SYMDEKO (tezacaftor 100 mg ivacaftor 150 mg) Dailymed

• Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring should be considered. Dosing should be interrupted in patients with significant elevations of transaminases, e.g., patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment. (5.1, 6)
• Hypersensitivity reactions: Anaphylaxis has been reported with SYMDEKO in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. (5.2)
• Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) substantially decrease exposure of ivacaftor and may decrease the exposure of tezacaftor, which may reduce therapeutic effectiveness. Therefore, co-administration is not recommended. (5.3, 7.1, 12.3)
• Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with SYMDEKO. Baseline and follow-up examinations are recommended in pediatric patients initiating SYMDEKO treatment. (5.4, 8.4)

5.1Transaminase (AST/ALT) Elevations

Elevated transaminases have been observed in patients with CF treated with SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations more frequent monitoring should be considered. In the event of significant elevations of transaminases, e.g., patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of transaminase elevations consider the benefits and risks of resuming treatment [see Adverse Reactions (6)].

5.2Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO.

5.3Concomitant Use with CYP3A Inducers

Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].

5.4Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with SYMDEKO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO [see Use in Specific Populations (8.4) and Patient Counseling Information (17)].

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

• Transaminase Elevations [see Warnings and Precautions (5.1)]
• Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2)]
• Cataracts [see Warnings and Precautions (5.4)]

The most common adverse drug reactions to SYMDEKO (occurring in ≥3% of patients) were headache, nausea, sinus congestion, and dizziness. (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 .

6.1Clinical 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 clinical practice.

The overall safety profile of SYMDEKO is based on data from 1001 patients in three double-blind, placebo-controlled, clinical trials: two parallel-group trials of 12 and 24 week duration and one cross-over design trial of 8 weeks duration. Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO). In the three placebo-controlled trials (Trials 1, 2, and 3), a total of 496 patients with CF age 12 years and older received at least one dose of SYMDEKO. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 1.6% for SYMDEKO-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in SYMDEKO-treated patients compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) SYMDEKO-treated patients vs. 0 placebo. There were no deaths in the placebo-controlled trials, and one death in the open label extension study due to respiratory failure and influenza infection in a patient who had discontinued SYMDEKO seven weeks prior.

The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV₁ (ppFEV₁), and geographic regions.

Table 5 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo controlled, parallel-group trials (Trials 1 and 3).

Table 5: Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO-Treated Patients and Greater than Placebo

Adverse Reactions (Preferred Term)	SYMDEKON=334n (%)	PlaceboN=343n (%)
Headache	49 (15)	44 (13)
Nausea	29 (9)	24 (7)
Sinus congestion	13 (4)	6 (2)
Dizziness	12 (4)	8 (2)

The safety data from the following trials are similar to that observed in Trials 1 and 3:

• an 8-week randomized, double-blind, placebo-controlled crossover study in 244 patients with CF age 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 2).
• a 24-week open-label study in 70 patients with CF age 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 4).

Laboratory abnormalities

Transaminase elevations

During the placebo-controlled trials in patients age 12 years and older, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × the upper limit of normal (ULN) was similar between SYMDEKO-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in SYMDEKO-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN.

During the 24-week, open-label study in patients age 6 to less than 12 years (Trial 4), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued SYMDEKO treatment due to transaminase elevations.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: anaphylaxis

Skin: rash

12.1 Mechanism of Action

Tezacaftor facilitates the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. For ivacaftor to function CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport.

CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR

The chloride transport response of mutant CFTR protein to tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.

The in vitro chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

Note that splice site mutations cannot be studied in the FRT assay.

Table 6 uls responsive CFTR mutations based on (1) a clinical FEV₁ response and/or (2) in vitro data in FRT cells, indicating that tezacaftor/ivacaftor increases chloride transport to at least 10% of normal over baseline. CFTR gene mutations that are not responsive to ivacaftor alone are not expected to respond to SYMDEKO except for F508del homozygotes.

Table 6: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO

546insCTA	E92K	G576A	L346P	R117G	S589N
711+3A→GClinical data for these mutations in Clinical Studies [see Clinical Studies (14.1 and 14.2)].	E116K	G576A;R668C Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.	L967S	R117H	S737F
2789+5G→A	E193K	G622D	L997F	R117L	S912L
3272-26A→G	E403D	G970D	L1324P	R117P	S945L
3849+10kbC→T	E588V	G1069R	L1335P	R170H	S977F
A120T	E822K	G1244E	L1480P	R258G	S1159F
A234D	E831X	G1249R	M152V	R334L	S1159P
A349V	F191V	G1349D	M265R	R334Q	S1251N
A455E	F311del	H939R	M952I	R347H	S1255P
A554E	F311L	H1054D	M952T	R347L	T338I
A1006E	F508C	H1375P	P5L	R347P	T1036N
A1067T	F508C;S1251N	I148T	P67L	R352Q	T1053I
D110E	F508del A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 6 to be indicated.	I175V	P205S	R352W	V201M
D110H	F575Y	I336K	Q98R	R553Q	V232D
D192G	F1016S	I601F	Q237E	R668C	V562I
D443Y	F1052V	I618T	Q237H	R751L	V754M
D443Y;G576A;R668C	F1074L	I807M	Q359R	R792G	V1153E
D579G	F1099L	I980K	Q1291R	R933G	V1240G
D614G	G126D	I1027T	R31L	R1066H	V1293G
D836Y	G178E	I1139V	R74Q	R1070Q	W1282R
D924N	G178R	I1269N	R74W	R1070W	Y109N
D979V	G194R	I1366N	R74W;D1270N	R1162L	Y161S
D1152H	G194V	K1060T	R74W;V201M	R1283M	Y1014C
D1270N	G314E	L15P	R74W;V201M;D1270N	R1283S	Y1032C
E56K	G551D	L206W	R75Q	S549N
E60K	G551S	L320V	R117C	S549R

