus, as they are responsible for a significant number physician knowledge of drug–drug interactions is of drug interactions relevant to CF. limited.13,14 Here we do not attempt a comprehensive Drug activity on CYP450 enzymes can result in either review of specific drug–drug interactions in CF manage- induction or inhibition of the enzyme (Fig. 1). Enzyme ment, which is well beyond the scope of a single review. induction causes enhanced metabolism of other drug This review seeks to re-introduce CF clinicians to the substrates, usually leading to decreased exposure and pharmacology of drug–drug interactions among medi- potentially reduced therapeutic efficacy. However, if the cations commonly used in CF and provide a framework enzyme substrate is a prodrug that requires metabolism to for understanding these interactions among medications one or more active metabolites, induction of the CYP450 outside the scope of this discussion. Two recent trends in enzyme can result in increased levels of active metabolite, CF care are the introduction of CFTR modulators and potentially resulting in toxicity. Onset and offset of enzyme emphasis on the importance of mental health in chronic induction is gradual, as it is dependent on steady state disease management.15 As a complement to other recent levels of the inducer as well as synthesis of new enzyme.16 reviews,3 we, therefore, focus on drugs impacted by Alternatively, CYP450 enzyme inhibition usually results the cytochrome P-450 (CYP450) enzyme system and in increased concentrations of drug substrates, potentially on interactions involving antimicrobials, psychotropic leading to toxicity. Onset of inhibition is faster, beginning medications, and CFTR modulators. with the initial doses of the inhibitor and reaching maximal effect at steady state.16 In addition to drug properties, an individual patient’s DRUG METABOLISM PATHWAYS: GENERAL genotype can play an important role in drug metabolism. CONSIDERATIONS Genetic polymorphisms of a given CYP450 gene can A large proportion of clinically relevant drug inter- result in variation of that enzyme’s activity. For the most actions are related to metabolism by the cytochrome part, patients can be classified as either poor metabolizers,

Fig. 1. Effects of CYP450 inducers and inhibitors on (A) CYP450-metabolized drug substrates and (B) CYP450-metabolized prodrugs.

Pediatric Pulmonology Drug–Drug Interactions in CF S63 extensive metabolizers, or ultrarapid metabolizers. A AUC of 23% and 43%, respectively.22,23 Other anti- classic example of the differences between different microbials can also be impacted by rifampin. Clarithro- phenotypes is response to codeine, which requires mycin is metabolized significantly by CYP3A4, with metabolism to its active metabolite morphine by plasma concentrations reduced by an average of 44% CYP2D6 in order for patients to receive benefit. In the when given in combination with rifampin.24 In contrast, case of poor metabolizers, these patients may not receive azithromycin is metabolized by other pathways and is not benefit from codeine because they are unable to convert impacted significantly. Doxycycline is also affected, with a the parent drug to its active metabolite; alternatively, reduction in AUC by 54% and half-life from 14 to 9 hr ultrarapid metabolizers may experience toxicity due to that may necessitate more frequent dosing when used in the overabundance of morphine derived from a seemingly combination.25 When utilizing a CYP3A4 inducer, such normal dose of codeine. As more is learned about the role as rifampin, with a substrate of the same enzyme, of specific pharmacogenetic mutations on patients’ consideration should be given to the need for increased response to medications, the clinician will need to take dose and/or frequency to account for potential drug–drug this into consideration when determining appropriate interactions. Changes in drug dosing should be individual- therapy and dosing. ized to the specific medications being used (Table 1). Commonly used drugs in CF management which have significant interaction with CYP450 enzymes are shown CYP3A4 Inhibitors in Table 1. CYP3A4 inhibitors relevant to many CF patients include azole antifungals, as mentioned above; clari- CYP3A4 Inducers thromycin; and some selective serotonin reuptake CYP3A4 is involved in the metabolism of approxi- inhibitors (SSRIs). In comparison with rifampin, these mately 50% of currently available medications.18 For that medications can result in increased concentrations of reason, it is often implicated in drug–drug interactions. affected substrates, which may lead to toxicity. One Rifampin and rifabutin are potent inducers of CYP3A4, notable example of such an interaction is that of azole increasing hepatic CYP3A4 content by 2.4- to 4.7-fold and antifungals and corticosteroids. Several case reports intestinal content by five- to eightfold.19 This induction note adverse effects, including hypothalamic-pituitary likely reaches maximal effect approximately 1 week after axis suppression, adrenal insufficiency, and growth failure, starting rifampin, based on pharmacokinetic principles. when inhaled corticosteroids were used chronically with 26–28 Among its numerous interactions, rifampin proves itraconazole or fluconazole. These reports point out particularly problematic when given concomitantly the potential interaction between medications that are quite with azole antifungals, which are themselves potent commonly utilized together (Table 1). CYP3A4 inhibitors of varying degrees. When adminis- CYP2C9/2C19 Inducers tered together, rifampin reduced voriconazole area under curve (AUC) by 96% and resulted in undetectable In addition to its activity on CYP3A4, rifampin is a itraconazole concentrations.20,21 Fluconazole and posa- potent inducer of both CYP2C9 and CYP2C19. In contrast, conazole are affected to a lesser extent, with decreases in rifabutin does not affect these enzymes. Although these

