lumacaftor/ivacaftor

Lumacaftor

Absorption: Some absorption follows oral administration; absorption is enhanced 2-fold by fat-containing foods.

Distribution: Widely distributed.

Protein Binding: >99%.

Metabolism/Excretion: Minimally metabolized via oxidation and glucuronidation; 51% excreted unchanged in feces; <1% excreted unchanged in urine.

Half-Life: 26 hr.

Ivacaftor

Absorption: Some absorption follows oral administration; absorption is enhanced 3-fold by fat-containing foods.

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Extensively metabolized by the liver, mostly by the CYP3A isoenzyme; one metabolite (M1) is pharmacologically active; 87.8% eliminated in feces; negligible urinary elimination.

Half-Life: 9 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Lumacaftor (PO)	within 1 wk	4 hr	12 hr
Ivacaftor (PO)	within 1 wk	4 hr	12 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

None.

Use Cautiously in:

Moderate or severe hepatic impairment (dose ↓ recommended);
Severe renal impairment (CCr <30 mL/min) or end stage renal disease;
Advanced lung disease (↑ risk of respiratory events);
OB: Use in pregnancy only if clearly needed;
Lactation: Use while breastfeeding only if potential maternal benefit outweighs potential risk to infant;
Pedi: Children 1 yr (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

CV: ↑blood pressure

Derm: rash

EENT: cataracts, rhinorrhea

GI: diarrhea, nausea, ↑liver enzymes, flatulence, hyperbilirubinemia

GU: amenorrhea, dysmenorrhea, menorrhagia

MS: ↑creatine kinase

Neuro: fatigue

Resp: dyspnea, chest discomfort

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA)

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A inducers including rifampin, rifabutin, phenobarbital, carbamazepine and phenytoin may ↓ ivacaftor levels and effectiveness; avoid concurrent use.
Lumacaftor may ↓ levels of CYP3A substrates, including hormonal contraceptive agents; avoid concurrent use with sensitive CYP3A substrates or those with a narrow therapeutic index, including cyclosporine, everolimus, midazolam, sirolimus, tacrolimus, or triazolam.
Strong CYP3A inhibitors including ketoconazole, itraconazole, posaconazole, voriconazole, and clarithromycin may ↑ ivacaftor levels; no dose adjustment required when initiating CYP3A inhibitor in patients currently receiving ivacaftor/lumacaftor; ↓ initial ivacaftor/lumacaftor dose for 1 wk when starting therapy in patient currently receiving strong CYP3A4 inhibitor and then proceed with recommended dose.
Lumacaftor may ↓ levels of CYP2B6 substrates, CYP2C8 substrates, CYP2C9 substrates, and CYP2C19 substrates.
Ivacaftor may ↑ levels of CYP2C9 substrates.
May ↑ or ↓ digoxin or warfarin levels.
May ↓ levels of citalopram, clarithromycin, corticosteroids, erythromycin, escitalopram, ibuprofen, itraconazole, ketoconazole, montelukast, posaconazole, proton pump inhibitors, repaglinide, sertraline, sulfonylureas, voriconazole.

Drug-Natural Products:

St. John's wort may ↓ ivacaftor levels and effectiveness; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥12 yr): Two lumacaftor 200 mg/ivacaftor 125 mg tablets every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 200 mg/ivacaftor 125 mg tablet once daily for 1 wk, then ↑ to two lumacaftor 200 mg/ivacaftor 125 mg tablets every 12 hr.
PO (Children 6–11 yr): Two lumacaftor 100 mg/ivacaftor 125 mg tablets every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 100 mg/ivacaftor 125 mg tablet once daily for 1 wk, then ↑ to two lumacaftor 200 mg/ivacaftor 125 mg tablets every 12 hr.
PO (Children 2–5 yr and ≥14 kg): One lumacaftor 150 mg/ivacaftor 188 mg granule packet every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 150 mg/ivacaftor 188 mg granule packet every other day for 1 wk, then ↑ to one lumacaftor 150 mg/ivacaftor 188 mg granule packet every 12 hr.
PO (Children 2–5 yr and <14 kg): One lumacaftor 100 mg/ivacaftor 125 mg granule packet every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 100 mg/ivacaftor 125 mg granule packet every other day for 1 wk, then ↑ to one lumacaftor 100 mg/ivacaftor 125 mg granule packet every 12 hr.
PO (Children 1–<2 yr and ≥14 kg): One lumacaftor 150 mg/ivacaftor 188 mg granule packet every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 150 mg/ivacaftor 188 mg granule packet every other day for 1 wk, then ↑ to one lumacaftor 150 mg/ivacaftor 188 mg granule packet every 12 hr.
PO (Children 1–<2 yr and 9–<14 kg): One lumacaftor 100 mg/ivacaftor 125 mg granule packet every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 100 mg/ivacaftor 125 mg granule packet every other day for 1 wk, then ↑ to one lumacaftor 100 mg/ivacaftor 125 mg granule packet every 12 hr.
PO (Children 1–<2 yr and 7–<9 kg): One lumacaftor 75 mg/ivacaftor 94 mg granule packet every 12 hr with fat-containing food; Initiation of therapy in patients receiving strong CYP3A inhibitor: One lumacaftor 75 mg/ivacaftor 94 mg granule packet every other day for 1 wk, then ↑ to one lumacaftor 75 mg/ivacaftor 94 mg granule packet every 12 hr.

