Invirase - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

INVIRASE 500 mg film-coated tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 500 mg of saquinavir as saquinavir mesilate.

Excipient with known effect : Lactose monohydrate: 38.5 mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Light orange to greyish or brownish orange film-coated tablet of oval cylindrical biconvex shape with the marking „SQV 500“ on the one side and „ROCHE“ on the other side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Invirase is indicated for the treatment of HIV-1 infected adult patients. Invirase should only be given in combination with ritonavir and other antiretroviral medicinal products (see section 4.2).

4.2 Posology and method of administration

Posology

Therapy with Invirase should be initiated by a physician experienced in the management of HIV infection.

In combination with ritonavir

The recommended dose of Invirase is 1000 mg (2 × 500 mg film-coated tablets) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. For treatment-naive patients initiating treatment with Invirase/ritonavir, the starting recommended dose of Invirase is 500 mg (1 × 500 mg film-coated tablet) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents for the first 7 days of treatment. After 7 days, the recommended dose of Invirase is 1000 mg two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. Patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from a non-nucleoside reverse transcriptase inhibitor based regimen, except rilpivirine (see section 4.5), without a wash-out period, should however initiate and continue Invirase at the standard recommended dose of 1000 mg two times daily with ritonavir 100 mg two times daily.

Renal impairment:

No dosage adjustment is necessary for patients with mild to moderate renal impairment. Caution should be exercised in patients with severe renal impairment (see section 4.4).

Hepatic impairment:

No dosage adjustment is necessary for HIV-infected patients with mild hepatic impairment. No dosage adjustment seems warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to increased variability of the exposure in this population. Invirase/ritonavir is contraindicated in patients with decompensated hepatic impairment (see sections 4.3 and 4.4).

Paediatric population:

The safety and activity of saquinavir boosted with ritonavir in HIV-infected patients less than 2 years have not been established. No dose recommendations for paediatric patients >2 years of age could be established that are both effective and below thresholds of concern for QT and PR interval prolongation.

Adults over 60 years:

The experience with Invirase in adults over 60 years is limited.

Method of administration

Invirase film-coated tablets should be swallowed whole and taken at the same time as ritonavir with or after food (see section 5.2).

4.3 Contraindications

Invirase is contraindicated in patients with:

• • hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• • decompensated liver disease (see section 4.4)
• • congenital or documented acquired QT prolongation
• • electrolyte disturbances, particularly uncorrected hypokalaemia
• • clinically relevant bradycardia
• • clinically relevant heart failure with reduced left-ventricular ejection fraction
• • previous history of symptomatic arrhythmias
• • concurrent therapy with any of the following drugs, which may interact and result in potentially life-threatening undesirable effects (see sections 4.4, 4.5 and 4.8):

• - drugs that prolong the QT and/or PR interval (see sections 4.4 and 4.5)

• – midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), triazolam (potential for prolonged or increased sedation, respiratory depression)

• – simvastatin, lovastatin (increased risk of myopathy including rhabdomyolysis)

• – ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine) (potential for acute ergot toxicity)

• – rifampicin (risk of severe hepatocellular toxicity) (see sections 4.4, 4.5, and 4.8)

• – quetiapine (risk of coma, see section 4.5).

• – lurasidone (potential for serious and/or life-threatening reactions, see section 4.5)

4.4 Special warnings and precautions for use

Considerations when initiating Invirase therapy: Invirase should not be given as the sole protease inhibitor. Invirase should only be given in combination with ritonavir (see section 4.2). Invirase is not recommended for use in combination with cobicistat as dosing recommendations for this combination have not been established.

Patients should be informed that saquinavir is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Patients should also be advised that they might experience undesirable effects associated with coadministered medications.

Cardiac conduction and repolarisation abnormalities:

Dose-dependent prolongations of QT and PR intervals have been observed in healthy volunteers receiving ritonavir-boosted Invirase (see section 5.1). Concomitant use of ritonavir-boosted Invirase with other medicinal products that prolong the QT and/or PR interval is therefore contraindicated (see section 4.3).

