Kivexa film-coated tablets

The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 and Article 107g(3) of Directive 2001/83/EC the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended, recommends by consensus the variation to the terms of the marketing authorisation(s) for the medicinal products containing the above referred active substance(s), concerning the following change(s):

Update of section 4.4 of the SmPC to add a warning/precaution regarding cardiovascular events. The Package leaflet is updated accordingly.

The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 and Article 107g(3) of Directive 2001/83/EC the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended, recommends by consensus the variation to the terms of the marketing authorisation(s) for the medicinal products containing the above referred active substance(s), concerning the following change(s):

Update of section 4.4 of the SmPC to add a warning/precaution regarding cardiovascular events. The Package leaflet is updated accordingly.

Further updates to Breastfeeding wording

Further updates to Breastfeeding wording.

Removed minor formatting issue in numbering on PIL on heading 'Possible Side Effects'

Type IAIN variation for CHMP adopted update to the product information for all approved HIV products, recommending the removal of the disease information relating to sexual transmission of HIV and amendment of the sections relating to breast-feeding.

Type IAIN variation for CHMP adopted update to the product information for all approved HIV products, recommending the removal of the disease information relating to sexual transmission of HIV and amendment of the sections relating to breast-feeding.

Type IAIN variation for CHMP adopted update to the product information for all approved HIV products, recommending the removal of the disease information relating to sexual transmission of HIV and amendment of the sections relating to breast-feeding.

Type II variation – Update to 3TC Elimination half-life
EMEA/H/C/WS2163

Pursuant to Article 16 of Commission Regulation (EC) No 1234/2008, ViiV Healthcare B.V. submitted to the European Medicines Agency on 30 September 2021 an application for a variation following a worksharing procedure according to Article 20 of Commission Regulation (EC) No 1234/2008.
The following changes were proposed:
Variation requested Type Annexes affected
C.I.4 C.I.4 - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data Type II I, II, IIIA and IIIB
Update of section 5.2 of the SmPC in order to add new information on the elimination half-life of lamivudine, based on final results from studies 204993 and 204994. Study 204993 was a phase I, relative oral bioavailability study of different fixed dose combinations of dolutegravir and lamivudine in healthy subjects. Study 204994 was an open-label, randomized, single dose, crossover, bioequivalence study of fixed-dose combination tablet(s) of dolutegravir and lamivudine versus dolutegravir and lamivudine single entities and food effect assessment in healthy volunteers.

In addition, the MAH took the opportunity to bring the PI in line with the latest QRD template version 10.2 and to introduce minor editorial changes.
The requested worksharing procedure proposed amendments to the Summary of Product Characteristics, Annex II, Labelling and Package Leaflet.

Type II variation – Update to 3TC Elimination half-life
EMEA/H/C/WS2163

Pursuant to Article 16 of Commission Regulation (EC) No 1234/2008, ViiV Healthcare B.V. submitted to the European Medicines Agency on 30 September 2021 an application for a variation following a worksharing procedure according to Article 20 of Commission Regulation (EC) No 1234/2008.
The following changes were proposed:
Variation requested Type Annexes affected
C.I.4 C.I.4 - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data Type II I, II, IIIA and IIIB
Update of section 5.2 of the SmPC in order to add new information on the elimination half-life of lamivudine, based on final results from studies 204993 and 204994. Study 204993 was a phase I, relative oral bioavailability study of different fixed dose combinations of dolutegravir and lamivudine in healthy subjects. Study 204994 was an open-label, randomized, single dose, crossover, bioequivalence study of fixed-dose combination tablet(s) of dolutegravir and lamivudine versus dolutegravir and lamivudine single entities and food effect assessment in healthy volunteers.

In addition, the MAH took the opportunity to bring the PI in line with the latest QRD template version 10.2 and to introduce minor editorial changes.
The requested worksharing procedure proposed amendments to the Summary of Product Characteristics, Annex II, Labelling and Package Leaflet.

PIL
Section 4 - Addition of UK(NI) adverse events reporting details
Update of local representative details for UK(NI)

SPC
Section 4.2 Renal Impairment
Section 4.4 Paragraph added 'Administration in subjects with moderate renal impairment'
Section 4.8 Undesirable effects- Addition of UK(NI) ADR reporting details
Minor formatting throughout.

Type II worksharing variation to update the section 4.5 of the SmPC and section 2 of the package leaflet with new information about the drug-drug interactions between abacavir and riociguat.
Furthermore, the MAH took the opportunity to introduce an excipient update in section 4.4 of the SmPC and section 2 of the package leaflet in line with the SmPC guideline. Moreover, minor editorial updates have been introduced throughout the Product Information.

Type II worksharing variation to update the section 4.5 of the SmPC and section 2 of the package leaflet with new information about the drug-drug interactions between abacavir and riociguat. 
Furthermore, the MAH took the opportunity to introduce an excipient update in section 4.4 of the SmPC and section 2 of the package leaflet in line with the SmPC guideline. Moreover, minor editorial updates have been introduced throughout the Product Information.

Change in the address of the Marketing Aurthorisation Holder

Chnage in the address of the Marketing Authorisation Holder

Section 7 updated: MAH transfer
Section 4.8 update: removal of the IE reporting information in the UK only SPC and removal of the UK reporting information in the IE only SPC.
 

Type IA (IN) PRAC recommended variation to add Autoimmune Hepatitis (AIH) to the SmPC sections 4.4 and 4.8.