Hepatic Impairment

(Adults and Children ≥12 yr): Moderate hepatic impairment: Two lumacaftor 200 mg/ivacaftor 125 mg tablets in AM and one lumacaftor 200 mg/ivacaftor 125 mg tablet in PM; Severe hepatic impairment: One lumacaftor 200 mg/ivacaftor 125 mg tablet in AM and one lumacaftor 200 mg/ivacaftor 125 mg tablet in PM.

Hepatic Impairment

(Children 6–11 yr): Moderate hepatic impairment: Two lumacaftor 100 mg/ivacaftor 125 mg tablets in AM and one lumacaftor 100 mg/ivacaftor 125 mg tablet in PM; Severe hepatic impairment: One lumacaftor 100 mg/ivacaftor 125 mg tablet in AM and one lumacaftor 100 mg/ivacaftor 125 mg tablet in PM.

Hepatic Impairment

(Children 2–5 yr and ≥14 kg): Moderate hepatic impairment: One lumacaftor 150 mg/ivacaftor 188 mg granule packet in AM and one lumacaftor 150 mg/ivacaftor 188 mg granule packet every other PM; Severe hepatic impairment: One lumacaftor 150 mg/ivacaftor 188 mg granule packet in AM.

Hepatic Impairment

(Children 2–5 yr and <14 kg): Moderate hepatic impairment: One lumacaftor 100 mg/ivacaftor 125 mg granule packet in AM and one lumacaftor 100 mg/ivacaftor 125 mg granule packet every other PM; Severe hepatic impairment: One lumacaftor 100 mg/ivacaftor 125 mg granule packet in AM.

Hepatic Impairment

(Children 1–<2 yr and ≥14 kg): Moderate hepatic impairment: One lumacaftor 150 mg/ivacaftor 188 mg granule packet in AM and one lumacaftor 150 mg/ivacaftor 188 mg granule packet every other PM; Severe hepatic impairment: One lumacaftor 150 mg/ivacaftor 188 mg granule packet in AM.

Hepatic Impairment

(Children 1–<2 yr and 9–<14 kg): Moderate hepatic impairment: One lumacaftor 100 mg/ivacaftor 125 mg granule packet in AM and one lumacaftor 100 mg/ivacaftor 125 mg granule packet every other PM; Severe hepatic impairment: One lumacaftor 100 mg/ivacaftor 125 mg granule packet in AM.

Hepatic Impairment

(Children 1–<2 yr and 7–<9 kg): Moderate hepatic impairment: One lumacaftor 75 mg/ivacaftor 94 mg granule packet in AM and one lumacaftor 75 mg/ivacaftor 94 mg granule packet every other PM; Severe hepatic impairment: One lumacaftor 75 mg/ivacaftor 94 mg granule packet in AM.

Availability ⬆ ⬇

Oral granules: lumacaftor 75 mg/ivacaftor 94 mg/pkt; lumacaftor 100 mg/ivacaftor 125 mg/pkt; lumacaftor 150 mg/ivacaftor 188 mg/pkt
Tablets: lumacaftor 100 mg/ivacaftor 125 mg; lumacaftor 200 mg/ivacaftor 125 mg

Assessment ⬆ ⬇

Assess respiratory status (chest discomfort, dyspnea, abnormal respiration) prior to and periodically during therapy.
Monitor BP periodically during therapy; may cause hypertension.
Obtain baseline and periodic ophthalmological exams on pediatric patients starting therapy; may cause cataracts.
Monitor for hypersensitivity reactions (angioedema, anaphylaxis). If signs or symptoms of serious hypersensitivity reactions (hives, rash, swelling of lips, face, dyspnea) occur, discontinue Orkambi and institute appropriate therapy.

Lab Test Considerations:

Determine patient's genotype prior to starting therapy. If genotype is unknown, use an FDA-cleared CF mutation test to detect presence of the F508del mutation on both alleles of the CFTR gene.
- Monitor ALT, AST, and bilirubin prior to starting therapy, every 3 mo during 1st yr of therapy, and annually thereafter. Monitor patients with a history of ALT, AST, or bilirubin ↑ more frequently. If ↑ ALT, AST, or bilirubin occur, monitored closely until resolved. If ALT or AST >5 × upper limit of normal (ULN) when not associated ↑ bilirubin, withhold therapy. If ALT or AST >3 × ULN when associated with bilirubin >2 × ULN, withhold therapy. Consider benefits and risks of resuming dosing, once ↑ levels resolve.

Implementation ⬆ ⬇

PO: Administer 2 tablets every 12 hrs with fat-containing food (eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products [whole milk, cheese, yogurt], etc).
- To administer granules, mix entire content of single-use packet with 1 tsp (5 mL) of age-appropriate soft food or liquid (puréed fruits, flavored yogurt or pudding, milk or juice). Food should be at room temperature or below. Mixture is stable for 1 hr.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take medication as directed. Take missed doses within 6 hrs with fat-containing food. If >6 hrs after usual dosing time, omit dose and resume normal schedule for following dose; do not double doses. Advise patient to read Patient Information prior to starting and with each Rx refill in case of changes.
May cause dizziness. Avoid driving and other activities requiring alertness until response to medication is known.
Advise patient to notify health care professional if signs and symptoms of liver problems (pain or discomfort in upper right abdomen, yellowing of skin or white of eyes, loss of appetite, nausea or vomiting, dark, amber-colored urine, confusion) or respiratory problems (shortness of breath, chest tightness) occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Rep: Advise females of reproductive potential to use a nonhormonal contraceptive during therapy and to notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Ivacaftor/lumacaftor may hormonal contraceptive exposure (oral, injectable, transdermal, implantable) and effectiveness; do not rely upon as effective method of contraception.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆ ⬇

Code ⬆