Since the magnitude of QT and PR prolongation increases with increasing concentrations of saquinavir, the recommended dose of ritonavir-boosted Invirase should not be exceeded. Ritonavir-boosted Invirase at a dose of 2000 mg once daily with ritonavir 100 mg once daily has not been studied with regard to the risk of QT prolongation and is not recommended. Other medicinal products known to increase the plasma concentration of ritonavir-boosted Invirase should be used with caution.

Women and elderly patients may be more susceptible to drug-associated effects on the QT and/or PR interval.

• • Clinical Management:

Consideration should be given for performing baseline and follow-up electrocardiograms after initiation of treatment, e.g. in patients taking concomitant medication known to increase the exposure of saquinavir (see section 4.5). If signs or symptoms suggesting cardiac arrhythmia occur, continuous monitoring of ECG should be performed. Ritonavir-boosted Invirase should be discontinued if arrhythmias are demonstrated, or if prolongation occurs in the QT or PR interval.

Patients initiating therapy with ritonavir-boosted Invirase :

• – An ECG should be performed on all patients prior to initiation of treatment: patients with a QT interval > 450 msec should not use ritonavir-boosted Invirase. For patients with a QT interval < 450 msec, an on treatment ECG is recommended.

• – For treatment-naive patients initiating treatment with Invirase/ritonavir 500/100 mg two

times daily for the first 7 days of treatment followed by Invirase 1000 mg two times daily with ritonavir 100 mg two times daily after 7 days and with a baseline QT interval < 450 msec, an on-treatment ECG is suggested after approximately 10 days of therapy.

• – Patients demonstrating a subsequent increase in QT-interval to > 480 msec or prolongation over pre-treatment by > 20 msec should discontinue ritonavir-boosted Invirase.

Patients stable on ritonavir-boosted Invirase and requiring concomitant medication with potential to increase the exposure of saquinavir or patients on medication with potential to increase the exposure of saquinavir and requiring concomitant ritonavir-boosted Invirase where no alternative therapy is available and the benefits outweigh the risks:

• – An ECG should be performed prior to initiation of the concomitant therapy: patients with a QT interval > 450 msec should not initiate the concomitant therapy (see section 4.5).

• – For patients with a baseline QT interval < 450 msec, an on-treatment ECG should be performed. For patients demonstrating a subsequent increase in QT-interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either ritonavir-boosted Invirase or the concomitant therapy or both.

• • Essential Patient Information:

Prescribers must ensure that patients are fully informed regarding the following information on cardiac conduction and repolarisation abnormalities:

• – Patients initiating therapy with ritonavir boosted Invirase should be warned of the arrhythmogenic risk associated with QT and PR prolongation and told to report any sign or symptom suspicious of cardiac arrhythmia (e.g., chest palpitations, syncope, presyncope) to their physician.

• – Physicians should enquire about any known familial history of sudden death at a young age as this may be suggestive of congenital QT prolongation.

• – Patients should be advised of the importance not to exceed the recommended dose.

• – Each patient (or patient’s care­giver) should be reminded to read the Package Leaflet included in the Invirase Package.

Liver disease: The safety and efficacy of saquinavir/ri­tonavir has not been established in patients with significant underlying liver disorders, therefore saquinavir/ri­tonavir should be used cautiously in this patient population. Invirase/ritonavir is contraindicated in patients with decompensated liver disease (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

No dosage adjustment seems warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to increased variability of the exposure in this population (see sections 4.2 and 5.2). There have been reports of exacerbation of chronic liver dysfunction, including portal hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver abnormalities.

Renal impairment: Renal clearance is only a minor elimination pathway, the principal route of metabolism and excretion for saquinavir being via the liver. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied and caution should be exercised when prescribing saquinavir/ri­tonavir in this population.

Patients with chronic diarrhoea or malabsorption: No information on boosted saquinavir and only limited information on the safety and efficacy of unboosted saquinavir is available for patients suffering from chronic diarrhoea or malabsorption. It is unknown whether patients with such conditions could receive subtherapeutic saquinavir levels.

Paediatric population: The safety and activity of saquinavir boosted with ritonavir in HIV-infected patients less than 2 years have not been established. No dose recommendations for paediatric patients >2 years of age could be established that are both effective and below thresholds of concern for QT and PR interval prolongation. Therefore, use in this population is not recommended.