12.2 Pharmacodynamics

Effects on Sweat Chloride

In Trial 1 (patients age 12 years and older who were homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8).

In Trial 2 (patients age 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between SYMDEKO and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo.

In Trial 4 (patients age 6 to less than 12 years) a reduction in sweat chloride was observed from baseline through Week 4 and sustained throughout the 24-week treatment period. Mean absolute change in sweat chloride from baseline through Week 24 was -14.5 mmol/L (95% CI: -17.4, -11.6).

Cardiac Electrophysiology

At a dose 3 times the maximum approved recommended dose, tezacaftor does not prolong the QT interval to any clinically relevant extent.

In a separate study of ivacaftor evaluating doses up to 3 times the maximum approved recommended dose, ivacaftor does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily.

Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 7.

Table 7: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF

	Drug	Cmax (mcg/mL)	Effective t½ (h)	AUC0-24h or AUC0-12h (mcg∙h/mL) AUC0-24h for tezacaftor and AUC0-12h for ivacaftor
Tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours	Tezacaftor	5.95 (1.50)	15.0 (3.44)	84.5 (27.8)
	Ivacaftor	1.17 (0.424)	13.7 (6.06)	11.3 (4.60)

Absorption

After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (t_max) of approximately 4 hours (2 to 6 hours). The median (range) t_max of ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state.

When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

Distribution

Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells.

Elimination

After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in patients with CF, the effective half-lives of tezacaftor and ivacaftor were approximately 15 (3.44) and 13.7 (6.06) hours, respectively.

Metabolism

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg ¹⁴C-tezacaftor to healthy male subjects, M1, M2, and M5 were the three major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor.

Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 is not considered pharmacologically active.

Excretion

Following oral administration of ¹⁴C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans.

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug.

Specific Populations

Based on population PK analyses, the PK exposure parameters of tezacaftor/ivacaftor in children and adolescents (ages 6 to <18 years) are similar to the AUCss range observed in adults when given in combination.

Pediatric patients age 6 to less than 12 years

Table 8: Tezacaftor/ivacaftor exposure by age group, mean (SD)

Age Group	Dose	tezacaftor AUCssmcg∙h/mLAUC 0-24h for tezacaftor and AUC 0-12h for ivacaftor	ivacaftor AUCssmcg∙h/mL
6 to <12 years Exposures in ≥30 kg weight range are predictions derived from the population PK model		71.3 (28.3)	8.5 (3.34)
  6 to <12 years (<30 kg)	tezacaftor 50 mg/ ivacaftor 75 mg	56.7 (22.3)	6.92 (2.07)
  6 to <12 years (≥30 kg)	tezacaftor 100 mg/ ivacaftor 150 mg	92.7 (21.9)	10.8 (3.52)

Pediatric patients age 12 to less than 18 years

Following oral administration of SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours, the mean (±SD) AUCss for tezacaftor and ivacaftor was 97.1 (35.8) mcg∙h/mL and 11.4 (5.50) mcg∙h/mL, respectively, similar to the mean AUCss in adult patients administered SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours.

Patients with Hepatic Impairment

Following multiple doses of tezacaftor and ivacaftor for 10 days, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had an approximately 36% increase in AUC and a 10% increase in C_max for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. In a separate study, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had similar ivacaftor C_max, but an approximately 2.0-fold increase in ivacaftor AUC_0-∞ compared with healthy subjects matched for demographics.

Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5-6) or severe hepatic impairment (Child-Pugh Class C, score 10-15) receiving SYMDEKO. The magnitude of increase in exposure in patients with severe hepatic impairment is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Patient Counseling Information (17)].

Patients with Renal Impairment

SYMDEKO has not been studied in patients with moderate or severe renal impairment (creatinine clearance ≤30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug).

In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in clinical trials indicated that mild renal impairment (N=147; eGFR 60 to less than 90 mL/min/1.73 m²) and moderate renal impairment (N=7; eGFR 30 to less than 60 mL/min/1.73 m²) did not affect the clearance of tezacaftor significantly [see Use in Specific Populations (8.7)].

