SYMDEKO (Page 4 of 9)

8.4 Pediatric Use

The safety and effectiveness of SYMDEKO for the treatment of CF have been established in pediatric patients age 6 to less than 18 years who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence [see Clinical Pharmacology (12.1) and Clinical Studies (14)].

Clinical trials included the following patients with CF:

• 12 to less than 18 years of age who are homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14)].
• 12 to less than 18 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].
• 6 to less than 12 years of age who are either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Pharmacology (12)]

The effectiveness of SYMDEKO in patients age 6 to less than 12 years was extrapolated from patients age 12 years and older with support from population pharmacokinetic analyses showing similar tezacaftor and ivacaftor exposure levels in patients age 6 to less than 12 years and in patients age 12 years and older [see Clinical Pharmacology (12.3)]. Safety of SYMDEKO in this population was derived from a 24-week, open-label, clinical trial in 70 patients age 6 to less than 12 years (mean age at screening 8.1 years) administered either tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg or tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg, 12 hours apart (Trial 4). The safety profile for patients in this trial was similar to that observed in Trials 1 and 3 [see Adverse Reactions (6.1)].

The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied.

Juvenile Animal Toxicity Data

Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.25 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals.

8.5 Geriatric Use

Clinical trials of SYMDEKO did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose 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 dose 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)].

8.7 Renal Impairment

SYMDEKO has not been studied in patients with moderate or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is recommended for mild and moderate renal impairment. Caution is recommended in patients with severe renal impairment or end-stage renal disease [Clinical Pharmacology (12.3)].

8.8 Patients with Severe Lung Dysfunction

Trial 1 and Trial 2 included a total of 39 SYMDEKO-treated patients with ppFEV₁ <40 at baseline (range 30-40); 23 patients in Trial 1 and 16 patients in Trial 2. There were 24 placebo-treated patients in Trial 1, and 15 placebo- and 13 ivacaftor-treated patients in Trial 2, with ppFEV₁ <40 at baseline. The safety and efficacy in this subgroup were comparable to the overall results observed in both Trials 1 and 2.

10 OVERDOSAGE

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

11 DESCRIPTION

SYMDEKO is co-packaged as a tezacaftor/ivacaftor fixed-dose combination tablet and an ivacaftor tablet. Both tablets are for oral administration.

Tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets and ivacaftor 75 mg tablets:

The tezacaftor/ivacaftor fixed-dose combination tablet is available as a white, capsule-shaped, film-coated tablet containing 50 mg of tezacaftor, 75 mg of ivacaftor, and the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The tablet film coat contains HPMC/hypromellose 2910, hydroxypropyl cellulose, talc and titanium dioxide.

The ivacaftor tablet is available as a light blue, capsule-shaped, film-coated tablet containing 75 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

Tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets and ivacaftor 150 mg tablets:

The tezacaftor/ivacaftor fixed-dose combination tablet is available as a yellow, capsule-shaped, film-coated tablet containing 100 mg of tezacaftor, 150 mg of ivacaftor, and the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The tablet film coat contains HPMC/hypromellose 2910, hydroxypropyl cellulose, iron oxide yellow, talc and titanium dioxide.

The ivacaftor tablet is available as a light blue, capsule-shaped, film-coated tablet containing 150 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

The active ingredients of SYMDEKO are described below.

Tezacaftor

Tezacaftor is a white to off-white powder that is practically insoluble in water (<5 microgram/mL). Its chemical name of tezacaftor is 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1Hindol-5-yl}cyclopropane-1-carboxamide. Its molecular formula is C₂₆ H₂₇ N₂ F₃ O₆ and its molecular weight is 520.50. Tezacaftor has the following structural formula:

Ivacaftor

Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). Pharmacologically it is a CFTR potentiator. Its chemical name is N -(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Its molecular formula is C₂₄ H₂₈ N₂ O₃ and its molecular weight is 392.49. Ivacaftor has the following structural formula:

12 CLINICAL PHARMACOLOGY

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 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

* Clinical data for these mutations in Clinical Studies [see Clinical Studies (14.1 and 14.2)]. † 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. ‡ 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.
546insCTA	E92K	G576A	L346P	R117G	S589N
711+3A→G *	E116K	G576A;R668C †	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 ‡	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