Adults over 60 years: The experience with Invirase in adults over 60 years is limited. Elderly patients may be more susceptible to drug-associated effects on the QT and/or PR interval.

Lactose intolerance: Invirase 500 mg film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients with haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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 can occur many months after initiation of treatment.

CYP3A4 Interactions : Saquinavir could interact and modify the pharmacokinetics of other drugs that are substrates for CYP3A4 and/or P-gp and should be used with caution. Conversely, other drugs that induce CYP3A4 may also reduce saquinavir plasma concentrations. Monitoring of saquinavir plasma concentration might be indicated. See table 1, section 4.5, for drugs known and/or having the potential to interact with saquinavir and specific recommendations.

Interaction with ritonavir: The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 100 mg ritonavir twice daily. Higher doses of ritonavir have been shown to be associated with an increased incidence of adverse events. Co-administration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with preexisting liver disease.

Interaction with tipranavir: Concomitant use of boosted saquinavir and tipranavir, co-administered with low dose ritonavir in a dual-boosted regimen, results in a significant decrease in saquinavir plasma concentrations (see section 4.5). Therefore, the co-administration of boosted saquinavir and tipranavir, co-administered with low dose ritonavir, is not recommended.

Interaction with HMG-CoA reductase inhibitors: Caution must be exercised if Invirase/ritonavir is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this situation a reduced dose of atorvastatin should be considered. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended with careful monitoring (see section 4.5).

Oral contraceptives: Because concentration of ethinyl estradiol may be decreased when coadministered with Invirase/ritonavir, alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered (see section 4.5).

Glucocorticoids: Concomitant use of boosted saquinavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Interaction with efavirenz: The combination of saquinavir and ritonavir with efavirenz has been shown to be associated with an increased risk of liver toxicity; liver function should be monitored when saquinavir and ritonavir are co-administered with efavirenz. No clinically significant alterations of either saquinavir or efavirenz concentration were noted in studies in healthy volunteers or in HIV-infected patients (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Most drug interaction studies with saquinavir have been completed with unboosted Invirase or unboosted saquinavir soft capsules. A limited number of studies have been completed with ritonavir boosted Invirase or ritonavir boosted saquinavir soft capsules.

Observations from drug interaction studies done with unboosted saquinavir might not be representative of the effects seen with saquinavir/ri­tonavir therapy. Furthermore, results seen with saquinavir soft capsules may not predict the magnitude of these interactions with Invirase/ritonavir.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90 % of the hepatic metabolism. Additionally, in vitro studies have shown that saquinavir is a substrate and an inhibitor for P-glycoprotein (P-gp). Therefore, medicinal products that either share this metabolic pathway or modify CYP3A4 and/or P-gp activity (see „Other potential interactions“ ) may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other medicinal products that are substrates for CYP3A4 or P-gp.

Ritonavir can affect the pharmacokinetics of other medicinal products because it is a potent inhibitor of CYP3A4 and P-gp. Therefore, when saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on other medicinal products (see the Summary of Product Characteristics for Norvir).

Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving Invirase/ritonavir (see sections 4.3, 4.4 and 5.1), additive effects on QT and PR interval prolongation may occur. Therefore, concomitant use of ritonavir-boosted Invirase with other medicinal products that prolong the QT and/or PR interval is contraindicated. The combination of Invirase/ritonavir with drugs known to increase the exposure of saquinavir is not recommended and should be avoided when alternative treatment options are available. If concomitant use is deemed necessary because the potential benefit to the patient outweighs the risk, particular caution is warranted (see section 4.4; for information on individual drugs, see Table 1).

Table 1: Interactions and dose recommendations with other medicinal products

Key: ^ reduced, f increased, o unchanged, ff markedly increased

4.6 Fertility, pregnancy and lactation

Pregnancy : Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo or foetus, the course of gestation and peri- and post-natal development. Clinical experience in pregnant women is limited: Congenital malformations, birth defects and other disorders (without a congenital malformation) have been reported rarely in pregnant women who had received saquinavir in combination with other antiretroviral agents. However, so far the available data are insufficient and do not identify specific risks for the unborn child. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus (see section 5.3).