Male and Female Patients

The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females.

Drug Interactions Studies

Drug interaction studies were performed with SYMDEKO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)].

Potential for Tezacaftor/Ivacaftor to Affect Other Drugs

Clinical studies (with rosiglitazone and desipramine – see Table 9) showed that ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, ivacaftor has the potential to inhibit CYP3A and P-gp, and may also inhibit CYP2C9. In vitro, ivacaftor was not an inducer of CYP isozymes. Ivacaftor is not an inhibitor of transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3.

Based on in vitro results, tezacaftor has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tezacaftor has a low potential to induce CYP3A, but it is not an inducer of CYP1A2 and CYP2B6. Tezacaftor has a low potential to inhibit transporters P-gp, BCRP, OATP1B3, OCT2, OAT1, or OAT3.

Clinical studies with midazolam showed that SYMDEKO is not an inhibitor of CYP3A. Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Co-administration of SYMDEKO with an ethinyl estradiol/ norethindrone oral contraceptive had no significant effect on the exposures of the hormonal contraceptives. Co-administration of SYMDEKO with pitavastatin, an OATP1B1 substrate, had no clinically relevant effect on the exposure of pitavastatin.

The effects of tezacaftor and ivacaftor (or ivacaftor alone) on the exposure of co-administered drugs are shown in Table 9 [see Drug Interactions (7)].

Potential for Other Drugs to Affect Tezacaftor/Ivacaftor

In vitro studies showed that ivacaftor and tezacaftor were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor and tezacaftor will be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp.

The effects of co-administered drugs on the exposure of tezacaftor and ivacaftor (or ivacaftor alone) are shown in Table 10 [seeDosage and Administration (2.4)and Drug Interactions (7)].

Table 9: Impact of Tezacaftor/Ivacaftor or Ivacaftor on Other Drugs

	Dose and Schedule			Mean Ratio (90% CI) of Other DrugsNo Effect=1.0
Drug	Dose	TEZ/IVA or IVA	Effect on Drug PK	AUC	Cmax
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
Midazolam	2 mg single oral dose	TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening	↔ Midazolam	1.12(1.01, 1.25)	1.13(1.01, 1.25)
Digoxin	0.5 mg single dose	TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening	↑ Digoxin	1.30(1.17, 1.45)	1.32(1.07, 1.64)
Oral Contraceptive	Ethinyl estradiol/ Norethindrone0.035 mg/1.0 mg once daily	TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening	↔ Ethinyl estradiol	1.12(1.03, 1.22)	1.15(0.99, 1.33)
			↔ Norethindrone	1.05(0.98, 1.12)	1.01(0.87, 1.19)
Pitavastatin	2 mg single dose	TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening	↑ PitavastatinEffect is not clinically significant – no dose adjustment is necessary	1.24(1.17, 1.31)	0.977(0.841, 1.14)
Rosiglitazone	4 mg single oral dose	IVA 150 mg twice daily	↔ Rosiglitazone	0.975(0.897, 1.06)	0.928(0.858, 1.00)
Desipramine	50 mg single dose	IVA 150 mg twice daily	↔ Desipramine	1.04(0.985, 1.10)	1.00(0.939; 1.07)

Table 10: Impact of Other Drugs on Tezacaftor/Ivacaftor or Ivacaftor

	Dose and Schedule			Mean Ratio (90% CI) of Tezacaftor and IvacaftorNo Effect = 1.0
Drug	Dose	TEZ/IVA or IVA	Effect on TEZ/IVA PK	AUC	Cmax
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
Itraconazole	200 mg twice a day on Day 1, followed by 200 mg once daily	TEZ 25 mg + IVA 50 mg once daily	↑ Tezacaftor	4.02(3.71, 4.63)	2.83(2.62, 3.07)
			↑ Ivacaftor	15.6(13.4, 18.1)	8.60(7.41, 9.98)
Ciprofloxacin	750 mg twice daily	TEZ 50 mg + IVA 150 mg twice daily	↔ Tezacaftor	1.08(1.03, 1.13)	1.05(0.99, 1.11)
			↑ Ivacaftor Effect is not clinically significant – no dose adjustment is necessary	1.17(1.06, 1.30)	1.18(1.06, 1.31)
Oral Contraceptive	Norethindrone/ethinyl estradiol 1.0 mg/0.035 mg once daily	TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening	↔ Tezacaftor	1.01(0.963, 1.05)	1.01(0.933, 1.09)
			↔ Ivacaftor	1.03(0.960, 1.11)	1.03(0.941, 1.14)
Rifampin	600 mg once daily	IVA 150 mg single dose	↓ Ivacaftor	0.114(0.097, 0.136)	0.200(0.168, 0.239)
Fluconazole	400 mg single dose on Day 1, followed by 200 mg once daily	IVA 150 mg twice daily	↑ Ivacaftor	2.95(2.27, 3.82)	2.47(1.93, 3.17)