Author: Roche Registration Ltd.


Long information

What is it and how is it used?

Invirase is an antiviral agent. It is a member of a class of medicines called protease inhibitors. It is for the treatment of infection with the human immunodeficiency virus (HIV).

Invirase is used by HIV-infected individuals over 16 years of age. Invirase is prescribed for use in combination with ritonavir and other antiretroviral medicines.

Table of Contents
What do you have to consider before using it?
How is it used?
What are possible side effects?
How should it be stored?
Further information

What do you have to consider before using it?

Do not take Invirase

- if you are allergic (hypersensitive) to saquinavir, ritonavir or any of the other ingredients (see section ?Important information about an ingredient of Invirase? and section ?What Invirase contains?).
- if you were born with or have

  • any condition with certain abnormal electrocardiogram (ECG, electrical recording of the heart) changes,
  • a salt imbalance in the blood, especially low concentrations of potassium in the blood (hypokalaemia) which are currently not corrected by treatment,
  • a very slow heart rate (bradycardia),
  • a weak heart (heart failure), or
  • a history of abnormal heart rhythms (arrhythmias) - if you are taking other medicines that result in certain abnormal ECG changes:
  • certain HIV antiviral agents (e.g. atazanavir, lopinavir),
  • certain heart medicines (amiodarone, bepridil, dofetilide, flecainide, hydroquinidine, ibutilide, lidocaine, propafenone, quinidine, sotalol),
  • medicines to treat depression (amitryptiline, imipramine, trazodone),
  • medicines used to treat severe mental disorders (e.g. clozapine, haloperidol, mesoridazine, phenothiazines, sertindole, sultopride, thioridazine, ziprasidone),
  • certain anti-infectives (e.g. clarithromycin, erythromycin, halofantrine, pentamidine, sparfloxacin)
  • certain narcotic analgesics (e.g. methadone),
  • medicines used to treat erectile dysfunction (sildenafil, vardenafil, tadalafil),
  • some other medicines (alfentanyl, cisapride, dapsone, diphemanil, disopyramide, fentanyl, mizolastine, quinine, vincamine) - if you have liver disease with severe disease symptoms (e.g. jaundice or hepatitis with liquid accumulation in the belly, mental confusion and/or bleeding from veins of the oesophagus). - if you are currently taking any of the following medicines:
  • terfenadine and astemizole (commonly used to treat allergy symptoms),
  • pimozide (for psychiatric problems),
  • ergot alkaloids (used to treat migraine attacks),
  • triazolam and oral (taken by mouth) midazolam (used to help you sleep and/or relieve anxiety),
  • rifampicin (used to prevent or treat tuberculosis),
  • simvastatin and lovastatin (used to lower blood cholesterol).

Take special care with Invirase

You should know that Invirase/ritonavir is not a cure for HIV infection and that you may continue to develop infections or other illnesses associated with HIV disease. You should, therefore, remain under the care of your doctor while taking Invirase/ritonavir.

Treatment with Invirase/ritonavir has not been shown to reduce the risk of transmission of HIV to others through sexual contacts or contamination with blood. Therefore, you must continue to take appropriate precautions to avoid giving the virus to others.

At present, there is only limited information on the use of Invirase/ritonavir in children under the age of 16 years and in adults over 60 years.

Abnormal heart rhythms (arrhythmias):

Invirase can change your heart?s ECG, especially if you are female or elderly. If you are taking any medicine that decreases your blood potassium levels talk to your doctor before taking Invirase. Contact your doctor immediately, if you experience palpitations or an irregular heartbeat during treatment. He/she may wish to perform an ECG to measure your heart rhythm.

Consult your doctor if you have a history of kidney disease.

Please speak with your doctor if you have a history of liver disease. Patients with chronic hepatitis B or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests for control of liver function.

There are certain conditions, which you may have, or have had, which require special care before or while taking Invirase/ritonavir. Therefore, before using this medicine, you should have told your doctor if you suffer from diabetes mellitus, diarrhoea, or if you have allergies (see section 4) or if you have an intolerance to some sugars (see section ?Important information about an ingredient of Invirase?).

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body?s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately (see section 4).

Redistribution, accumulation or loss of body fat may occur in patients receiving combination antiretroviral therapy. Contact your doctor if you notice changes in body fat (see section 4).

Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Invirase/ritonavir may be taken with a number of other medications that are commonly used in HIV infection.

