DRUG INTERACTIONS

Summary

­ • Strong CYP3A inducers: Avoid co-administration. 

• Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when co-administered. Avoid food or drink containing grapefruit. 

Details-

1.Potential for other drugs to affect elexacaftor/tezacaftor/ivacaftor

 Inducers of CYP3A Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A).

Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy.

Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%.

Elexacaftor and tezacaftor exposures are expected to decrease during co-administration with strong CYP3A inducers. Therefore, co-administration of TRIKAFTA with strong CYP3A inducers is not recommended

Examples of strong CYP3A inducers include: • rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) 

2.Inhibitors of CYP3A Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0 to 4.5-fold.

When co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dosage of TRIKAFTA should be reduced when co-administered with strong CYP3A inhibitors

Examples of strong CYP3A inhibitors include: • ketoconazole, itraconazole, posaconazole, and voriconazole                                                                                         • telithromycin and clarithromycin Simulations indicated that co-administration with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9 to 2.3-fold and 2.1-fold, respectively. Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold.

3.Moderate 3A inhibitors                                                                                             The dosage of TRIKAFTA should be reduced when co administered CYPwith moderate 3A inhibitors

Examples of moderate CYP3A inhibitors include: • fluconazole                                   • erythromycin Co-administration of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA

4.Ciprofloxacin

Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor. Therefore, no dose adjustment is necessary during concomitant administration of TRIKAFTA with ciprofloxacin 

 5.CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co administration of TRIKAFTA with warfarin is recommended.

6.Other medicinal products for which exposure may be increased by TRIKAFTA include glimepiride and glipizide; these medicinal products should be used with caution 

6. Transporters

Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.

Administration of TRIKAFTA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions.

When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus, and tacrolimus, caution and appropriate monitoring should be used 

Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Co-administration of TRIKAFTA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide.

When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3)]. Bilirubin is an OATP1B1 and OATP1B3 substrate.

7. Hormonal Contraceptives

TRIKAFTA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. TRIKAFTA is not expected to have an impact on the efficacy of oral contraceptives.

CI-  None.                                                                                                             WARNINGS -

ADVERSE REACTIONS

­ The most common adverse drug reactions

to TRIKAFTA (occurring in =5% of patients and at a frequency higher than placebo by =1%) were -headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis and blood bilirubin increased. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Liver Function Test Elevations and Monitoring

Inform patients that elevation in transaminases has occurred in patients treated with TRIKAFTA.

Elevations in bilirubin have also been observed with TRIKAFTA treatment. Liver function tests (ALT, AST, and bilirubin) should be assessed prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter.

More frequent monitoring should be considered in patients with a history of hepatobiliary disease or liver function test elevations 

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins.

Co-administration of TRIKAFTA with strong CYP3A inducers (e.g., rifampin, St. John’s wort) is not recommended, as they may reduce the efficacy of TRIKAFTA.

Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole.

Advise the patient not to take the evening dose of ivacaftor.                                       Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets and one ivacaftor tablet taken on alternate days is recommended when co-administered with moderate CYP3A inhibitors, such as fluconazole. 

Advise the patient not to take the evening dose of ivacaftor.

Food or drink containing grapefruit should be avoided

Use in Patients with Hepatic Impairment TRIKAFTA has not been studied in patients with moderate or severe hepatic impairment.

Inquire and/or assess whether patients have liver impairment.

Patients with severe hepatic impairment (Child-Pugh Class C, score 10-15) should not be treated with TRIKAFTA.

Use of TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B, score 7-9) unless the benefit exceeds the risk.

If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution and at a reduced dose.

Liver function tests should be closely monitored.

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6)

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving ivacaftor-containing regimens. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating treatment with TRIKAFTA

Administration 

Inform patients that TRIKAFTA is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement.

Examples include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.

Patients should be informed about what to do in the event they miss a dose of elexacaftor/tezacaftor/ivacaftor tablets or ivacaftor tablet:

• If 6 hours or less have passed since the missed morning or evening dose is usually taken, patients should be instructed to take the prescribed dose with fat-containing food as soon as possible.

• If more than 6 hours have passed since: o the time the morning dose is usually taken, patients should be instructed to take the morning dose as soon as possible, and not take the evening dose.

Patients should take the next scheduled morning dose at the usual time.

 TRIKAFTA™ (elexacaftor/tezacaftor/ivacaftor; ivacaftor) Tablets

o the time the evening dose is usually taken, patients should be instructed to not take the missed evening dose. Patients should take the next scheduled morning dose at the usual time.

• Patients should be instructed to not take the morning and evening doses at the same time.

• Patients should be advised to contact their health care provider if they have questions.

Manufactured for

Vertex Pharmaceuticals Incorporated 50 Northern Avenue Boston, MA 02210 Approved October 2019 TRIKAFTA, VERTEX and associated logos are trademarks or registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2019 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone.

Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

2. Pharmacodynamics

Sweat Chloride Evaluation

In Trial 1 (patients with an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive ivacaftor and tezacaftor/ivacaftor), a reduction in sweat chloride was observed from baseline at Week 4 and sustained through the 24-week treatment period 

In Trial 2 (patients homozygous for the F508del mutation), a reduction in sweat chloride was observed from baseline at Week 4 

Cardiac Electrophysiology

At doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent.

3. Pharmacokinetics

The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF.