Breast-feeding : There are no laboratory animal or human data available on secretion of saquinavir in breast milk. The potential for adverse reactions to saquinavir in nursing infants cannot be assessed, and therefore, breast-feeding should be discontinued prior to receiving saquinavir. It is recommended that HIV-infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects on ability to drive and use machines

Invirase may have a minor influence on the ability to drive and use machines. Dizziness, fatigue and visual impairment have been reported during treatment with Invirase. No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

• a. Summary of the safety profile

Limited data is available from two clinical studies where the safety of saquinavir soft capsule (1000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks was studied in 311 patients.

The following adverse events with an at least possible relationship to ritonavir boosted saquinavir (i.e. adverse reactions) were reported most frequently: nausea, diarrhoea, fatigue, vomiting, flatulence, and abdominal pain.

The following adverse events were reported with the highest severity (grades 3 and 4): anaemia, diabetes mellitus, diarrhoea, nausea, vomiting and fatigue.

For comprehensive dose adjustment recommendations and drug-associated adverse reactions for ritonavir and other medicinal products used in combination with saquinavir, physicians should refer to the Summary of Product Characteristics for each of these medicinal products.

• b. Tabulated list of adverse reactions

Adverse reactions from two pivotal studies of saquinavir soft capsule (1000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks are summarised in Table 2. Also included are serious and non-serious adverse reactions from post-marketing spontaneous reports for which a causal relationship to saquinavir cannot be excluded.

Adverse reactions are presented according to the MedDRA system organ classification. The frequency groupings according to MedDRA convention are: Very common (> 1/10); common (> 1/100 to <1/10); uncommon (> 1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).

Table 2: Incidences of Adverse Reactions and marked laboratory abnormalities in clinical studies and post-marketing experience in adult patients.

• c. Description of selected adverse reactions

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophilic patients type A and B treated with protease inhibitors (see section 4.4).

Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside analogues. Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. 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).

• d. Paediatric population

Limited safety data are available from a paediatric study (NV20911, n=18) in which the safety of saquinavir hard capsules (50 mg/kg bid, not to exceed 1000 mg bid) used in combination with low dose ritonavir oral solution (3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body weight from 15 to 40 kg and 100 mg bid for body weight >40 kg) has been studied in paediatric patients aged 4 months to 6 years old.

Four patients in the study experienced five adverse events that were considered related to trial treatment. These events were vomiting (3 patients), abdominal pain (1 patient) and diarrhoea (1 patient). No unexpected adverse events were observed in this study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

There is limited experience of overdose with saquinavir. Whereas acute or chronic overdose of saquinavir alone did not result in major complications, in combination with other protease inhibitors, overdose symptoms and signs such as general weakness, fatigue, diarrhoea, nausea, vomiting, hair loss, dry mouth, hyponatraemia, weight loss and orthostatic hypotension have been observed. There is no specific antidote for overdose with saquinavir. Treatment of overdose with saquinavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, prevention of further absorption can be considered. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Antiviral agent, ATC code J05A E01

Mechanism of action: The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins. Saquinavir selectively inhibits the HIV protease, thereby preventing the creation of mature infectious virus particles.

QT and PR prolongation on electrocardiogram: The effects of therapeutic (1000/100 mg twice daily) and supra-therapeutic (1500/100 mg twice daily) doses of Invirase/ritonavir on the QT interval were evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg) study in healthy male and female volunteers aged 18 to 55 years old (N=59). On Day 3 of dosing, ECG measurements were done over a period of 20 hours. The Day 3 timepoint was chosen since the pharmacokinetic exposure was maximum on that day in a previous 14-day multiple dose pharmacokinetic study. On Day 3, mean Cmaxvalues were approximately 3-fold and 4-fold higher with the therapeutic and supra-therapeutic doses, respectively, relative to the mean Cmax observed at steady state with the therapeutic dose administered to HIV patients. On Day 3, the upper 1-sided 95% confidence interval of the maximum mean difference in pre-dose baseline-corrected QTcS (study specific heart rate corrected QT) between the active drug and placebo arms was > 10 msec for the two ritonavir-boosted Invirase treatment groups (see results in Table 3). While the supra-therapeutic dose of Invirase/ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of Invirase/ritonavir, it is not sure if maximum effect for both doses has been observed. In the therapeutic and the supra-therapeutic arm 11% and 18% of subjects, respectively, had a QTcS between 450 and 480 msec. There was no QT prolongation > 500 msec and no torsade de pointes in the study (see also section 4.4).

