Symdeko

SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the

[see

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 lists responsive

CFTR

mutations based on (1) a clinical FEV₁response 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 (14.1and 14.2)] .	E116K	G576A;R668CComplex/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	F508delA 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

and

14 CLINICAL STUDIES

Dose Ranging

:

Dose selection for the clinical program primarily consisted of one double-blind, placebo-controlled, multiple-cohort trial which included 176 patients with CF (homozygous for the

F508del

mutation) 18 years of age and older with a screening ppFEV1≥40. In the study, 34 and 106 patients, respectively, received tezacaftor at once-daily doses of 10 mg, 30 mg, 100 mg, or 150 mg alone or in combination with ivacaftor 150 mg q12h, and 33 patients received placebo. During the 28-day treatment period, dose-dependent increases in mean ppFEV₁change from baseline were observed with tezacaftor in combination with ivacaftor. Tezacaftor/ivacaftor in general had a greater mean treatment effect than tezacaftor alone. No additional benefit was observed at tezacaftor doses greater than 100 mg daily.

Efficacy

:

The efficacy of SYMDEKO in patients with CF aged 12 years and older was evaluated in three double-blind, placebo-controlled trials (Trials1, 2, and 3).

Trial 1 was a 24-week randomized, double-blind, placebo-controlled, two-arm study in patients with CF who were homozygous for the

F508del

mutation in the

CFTR

gene.

Trial 2 was a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover study in patients with CF who were heterozygous for the

F508del

mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor. Mutations predicted to be responsive were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and

in vitro

responsiveness to tezacaftor/ivacaftor

[see Clinical Studies (14.2)]

. Patients were randomized to and received sequences of treatment that included SYMDEKO, ivacaftor, and placebo.

Trial 3 was a 12-week randomized, double-blind, placebo-controlled, two-arm study in patients with CF who were heterozygous for the

F508del

mutation and a second

CFTR

mutation predicted to be unresponsive to tezacaftor/ivacaftor. Mutations predicted to be non-responsive were selected for the study based on biologic plausibility (mutation class), clinical phenotype (pancreatic insufficiency), biomarker data (sweat chloride), and

in vitro

testing to tezacaftor and/or ivacaftor.

Patients in all trials continued on their standard-of-care CF therapies (e.g

.

, bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline) and were eligible to roll over into a 96-week open-label extension. Patients had a ppFEV₁at screening between 40-90%. Patients with a history of colonization with organisms associated with a more rapid decline in pulmonary status such as

Burkholderia cenocepacia

,

Burkholderia dolosa

, or

Mycobacterium abscessus

, or who had 2 or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥3 × ULN or total bilirubin ≥2 × ULN) or AST or ALT ≥5 × ULN, were excluded from the trials.

14.1 Trial in Patients with CF Who Were Homozygous for the

F508del

Mutation in the

CFTR

Gene (Trial 1)

Trial 1 evaluated 504 patients (248 SYMDEKO, 256 placebo) with CF aged 12 years and older (mean age 26.3 years). The mean ppFEV₁at baseline was 60.0% (range: 27.8% to 96.2%). The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV₁through Week 24. Treatment with SYMDEKO resulted in a statistically significant improvement in ppFEV₁. The treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV₁from baseline through Week 24 was 4.0 percentage points (95% CI: 3.1, 4.8;

P<

0.0001). These changes persisted throughout the 24-week treatment period (Figure 1). Improvements in ppFEV₁were observed regardless of age, sex, baseline ppFEV₁, colonization with

Pseudomonas

, concomitant use of standard-of-care medications for CF, and geographic region.

Key secondary efficacy variables included relative change from baseline in ppFEV₁through Week 24; number of pulmonary exacerbations from baseline through Week 24; absolute change in BMI from baseline at Week 24, and absolute change in CFQ-R Respiratory Domain Score (a measure of respiratory symptoms relevant to patients with CF, such as cough, sputum production, and difficulty breathing) from baseline through Week 24. For the purposes of this trial, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. See Table 11for a summary of key secondary outcomes in Trial 1.

