Symkevi 100 mg/150 mg film coated tablets and 50 mg/ 75 mg film coated tablets

• Various editorial revisions throughout
• Change to revision date
• Change to date of last renewal
• Removal of black triangle
• Addition of juvenile toxicity studies text in 5.3, Tezacaftor

Minor typographical changes throughout the PI.

Studies were updated to reference study number as follows: study 1 updated to 661-106, study 2 updated to 661-108, study 3 updated to 661-110, study 4 updated to 661-115, study 5 updated to 661-113.

Section 4 Clinical Particulars

4.2 Posology and Method of Administration

Dose recommendations table (Table 2) for concomitant use with moderate or strong CYP3A inhibitors updated for the 6 to less than 12 years age group.

4.8 Undesirable Effects

Safety data was updated to include rollover study in children aged 6 to less than 12 years of age.

Section 5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Effects on Sweat Chloride

Addition of sweat chloride data from rollover study 661-116 part A for patients aged 6 and older.

Clinical Efficacy and Safety

Addition of information regarding rollover study 661-116 part A, a 96-week study to evaluate the safety and efficacy of long-term treatment with Symkevi in combination with ivacaftor in patients 6 years and older.

5.2 Pharmacokinetic Parameters

Renal Impairment

Revision to the number of patients using tezacaftor alone or tezacaftor in combination with ivacaftor in phase 2/3 clinical studies and addition of information on moderate renal impairment (eGFR).

Clarification of manufacturer address to specify location within the United Kingdom (Northern Ireland)

Summary of change 

• Section 7 Marketing Authorisation Holder  (Address change)

1. NAME OF THE MEDICINAL PRODUCT

Addition of new strength for Symkevi- Symkevi 50 mg/75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Update to include Symkevi 50 mg/75 mg film-coated tablets composition and update Symkevi 100 mg/ 150 mg strength.

3. PHARMACEUTICAL FORM

       Addition of the description of the Symkevi 50 mg/75 mg tablet appearance.

 4.1 Therapeutic indications

Update to indication for Symkevi to state that Symkevi is indicated in a combination regimen for treatment in patients with cystic fibrosis aged 6 years and older who are homozygous for the F508del mutation or heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272‑26A→G, and 3849+10kbC→T.

4.2 Posology and method of administration

Update to include a table with dosing recommendations (Table 1) for patients aged 6 years and older as a result of the new strength.

Concomitant use of CYP3A inhibitors

Moderate CYP3A inhibitors updated to include verapamil. Addition of examples of strong CYP3A inhibitors.

Dosing recommendation table for concomitant use with moderate and strong CYP3A inhibitors updated and combined into a single table (Table 2).

Special populations

Elderly people subsection updated to remove “in combination with ivacaftor”

Hepatic impairment subsection updated to add a statement for patients with mild hepatic impairment (no dose adjustment is necessary for Symkevi).

Table with dosing recommendations for use in patients with hepatic impairment (Table 3) updated and reformatted.

Paediatric population

Update to statement to state that “The safety and efficacy of Symkevi in children aged less than 6 years has not yet been established”.

Method of administration

Clarification added regarding tablet formulation that they should not be chewed, crushed or broken before swallowing “because there are no clinical data currently available to support other methods of administration”.

Removal of Seville oranges as example of a food and drink to be avoided during treatment.

4.4                Special warnings and precautions for use

Removal of “in combination with ivacaftor”

Effect on liver function tests

Removal of “Assessments of transaminases (ALT) or (AST)” which has been rephrased to “Liver function tests”.

Renal impairment

Removal of “while using Symkevi in combination with ivacaftor” from statement on caution being recommended in patients with severe renal impairment or end-stage renal disease.

Addition of header “Paediatric population” for “Cataracts” subsection and administrative edit to state “ivacaftor-containing regimens”.

Administrative edit to “Sodium content” header

CYP3A inhibitors

Removal of Seville oranges as a type of food or drink to be avoided during treatment with CYP3A inhibitors.

4.8             Undesirable effects

Administrative edits.

Adverse reactions table updated to combine the two tables that were previously in the SmPC for Symkevi in combination with ivacaftor and ivacaftor monotherapy. Adverse reactions observed during clinical studies with IVA/TEZ in combination with ivacaftor are denoted by an asterisk*.

Paediatric population

Addition of safety related information on transaminase elevations from the 24-week, open label Phase 3 study in patients aged 6 to less than 12 years of age.

5.1 Pharmacodynamic properties

Administrative edits throughout section.

Addition of “effect on sweat chloride” information related to study 4 (patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity).

Paediatric population

 Addition of Study 4 data (including patients aged 6 to <12 years and table showing effect of Symkevi on efficacy parameters for Study 4.

