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Lumacaftor And Ivacaftor

FDA Drug Information • Also known as: Orkambi

Brand Names
Orkambi
Drug Class
Cystic Fibrosis Transmembrane Conductance Regulator Potentiator [EPC]
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION The active ingredients in ORKAMBI tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and ivacaftor, a CFTR potentiator, which has the following chemical name: N -(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The molecular formula for lumacaftor is C 24 H 18 F 2 N 2 O 5 and for ivacaftor is C 24 H 28 N 2 O 3 . The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively. The structural formulas are: lumacaftor ivacaftor Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 µg/mL). ORKAMBI is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI is also available as a pink, oval-shaped, film-coated tablet for oral administration containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink...

What Is Lumacaftor And Ivacaftor Used For?

1 INDICATIONS AND USAGE ORKAMBI is 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. ORKAMBI is a combination of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and lumacaftor, 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. ( 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 .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Age Group Weight Dose Administration 1 through 2 years 7 kg to < 9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg granules Mixed with one teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat-containing food 9 kg to < 14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) Taken orally every 12 hours with fat-containing food 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Reduce dosage 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 dosage for the first week of treatment. ( 2.3 , 7.1 , 12.3 ) 2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older The recommended dosage of ORKAMBI in adults and pediatric patients aged one year and older is based on patient's age and weight as described in Table 1. Table 1: Recommended Oral Dosage of ORKAMBI in Patients Aged 1 Year and Older Age Group Weight ORKAMBI Daily Dose (every 12 hours) Morning Dose Evening Dose 1 through 2 years 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Administration Instructions for ORKAMBI Oral Granules The entire content of each packet of oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice. Food should be at room temperature or below....

Side Effects (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) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3) ] Intracranial Hypertension [see Warnings and Precautions (5.4) ] Respiratory Events [see Warnings and Precautions (5.5) ] Effect on Blood Pressure [see Warnings and Precautions (5.6) ] Cataracts [see Warnings and Precautions (5.8) ] 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 aged 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 two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). In addition, the following clinical trials have been conducted: A 24-week, open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation. A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation. A 24-week, open-label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV 1 <40). A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation. A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del - CFTR mutation. Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 patients received placebo. 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 3 shows adverse reactions occurring in ≥5% of patients with CF aged 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 3: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Aged 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)...

Drug Interactions

5.7 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 (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 [see Adverse Reactions (6.1) , Drug Interactions (7.3 , 7.11) , and Clinical Pharmacology (12.3) ] . 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, St. John's wort [ Hypericum perforatum ]) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . 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 dosage 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 dosage as recommended 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 dosage 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...

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

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 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 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 (EFD) study, pregnant rats were administered lumacaftor at oral doses of 500, 1000, or 2000 mg/kg/day during the period of organogenesis from gestation days 7-17. Lumacaftor 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 EFD study, pregnant rabbits were administered lumacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of...

Overdosage

10 OVERDOSAGE There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ORKAMBI (lumacaftor 200 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, printed with "2V125" in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-809-01 ORKAMBI (lumacaftor 100 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, printed with "1V125" in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-700-02 ORKAMBI (lumacaftor/ivacaftor) oral granules are supplied as small white to off-white granules and enclosed in unit-dose packets as follows: 56-count carton (contains 56 unit-dose packets of lumacaftor 75 mg/ivacaftor 94 mg per packet) NDC 51167-122-01 56-count carton (contains 56 unit-dose packets of lumacaftor 100 mg/ivacaftor 125 mg per packet) NDC 51167-900-01 56-count carton (contains 56 unit-dose packets of lumacaftor 150 mg/ivacaftor 188 mg per packet) NDC 51167-500-02 Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.