TABLE 1— CYP450 Enzyme Interactions (Moderate or Strong) With Some Commonly Used Medications in CF and Mental Health Discussed in This Review

Cytochrome Inducers1 Inhibitors2 Substrates3 CYP3A4 Rifabutin, rifampin Clarithromycin, erythromycin, Citalopram, clarithromycin, corticosteroids, fluconazole, itraconazole, cyclosporine, doxycycline, erythromycin, posaconazole, voriconazole escitalopram, guanfacine, itraconazole, lansoprazole, midazolam, mirtazapine, rifabutin, tacrolimus, voriconazole CYP2C9 Rifampin Fluconazole, omeprazole, voriconazole Fluoxetine, ibuprofen, voriconazole CYP2C19 Rifampin Esomeprazole, fluconazole, Citalopram, escitalopram, esomeprazole, fluoxetine, omeprazole, lansoprazole, omeprazole, pantoprazole, sertraline, voriconazole posaconazole, voriconazole CYP1A2 Rifampin Ciprofloxacin Duloxetine, mirtazapine, theophylline CYP2D6 Duloxetine, fluoxetine, paroxetine, sertraline Atomoxetine, fluoxetine, mirtazapine, paroxetine

1Inducers increase CYP450 enzyme activity and therefore tend to reduce exposure to substrates of the enzyme. 2Inhibitors decrease CYP450 enzyme activity and therefore tend to increase exposure to substrates of the enzyme. 3Substrates are drugs which are metabolized by the CYP450 enzyme.