​​​​​​​​​​​​​​5.2 Pharmacokinetic properties

Administrative edit subsection on renal impairment to clarify that “Tezacaftor alone or in combination with” ivacaftor has not been studied with moderate or severe renal impairment.

Paediatric population

Updated table (Table 9) to include data for mean tezacaftor and ivacaftor exposure by age group for patients aged 6 to <12 years of age.

6.1       List of excipients

Administrative edits to include tablet film coat information for both Symkevi 50 mg/75 mg and Symkevi 100 mg/150 mg.

6.3       Shelf life

Shelf-life updated to include information for both strengths.

Symkevi 100 mg/150 mg film coated tablets

4 years

Symkevi 50 mg/75 mg film coated tablets

3 years

8.         MARKETING AUTHORISATION NUMBER(S)

Addition of MAH number for the 50mg/75 mg license for Symkevi.

Addition of Symkevi 50 mg/75mg film-coated tablets to PIL. Combined PIL with Symkevi 100 mg/150mg film-coated tablets.

Section 1. What is Symkevi and what is it used for

Update to indication to change the age to 6 years and over:

“Symkevi taken with ivacaftor is for long-term treatment of patients aged 6 and over who have CF with certain genetic mutations that result in reduced amount and/or function of the CFTR protein.”

Section 2. What you need to know before you take Symkevi

Update of age to 6 years in subsection title “Children under 6”

Also statement updated to align with indication “Symkevi is not to be used in children under the age of 6 years. It is not known if Symkevi is safe and effective in children under 6”.

Symkevi with food and drink

Removal of Seville oranges as type of food and drink to avoid during treatment with Symkevi.

Driving and using machines

Statement related to dizziness updated to remove “in combination with ivacaftor”

Sodium statement header updated.

Section 3. How to take Symkevi

Recommended dose information updated to specify dosage for age groups from 6 years and older to 12 years and older. Information related to weight and dosage also provided for patients < 30 kg and ≥ 30 kg.

Section 4.            Possible side effects

Administrative edits to sub-headers in this section.

Section 6.            Contents of the pack and other information

Addition of information related to the Symkevi 50 mg tezacaftor/75 mg ivacaftor tablet strength.

Administrative update to information related to Symkevi 100 mg tezacaftor/150 mg ivacaftor tablet strength.

What Symkevi looks like and contents of the pack

Addition of information regarding the appearance of Symkevi 50 mg/75 mg film‑coated tablets

Marketing Authorisation Holder

Administrative edit to the subsection header

Update to Section 5. How to store Symkevi

Minor editorial change:

Previous text:

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date that is stated on the package after EXP. The expiry date refers to the last day of that month.

Updated text:

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month.

Minor administrative changes throughout SmPC

Update to section 4.4 Special Warnings and Precautions for Use

Addition of “content” to “Sodium content”

Update to delete text from section 4.5 Interaction with other medicinal products and other forms of interaction

Deletion of:

Symkevi may inhibit OATP1B1 and increase the exposures of medicinal products that are substrates of OATP1B1. When used concomitantly with OATP1B1 substrates, caution should be used.

Update to section 4.8 Undesirable effects

Data related to Study 661-110 ( Study 3) updated to include additional patients and information.

Previous text:

Safety data from an interim safety analysis performed on 867 patients in a long‑term safety and efficacy rollover study (Study 3), including 326 patients with ≥48 weeks of cumulative treatment with Symkevi given in combination with ivacaftor, were consistent with the safety data from the placebo‑controlled Phase 3 studies.

Updated text:

The safety data from 1042 patients 12 years and older treated with Symkevi in combination with ivacaftor for up to an additional 96 weeks in a long‑term safety and efficacy rollover study (study 3)  were consistent with the safety data from the placebo‑controlled Phase 3 studies.

Update to Section 5.1 Pharmacodynamic properties

Header updated to “Clinical efficacy and safety”

Updates to information related to Study 3

Previous text:

Long‑term safety and efficacy rollover study (Study 3)

An ongoing, Phase 3, open‑label, multicenter, rollover, 96‑week study to evaluate the safety and efficacy of long‑term treatment with Symkevi in combination with ivacaftor is being conducted with patients from Studies 1 (n=459) and 2 (n=226). An interim analysis was conducted through Week 24 for patients from Study 1 and Week 16 for patients from Study 2. As efficacy was a secondary objective for Study 3 there was no multiplicity adjustment.

Patients who received placebo in both Study 1 and Study 2 demonstrated improvements in ppFEV₁ when treated with Symkevi in combination with ivacaftor in Study 3 [Study 1: within‑group change=4.2 (0.5) percentage points, Study 2: within‑group change=4.9 (0.6) percentage points]. Patients who received Symkevi in combination with ivacaftor in Study 1 and Study 2, and continued on treatment, showed sustained improvements in ppFEV₁ through 48 weeks (Week 24 Study 3) and through 24 weeks (Week 16 Study 3), respectively.

