What Invirase contains
The active substance is saquinavir. One film-coated tablet of Invirase contains 500 mg of saquinavir as saquinavir mesilate. The other ingredients are microcrystalline cellulose, croscarmellose sodium, povidone, lactose monohydrate 38.5 mg, magnesium stearate, hypromellose, titanium dioxide E 171, talc, glycerol triacetate, iron oxide yellow E172 and iron oxide red E172.
What Invirase looks like and contents of the pack
Invirase 500 mg film-coated tablets are light orange to greyish or brownish orange tablets of oval shape with the marking "SQV 500" on the one side and "ROCHE" on the other side. One plastic (HDPE) bottle contains 120 tablets.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Roche Registration Limited,
6 Falcon Way,
Welwyn Garden City,
Roche Pharma AG,
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
LuxembourgLuxemburg Voirsiehe BelgiqueBelgien BelgiëBelgiqueBelgien N.V. Roche S.A. TélTel 32 0 2 525 82 11
359 2 818 44 44 Magyarország Roche Magyarország Kft. Tel 36 - 23 446 800
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This leaflet was last approved in
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, ANNEX II AND PACKAGE LEAFLET PRESENTED BY THE EUROPEAN MEDICINES AGENCY
Overall summary of the scientific evaluation of Invirase
Invirase (saquinavir [SQV]) is an inhibitor of the HIV viral protease preventing the creation of mature infectious virus particles. Invirase is approved in several countries including the United States, Switzerland, Canada and Australia, and was the first protease inhibitor (PI) approved for the treatment of HIV-infected adult patients in the European Union via the Centralised procedure in 1996. Invirase is recommended to be used only in combination with ritonavir (r) and other antiretroviral medicinal products. The recommended dose is 1000 mg twice daily (bid) with ritonavir 100 mg twice daily. Invirase is available in 200 mg capsules and 500 mg tablets.
A publication in The Lancet reported cases of QT prolongation in patients receiving PIs and showed dose dependent blockage of hERG channels in vitro for saquinavir, lopinavir (LPV), nelfinavir and ritonavir. The Marketing Authorisation Holder (MAH) of Invirase conducted two studies (supra-therapeutic dose finding study [NP 21562] and thorough QTc study [NP 21249]) to investigate the effect of saquinavir boosted with ritonavir (SQV/r) on the QT interval in healthy volunteers. These studies were assessed by the CHMP in the scope of a type II variation in June 2010 (EMEA/H/C/113/II/085). The thorough QTc-study showed a dose dependent, significant prolongation of the QT interval and PR interval with both therapeutic and supra-therapeutic dose regimens of saquinavir.
Based on the data available in the framework of the type II variation and on the increase of the QT prolongation observed, the European Commission initiated a review under Article 20 of Regulation (EC) No 726/2004.
The efficacy of saquinavir in HIV-infected patients has been demonstrated in the past 14 years. Invirase was the first PI being approved followed by other nine PIs, some of which are currently considered first line treatment. Invirase has been recognised as currently being used in second- or third-line therapy as an alternative PI in patients who are intolerant to or have experienced clinical adverse events (e.g. diarrhea) or laboratory abnormalities (e.g. increased liver function tests or lipid levels).
There is some uncertainty about the superior tolerability and better lipid profile claimed for Invirase compared to other PIs since the studies of comparative efficacy and tolerability for saquinavir versus other PIs (indinavir, lopinavir) have some limitations due to their design and compliance to treatment (higher pill burden of SQV/r 1000mg/100mg bid). However, some European guidelines still refer Invirase in first line treatment.
Results of a thorough QT/QTc study (NP 21249) in healthy volunteers demonstrated dose dependent QT and PR prolongation with the therapeutic dose of saquinavir 1000 mg boosted with ritonavir 100 mg bid on day 3 and has identified an average maximum prolongation of QT interval by 18.86 milliseconds (ms) at 12 hours post dose compared to a single dose of moxifloxacin 400 mg of 12.18 ms at 4 hrs post dose. There were no reports of QT prolongation >500 ms nor of Torsades de Points (TdP) in this study. There was one case of first degree atriovascular (AV) block that resulted in discontinuation of treatment.
The QT prolongation seen in this study was greater than that seen with moxifloxacin control. Dedicated QT studies of other protease inhibitors have not shown such degree of prolongation. However cross-study comparisons should be interpreted with caution due to differences in study drugs, doses chosen, timing of ECG monitoring relative to maximal plasma concentrations, design, conduct and analysis.
The MAH provided additional ECG data and PK/PD analyses from the thorough QT/QTc study and ECG data from several clinical pharmacology studies.
The additional QTc values from study NP 21249, indicate declining effect on QTc after 12h and 20h for the 1000/100mg and 1500/100mg SQV/r dose, respectively. The post-hoc exploratory PK/PD analysis provides evidence of dose dependence of SQV-induced QTc prolongation suggesting a linear relationship between C max and observed QTc increase. ECG data provided from other clinical pharmacology studies, although with methodological limitations showed no signal for delayed and progressive increases of QT intervals for SQV/r dose of 1000/100mg given for 2 ? 4 weeks. Overall, no signal for delayed and progressive increases of QT intervals is detectable from the additional analyses provided.