Table 11: Key Secondary Efficacy Analyses, Full Analysis Set (Trial 1)A hierarchical testing procedure was performed for primary and secondary endpoints vs placebo; at each step,

P

≤0.05 and all previous tests also meeting this level of significance were required for statistical significance.

		Placebo N=256	SYMDEKO N=248
BMI: body mass index; CI: confidence interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised; IVA: ivacaftor; NA: not applicable; ppFEV1: percent predicted forced expiratory volume in 1 second;
Relative change in ppFEV1from baseline through Week 24 (%)	Treatment difference (95% CI)	-	6.8 (5.3, 8.3)
	P value	NA	P< 0.0001Indicates statistical significance confirmed in the hierarchical testing procedure. Other efficacy measures considered not statistically significant.
Number of pulmonary exacerbations from baseline through Week 24	Number of events (event rate per yearEstimated event rate per year calculated using 48 weeks per year.) Rate ratio (95% CI)	122 (0.99)	78 (0.64) 0.65 (0.48, 0.88)
	P value	NA	P =0.0054
Absolute change in BMI from baseline at Week 24 (kg/m2)	Treatment difference (95% CI)	-	0.06 (-0.08, 0.19)
Absolute change in CFQ-R Respiratory Domain Score from baseline through Week 24 (points)	Treatment difference (95% CI)	-	5.1 (3.2, 7.0)

Figure 1: Absolute Change From Baseline in Percent Predicted FEV₁at Each Visit in Trial 1

14.2 Trial in Patients with CF Who Were Heterozygous for the

F508del

Mutation and a Second Mutation Predicted to be Responsive to Tezacaftor/Ivacaftor (Trial 2)

Trial 2 evaluated 244 patients with CF aged 12 years and older (mean age 34.8 years). The mean ppFEV₁at baseline was 62.3% (range: 34.6 to 93.5). Of the 244 patients included in the efficacy analysis, 146 patients had a splice mutation and 98 patients had a missense mutation as the second allele. 161 patients received SYMDEKO, 156 patients received ivacaftor, and 161 patients received placebo. The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV₁averaged at Weeks 4 and 8 of treatment. The key secondary efficacy endpoint was absolute change in CFQ-R Respiratory Domain Score from study baseline averaged at Weeks 4 and 8 of treatment. For the overall population, treatment with SYMDEKO compared to placebo resulted in significant improvement in ppFEV₁(6.8 percentage points [95% CI: 5.7, 7.8];

P

<0.0001) and CFQ-R Respiratory Domain Score (11.1 points (95% CI: 8.7, 13.6);

P

<0.0001). Treatment difference for ppFEV₁between ivacaftor- and placebo-treated patients was 4.7 percentage points (95% CI: 3.7, 5.8;

P

<0.0001) and 2.1 percentage points (95% CI: 1.2, 2.9;

P

<0.0001) between SYMDEKO- and ivacaftor-treated patients, which were statistically significant. Improvements in ppFEV₁were observed regardless of age, baseline ppFEV₁, sex, mutation class, colonization with

Pseudomonas

, concomitant use of standard-of-care medications for CF, and geographic region. Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutations (Table 12).

Table 12: Effect of SYMDEKO for Efficacy Variables in Splice and Missense CFTR Mutation Subgroups

