Symkevi 100 mg/150 mg film coated tablets

  • Name:

    Symkevi 100 mg/150 mg film coated tablets

  • Company:
    info
  • Active Ingredients:

    Tezacaftor 100mg, Ivacaftor 150mg

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 20/08/20

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Summary of Product Characteristics last updated on medicines.ie: 20/8/2020
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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Vertex Pharmaceuticals (Ireland) Limited

Vertex Pharmaceuticals (Europe) Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Kaftrio 75 mg, 50 mg, 100 mg film coated tablets Active Ingredients Ivacaftor, Tezacaftor, Elexacaftor
Medicine Name Kalydeco 150 mg film-coated tablets Active Ingredients Ivacaftor
Medicine Name Kalydeco 25mg, 50mg and 75mg granules sachets Active Ingredients Ivacaftor
Medicine Name Orkambi 100 mg/125 mg granules and 150 mg/188 mg granules Active Ingredients Ivacaftor, Lumacaftor
Medicine Name Orkambi 200 mg/125 mg tablets and 100mg/125mg tablets Active Ingredients Ivacaftor, Lumacaftor
Medicine Name Symkevi 100 mg/150 mg film coated tablets Active Ingredients Tezacaftor 100mg, Ivacaftor 150mg
1 - 0 of 6 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 20 August 2020 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose

Free text change information supplied by the pharmaceutical company

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.

 

 

Updated on 20 August 2020 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 21 April 2020 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 15 April 2020 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 

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.

Updated on 8 February 2019 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 8 February 2019 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change of address for MAH

Updated on 6 December 2018 SmPC

Reasons for updating

  • New SmPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

New Medicine

Updated on 6 December 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

New Medicine

Updated on 8 November 2018 PIL

Reasons for updating

  • New PIL for new product