This document provides information on the drugs Ivacaftor and Lumacaftor, which are used to treat cystic fibrosis. It begins with drug descriptions and indications, then discusses the drugs' mechanisms of action, pharmacodynamics, dosing, administration, side effects, clinical trials, and used to treat cystic fibrosis. Key information includes that Ivacaftor and Lumacaftor work together to correct mutated CFTR genes causing cystic fibrosis, are dosed together twice daily, and clinical trials aim to evaluate their safety and efficacy alone and in combination for treating cystic fibrosis.

1. IVACAFTOR AND LUMACAFTOR
Anatomic Therapeutic Chemical (ATC)Classification
R07AX02
Ranjit Saha (Pharm.D)
CHITKARA UNIVERSITY

2. DRUG DESCRIPTION
 Lumacaftor and Ivacaftor
 Brand name : orkambi
 Cystic Fibrosis Transmembrane Conductance Regulator Potentiator
 Ivacaftor approved by the FDA in the following formulation(s):
 Ivacaftor And Lumacaftor - Granule;oral
• Manufacturer: VERTEX PHARMS INC
• Approval Date March 17, 2015
• Strength(s): 50mg/PACKET, 75mg/PACKET
Dosage form - Tablet;oral

3. Orkambi
It is a combination of two categories of
molecules, FDA-approved ivacaftor (known by
its brand-name Kalydeco) and experimental
therapy lumacaftor (known also as VX-809),
both of which help in correcting the mutated
genes in patients with cystic fibrosis – a novel
therapeutic approach designed to treat the root
cause of cystic fibrosis instead of treating the
severity of symptoms.

4. INDICATIONS
 Cystic Fibrosis
 Pharmacologic Category: Cystic fibrosis Transmembrane Conductance
Regulator Potentiator

5. Clinical Pharmacology
 Mechanism of Action
 Lumacaftor
 CFTR corrector
 Corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell
surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the
CFTR protein
 Ivacaftor
 CFTR potentiator
 The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs;
ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating)
of mutated CFTR proteins mutations in the CFTR gene.

6. Pharmacodynamics/kinetics
 Onset of action: FEV1 increased, sweat chloride decreased within ~2 weeks
 Absorption: Variable; increased (by two- to fourfold) with fatty foods
 Distribution: Vd: 353 L
 Protein binding: ~99%; primarily to alpha1 acid glycoprotein, albumin

7. Pharmacodynamics/kinetics
 Metabolism: Hepatic; extensive via CYP3A; forms 2 major metabolites (M1 [active; 1/6
potency] and M6 [inactive])
 Half-life elimination: ~12 hours
 Time to peak: ~4 hours
 Excretion: Feces (88%, 65% of administered dose as metabolites); urine (minimal,
as unchanged drug)

8. Organs Affected
 Lungs
 Pancreas
 Small intestine
 Stomach
 Pancreatic duct

9. Doses
Adult
 Cystic fibrosis: Oral: Tablet: 150 mg every 12 hours
Pediatric
 Cystic fibrosis: Oral:Granules:
Children 2 to <6 years:
<14 kg: 50 mg packet every 12 hours
≥14 kg: 75 mg packet every 12 hours
 Tablet: Children ≥6 years and Adolescents: Refer to adult dosing.
 Missed dose: If dose is missed within 6 hours of the usual time it is taken, take the dose
as soon as possible; otherwise, skip the missed dose and resume the normal dosing schedule

10. Doses
Dosing Renal Impairment
 Mild to moderate impairment (CrCl >30 mL/minute): No dosage adjustment
necessary (has not been studied).
 Severe impairment CrCl ≤30 (mL/minute): There are no dosage adjustments
provided in the manufacturer's labeling (has not been studied); use with caution.
 End-stage renal disease (ESRD): There are no dosage adjustments provided in
the manufacturer's labeling (has not been studied); use with caution.

11. Doses
Dosing Hepatic Impairment
 Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
 Moderate impairment (Child-Pugh class B):
 Children ≥6 years, Adolescents, and Adults: 150 mg once daily
 Children 2 to <6 years:
<14 kg: 50 mg granule packet once daily
≥14 kg: 75 mg granule packet once daily
Contd….

12. Doses
 Severe impairment (Child-Pugh class C): Has not been studied; use with caution
 US labeling:
 Children ≥6 years, Adolescents, and Adults: 150 mg once daily or less frequently.
 Children 2 to <6 years:
<14 kg: 50 mg granule packet once daily or less frequently
≥14 kg: 75 mg granule packet once daily or less frequently

13. Storages
Store at controlled room temperature (20-25°C [68-
77°F]); excursions permitted to 15-30°C (59-86°F)
Patient Handout
A Patient Handout is not currently available for this
monograph.