The hypothetical highest risk of QT prolongation and arrhythmias for individual patients during phases of highest drug exposure, such as during the first week of therapy (as indicated by the results of the thorough QT/QTc study on day 3) or when concomitant treatment with drugs significantly increasing SQV exposure is initiated, was confirmed by the additional PK-PD data submitted.
No new safety data was presented during this review. Post marketing data identified one death due to TdP in 1996 (before ritonavir was added to boost Invirase). This case was confounded by several factors including concomitant medication with products (methadone, haloperidol, clindamycin, pyrimethamine, and sulfadiazine) that are known to cause QT prolongation/TdP and are now contraindicated. Two other cases of QT prolongation were identified with medicinal products known to cause QT prolongation: astemizole (1996; before boosting) and Invirase/r-ciprofloxacin-LPV/r-diltiazem 2007; after boosting). There were no post marketing experience reports of PR prolongation or AV block (1 st, 2 nd, 3 rd degree) associated with Invirase or concomitant Invirase/r in post-marketing data. Overall, no cardiovascular signal was detected from post-marketing data but the patients exposure has been rather limited (compared with other PIs) and underreporting or misclassification cannot be excluded. The comparison of saquinavir/r with more recent and frequently prescribed PIs like lopinavir/r or atazanavir, which showed a small signal in QT studies but reported more cases of TdP during post marketing is difficult.
Based on the above the MAH submitted PK/PD data in healthy volunteers and HIV infected patients to support an initial lower dosing regimen (i.e. 500/100 mg of Invirase/r bid) during the first week in treatment-naïve patients starting treatment with RTV-boosted Invirase (followed by the approved dose of 1000/100mg Invirase/r bid) as a measure to minimise the risk for QT prolongation identified for this group of patients considered to be at highest risk.
The proposed regimen is expected to provide the required safety during the time of treatment initiation together with adequate efficacy in treatment-naïve patients. To further confirm the increased safety (with regards to QT prolongation) with the newly regimen while maintaining similar efficacy, the CHMP requested the MAH to perform a clinical study specifically investigating the PK and QT prolongation in HIV patients initiating de novo treatment with SQV/r. The study protocol will be submitted to the CHMP for review and agreement.
In addition, and considering that contraindications for concomitant use of Invirase with QT prolonging medicinal products are already in place, the CHMP agreed on the need for the MAH to specifically report in PSURs off-label cases with concomitant use of Invirase with these recently contraindicated medicinal products. To allow this close monitoring the PSUR cycle has been shortened for yearly submission.
Furthermore, the CHMP agreed to detailed recommendations for ECG monitoring in the SmPC in view of the fact that the risk for QT prolongation is different for patients starting treatment with Invirase/r than for patients stable on Invirase/r treatment. For patients demonstrating a clinically relevant increase in QT interval with concomitant therapy, either RTV-boosted Invirase or the concomitant therapy or both should be discontinued. To address the fact that there are treatment guidelines that recommend off-label dosing of SQV/rtv 2000/100mg once daily and that this regimen, not being approved, might pose patients at higher risk of arrhythmias due to increased exposure, the CHMP agreed to strengthen the warnings on cardiovascular risks to clearly mention that the recommended dose should not be exceeded.
Taken this into account, the benefit/risk balance for Invirase remains is favourable for HIV-1 infected patients in accordance with the above mentioned recommendations and as stated in the annexes to this Opinion.
Grounds for amendment of the Summary of Product Characteristics, Annex II and Package Leaflet
The Committee considered the procedure under Article 20 of Regulation EC No 7262004, for Invirase initiated by the European Commission.
The Committee reviewed all preclinical and clinical efficacy and safety data submitted by the MAH in relation to the cardiovascular risk of Invirase
The Committee confirmed the evidence of dose dependence of SQV-induced QTc prolongation suggesting a linear relationship between the maximum concentration and observed QTc increase. Therefore, a higher risk of QT prolongation and arrhythmias for individual patients during phases of highest exposure of the product, such as during the first week of therapy The Committee, considering pharmacokineticpharmacodynamic data in healthy volunteers and HIV infected patients, concluded on an initial lower dosing regimen i.e. 500100 mg of Inviraser twice a day during the first week in treatment-naïve patients starting treatment with RTV-boosted Invirase
The CHMP concluded that the Product Information for Invirase should further detail the precautions for use with regards to the monitoring of the ECG and strengthen the warning that the recommended dose for Invirase should not be exceeded. A Risk Management Plan has been agreed for Invirase including a clinical study to determine the effect of the modified saquinavir-boosted by ritonavir reduced dose regimen 500100 mg for the 1st week followed by 1000100 mg for the 2nd week on the QTc interval and pharmacokinetics in HIV-1 infected patients. The increase frequency of the submission of PSURs on a yearly basis was also included in the Risk Management Plan.
The Committee, as a consequence, concluded that benefit still outweighs the risks in the currently authorised therapeutic indication for Invirase.