There are some medications that must not be taken with Invirase/ritonavir (see section "Do not take

Invirase") or that require dosage reduction of that medicine or Invirase or ritonavir. Ask your doctor or pharmacist for more information about taking Invirase/ritonavir with other medicines.

Medicines that can interact with saquinavir andor ritonavir include other HIV antiviral agents e.g. nelfinavir, indinavir, nevirapine, delavirdine, efavirenz, some medicines affecting the immune system e.g. ciclosporin, sirolimus rapamycin, tacrolimus, various steroids e.g. dexamethasone, ethinyl estradiol, fluticasone, certain heart medicines e.g. calcium channel blockers, quinidine, digoxin, medicines used to lower blood cholesterol e.g. statins, antifungals ketoconazole, itraconazole, anticonvulsants e.g. phenobarbital, phenytoin, carbamazepine, sedative agents e.g. midazolam administered by injection, certain antibiotics e.g. quinupristindalfopristin, rifabutin, medicines to treat depression e.g. nefazodone, tricyclic antidepressants, medicines for anticoagulation warfarin, herbal preparations containing St. Johns wort or garlic capsules, some medicines that treat diseases related to the acid in the stomach e.g. omeprazole or other proton pump inhibitors

Therefore you should not take Invirase/ritonavir with other medicines without your doctor?s consent.

If you are taking an oral contraceptive to prevent pregnancy, you should use an additional or different type of contraception since ritonavir may reduce the effectiveness of oral contraceptives.

Taking Invirase with food and drinkInvirase must be taken together with ritonavir and with or after food.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. Inform your doctor if you are pregnant or planning to become pregnant. This medicine should be taken during pregnancy only after consultation with your doctor.

You should not breast-feed your baby if you are taking Invirase/ritonavir.

Driving and using machines

Invirase has not been tested for its effect on your ability to drive a car or operate machinery. However, dizziness and fatigue have been reported during treatment with Invirase. Do not drive or operate machines if you experience these symptoms.

Important information about an ingredient of Invirase

Each film-coated tablet contains lactose (monohydrate) 38.5 mg. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How is it used?

Always take Invirase/ritonavir exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Invirase is provided as 500 mg film-coated tablet. For patients in whom the 500 mg film-coated tablet is not suitable, Invirase is also available in the form of 200 mg hard capsules. Your doctor will prescribe Invirase in combination with Norvir (ritonavir) and other HIV medicines. The dosage of Invirase is two 500 mg film-coated tablets with one 100 mg capsule of Norvir (ritonavir) two times daily. If you have not received other HIV medicines before and you are taking Invirase for the first time, you should take a reduced dosage of Invirase of one 500 mg film coated tablet with one 100 mg capsule of Norvir (ritonavir) two times daily for the first week. After the first week you should continue with the standard Invirase dosage of two 500 mg film-coated tablets with one 100 mg capsule of Norvir (ritonavir) two times daily. Patients who switch immediately without pause between the treatment regimens from another protease inhibitor in combination with Norvir (ritonavir) or from a non-nucleoside reverse transcriptase inhibitor based regimen should initiate and continue with the standard recommended dosage of Invirase of two 500 mg film-coated tablets two times daily with ritonavir 100 mg two times daily. Invirase should be taken at the same time as Norvir (ritonavir) and with or after food.

The film-coated tablets should be swallowed whole together with water.

If you take more Invirase than you shouldIf you have taken more than the prescribed dose of Invirase/ritonavir you must contact your doctor or pharmacist.

If you forget to take Invirase

Do not take a double dose to make up for a forgotten individual dose. If you forget to take one dose, take this dose as soon as you remember together with some food. Then go on with the regular schedule as prescribed. Do not change the prescribed dose yourself.

If you stop taking Invirase
Continue to take this medicine until your doctor tells you otherwise.

What are possible side effects?

Like all medicines, Invirase/ritonavir can cause side effects, although not everybody gets them.

When treating HIV infection it is not always possible to differentiate between unwanted effects caused by Invirase or by any other medicines you take at the same time or by the complications of the infection. For these reasons it is very important to inform your doctor of any change in your condition.

The most frequently (in more than ten in a hundred) reported side effects of saquinavir taken with ritonavir concern the gastrointestinal tract, with feeling sick, diarrhoea, tiredness, vomiting, wind and abdominal pain being the most common. Also, changes in laboratory markers (e.g., blood or urine tests) have been reported very commonly.