Mutation (n)	Absolute Change in percent predicted FEV1Average of Week 4 and 8 values.Absolute change in ppFEV1by individual mutations is an ad hoc analysis.	Absolute Change in CFQ-R Respiratory Domain Score (Points) Absolute change in CFQ-R Respiratory Domain Score and absolute change in sweat chloride by mutation subgroups and by individual mutations are ad hoc analyses.	Absolute Change in Sweat Chloride (mmol/L)
(n=) patient numbers analysed.
Splice mutations (n= 93 for TEZ/IVA, n=97 for PBO) Results shown as difference in mean (95% CI) change from study baseline for SYMDEKO vs. placebo-treated patients:
	7.4 (6.0, 8.7)	9.5 (6.3, 12.7)	-5.4 (-8.0, -2.7)
By individual splice mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for SYMDEKO-treated patients
2789+5G→A (25)	8.6 (-1.5, 23.4)	12.0 (-8.3, 38.9)	-3.2 (-16.5, 9.0)
3272-26A→G (23)	5.7 (-2.1, 25.9)	5.7 (-22.2, 44.4)	-3.8 (-22.3, 16.5)
3849+10kbC→T (43)	5.8 (-7.2, 22.3)	8.2 (-25.0, 47.2)	-5.6 (-27.0, 8.5)
711+3A→G (2)	4.3 (2.0, 6.7)	-4.2 (-5.6, -2.8)	-15.4 (-21.0, -9.8)
E831X Patients enrolled did not receive tezacaftor/ivacaftor treatment. (0)	NA	NA	NA
Missense mutations (n=66 for TEZ/IVA, n=63 for PBO) Results shown as difference in mean (95% CI) change from study baseline for SYMDEKO vs. placebo-treated patients:
	5.9 (4.2, 7.5)	13.4 (9.6, 17.3)	-16.3 (-19.7, -12.9)
By individual missense mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for SYMDEKO-treated patients
D579G (2)	8.1 (-0.2, 16.4)	11.1 (5.6, 16.7)	-23.1 (-24.8, -21.5)
D110H (1)	-1.0 (-1.0, -1.0)	-11.1 (-11.1, -11.1)	-22.5 (-22.5, -22.5)
D1152H (21)	3.8 (-2.5, 12.5)	15.2 (-8.3, 55.6)	-4.1 (-15.0, 11.5)
A455E (11)	8.5 (2.6, 16.1)	11.6 (-11.1, 44.4)	-0.3 (-8.8, 14.0)
L206W (4)	3.0 (-4.5, 10.2)	12.5 (-2.8, 38.9)	-36.1 (-44.5, -27.5)
P67L (11)	9.4 (0.0, 31.9)	11.7 (-12.5, 72.2)	-29.3 (-50.0, 0.8)
R1070W (2)	6.1 (2.0, 10.1)	29.2 (16.7, 41.7)	-13.8 (-26.8, -0.8)
R117C (1)	2.9 (2.9, 2.9)	16.7 (16.7, 16.7)	-38.8 (-38.8, -38.8)
R347H (2)	-0.5 (-2.8, 1.7)	5.6 (-5.6, 16.7)	-13.8 (-19.0, -8.5)
R352Q (2)	4.9 (2.6, 7.1)	8.3 (8.3, 8.3)	-43.3 (-49.8, -36.8)
S945L (7)	9.6 (0.7, 19.5)	11.3 (-4.2, 25.0)	-29.0 (-42.5, -8.0)
S977F (2)	10.1 (5.5, 14.7)	-1.4 (-8.3, 5.6)	-13.9 (-22.3, -5.5)

In an analysis of BMI at Week 8, an exploratory endpoint, patients treated with SYMDEKO had a mean improvement of 0.2 kg/m²(95% CI [0.0, 0.3]), 0.1 kg/m²(95% CI [-0.1, 0.3]), and 0.3 kg/m²(95% CI [0.1, 0.5]) versus placebo for the overall, splice, and missense mutation populations of patients, respectively.