Pediatric Pulmonology S64 Jordan et al. enzymes are not as commonly involved in drug metabo- like rifampin and clarithromycin, and the azole anti- lism as CYP3A4, they still present several challenges fungals are known contributors to significant drug– regarding drug–drug interactions. In particular, many drug interactions found in the CF population. Other non-steroidal anti-inflammatory drugs (NSAIDs) are potentially clinically significant interactions involving substrates of CYP2C9.29 Evidence supporting this antimicrobials include additive QT prolongation and interaction is limited, but it is important to consider, nephrotoxicity. particularly for patients utilizing high-dose ibuprofen for QT Prolongation its anti-inflammatory properties. Patients started on Many medications can contribute to QT-interval rifampin may require additional monitoring of ibuprofen prolongation. Two classes of antibiotics often used in concentrations around 2–4 weeks after initiation to the CF population that can contribute to this phenomenon ensure that levels remain within the therapeutic range. are macrolides and fluoroquinolones. Within the macro- Additionally, patients may require higher doses in order to lide antibiotic class, clarithromycin and erythromycin achieve pain relief. appear to contribute most significantly to potential QT prolongation.36 A retrospective study in 2012 noted an CYP2C9/2C19 Inhibitors increased risk of cardiovascular death in adult patients Inhibitors of CYP2C19 include fluconazole, voricona- taking azithromycin, which ultimately resulted in a U.S. zole, and the proton pump inhibitors (PPIs).30 Some PPIs, Food and Drug Administration (FDA) issued Drug Safety particularly omeprazole, also inhibit CYP2C9 to varying Communication focused on azithromycin’s risk of degrees. The interaction between these two drug classes potentially fatal heart rhythms.37,38 Within the fluoro- is variable. When given together, omeprazole resulted quinolone class, moxifloxacin appears to contribute more in an increase in voriconazole AUC by 41%, while than ciprofloxacin and levofloxacin to QT prolongation.39 co-administration of esomeprazole with posaconazole As more medications are implicated in QT prolongation, resulted in a decrease in posaconazole AUC by it is important for the clinician to assess a patient’s risk 32%.31,32,23 Some variability in results is likely attributable factors as well as potential medications that may to the fact that posaconazole absorption is pH-dependent, contribute. Resources are available online, including 1 with decreased gastric pH being ideal for optimal CredibleMeds , a database that can assist the clinician in absorption. Monitoring of pharmacokinetic concentrations determining the likelihood that a particular medication of azole antifungals, where possible, is recommended when may contribute to QT prolongation through its risk- these medications are utilized in combination with PPIs to stratification process.40 ensure patients reach therapeutic levels, since the potential Nephrotoxicity for both treatment failure and toxicity exists. Azole trough Another important category of drug–drug interactions concentrations can be obtained 5–7 days after adding to consider in CF patients is use of concomitant potentially interacting medications, as this should reflect nephrotoxic antimicrobials. Many commonly utilized the new steady state of the azole antifungal. Additionally, antibiotics can contribute to nephrotoxicity, including many of the SSRIs are substrates of CYP2C19, including vancomycin, aminoglycosides, piperacillin/tazobactam, citalopram and escitalopram (Table 1). Because PPIs sulfamethoxazole/trimethoprim, carbapenems, and colis- inhibit CYP2C19, their use with SSRIs may result in tin. The 2005 TOPIC study demonstrated decreased increased exposure to the SSRI. In particular, citalopram nephrotoxicity with extended-interval dosing of tobra- prescribing information recommends limiting the dose to a mycin, with a mean change in creatinine of À4.5% for maximum of 20 mg/day in patients receiving a CYP2C19 33 patients receiving once daily tobramycin versus 3.7% for inhibitor, such as esomeprazole or omeprazole. Canadian those receiving traditional three times daily dosing.41 prescribing information for escitalopram, the S-isomer of Care should be taken to avoid combinations of citalopram, recommends limiting dosing to 10 mg/day nephrotoxic medications where possible and to ensure when used in combination with omeprazole; however, U.S. close monitoring for renal function in patients who require product labeling does not contain this recommenda- multiple nephrotoxins. tion.34,35 Patients taking other SSRIs should be monitored for efficacy when taking in combination with a PPI. Mental Health Drugs CF, like other chronic diseases, carries risk of mental SPECIFIC DRUG TYPES COMMONLY USED IN health issues including depression and anxiety.42 Thus, the CF CARE CF clinician faces a high likelihood of encountering children who are being considered for or treated with Antimicrobials and Drug–Drug Interactions pharmacologic agents for mental health indications, some As previously discussed, antimicrobials used in the of which (e.g., SSRIs and psychostimulants) may have treatment of non-tuberculous mycobacterial infections, significant interaction with commonly used drugs for CF Pediatric Pulmonology Drug–Drug Interactions in CF S65 lung disease. While therapeutic drug monitoring for compromised liver and/or kidney function.50 Guanfacine psychotropic