Updated text:

Long‑term safety and efficacy rollover study (Study 3)

Study 3 was a Phase 3, open‑label, multicenter, rollover, 96‑week study to evaluate the safety and efficacy of long‑term treatment with Symkevi in combination with ivacaftor in patients from studies 1 (n=462) and 2 (n=227). Efficacy was a secondary objective for study 3 and the efficacy endpoints were not adjusted for multiplicity.

Patients who received placebo in both study 1 and study 2 demonstrated improvements in ppFEV₁ when treated with Symkevi in combination with ivacaftor in study 3 [Study 1: within‑group change=2.1(95% CI: 0.8, 3.3) percentage points, study 2: within‑group change=4.1 (95% CI: 2.2, 6.0)) percentage points]. Patients who received Symkevi in combination with ivacaftor in the parent studies and continued on treatment,  showed a slight attenuation in ppFEV₁ in the extension study, however the overall treatment effect was still positive through 120 weeks and 104 weeks for study 1 and study 2, respectively.

Paediatric population

Previous text:

Adolescent patients with CF who were homozygous for the F508del mutation in the CFTR gene

The mean absolute change (SE) from baseline in ppFEV₁ was 3.5 (0.6) percentage points in the Symkevi in combination with ivacaftor group and ‑0.4 (0.6) percentage points in the placebo group in Study 1. Patients who received Symkevi in combination with ivacaftor in Study 1 and continued on treatment showed sustained improvements in ppFEV₁ through 48 weeks [within‑group change=-0.8 (0.8) percentage points from Study 3 baseline]. Patients who were previously treated with placebo and received Symkevi in combination with ivacaftor in Study 3 showed an increase of 5.3 (0.7) percentage points.

The mean absolute change (SE) from baseline in BMI z-value was -0.01(0.05) kg/m² in the Symkevi in combination with ivacaftor group and 0.00 (0.05) kg/m² in the placebo group in Study 1. In Study 3, the change in BMI z-value in the Symkevi in combination with ivacaftor group was maintained and patients previously treated with placebo showed an increase of 0.10 (0.05) kg/m².

Adolescent patients with CF who were heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity

The mean absolute change (SE) from baseline in ppFEV₁ was 11.7 (1.2) percentage points in the Symkevi in combination with ivacaftor group, 7.6 (1.2) percentage points in the ivacaftor group and ‑0.4 (1.2) percentage points in the placebo group in Study 2. Patients who received Symkevi in combination with ivacaftor in Study 2 and continued on treatment showed sustained improvements in ppFEV₁ through 24 weeks [within‑group change=0.7 (1.5) percentage points from Study 3 baseline]. Patients who were previously treated with ivacaftor and placebo and received Symkevi in combination with ivacaftor in Study 3 showed an increase of 1.6 (1.6) percentage points and 7.2 (1.2) percentage points, respectively. 

The mean absolute change (SE) from baseline in BMI z-value was 0.24 (0.07) kg/m² in the Symkevi in combination with ivacaftor group, 0.20 (0.07) kg/m² in the ivacaftor group and 0.04 (0.07) kg/m² in the placebo group in Study 2. In Study 3, the change in BMI z-value in the Symkevi in combination with ivacaftor group was maintained. 

Updated text:

Adolescent patients with CF who were homozygous for the F508del mutation in the CFTR gene

The mean absolute change (SE) from baseline in ppFEV₁ was 3.5 (0.6) percentage points in the Symkevi in combination with ivacaftor group and ‑0.4 (0.6) percentage points in the placebo group in study 1. Patients who received Symkevi in combination with ivacaftor in study 1 and continued on treatment showed sustained improvements in ppFEV₁ through 96 weeks in study 3 [within‑group change=1.5 (1.6) percentage points]. Patients who were previously treated with placebo and received Symkevi in combination with ivacaftor in study 3 showed an increase of 0.9 (1.7) percentage points.

The mean absolute change (SE) from baseline in BMI z-value was -0.01(0.05) kg/m² in the Symkevi in combination with ivacaftor group and 0.00 (0.05) kg/m² in the placebo group in study 1. In study 3, the change in BMI z-value in the Symkevi in combination with ivacaftor group was maintained and patients previously treated with placebo showed an increase of 0.12 (0.07) kg/m².