SmPC Section 4.4 Warnings:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

SmPC Section 4.8 Undesirable events:
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. (see section 4.4).

Section 4.4: a minor amendment has been implemented throughout the SmPC in order to update the clinical terminology of Pneumocystis carinii pneumonia to Pneumocystis jiroveci pneumonia.

Section 4.5: add information regarding the interaction between lamivudine and sorbitol

Section 4.8: UK reporting details updated in line with EMA Appendix V

Section 5.1 – antiviral activity update

Description of change to SPC:

Update to Section 6.5 –  description of CR enclosure added

Section 8 – deletion of 001 licence number

Update of sections 4.1, 4.2, 4.3, 4.4 and 4.8 of the SmPC to revise the information on hypersensitivity reactions

Reverted back to previous version of SPC on medicines.ie

Update of sections 4.1, 4.2, 4.8, 5.1 and 5.2 of the SmPC to include an update to the once-daily dosing recommendation for Kivexa to lower the threshold for use in paediatric patients from >40kg to >25 kg, which will harmonize the EU dosing recommendations with those in the WHO treatment guidelines, based on data from study COL105677 (ARROW).

Update of sections 4.1, 4.2, 4.3, 4.4 and 4.8 of the SmPC to revise the information on hypersensitivity reactions

Update to SPC – please refer to attached tracked document for detailed changes.  The following sections have been updated:

·         Section 2 – description of excipient

·         Section 4.1 - Indications section reworded, removal of screening before re-initiation of ABC in patients with  unknown HLA B*5707 status

·         Section 4.2 – layout of information changed, rewording of use in paediatric population and use in renal impairment

·         Section 4.3 – HIV transmission labelling update, formatting changes, rewording of use in patients with hep B/C

·         Section 4.5 – statement added to re-iterate that Kivexa should not be used with any other products containing lamividine (now mentioned in Section 4.4 & 4.5), DI with emtricitatbine/lamivudine added to table, re-wording of recommendation for use of Kivexa with anti-infective products

·         Section 4.6 – Pregnancy/lactation wording updated

·         Section 4.8 - Angioedema added as rare ADR, QRD update to include reporting details

·         Section 5.1, 5.3, 6.1, 6.5 & 9 all updated

·         There are a number of editorial changes in sections 4.5, 10

·         The following text was added to section 4.4 of the SPC with regards to cladribine

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

·         The following text was added to section 4.5 of the SPC with regards to autoimmune disorders

4.2       Posology and method of administration

Added subheading ‘Posology’.

4.3       Contraindications

Added the following contraindication:

Kivexa should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

4.5       Interaction with other medicinal products and other forms of interaction

Added warning that the co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure and the co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.

Interaction data was updated in line with the tabular format described in the HIV guideline

4.6       Fertility, pregnancy and lactation

Updated statements regarding use in pregnancy, lactation and added statement regarding fertility.

Added ‘fertility’ to the heading

5.1       Pharmacodynamic properties

Updated in line with the Annex B template of the guideline on the clinical development of medicinal products for the treatment of HIV infection, as requested by the CHMP: Restructured with data obtained from literature review and reports previously submitted by the MAH, in line with the HIV guideline EMEA/CPMP/EWP/633/02. The revision concerned the data on in vitro antiviral activity against HIV-1, including non-B subtypes, and HIV-2 for the individual drug components abacavir and lamivudine and/or in combination; data on the impact of selection for additional resistance mutations upon the susceptibility to abacavir or lamivudine in-vitro and in vivo and for therapy-naive versus experienced patients. Furthermore the clinical experience data was organised under separate headings for treatment naïve patients and treatment-experienced patients. In addition the results of treatment-naïve studies CNA30021, EPZ104057 (HEAT), CNA109586 (ASSERT) are now presented in the proposed tabulated format. The tables for CNA30021, EPZ104057 (HEAT) and CNA109586 (ASSERT) have been updated with additional sub-group analyses for baseline ribonucleic acid (RNA) for each of the studies and also for baseline CD4 categories for the CNA30021 study. Data from studies CAL30001 and ESS30008 has been revised to expand on the statistical test results of the analyses. Two tables were introduced from CAL30001 and CNA30021 studies on the Proportion of Patients with <50 cps/mL at Week 48 by Genotypic

4.1       Therapeutic indications

Added reference to sections 4.4 and 5.1 of the SPC

4.4       Special warnings and precautions for use

Added a new sub-heading ‘Risk of virological failure’, under which the following statement was added to the existing statement regarding Triple nucleoside therapy:

- The risk of virological failure with Kivexa might be higher than with other therapeutic options (see section 5.1).

Amended text Highlighted in Red 

4.4   Special warnings and precautions for use

………………

Myocardial Infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk.  Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction.  To date, there is no established biological mechanism to explain a potential increase in risk.  When prescribing Ziagen, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: 'nucleoside reverse transcriptase inhibitors (NTRIs).Antivirals for treatment of HIV infections, combinations. ATC code: J05AR02.

In vivo resistance (Therapy experienced patients): The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy and confer high-level resistance to lamivudine. In vitro data tend to suggest that the continuation of lamivudine in antiretroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTIs should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available.

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32 %, Cmax24,ss + 99 % and Ctrough + 18 %) compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC24,ss and Cmax24,ss) or lower (Ctrough – 24 %) for the lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen. Overall, tThese data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021- See Clinical experience).