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:

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:

Chemical Structure
(click image for full-size original)

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:

Chemical Structure
(click image for full-size original)

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

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.