14. Side Effects
Most common
 Shortness of breath and/or chest tightness
 Upper respiratory tract infection (common cold), including sore throat, stuffy or runny nose
 Gastrointestinal symptoms, including nausea, diarrhea, or gas
 Rash
 Fatigue
 Flu or flu-like symptoms
 Increase in muscle enzyme levels
 Irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual
bleeding

15. Used In Cystic Fibrosis Diseases
 Cystic Fibrosis
Cystic fibrosis is a disease that causes mucus in the body to become
thick, dry, and sticky. This glue-like mucus builds up and causes
problems in many of the body's organs, especially the lungs and
pancreas. Cystic fibrosis is also known as mucoviscidosis, pulmonary
fibrosis, and pancreatic cystic fibrosis. Approximately 30,000 people in
the United States have cystic fibrosis.

16. Cystic Fibrosis
Cystic fibrosis is a disease
that causes mucus in the
body to become thick, dry,
and sticky.

17. Adverse Drug
Reaction
Adverse Reactions Orkambi
N=369(%)
Placebo
N=360(%)
Dyspnea 48 (13) 29 (8)
Nasopharyngitis 48 (13) 40 (11)
Nausea 46 (13) 28 (8)
Dirrahea 45 (12) 31 (8)
Upper respiratory tract
infection
37 (10) 20 (5)
fatique 34 (9) 29 (8)
Respiration abnormal 32 (9) 22 (6)
Blood creatinine
phosphokinase
increased
27 (7) 20 (5)
Rash 25 (7) 7 (2)
Flatulence 24 (7) 11 (3)
rhinorrhea 21 (6) 15 (4)
influenja 19 (5) 8 (2)
(ADR)

18. overdose
 If overdose is suspected, contact a poison control center or
emergency room immediately.

19. Clinical Trials
Purpose
The Purpose of the study is to examine drug drug interaction effects
ofcifroloxacin , itroconazole and rifampin on the pharmacokinetics of
lumacaftor in combination with ivacaftor on lung function.
Condition Intervention Phase
Cystic Fibrosis Drug: Lumacaftor
Drug: Ivacaftor
Drug: Ciprofloxacin
Drug: Itraconazole
Drug: Rifampin
Phase 1

20. Study Type : Interventional
Study Design: Allocation : NOT RANDOMISED
End point classification : pharmacokinetics study
Intervention Model : Single Group Assignment
Masking : Open Label
Primary Purpose : Treatment
Official Site: To Examine Effects of Cifroloxacin , Itroconazole and Rifampin on the
Pharmacokinetics of Lumacaftor in combination with Ivacaftor in health adult subjects

21. Arms Assigned Interventions
Experimental: Treatment Group (Cohort 1)Subjects will
take lumacaftor in combination with ivacaftor for 14
days. Beginning on Day 15, subjects will
take lumacaftor in combination with ivacaftorand
ciprofloxacin through Day 21.
Drug: Lumacaftortablet, 200mg taken every 12 hours
Other Name: VX-809
Drug: Ivacaftortablet, 250mg taken every 12 hours
Other Name: VX-770
Drug: Ciprofloxacin750 mg taken every 12 hours
Experimental: Treatment Group (Cohort 2)Subjects will
take lumacaftor in combination with ivacaftor for 14
days. Beginning on Day 15, subjects will
take lumacaftor in combination with ivacaftorand
itraconazole through Day 21.
Drug: Lumacaftor tablet, 200mg taken every 12 hours
Other Name: VX-809
Drug: Ivacaftortablet, 250mg taken every 12 hours
Other Name: VX-770
Drug: Itraconazole200mg taken once daily

22. Clinical Trials
Purpose
The purpose of this study is to evaluate of the
safety,efficacy,pharmacokinetics and pharmacodynamics effect of
lumacaftor (vx-809) alone and when coadministered with ivacaftor (vx-
770) in participants with cystic fibrosis,homozygous or heterozygous for
the F508Del-CFTR mutation.
Condition Intervention Phase
Cystic Fibrosis Drug: Lumacaftor
Drug: Ivacaftor
Drug: Lumacaftor
Placebo
Drug: Ivacaftor Pla
cebo
Phase 2

23. Study type : Interventional
Study Design : Allocation : Randomized
End Point Classification: Safety/Efficacy study
Intervention Model : factorial Assignment
Masking : Double Blind (subject,caregiver,Investigator)
Primary Purpose : Treatment
Official title : A phase 2, multicenter, Double-Binded, Placebo-controlled, Multiple Dose study
to evaluate safety, Tolerability,Efficacy, Pharmacokinetics and Pharmacodynamics of Lumacaftor
Monotherapy, and Lumacaftor and Ivacaftor combination therapy in subjects with cstic
Fibrosis Homozygous or heterozygous for the F508eely Heterozygous for the F508del-CFTR
Mutation
Clinical Trials

