vanzacaftor/tezacaftor/deutivacaftor

Vanzacaftor

Absorption: Extent of absorption following oral administration unknown; absorption is enhanced 4-fold and 6-fold by low-fat and high-fat foods, respectively.

Distribution: Well distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; 92% excreted in feces (primarily as metabolites); <1% excreted in urine.

Half-Life: 93 hr.

Tezacaftor

Absorption: Extent of absorption following oral administration unknown.

Distribution: Widely distributed to tissues.

Protein Binding: 99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; 72% excreted in feces as unchanged drug or metabolite; 14% excreted in urine (primarily as metabolite).

Half-Life: 22.5 hr.

Deutivacaftor

Absorption: Extent of absorption following oral administration unknown; absorption is enhanced 3-fold and 4-fold by low-fat and high-fat foods, respectively.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; excretion pathway unknown.

Half-Life: 19 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Vanzacaftor (PO)	unknown	8 hr	24 hr
Tezacaftor (PO)	unknown	2 hr	24 hr
Deutivacaftor (PO)	unknown	4 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Severe hepatic impairment.

Use Cautiously in:

Severe renal impairment or end-stage renal disease;
Moderate hepatic impairment (not recommended; if necessary, use only if benefit outweighs risk);
OB: Safety not established in pregnancy;
Lactation: Safety not established in breastfeeding;
Pedi: Children <6 yr (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

CV: ↑BP

Derm: rash

EENT: nasopharyngitis, oropharyngeal pain, cataracts, rhinorrhea, sinus congestion, sinusitis

GI: abdominal pain, constipation, diarrhea, HEPATOTOXICITY , nausea, vomiting

MS: ↑CK, arthralgia, back pain

Neuro: fatigue, headache

Resp: cough, upper respiratory tract infection, dyspnea, hemoptysis

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), influenza

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A inducers, including carbamazepine and rifampin, and moderate CYP3A inducers, including efavirenz, may ↓ vanzacaftor, tezacaftor, and deutivacaftor levels and effectiveness; concurrent use not recommended.
Strong CYP3A inhibitors, including clarithromycin and itraconazole, as well as moderate CYP3A inhibitors, including erythromycin, fluconazole, and verapamil, may ↑ vanzacaftor, tezacaftor, and deutivacaftor levels and risk of toxicity; ↓ vanzacaftor/tezacaftor/deutivacaftor dose.
May ↑ levels and risk of toxicity of P-glycoprotein substrates, including digoxin.
May ↑ levels and risk of toxicity of breast cancer resistance protein substrates, including rosuvastatin.
May ↑ levels and risk of toxicity of CYP2C9 substrates, including warfarin.

Drug-Food:

Grapefruit juice may ↑ vanzacaftor, tezacaftor, and deutivacaftor levels and risk of toxicity; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥12 yr): Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once daily. Concurrent use of strong CYP3A inhibitor: One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once weekly. Concurrent use of moderate CYP3A inhibitor: One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.
PO (Children 6–12 yr and ≥40 kg): Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once daily. Concurrent use of strong CYP3A inhibitor: One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once weekly. Concurrent use of moderate CYP3A inhibitor: One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.
PO (Children 6–12 yr and <40 kg): Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once daily. Concurrent use of strong CYP3A inhibitor: Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once weekly. Concurrent use of moderate CYP3A inhibitor: Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day.

Availability ⬆ ⬇

Tablets: vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg; vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg

Assessment ⬆ ⬇

Assess for improvements in pulmonary function and ↓ in pulmonary exacerbations.
Monitor for signs/symptoms of hepatotoxicity (jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites).
Monitor for hypersensitivity reactions (anaphylaxis, rash, urticaria, pruritus); implement supportive measures (epinephrine) if indicated.
Pedi: Obtain baseline and follow-up ophthalmological examinations in pediatric patients due to risk of cataracts. Monitor weight and growth parameters regularly.

Lab Test Considerations:

Confirm >1 F508del CFTR mutation or another mutation known to be responsive to vanzacaftor/tezacaftor/deutivacaftor.
Before starting therapy, obtain ALT, AST, alkaline phosphatase, and bilirubin. Monitor every month during the 1st 6 mo, then every 3 mo during the next 12 mo, then at least yearly thereafter. Discontinue for significant elevations in liver function tests or in the event of signs/symptoms of liver injury. If abnormalities resolve, resume treatment only if the benefit is expected to outweigh the risk.

Implementation ⬆ ⬇

PO: Administer with fat-containing food (eggs, butter, peanut butter, whole milk, cheese, yogurt) at the same time each day. DNC: Swallow tablets whole; do not crush, chew, or split.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Advise patient to take as directed with food that contains fat. If <6 hr have passed since a missed dose, take the missed dose as soon as possible and continue on the original schedule. If >6 hr have passed since a missed dose, skip the missed dose, and continue on the original schedule the next day.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
Advise patient to stop treatment if symptoms of liver injury occur (jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) and notify health care provider immediately.
Advise patient to avoid foods or drinks that contain grapefruit.
Advise patient to discontinue treatment and notify health care provider if signs/symptoms of a hypersensitivity reactions (rash, hives, itching, facial swelling, tightness of the chest, wheezing) occur. Advise to seek immediate medical attention if needed.
Advise patient or caregiver that baseline and follow-up ophthalmological examinations are needed in pediatric patients receiving vanzacaftor/tezacaftor/deutivacaftor.
Rep: Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected or if breastfeeding.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