Table 3: Maximum mean of ddQTcS^ (msec) on day 3 for therapeutic dose of Invirase/ritonavir, supra-therapeutic dose of Invirase/ritonavir and active control moxifloxacin in healthy volunteers in Thorough QT (TQT) Study

arms

A 400 mg was administered only on Day 3

Note: QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for females, which are similar to

Fridericia’s co­rrection (QTcF=QT/RR0.333).

In this study, PR interval of > 200 msec was also observed in 40% and 47% of subjects receiving Invirase/ritonavir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3. PR intervals of > 200 msec were seen in 3% of subjects in the active control group (moxifloxacin) and 5% in the placebo arm. The maximum mean PR interval changes relative to the pre-dose baseline value were 25 msec and 34 msec in the two ritonavir-boosted Invirase treatment groups, 1000/100 mg twice daily and 1500/100 mg twice daily, respectively (also see section 4.4).

Events of syncope/presyncope occurred at a higher than expected rate and were seen more frequently under treatment with saquinavir (11 of 13). The clinical relevance of these findings from this study in healthy volunteers to the use of Invirase/ritonavir in HIV-infected patients is unclear, but doses exceeding Invirase/ritonavir 1000/100 mg twice daily should be avoided.

The effect of treatment initiation with a dosing regimen of Invirase/ritonavir 500 /100 mg twice daily in combination with 2 NRTIs for the first 7 days of treatment followed by Invirase/ritonavir 1000 / 100 mg twice daily in combination with 2 NRTIs in the subsequent 7 days on QTc interval, PK, and viral load was evaluated in an open-label 2-week observational study in 23 HIV-1 infected, treatmentnaive patients initiating Invirase/ritonavir therapy. ECG and PK measurements were collected on Days 3, 4, 7, 10, and 14 of treatment with the modified Invirase/ritonavir treatment. The primary study variable was maximal change from dense predose baseline in QTcF (AQTcFdense). The modified Invirase/ritonavir regimen reduced mean maximum AQTcFdense in the first week of treatment compared with the same value in healthy volunteers receiving the standard Invirase/ritonavir dosing regimen in the TQT study on Day 3, (Table 4) based on cross-study comparison in a different population. Only 2/21 (9%) patients across all study days had maximum QTcF change from dense predose baseline > 30 ms following administration of the modified Invirase/ritonavir regimen in the treatment-naive HIV-1 infected patient population; and the maximum mean change from dense predose baseline in QTcF was < 10 ms across all study days. These results suggest that the QTc liability is reduced with the modified Invirase/ritonavir dosing regimen, based on a cross-study comparison in a different population (Table 4). The proportion of patients with a reported PR interval prolongation > 200 ms in this study ranged from 3/22 (14%) (day 3) to 8/21 (38%) (day14).

Following the modified Invirase/ritonavir regimen, saquinavir exposure during the first week peaked on Day 3 and declined to the lowest exposure on Day 7 with ritonavir induction effects, while Day 14 saquinavir PK parameters (following full doses of Invirase/ritonavir in the second week) approached the range of historical mean values for saquinavir steady-state values in HIV-1 infected patients (Table 9). Mean Invirase Cmax with the modified Invirase/ritonavir regimen was approximately 53–83% lower across study days in the HIV-1 infected patients relative to the mean Cmax achieved in healthy volunteers in the TQT study on Day 3. Continuous declines in HIV-RNA were observed in all treatment-naive patients receiving the modified Invirase/ritonavir dosing regimen over the 2-week treatment period, suggesting HIV viral suppression during the time of the study. No long-term efficacy was evaluated with the modified regimen.