The pharmacokinetic parameters for elexacaftor, tezacaftor, and ivacaftor in patients with CF aged 12 years and older are shown in Table 4

. Pharmacokinetic Parameters of TRIKAFTA Components Elexacaftor Tezacaftor Ivacaftor

General Information AUC (SD), mcg·h/mLa 162 (48.1)b 94.5 (24.0)b 11.7 (4.01)c Cmax, (SD), mcg/mLa 8.7 (2.1) 6.8 (1.5) 1.2 (0.3)

Time to Steady State, days Within 14 days Within 8 days Within 3-5 days

Accumulation Ratio 2.3 1.6 2.4 

TRIKAFTA™ (elexacaftor/tezacaftor/ivacaftor; ivacaftor) :Pharmacokinetic Parameters of TRIKAFTA Components Elexacaftor Tezacaftor Ivacaftor

Absorption

Absolute Bioavailability 80% Not determined Not determined Median Tmax (range), hours 6 (4 to 12) 3 (2 to 4) 4 (3 to 6)

Effect of Food

AUC increases 1.9- to 2.5-fold (moderate-fat meal) No clinically significant effect Exposure increases 2.5- to 4-fold

Distribution

Mean (SD) Apparent Volume of Distribution, Ld 53.7 (17.7) 82.0 (22.3) 293 (89.8) Protein Bindinge > 99% approximately 99% approximately 99%

Elimination

Mean (SD) Effective Half-Life, hoursf 29.8 (10.6) 17.4 (3.66) 15.0 (3.92) Mean (SD) Apparent Clearance, L/hours 1.18 (0.29) 0.79 (0.10) 10.2 (3.13)

Metabolism

Primary Pathway CYP3A4/5 CYP3A4/5 CYP3A4/5

Active Metabolites M23-ELX M1-TEZ M1-IVA

Metabolite Potency Relative to Parent Similar Similar approximately 1/6th of parent

Excretion

Primary Pathway • Feces: 87.3% (primarily as metabolites)

• Urine: 0.23% • Feces: 72% (unchanged or as M2-TEZ) • Urine: 14% (0.79% unchanged) • Feces: 87.8% • Urine: 6.6%

a Based on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 year and older. b AUC0-24h. c AUC0-12h. d Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. e Elexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin. f

Mean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively.

g Following radiolabeled doses. Specific Populations Pediatric patients 12 to less than 18 years of age

The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetic (PK) analyses.

Following oral administration of TRIKAFTA to patients 12 to less than 18 years of age (elexacaftor 200 mg QD/tezacaftor 100 mg QD/ivacaftor 150 mg Q12h), the mean (±SD) AUCss was 149 (38.7) mcg·h/mL, 97.1 (23.7) mcg·h/mL and 10.6 (3.35) mcg·h/mL, respectively for elexacaftor, tezacaftor and ivacaftor, similar to the AUCss in adult patients.

Patients with Renal Impairment

Renal excretion of elexacaftor, tezacaftor, and ivacaftor is minimal. Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in patients with severe (eGFR <30 mL/min/1.73 m2 ) renal impairment or end stage renal disease.

Based on population PK analyses, the clearance of elexacaftor and tezacaftor was similar in patients with mild (eGFR 60 to <90 mL/min/1.73 m2 ) or moderate (eGFR 30 to <60 mL/min/1.73 m2 ) renal impairment relative to patients with normal renal function 

Patients with Hepatic Impairment

Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with hepatic impairment. Similar to tezacaftor and ivacaftor, higher exposure of elexacaftor is expected in patients with moderate (Child-Pugh Class B, score 7 to 9) and severe hepatic impairment (Child-Pugh Class B, score 10-15)

Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher in Cmax for tezacaftor, and a 1.5-fold higher AUC but similar Cmax for ivacaftor compared with healthy subjects matched for demographics. Ivacaftor

In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor Cmax, but an approximately 2.0-fold higher ivacaftor AUC0-8 compared with healthy subjects matched for demographics.

Male and Female Patients Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females.

Drug Interactions Studies

Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies

TRIKAFTA™ (elexacaftor/tezacaftor/ivacaftor; ivacaftor) Tablets Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs

Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9, and CYP3A.

However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6.

Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6.

Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co-administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold in a clinical study.

Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary There are limited and incomplete human data from clinical trials on the use of TRIKAFTA or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk.

Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits. 

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.

2. Lactation Risk Summary

There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRIKAFTA and any potential adverse effects on the breastfed child from TRIKAFTA or from the underlying maternal condition.

3. Pediatric Use

The safety and effectiveness of TRIKAFTA for the treatment of CF in pediatric patients 12 years and older who have at least one F508del mutation in the CFTR gene has been established.

4. Geriatric Use

Clinical studies of TRIKAFTA did not include any patients aged 65 years and older.

5. Renal Impairment

TRIKAFTA has not been studied in patients with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended in patients with mild (eGFR 60 to <90 mL/min/1.73 m2 ) or moderate (eGFR 30 to <60 mL/min/1.73 m2 ) renal impairment.

Use with caution in patients with severe (eGFR <30 mL/min/1.73 m2 ) renal impairment or end-stage renal disease 

6. Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh Class C) should not be treated with TRIKAFTA.

Use of TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment,

TRIKAFTA should be used with caution and at a reduced dose.

Liver function tests should be closely monitored. No dose modification is recommended for patients with mild hepatic impairment (Child-Pugh Class A)

7. Patients with Severe Lung Dysfunction

Trial 1 included a total of 18 patients receiving TRIKAFTA with ppFEV1 <40 at baseline. The safety and efficacy in this subgroup were comparable to those observed in the overall population.

 OVERDOSAGE

No specific antidote is available for overdose with TRIKAFTA. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.