Other, less frequently reported side effects ( in more than one in a hundred but less than one in ten persons), which may occur are: rash, itching, eczema and dry skin, hair loss, dry mouth, headache, peripheral neuropathy (a disturbance of the nerves in the feet and hands that may take the form of numbness, pins and needles, shooting or burning pain), co-ordination problems, fainting, confusion, weakness, dizziness, depression, anxiety, mood swings, night sweats and hot flushes, inability to sleep, libido problems, taste alteration, warts, mouth ulcers, dehydration, abdominal discomfort, indigestion, fever, pain, constipation, decreased as well as increased appetite, inflammation of gastrointestinal tract, piles, discoloured faeces, visual disturbance, eye pain, raised blood pressure, infections of the respiratory tract, muscle spasms, joint pain, blood collection in the joint, painful urination and infections of the urinary tract, fever and shivering, shortness of breath and chest pain.

Furthermore, inflammation of the liver, fits, allergic reactions, sleepiness and abnormal renal function have been reported.

Your doctor will test your blood regularly to detect possible abnormalities.

Cases of diabetes mellitus or increased blood sugar levels have been reported in patients receiving this treatment or another protease inhibitor.

In patients with haemophilia type A and B, there have been reports of increased bleeding while taking this treatment or another protease inhibitor. Should this happen to you, seek immediate advice from your doctor.

Combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (?buffalo hump?). The cause and long-term health effects of these conditions are not known at this time. Combination antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipaemia (increased fats in the blood) and resistance to insulin.

There have been reports of muscle pain, tenderness or weakness, particularly with combination antiretroviral therapy including protease inhibitors and nucleoside analogues. On rare occasions these muscle disorders have been serious (rhabdomyolysis).

If you experience any side effects that are not in this leaflet, please tell your doctor or pharmacist. Also, tell your doctor if you have any severe or unusual symptoms or if any side effect that you think you may have gets worse or persists.

How should it be stored?

Keep out of the reach and sight of children.

Invirase does not require any special storage conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

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,
Shire Park,
Welwyn Garden City,
AL7 1TW,
United Kingdom.

Manufacturer

Roche Pharma AG,
Emil-Barell-Strasse 1,
79639 Grenzach-Wyhlen,
Germany.

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

Malta See United Kingdom eská republika Roche s. r. o. Tel 420 - 2 20382111 Danmark Roche as Tlf 45 - 36 39 99 99 Nederland Roche Nederland B.V. Tel 31 0 348 438050

Deutschland Roche Pharma AG Tel 49 0 7624 140 Norge Roche Norge AS Tlf 47 - 22 78 90 00

Eesti Roche Eesti OÜ Tel 372 - 6 177 380 Österreich Roche Austria GmbH Tel 43 0 1 27739

Roche Hellas A.E. 30 210 61 66 100 Polska Roche Polska Sp.z o.o. Tel 48 - 22 345 18 88

España Roche Farma S.A. Tel 34 - 91 324 81 00 Portugal Roche Farmacêutica Química, Lda Tel 351 - 21 425 70 00

France Roche Tél 33 0 1 46 40 50 00 România Roche România S.R.L. Tel 40 21 206 47 01

Ireland Roche Products Ireland Ltd. Tel 353 0 1 469 0700 Slovenija Roche farmacevtska druba d.o.o. Tel 386 - 1 360 26 00

Slovenská republika Roche Slovensko, s.r.o. Tel 421 - 2 52638201 Ísland Roche as co Icepharma hf Sími 354 540 8000

Italia Roche S.p.A. Tel 39 - 039 2471 SuomiFinland Roche Oy PuhTel 358 0 10 554 500

K .. . 357 - 22 76 62 76 Sverige Roche AB Tel 46 0 8 726 1200

Latvija Roche Latvija SIA Tel 371 6 7039831 United Kingdom Roche Products Ltd. Tel 44 0 1707 366000

Lietuva

UAB ?Roche Lietuva?
Tel: +370 5 2546799

This leaflet was last approved in

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, ANNEX II AND PACKAGE LEAFLET PRESENTED BY THE EUROPEAN MEDICINES AGENCY

Scientific conclusions

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.

Efficacy

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.

Safety

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.

Benefit/risk balance

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

Whereas

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.

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