medications is advocated by some,43 proac- is primarily metabolized by CYP3A4. The clinician tive awareness and adjustment of dosing may be more should consider increasing its dose by twofold when practical in pediatric patients. adding a strong CYP3A4 inducer such as rifampin. Conversely, guanfacine dose should be reduced twofold SSRI and Linezolid in the presence of a strong CYP3A4 inhibitor such as Linezolid is a weak inhibitor of monoamine oxidase azole antifungals or clarithromycin. (MAO), the enzyme responsible for metabolism of the Atomoxetine is a norepinephrine reuptake inhibitor neurotransmitters epinephrine, norepinephrine, serotonin, used for treatment of ADHD. It is metabolized primarily and dopamine. Its affinity for MAO gives linezolid the through the CYP2D6 enzymatic pathway. Thus, it should theoretical potential to cause serotonin toxicity, especially be initiated at reduced dose in patients receiving strong when used in combination with another serotonergic agent. CYP2D6 inhibitors (e.g., paroxetine and fluoxetine). Serotonin syndrome is a triad of symptoms, including There have been reports of atomoxetine use associated mental status changes, neuromuscular abnormalities, and with severe liver damage52; thus, caution should be autonomic hyperactivity.44 A literature review in 2006 exercised in its use in patients with CF related liver identified 13 cases of serotonin syndrome when linezolid disease. It has been advocated to hold atomoxetine during was used concomitantly with SSRIs or other agents used for treatment of CF patients with linezolid, a monoamine treatment of depression and anxiety including paroxetine, oxidase inhibitor.53 fluoxetine, mirtazapine, and sertraline,45 and 29 cases Stimulant-based therapies approved in the United (13 serious) were reported in a post marketing survey.46 States for treatment of ADHD include the amphetamines Other SSRIs used for treatment of anxiety or depression in and methylphenidate. These agents inhibit dopamine children and adolescents include duloxetine, citalopram, transporter and norepinephrine transporter, thereby and escitalopram. A low incidence (3%) of serotonin inhibiting the reuptake of these neurotransmitters. Both syndrome was reported by Taylor et al.47 who suggested that stimulants also inhibit MAO, the enzyme that metabolizes a washout period after stopping SSRI is not necessary for these catecholamines.50 Examples of stimulants used in patients needing linezolid treatment. Similarly, Butterfield treatment of ADHD include amphetamine, lisdexamfet- et al.48 reported an evaluation of concomitant use of amine, methylphenidate, and dexmethylphenidate. Line- linezolid and serotonergic agents from 20 Phase III and IV zolid is a mild nonselective MAO inhibitor and thus in comparator-controlled clinical studies on treatment of combination with these agents, has the potential to trigger various Gram-positive infections and found a low (<1%) excessive adrenergic activity.54 While this effect has incidence of serotonin syndrome. Thus, while the actual been mild when directly tested,55 it is recommended to incidence of serotonin syndrome resulting from concomi- utilize lower initial doses of these drugs in combination tant SSRI and linezolid use appears to be quite low, the with linezolid, and to monitor for side effects such as frequent use of these agents in CF patients suggests the need hypertension.56 for CF clinicians to be cautious. Preclinical studies suggest that tedizolid, a novel oxazolidinone antibiotic with a longer half-life and greater potency against gram-positive CFTR Modulators bacteria than linezolid, shows little actual MAO inhibition The development of CFTR modulators and potentiators and may therefore have lower risk for adverse interactions heralds an exciting new era of personalized treatment for with serotonergic agents.49 Tedizolid is currently in clinical CF patients, with agents specific for mutation class trials. targeting the basic molecular defect. As these agents are used chronically and many existing CF treatments will Attention Deficit Hyperactivity Disorder (ADHD) Medications Guanfacine is a selective [alpha]2A-adrenoreceptor need to be continued, it is important that clinicians be agonist that activates central nervous system norepinephrine aware of potential drug-drug interactions (Tables 2 and 3). receptors. This action results in reduced peripheral Ivacaftor sympathetic tone, which was its original indication as an Ivacaftor is a novel CFTR modulator approved for use antihypertensive. It should not be withdrawn suddenly in patients ages 2 and older with one of nine gating because of risk of hypertensive crisis, and hence, patients mutations, including G551D and R117H. Ivacaftor itself or their parents should be educated about the need for is a substrate of CYP3A4 and is, therefore, affected when perfect adherence.50 It is used clinically as either given in combination with other medications that act on monotherapy or adjunct therapy (along with psychosti- CYP3A4. According to the prescribing information mulants) for the treatment of ADHD because of its available, the dosing frequency should be reduced to hypothesized action of increasing network connections once daily in patients also taking moderate CYP3A4 in the prefrontal cortex.51 Dose reductions and monitor- inhibitors, such as fluconazole, and to twice weekly in ing are recommended if used in patients with patients taking strong CYP3A4 inhibitors, including Pediatric Pulmonology S66 Jordan et al.

