Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 18 January 2018

Indication(s)

1 INDICATIONS AND USAGE ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 6 years 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. ORKAMBI is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, indicated for the treatment of cystic fibrosis (CF) in patients age 6 years 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. (1) 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. (1) 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Use in Patients with Advanced Liver Disease [see Warnings and Precautions (5.1)] Liver-related Events [see Warnings and Precautions (5.2)] Respiratory Events [see Warnings and Precautions (5.3)] Effect on Blood Pressure [see Warnings and Precautions (5.4)] The most common adverse reactions to ORKAMBI (occurring in ≥5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in 2 double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). Of the 1108 patients, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 received placebo. Additional safety data in 58 patients with CF aged 6 through 11 years who are homozygous for the F508del-CFTR mutation were obtained from a 24-week, open-label, multicenter Phase 3 safety trial (Trial 3). The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo. 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. Table 2 shows adverse reactions occurring in ≥5% of patients with CF ages 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials. Table 2: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Ages 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration Adverse Reaction (Preferred Term) ORKAMBI N=369 (%) Placebo N=370 (%) Dyspnea 48 (13) 29 (8) Nasopharyngitis 48 (13) 40 (11) Nausea 46 (13) 28 (8) Diarrhea 45 (12) 31 (8) Upper respiratory tract infection 37 (10) 20 (5) Fatigue 34 (9) 29 (8) Respiration abnormal 32 (9) 22 (6) Blood creatine phosphokinase increased 27 (7) 20 (5) Rash 25 (7) 7 (2) Flatulence 24 (7) 11 (3) Rhinorrhea 21 (6) 15 (4) Influenza 19 (5) 8 (2) The safety profile from the 24-week, open-label, multicenter Phase 3 safety trial in 58 patients aged 6 through 11 years with CF who are homozygous for the F508del-CFTR mutation (Trial 3) was similar to that observed in Trials 1 and 2. Additional information on selected adverse reactions from these trials is detailed below. Description of Selected Adverse Drug Reactions Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN elevations was similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 × ULN) associated with bilirubin elevation >2 × ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 × ULN. Among 6 patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of ORKAMBI [see Warnings and Precautions (5.1, 5.2)]. During the 24-week, open-label Phase 3 clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 × ULN was 5%, 9%, and 19%. No patients had an increase in total bilirubin levels > 2 × ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see Warnings and Precautions (5.3)]. During the 24-week, open-label Phase 3 clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58). Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%) [see Warnings and Precautions (5.5) and Drug Interactions (7.11)]. Increased Blood Pressure In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo. The proportion of patients who experienced a systolic blood pressure value >140 mmHg or a diastolic blood pressure >90 mmHg on at least two occasions was 3.6% and 2.2% in patients treated with ORKAMBI, respectively, compared with 1.6% and 0.5% in patients who received placebo [see Warnings and Precautions (5.4)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Adults and pediatric patients age 12 years and older: two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours. (2.1) Pediatric patients age 6 through 11 years: two tablets (each containing lumacaftor 100 mg/ivacaftor 125 mg) taken orally every 12 hours. (2.1) Reduce dose in patients with moderate or severe hepatic impairment. (2.2, 8.6, 12.3) When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dose for the first week of treatment. (2.3, 7.1, 12.3) 2.1 Dosing Information in Adults and Children Age 6 Years and Older Table 1: Dosage of ORKAMBI in Patients Age 6 Years and Older Age ORKAMBI Dose Total Daily Dose 6 through 11 years Take two lumacaftor 100 mg/ivacaftor 125 mg tablets every 12 hours with fat-containing food. lumacaftor 400 mg/ivacaftor 500 mg 12 years and older Take two lumacaftor 200 mg/ivacaftor 125 mg tablets every 12 hours with fat-containing food. lumacaftor 800 mg/ivacaftor 500 mg Examples of appropriate fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. If a patient misses a dose and remembers the missed dose within 6 hours, the patient should take the dose with fat-containing food. If more than 6 hours elapsed after the usual dosing time, the patient should skip that dose and resume the normal schedule for the following dose. A double dose should not be taken to make up for the forgotten dose [see Clinical Pharmacology (12.3) and Patient Counseling Information (17)]. 2.2 Dosage Adjustment for Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening is recommended for patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening, or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors No dose adjustment is necessary when CYP3A inhibitors are initiated in patients already taking ORKAMBI. However, when initiating ORKAMBI in patients currently taking strong CYP3A inhibitors (e.g., itraconazole), reduce ORKAMBI dose to 1 tablet daily for the first week of treatment. Following this period, continue with the recommended daily dose. If ORKAMBI is interrupted for more than 1 week and then re-initiated while taking strong CYP3A inhibitors, patients should reduce ORKAMBI dose to 1 tablet daily for the first week of treatment re-initiation. Following this period, continue with the recommended daily dose.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). 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 approximately 7 (rats) and 45 (rabbits) times the exposure at the MRHD. No adverse developmental effects were observed after oral administration of either lumacaftor or ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively (see Data ). There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Lumacaftor In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7-17, lumacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, lumacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 5 times the MRHD (on an AUC basis at maternal oral doses up to 200 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits. Ivacaftor In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 8.2 Lactation Risk Summary There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both lumacaftor and ivacaftor are excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ORKAMBI and any potential adverse effects on the breastfed child from ORKAMBI or from the underlying maternal condition. Data Lumacaftor Lacteal excretion of lumacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-lumacaftor administered 9 to 11 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for lumacaftor in milk were approximately 40% of plasma levels. Ivacaftor Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels. 8.3 Females and Males of Reproductive Potential 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 [see Warnings and Precautions (5.5) and Drug Interactions (7.11)]. 8.4 Pediatric Use The efficacy of ORKAMBI in children ages 6 through 11 years is extrapolated from efficacy in patients ages 12 years and older homozygous for the F508del mutation in the CFTR gene with support from population pharmacokinetic analyses showing similar drug exposure levels in patients ages 12 years and older and in children ages 6 through 11 years [see Clinical Pharmacology (12.3)]. Additional safety data were obtained from a 24-week, open-label, Phase 3 clinical trial in 58 patients aged 6 through 11 years, mean age 9 years (Trial 3). Trial 3 evaluated subjects with a screening ppFEV1 ≥40 [mean ppFEV1 91.4 at baseline (range: 55 to 122.7)]. The safety profile of ORKAMBI in children 6 through 11 years of age was similar to those in patients 12 years and older [see Adverse Reactions (6.1)]. In Trial 3, spirometry (ppFEV1) was assessed as a planned safety endpoint. The within-group LS mean absolute change from baseline in ppFEV1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV1 was also assessed. The within-group LS mean absolute change in ppFEV1 from Week 24 at Week 26 was -3.2 percentage points. The safety and efficacy of ORKAMBI in patients with CF younger than age 6 years have not been established. 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 [see Warnings and Precautions (5.6)]. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.3 to 2 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals. 8.5 Geriatric Use CF is largely a disease of children and young adults. Clinical trials of ORKAMBI did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening is recommended for patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening, or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 8.7 Renal Impairment ORKAMBI has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild and moderate renal impairment. Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease. 8.8 Patients with Severe Lung Dysfunction The Phase 3 trials (Trials 1 and 2) included 29 patients receiving ORKAMBI with ppFEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with ppFEV1 ≥40. 8.9 Patients After Organ Transplantation ORKAMBI has not been studied in patients with CF who have undergone organ transplantation. Use in transplanted patients is not recommended due to potential drug-drug interactions [see Drug Interactions (7.3)].

