IMPORTANT SAFETY INFORMATION FOR ORKAMBI™ (lumacaftor/ivacaftor)
Use in Patients With Advanced Liver Disease
• Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF 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 greater than 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 greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing
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. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy
Drug Interactions
Substrates of CYP3A
• Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI (lumacaftor/ivacaftor) 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. Consider an alternative to midazolam and triazolam. Avoid the use of ORKAMBI with cyclosporine, everolimus, sirolimus, and tacrolimus
• 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 (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). 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 (e.g., rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort) is not recommended
Cataracts
• Cases of non-congenital lens opacities have been reported in pediatric patients treated with 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, 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
• The most common adverse reactions in Phase 3 trials occurring in ≥5% of patients treated with ORKAMBI (N=369) compared to placebo (N=370) were dyspnea (13% vs 8%), nasopharyngitis (13% vs 11%), nausea (13% vs 8%), diarrhea (12% vs 8%), upper respiratory tract infection (10% vs 5%), fatigue (9% vs 8%), respiration abnormal (9% vs 6%), blood creatine phosphokinase increased (7% vs 5%), rash (7% vs 2%), flatulence (7% vs 3%), rhinorrhea (6% vs 4%), and influenza (5% vs 2%)
Potential Additional Drug Interactions
• ORKAMBI has the potential to affect other drugs including CYP2B6 and CYP2C substrates, digoxin and other P-gp substrates, anti-allergics and systemic corticosteroids, antibiotics, antifungals, anti-inflammatories, antidepressants, hormonal contraceptives, oral hypoglycemics, acid reducing drugs, and warfarin. For additional information regarding drug interactions, see full Prescribing Information
INDICATIONS AND USAGE
ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (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.
ORKAMBI Rx
Pharmacological Class:
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.
Active Ingredient(s):
Lumacaftor, ivacaftor 200mg/125mg; tabs.
Company
Vertex Pharmaceuticals
Indication(s):
Treatment of cystic fibrosis (CF) in patients ≥12yrs who are homozygous for the F508del mutation in the CFTR gene. Limitations of use: efficacy and safety not established in patients with CF other than those homozygous for the F508del mutation.
Pharmacology:
Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.
Clinical Trials:
The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was eva luated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received Orkambi twice daily. Trial 1 eva luated 549 patients with CF who were ≥12 years (mean age 25.1 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.7 at baseline (range: 31.1–94.0)]. Trial 2 eva luated 559 patients ≥12 years (mean age 25.0 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.5 at baseline (range: 31.3–99.8)].
Patients in both trials were randomized 1:1:1 to receive either Orkambi (lumacaftor 400mg q12h/ivacaftor 250mg q12h; or lumacaftor 600mg once daily/ivacaftor 250mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (eg, bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline).
The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001).
For more clinical trial data, see full labeling.
Legal Classification:
Rx
Adults:
Take with fat-containing food (eg, eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products). 2 tabs every 12hrs. Currently taking strong CYP3A inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, telithromycin, clarithromycin): initially 1 tab once daily for 1st week then continue with recommended daily dose. Hepatic impairment (moderate): 2 tabs in the AM and 1 tab in the PM; (severe): 1 tab in the AM and 1 tab in the PM, or less; use with caution.
Children:
Not established.
Warnings/Precautions:
If genotype is unknown, use an FDA cleared CF mutation test to detect the presence of the F508del mutation on both alleles of the CFTR gene. Advanced hepatic impairment. Assess ALT/AST and bilirubin levels prior to initiating therapy, every 3 months during the first year of treatment, and annually thereafter. If ALT/AST or bilirubin levels increased, monitor closely until resolved. Interrupt dosing if ALT/AST is >5XULN or if ALT/AST is >3XULN with bilirubin elevations >2XULN; after resolution, consider restarting. Monitor for respiratory events during treatment initiation. Perform baseline and follow-up eye exams. Severe renal impairment (CrCl ≤30mL/min) or ESRD. Pregnancy (Cat.B). Nursing mothers.
Interaction(s)
See Adults. Concomitant strong CYP3A inducers (eg, rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John’s wort): not recommended. Concomitant sensitive CYP3A substrates or those with a narrow therapeutic index (eg, midazolam, triazolam, cyclosporine, everolimus, sirolimus, tacrolimus): not recommended. May affect CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp substrates. Monitor digoxin. May antagonize montelukast, systemic corticosteroids (eg, prednisone, methylprednisolone), ibuprofen, citalopram, escitalopram, sertraline, omeprazole, esomeprazole, lansoprazole, ranitidine; dose adjustment may be needed. May antagonize clarithromycin, erythromycin, telithromycin; consider alternatives (eg, ciprofloxacin, azithromycin, levofloxacin). Concomitant itraconazole, ketoconazole, posaconazole, voriconazole: not recommended; if necessary, monitor closely or consider alternatives (eg, fluconazole). May antagonize repaglinide or affect sulfonylureas; dose adjustment may be needed. Concomitant warfarin; monitor INR. May reduce effectiveness of hormonal contraceptives and increase menstruation abnormality events; avoid.
Adverse Reaction(s)
Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased blood creatinine phosphokinase, rash, flatulence, rhinorrhea, influenza.
How Supplied:
Tabs—112
LAST UPDATED:
9/11/2015 |