TABLE 2— Ivacaftor Drug–Drug Interactions

Mechanism of Drug name/class interaction Effect of interaction Suggested intervention Azole antifungals (itraconazole, CYP3A4 inhibition Increases ivacaftor When used in combination, decrease ketoconazole, voriconazole, exposure ivacaftor dose to twice weekly posaconazole) Fluconazole CYP3A4 inhibition Increases ivacaftor When used in combination, decrease exposure ivacaftor dose to daily Macrolides (erythromycin, CYP3A4 inhibition Increases ivacaftor When used in combination with erythromycin, clarithromycin) exposure decrease ivacaftor dose to daily. When used in combination with clarithromycin, decrease ivacaftor dose to twice weekly Does not apply to azithromycin Rifampin/rifabutin CYP3A4 induction Decreases ivacaftor Avoid combination exposure Immunosuppressants (cyclosporine, CYP3A4 inhibition Increases Monitor immunosuppressant levels; will everolimus, sirolimus, tacrolimus) immunosuppressant likely require decreased levels immunosuppressant doses Benzodiazepines (midazolam) CYP3A4 inhibition Increases Consider an alternative agent; monitor for benzodiazepine toxicity exposure Ibuprofen CYP2C9 inhibition Increases ibuprofen Recommend checking levels 2–4 weeks after exposure initiation; may require lower doses

ketoconazole, itraconazole, posaconazole, voriconazole, AUC of midazolam by 54%, and also decreased the oral telithromycin, and clarithromycin.57 Additionally, pa- clearance by 35% and increased the half-life from tients should avoid grapefruit juice and Seville oranges 4.1 to 5.5 hr. Based on this data, it is important to while taking ivacaftor, as these may also increase consider dose adjustments and appropriate monitoring ivacaftor concentrations due to CYP3A4 inhibition. when giving ivacaftor concomitantly with substrates of Although evidence in patients on adjusted therapy is CYP3A4 and P-gp, including benzodiazepines, cyclo- limited, one sibling case report noted similar improve- sporine, and tacrolimus. Timing of drug levels should be ments in lung function, sweat chloride level, and weight based on the half-life of the medication being examined. over 36 weeks in two siblings taking ivacaftor.58 One Ivacaftor given with a contraceptive resulted in a 22% sibling was given the standard dose of ivacaftor, 150 mg increase in ethinyl estradiol maximum concentration, twice daily, while the other was prescribed 150 mg but AUC was not impacted. For this reason, the co- twice weekly because he was also on itraconazole. administration of ivacaftor with oral contraceptives is Interestingly, the sibling who was on the reduced dose not expected to impact the safety or efficacy of the experienced an increase in FEV1 from 47% to 84% contraceptive. predicted, while his sibling’s FEV1 increased from 55% to 71% predicted over the same time period. In patients Lumacaftor/ivacaftor taking strong CYP3A4 inducers, such as rifampin, Lumacaftor/ivacaftor is the first FDA-approved com- phenobarbital, carbamazepine, phenytoin, and St. John’s bination potentiator/corrector therapy for patients 12 years Wort (a medicinal plant used as an antidepressant), and older who are homozygous for the delF508 ivacaftor should be avoided. Co-administration of ivacaftor mutation.60 Lumacaftor/ivacaftor, similar to ivacaftor with rifampin resulted in an approximately ninefold alone, is a substrate of CYP3A4 and therefore requires decrease in AUC. dose adjustment when initiating in patients taking strong Ivacaftor also acts as a weak CYP3A4 and P- CYP3A4 inhibitors. In this scenario, patients should glycoprotein (P-gp) inhibitor. Recently, a four-part receive one tablet daily for the first week of treatment, pharmacokinetic study pairing ivacaftor with medications after which time the dose can be increased to the usual that are sensitive substrates of CYP2C8 (rosiglitazone), dose of two tablets twice daily. Without dose adjustment, CYP3A4 (midazolam), and CYP2D6 (desipramine), as co-administration of lumacaftor/ivacaftor with itracona- well as a combined oral contraceptive demonstrated zole, a strong CYP3A4 inhibitor, resulted in increased ivacaftor’s effect on each.59 When given in combination, exposure to ivacaftor by 4.3-fold. Similar to ivacaftor, ivacaftor had minimal effect on the AUC of rosiglitazone lumacaftor/ivacaftor should be avoided in combination and desipramine. However, ivacaftor did increase the with strong CYP3A4 inducers due to the potential for Pediatric Pulmonology Drug–Drug Interactions in CF S67