Interactions

7 DRUG INTERACTIONS See Full Prescribing Information for a complete list. (2.3, 7, 12.3) Potential for Other Drugs to Affect Lumacaftor/Ivacaftor 7.1 Inhibitors of CYP3A 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 (lumacaftor 200 mg/ivacaftor 125 mg total daily dose for patients aged 12 years and over; lumacaftor 100 mg/ ivacaftor 125 mg total daily dose for patients aged 6 through 11 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 [see Dosage and Administration (2.3)]. 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. 7.2 Inducers of CYP3A 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. No dose adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs 7.3 CYP3A Substrates 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)] such as: Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines). Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI). 7.4 CYP2B6 and CYP2C Substrates 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. 7.5 Digoxin and Other P-gp Substrates 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. 7.6 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. 7.7 Antibiotics 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. 7.8 Antifungals 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. 7.9 Anti-inflammatories 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. 7.10 Antidepressants 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. 7.11 Hormonal Contraceptives 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 [see Adverse Reactions (6.1)]. Avoid concomitant use unless the benefit outweighs the risks. 7.12 Oral Hypoglycemics 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. 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids 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. 7.14 Warfarin ORKAMBI may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with ORKAMBI is required. 7.15 Concomitant Drugs That Do Not Need Dose Adjustment 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.

More information

Category Value
Authorisation number NDA206038
Agency product number 1Y740ILL1Z
Orphan designation No
Product NDC 51167-809,51167-700
Date First Approved 02-07-2015
Date Last Revised 16-12-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder Vertex Pharmaceuticals Incorporated