Adolescent patients with CF who were heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity

The mean absolute change (SE) from baseline in ppFEV₁ was 11.7 (1.2) percentage points in the Symkevi in combination with ivacaftor group, 7.6 (1.2) percentage points in the ivacaftor group and ‑0.4 (1.2) percentage points in the placebo group in study 2. Patients who received Symkevi in combination with ivacaftor in study 2 and continued on treatment showed sustained improvements in ppFEV₁ through 96 weeks in study 3 [within‑group change=16.9 (4.0) percentage points]. Patients who were previously treated with ivacaftor or placebo and received Symkevi in combination with ivacaftor in study 3 showed an increase of 4.1 (4.5) percentage points and 6.0 (3.5) percentage points, respectively. 

The mean absolute change (SE) from baseline in BMI z-value was 0.24 (0.07) kg/m² in the Symkevi in combination with ivacaftor group, 0.20 (0.07) kg/m² in the ivacaftor group and 0.04 (0.07) kg/m² in the placebo group in study 2. In study 3, the change in BMI z-value were maintained in the Symkevi in combination with ivacaftor group (0.29 (0.22) kg/m², in the ivacaftor group 0.23 (0.27) kg/m², and in the placebo group 0.23 (0.19) kg/m². 

Updates to Section 5.2  Pharmacokinetic properties

Deletion of sentence related to potential reduced activity of CYP3A4

Previous text:

Biotransformation

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg ¹⁴C‑tezacaftor to healthy male subjects, M1‑TEZ, M2‑TEZ, and M5‑TEZ were the three major circulating metabolites of tezacaftor in humans, contributing to 15%, 31%, and 33% of total radioactivity, respectively. Under steady-state, for each of the metabolites, exposure to M1‑TEZ, M2‑TEZ and M5‑TEZ is approximately 1.5-fold higher than for tezacaftor. M1-TEZ has similar potency to that of tezacaftor and is considered pharmacologically active. M2‑TEZ is much less pharmacologically active than tezacaftor or M1‑TEZ, and M5‑TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3‑TEZ, 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‑IVA and M6‑IVA are the two major metabolites of ivacaftor in humans. M1‑IVA has approximately one‑sixth the potency of ivacaftor and is considered pharmacologically active. M6‑IVA is not considered pharmacologically active.

The effect of the potentially reduced activity of CYP3A4 in patients carrying the CYP3A4*22 variant on tezacaftor and ivacaftor exposures is not known.

The effect of the CYP3A4*22 heterozygous genotype on tezacaftor and ivacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of tezacaftor and ivacaftor is considered necessary. No data are available for CYP3A4*22 homozygous genotype patients.

Updated text:

Biotransformation

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg ¹⁴C‑tezacaftor to healthy male subjects, M1‑TEZ, M2‑TEZ, and M5‑TEZ were the three major circulating metabolites of tezacaftor in humans, contributing to 15%, 31%, and 33% of total radioactivity, respectively. Under steady-state, for each of the metabolites, exposure to M1‑TEZ, M2‑TEZ and M5‑TEZ is approximately 1.5-fold higher than for tezacaftor. M1-TEZ has similar potency to that of tezacaftor and is considered pharmacologically active. M2‑TEZ is much less pharmacologically active than tezacaftor or M1‑TEZ, and M5‑TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3‑TEZ, 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‑IVA and M6‑IVA are the two major metabolites of ivacaftor in humans. M1‑IVA has approximately one‑sixth the potency of ivacaftor and is considered pharmacologically active. M6‑IVA is not considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on tezacaftor and ivacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of tezacaftor and ivacaftor is considered necessary. No data are available for CYP3A4*22 homozygous genotype patients.

Update to Section 6.3 Shelf life

Updated shelf-life from 30 months to 4 years

Change to section 6.3 - Shelf-life extension from 30 months to 4 years.

Change to section 4.5          Interaction with other medicinal products and other forms of interaction

New subsection for OATP1B1 substrates added as Symkevi in combination with ivacaftor has been studied with pitavastatin (OATP1B1 substrate):

Symkevi in combination with ivacaftor has been studied with pitavastatin, an OATP1B1 substrate, and was found to have no clinically relevant effect on the exposure of pitavastatin (1.24 fold increased exposure based on AUC).  No dose adjustment of OATP1B1 substrates is required when co-administered with Symkevi.

Previous wording deleted:

Symkevi may inhibit OATP1B1 and increase the exposures of medicinal products that are substrates of OATP1B1. When used concomitantly with OATP1B1 substrates, caution should be used.

Change to section 5.2     Pharmacokinetic properties

Clarification of CYP3A4 activity in patients carrying the CYP3A4*22 variant as follows:

The effect of the CYP3A4*22 heterozygous genotype on tezacaftor and ivacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of tezacaftor and ivacaftor is considered necessary. No data are available for CYP3A4*22 homozygous genotype patients.

Previous wording deleted:

The effect of the potentially reduced activity of CYP3A4 in patients carrying the CYP3A4*22 variant on tezacaftor and ivacaftor exposures is not known.

Change of address for MAH

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