14.3 Trial in Patients with CF Who Were Heterozygous for the

F508del

Mutation and a Second Mutation Not Predicted to be Responsive to Tezacaftor/Ivacaftor (Trial 3)

Trial 3 evaluated 168 patients with CF (83 SYMDEKO and 85 placebo) aged 12 years and older (mean age 26.1 years) who were heterozygous for the

F508del

mutation and had a second

CFTR

mutation predicted to be unresponsive to tezacaftor/ivacaftor. CF patients with the

F508del

mutation and one of the following mutations in the

CFTR

gene were enrolled in the study (listed in decreasing frequency):

W1282X, G542X, N1303K, 621+1G>T, 1717-1G>A, 1898+1G>A, CFTRdele2,3

,

2183delAA>G

,

2184insA

,

R1162X

,

R553X, 3659delC, 3905insT, G970R, I507del, R1066C, R347P, 1154insTC, 1811+1.6kbA>G, 2184delA, 405+1G>A, E60X, G85E, L1077P, Q39X, S466X, Y1092X, 1078delT, 1248+1G>A, 1677delTA, 1812-1G>A, 2869INSG, 3120+1G>A, 394delTT, 457TAT>G, 711+1G>T, 711+5G>A, 712-1G>T, G673x, L1065P, Q220X, Q493X, R709X, V520F.

The mean ppFEV₁at baseline was 57.5% [range: 31.0 to 96.7]. The primary efficacy endpoint was changed from baseline in absolute ppFEV₁through Week 12. The overall treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV₁from baseline through Week 12 was 1.2 percentage points (95% CI: -0.3, 2.6). This study was terminated following the planned interim analysis because the pre-specified futility criteria were met.

]

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a

• Pediatric patients aged 6 to less than 12 years weighing less than 30 kg: one tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 75 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. (
  2.1 General Dosage Information

  Swallow the tablets whole.

  SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats, etc.

  [see Clinical Pharmacology (12.3)]

  .
  ,
  2.2 Recommended Dosage in Adults, Adolescents, and Children Aged 6 Years and Older

  Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1. The morning and the evening doses should be taken approximately 12 hours apart.

  Table 1: Recommended Dosage for Patients Aged 6 Years and Older

  Age	Morning (one tablet)	Evening (one tablet)
  6 to <12 years weighing <30 kg	tezacaftor 50 mg/ivacaftor 75 mg	ivacaftor 75 mg
  6 to <12 years weighing ≥30 kg	tezacaftor 100 mg/ivacaftor 150 mg	ivacaftor 150 mg
  ≥12 years	tezacaftor 100 mg/ivacaftor 150 mg	ivacaftor 150 mg

  Information for Missed Doses:

  If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time.
  ,
  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)	AUC0-24hor AUC0-12h (mcg∙h/mL)AUC0-24hfor tezacaftor and AUC0-12hfor 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_maxof 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 mg¹⁴C-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 of¹⁴C-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 aged 6 to less than 12 years

  Table 8: Tezacaftor/Ivacaftor Exposure by Age Group, Mean (SD)

  Age Group	Dose	Tezacaftor AUCss mcg∙h/mLAUC0-24hfor tezacaftor and AUC0-12hfor ivacaftor	Ivacaftor AUCss mcg∙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 aged 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_maxfor 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

  [see Dosage 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 Drugs No 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/ Norethindrone 0.035 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 dosage 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 Ivacaftor No 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)
  			↑ IvacaftorEffect is not clinically significant – no dosage 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)
  )
• Adults and pediatric patients aged 12 years and older or pediatric patients aged 6 to less than 12 years weighing 30 kg or more: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. (
  2.1 General Dosage Information

  Swallow the tablets whole.

  SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats, etc.

  [see Clinical Pharmacology (12.3)]

  .
  ,
  2.2 Recommended Dosage in Adults, Adolescents, and Children Aged 6 Years and Older

  Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1. The morning and the evening doses should be taken approximately 12 hours apart.