TABLE 3— Lumacaftor/Ivacaftor Drug–Drug Interactions

Mechanism of Drug name/class interaction Effect of interaction Suggested intervention Azole antifungals CYP3A4 induction and Decreases azole levels Avoid when possible; azoles likely to be (fluconazole, itraconazole, inhibition1 ineffective ketoconazole, voriconazole, posaconazole) Increases lumacaftor/ivacaftor If starting lumacaftor/ivacaftor in patient on exposure azole already, start with one tablet daily for 1 week, then increase to recommended daily dose Benzodiazepines (midazolam) CYP3A4 induction Decreases benzodiazepine Consider an alternative agent exposure Macrolides (erythromycin, CYP3A4 induction Decreases macrolide exposure If initiating lumacaftor/ivacaftor in patient on clarithromycin) clarithromycin, start with one tablet daily for 1 week, then increase to recommended daily dose Increases lumacaftor/ivacaftor Does not apply to azithromycin1 exposure Rifampin/rifabutin CYP3A4 induction Decreases lumacaftor/ivacaftor Avoid combination exposure Immunosuppressants CYP3A4 induction Decreases immunosuppressant Avoid combination; will require increased (cyclosporine, everolimus, levels immunosuppressant doses sirolimus, tacrolimus) Corticosteroids CYP3A4 induction Decreases steroid exposure Monitor for effectiveness; may require higher steroid doses Proton pump inhibitors CYP2C19 induction Decreased PPI exposure Monitor for effectiveness (omeprazole, lansoprazole, pantoprazole) H2-receptor antagonists CYP2C19 induction Decreased H2-receptor Monitor for effectiveness (ranitidine, famotidine) antagonist exposure Hormonal contraceptives Decreased contraceptive Avoid if possible; hormonal contraceptives effectiveness should not be relied upon as sole method of contraception Increased menstrual abnormality Applies to oral, injectable, transdermal, and events implantable contraceptives SSRIs (citalopram, CYP2C9 induction Decreased SSRI exposure Monitor for effectiveness; may require higher escitalopram, sertraline) SSRI doses Ibuprofen CYP2C9 induction Decreased ibuprofen exposure Recommend rechecking levels 2–4 weeks after initiation; may require higher ibuprofen doses

1Lumacaftor/ivacaftor is an inducer/substrate and the azoles are inhibitors/substrates. reduced effectiveness with reduced drug exposure. When midazolam, cyclosporine, everolimus, sirolimus, and given in combination with rifampin, exposure to ivacaftor tacrolimus. Levels of some antibiotics, including clari- was decreased by 57%. thromycin and erythromycin, are also reduced when Lumacaftor/ivacaftor acts on several of the CYP450 combined with lumacaftor/ivacaftor, and alternatives enzymes, including induction of CYP3A4, CYP2C9, should be considered. CYP2C19, CYP2B6, as well as P-gp. The induction of Although the mechanism of the interaction is not well CYP3A4 is most notable, as lumacaftor/ivacaftor has a defined, hormonal contraceptive exposure may be net strong induction of these enzymes. Because the azole reduced when used in combination with lumacaftor/ antifungals are substrates of CYP3A4, it is likely that the ivacafator. This potentially affects all routes of contracep- strong induction of CYP3A4 by lumacaftor/ivacaftor will tive administration, including oral, injectable, transdermal, reduce the concentrations of azole antifungals signifi- and implantable. Because of this, hormonal contraceptives cantly, possibly making them ineffective. Therefore, it is should not be relied on as the sole method of contraception recommended to consider other antifungal agents that are in patients taking lumacaftor/ivacaftor. Patients should be less likely to be impacted by lumacaftor/ivacaftor. Other counseled to utilize other methods of contraception. CYP3A4 substrates, including those that are sensitive Lumacaftor/ivacaftor also exhibits in vitro induction of or have narrow therapeutic index, should be avoided in CYP2C9 and CYP2C19, which can affect exposure to combination with lumacaftor/ivacaftor. These include several medications classes often utilized in CF patients.

Pediatric Pulmonology S68 Jordan et al.

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