24. Arms Assigned Interventions
Placebo Comparator: Cohort 1: PlaceboParticipants homozygous (HO)
for the F508del-CF transmembrane conductance regulator gene (CFTR)
mutation received lumacaftor matched placebo once daily (qd) (Day 1
through Day 14), followed by lumacaftor matched placebo qd in
combination with ivacaftor matched placebo every 12 hours (q12h) (Day
15 through Day 21).
Drug:LumacaftorPlaceboMatching placebo tablet.
Drug:IvacaftorPlaceboMatching placebo tablet.
Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg
q12hParticipants homozygous for the F508del-CFTR mutation received
200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14),
followed by 200 mg of lumacaftorqd in combination with 150 mg
of ivacaftor (IVA) q12h (Day 15 through Day 21).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA
Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg
q12hParticipants homozygous for the F508del-CFTR mutation received
200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by
200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h
(Day 15 through Day 21).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA

25. Placebo Comparator: Cohort 2 and 3: Placebo (HO and
HE)Participants homozygous or heterozygous for the F508del-CFTR
mutation received lumacaftor matched placebo qd (Day 1 through
Day 28), followed by lumacaftormatched placebo in combination
with ivacaftor matched placebo q12h (Day 29 through Day 56).
Drug:LumacaftorPlaceboMatching placebo tablet.
Drug:IvacaftorPlaceboMatching placebo tablet.
Experimental: Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250
mg q12h (HO)Participants homozygous for the F508del-CFTR
mutation received 200 mg of lumacaftor alone qd (Day 1 through Day
28), followed by 200 mg of lumacaftor qd in combination with 250
mg of ivacaftor q12h (Day 29 through Day 56).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA
Experimental: Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250
mg q12h (HO)Participants homozygous for the F508del-CFTR
mutation received 400 mg of lumacaftor alone qd (Day 1 through Day
28), followed by 400 mg of lumacaftor qd in combination with 250
mg of ivacaftor q12h (Day 29 through Day 56).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA

26. Experimental: Cohort 2: LUM 600 mg qd/LUM 600 mg
qd+IVA 250 mg q12h (HO&HE)Participants homozygous or
heterozygous for the F508del-CFTR mutation received 600 mg
of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg
oflumacaftor qd in combination with 250 mg of ivacaftor q12h (Day
29 through Day 56).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA
Experimental: Cohort 3: LUM 400 mg q12h/LUM 400 mg
q12h+IVA 250 mg q12h (HO)Participants homozygous for the
F508del-CFTR mutation received 400 mg of lumacaftor alone q12h
(Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in
combination with 250 mg of ivacaftor q12h (Day 29 through Day
56).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA

27. Placebo Comparator: Cohort 4: PlaceboParticipants
heterozygous for the F508del-CFTR mutation
received lumacaftor matched placebo in combination
with ivacaftor matched placebo q12h (Day 1 through Day
56).
Drug:LumacaftorPlaceboMatching placebo tablet.
Drug:IvacaftorPlaceboMatching placebo tablet.
Experimental: Cohort 4: LUM 400 mg q12h+IVA 250 mg
q12hParticipants heterozygous for the F508del-CFTR
mutation received 400 mg of lumacaftor q12h in
combination with 250 mg of ivacaftor q12h (Day 1 through
Day 56).
Drug:LumacaftorTablet
Other Name: VX-809, LUM
Drug:IvacaftorTablet.
Other Name: VX-770, IVA

28.  Worsening liver function, including hepatic encephalopathy, in patients with advanced liver
disease reported
 Elevated transaminases have been reported and may require therapy interruption (see
Dosage Modifications)
 Respiratory events (eg, chest discomfort, dyspnea, abnormal respiration) were observed
more commonly in patients during initiation compared with placebo
 Cases of noncongenital lens opacities have been reported in pediatric patients treated with
ivacaftor
 Lumacaftor is a strong inducer of CYP3A; coadministration with sensitive CYP3A
substrates or those with a narrow therapeutic index is not recommended
 Ivacaftor is a substrate of CYP3A4 and CYP3A5; coadministration with strong inducers is
not recommended because of significantly reduced systemic exposure of ivacaftor
Cautions

29. References
 https://clinicaltrials.gov/ct2/results?term=ivacaftor+and+lumacaftor&Search=Sear
ch
 https://clinicaltrials.gov/ct2/show/NCT01768663?term=ivacaftor+and+lumacaftor
&rank=2
 https://clinicaltrials.gov/ct2/show/NCT01225211?term=ivacaftor+and+lumacaftor
&rank=9
 http://reference.medscape.com/drug/orkambi-lumacaftor-ivacaftor-1000000#5
 http://reference.medscape.com/drug/orkambi-lumacaftor-ivacaftor-1000000#10
 http://reference.medscape.com/drug/orkambi-lumacaftor-ivacaftor-1000000#11