  Table 1: Recommended Dosage for Patients Aged 6 Years and Older

  Age	Morning (one tablet)	Evening (one tablet)
  6 to <12 years weighing <30 kg	tezacaftor 50 mg/ivacaftor 75 mg	ivacaftor 75 mg
  6 to <12 years weighing ≥30 kg	tezacaftor 100 mg/ivacaftor 150 mg	ivacaftor 150 mg
  ≥12 years	tezacaftor 100 mg/ivacaftor 150 mg	ivacaftor 150 mg

  Information for Missed Doses:

  If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time.
  ,
  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)	AUC0-24hor AUC0-12h (mcg∙h/mL)AUC0-24hfor tezacaftor and AUC0-12hfor 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_maxof 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 mg¹⁴C-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 of¹⁴C-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 aged 6 to less than 12 years

  Table 8: Tezacaftor/Ivacaftor Exposure by Age Group, Mean (SD)

  Age Group	Dose	Tezacaftor AUCss mcg∙h/mLAUC0-24hfor tezacaftor and AUC0-12hfor ivacaftor	Ivacaftor AUCss mcg∙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 aged 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_maxfor 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

  [see Dosage 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 Drugs No 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/ Norethindrone 0.035 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 dosage 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 Ivacaftor No 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)
  			↑ IvacaftorEffect is not clinically significant – no dosage 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)
  )
• Reduce dosage in patients with moderate and severe hepatic impairment. (
  2.3 Recommended Dosage for Patients with Hepatic Impairment

  For dosage adjustment for patients with hepatic impairment, refer to Table 2.

  Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be higher than in patients with moderate hepatic impairment. Therefore, SYMDEKO should be used with caution at an adjusted dosage after weighing the risks and benefits of treatment in these patients

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].

  Table 2: Recommended Dosage for Patients with Hepatic Impairment

  Hepatic Impairment	Morning		Evening
  	Patients Aged 6 to <12 Years Weighing <30 kg	Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years	All Patients
  Mild (Child-Pugh Class A)	No dose adjustment	No dose adjustment	No dose adjustment
  Moderate (Child-Pugh Class B)	One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily	One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily	No ivacaftor dose
  Severe (Child-Pugh Class C)	One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily (or less frequently)	One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently)
  ,
  8.6 Hepatic Impairment

  No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dosage of SYMDEKO is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). There is no experience in patients with severe hepatic impairment (Child-Pugh Class C), but tezacaftor/ivacaftor exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage in patients with severe hepatic impairment after weighing the risks and benefits of treatment

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .
  ,
  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)	AUC0-24hor AUC0-12h (mcg∙h/mL)AUC0-24hfor tezacaftor and AUC0-12hfor 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_maxof 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 mg¹⁴C-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 of¹⁴C-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 aged 6 to less than 12 years

  Table 8: Tezacaftor/Ivacaftor Exposure by Age Group, Mean (SD)

  Age Group	Dose	Tezacaftor AUCss mcg∙h/mLAUC0-24hfor tezacaftor and AUC0-12hfor ivacaftor	Ivacaftor AUCss mcg∙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 aged 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_maxfor 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

  [see Dosage 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 Drugs No 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/ Norethindrone 0.035 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 dosage 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 Ivacaftor No 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)
  			↑ IvacaftorEffect is not clinically significant – no dosage 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)
  )
• See full prescribing information for dosage modifications due to drug interactions with SYMDEKO. (
  2.4 Dosage Adjustment for Patients Taking Drugs that are CYP3A Inhibitors

  The dosing regimen of SYMDEKO should be adjusted when co-administered with moderate and strong CYP3A inhibitors.

  Moderate CYP3A inhibitors:

  When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin), the dosing regimen should be adjusted as in Table 3

  [see Drug Interactions (7.2), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .

  Table 3: Dosing Schedule for Concomitant Use of SYMDEKO with Moderate CYP3A Inhibitors

  	Day 1	Day 2	Day 3	Day 4Continue dosing with tezacaftor/ivacaftor or ivacaftor tablets on alternate days.
  Patients Aged 6 to <12 Years Weighing <30 kg
  Morning
  Tezacaftor 50 mg/ivacaftor 75 mg tablet	✓	-	✓	-
  Ivacaftor 75 mg tablet	-	✓	-	✓
  Evening
  Ivacaftor 75 mg tablet	-	-	-	-
  Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years
  Morning
  Tezacaftor 100 mg/ivacaftor 150 mg tablet	✓	-	✓	-
  Ivacaftor 150 mg tablet	-	✓	-	✓
  Evening
  Ivacaftor 150 mg tablet	-	-	-	-

  Strong CYP3A inhibitors:

  When co-administered with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dosing regimen should be adjusted as in Table 4

  [see Drug Interactions (7.2), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .

  Table 4: Dosing Schedule for Concomitant Use of SYMDEKO with Strong CYP3A Inhibitors

  	Day 1	Day 2 and Day 3	Day 4Continue dosing with tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart.
  Patients Aged 6 to <12 Years Weighing <30 kg
  Morning
  Tezacaftor 50 mg/ivacaftor 75 mg tablet	✓	-	✓
  EveningThe evening dose of ivacaftor should not be taken on any day.
  Ivacaftor 75 mg tablet	-	-	-
  Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years
  Morning
  Tezacaftor 100 mg/ivacaftor 150 mg tablet	✓	-	✓
  Evening
  Ivacaftor 150 mg tablet	-	-	-

  Food or drink containing grapefruit should be avoided during treatment with SYMDEKO

  [see Drug Interactions (7.2)and Patient Counseling Information (17)]

  .
  ,
  7.2 Inhibitors of CYP3A

  Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (AUC) by 4.0-fold and ivacaftor by 15.6-fold. When co-administered with strong CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted

  [see Dosage and Administration (2.4), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .

  Examples of strong CYP3A inhibitors include:

  • ketoconazole, itraconazole, posaconazole, and voriconazole
  • telithromycin and clarithromycin

  Co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0-fold. Simulation suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2.0-fold. When co-administered with moderate CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted

  [see Dosage and Administration (2.4), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .

  Examples of moderate CYP3A inhibitors include:

  • fluconazole
  • erythromycin

  Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with SYMDEKO

  [see Dosage and Administration (2.4), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]

  .
  ,
  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)	AUC0-24hor AUC0-12h (mcg∙h/mL)AUC0-24hfor tezacaftor and AUC0-12hfor 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_maxof 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 mg¹⁴C-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 of¹⁴C-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 aged 6 to less than 12 years

  Table 8: Tezacaftor/Ivacaftor Exposure by Age Group, Mean (SD)

  Age Group	Dose	Tezacaftor AUCss mcg∙h/mLAUC0-24hfor tezacaftor and AUC0-12hfor ivacaftor	Ivacaftor AUCss mcg∙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 aged 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_maxfor 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

  [see Dosage 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 Drugs No 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/ Norethindrone 0.035 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 dosage 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 Ivacaftor No 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)
  			↑ IvacaftorEffect is not clinically significant – no dosage 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)
  )

Tablets: Tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets co-packaged with ivacaftor 75 mg tablets

• Tezacaftor 50 mg/ivacaftor 75 mg tablets are white, oblong-shaped, and debossed with "V50" on one side and plain on the other.
• Ivacaftor 75 mg tablets are light blue, oblong-shaped, and printed with "V 75" in black ink on one side and plain on the other.

Tablets: Tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablets

• Tezacaftor 100 mg/ivacaftor 150 mg tablets are yellow, oblong-shaped, and debossed with "V100" on one side and plain on the other.
• Ivacaftor 150 mg tablets are light blue, oblong-shaped, and printed with "V 150" in black ink on one side and plain on the other.

There are limited and incomplete human data from clinical trials and postmarketing reports on the use of SYMDEKO or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits. In animal reproduction studies, oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the maximum recommended human dose (MRHD) in rats and 0.2 times the MRHD in rabbits (based on summed AUCs for tezacaftor and M1 metabolite). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 6 and 16 times the exposure at the MRHD, respectively. No adverse developmental effects were observed after oral administration of either tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 and 4 times the exposures at the MRHD, respectively (

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.