Table 4: Summary of Electrocardiogram Parameters following administration of the Modified Invirase/ritonavir Regimen in Treatment Naïve HIV-1 infected Patients initiating treatment with Invirase/ritonavir

Historical data from the thorough QT study conducted in healthy volunteers

Antiviral activity in vitro: Saquinavir demonstrates antiviral activity against a panel of laboratory strains and clinical isolates of HIV-1 with typical EC50 and EC90 values in the range 1–10 nM and 5–50 nM, respectively, with no apparent difference between subtype B and non-B clades. The corresponding serum (50% human serum) adjusted EC50 ranged from 25–250 nM. Clinical isolates of HIV-2 demonstrated EC50 values in the range of 0.3–2.4 nM.

Resistance

Antiviral activity according to baseline genotype and phenotype:

Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and analysis of a large hospital cohort (Marcelin et al 2007).

Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was shown to be a predictive factor of virological outcome. Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.

Marcelin et al (2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to saquinavir/ri­tonavir (1000/100 mg twice daily) in 138 saquinavir naive patients. The presence of 3 or more mutations was associated with reduced response to saquinavir/ri­tonavir. The association between the number of these saquinavir-associated resistance mutations and virological response was confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see Table 5). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.

Table 5: Virological response to saquinavir/ri­tonavir stratified by the number of baseline saquinavir-associated resistance mutations

*    Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T,

V82A/F/S/T, I84V, L90M

Clinical results from studies with treatment naïve and experienced patients

In the MaxCmin1 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg twice daily plus 2 NRTIs/Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) was compared to indinavir/ritonavir 800/100 mg twice daily plus 2 NRTIs/NNRTIs in over 300 (both protease inhibitor treatment naïve and experienced) subjects. The combination of saquinavir and ritonavir exhibited a superior virological activity compared with the indinavir and ritonavir arm when switch from the assigned treatment was counted as virological failure.

In the MaxCmin2 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg twice daily plus 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir 400/100 mg twice daily plus 2 NRTIs/NNRTIs in 324 (both protease inhibitor treatment naïve and experienced) subjects. None of

the subjects in the lopinavir/ritonavir arm had been exposed to lopinavir prior to randomisation whereas 16 of the subjects in the saquinavir/ri­tonavir arm had previously been exposed to saquinavir.

Table 6: Subject Demographics MaxCminl and Ma\Cmrn2"

t data from clinical study report

Clinical results from paediatric studies

The pharmacokinetics, safety and activity of saquinavir have been evaluated in an open label, multicenter study in 18 children aged 4 months to less than 6 years old in which saquinavir (50 mg/kg bid up to the adult dose of 1000 mg bid) was administered in combination with ritonavir oral solution (3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body weight from 15 to 40 kg and 100 mg bid for body weight >40 kg) plus >2 background ARVs. The infants and young children were stratified into 2 groups: Group A “Low Age Group” 4 months to less than 2 years old (n=5) and Group B “High Age Group” children 2 years to less than 6 years old (n=13).

In the “High Age Group”, the number of patients with a viral load <400 copies/mL at week 48 was 11 of 13. The number of patients with viral load <50 copies/mL was 9 of 13 for the same period. The CD4 lymphocyte count expressed as percentage mean CD4 increased by a mean of 2.97% over the same 48 week period. The size of the study was too small to allow conclusions on clinical benefit.

5.2 Pharmacokinetic properties

Saquinavir is essentially completely metabolised by CYP3A4. Ritonavir inhibits the metabolism of saquinavir, thereby increasing („boosting“) the plasma levels of saquinavir.

Absorption: In HIV-infected adult patients, Invirase in combination with ritonavir at doses of 1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with saquinavir soft capsules 1200 mg tid (see Table 8). The pharmacokinetics of saquinavir is stable during long-term treatment.

Table 8: Mean (% CV) AUC, Cmax and Cmin of saquinavir in patients following multiple dosing of Invirase, saquinavir soft capsules, Invirase/ritonavir, and saquinavir soft capsules/ritonavir

t = dosing interval, i.e. 8 hour for tid and 12 h for bid dosing.

Cmin = the observed plasma concentration at the end of the dose interval. bid = twice daily tid = three times daily

• * results are geometric mean (min – max)

• 1 derived from tid or bid dosing schedule

• 11 Ctrough values

Absolute bioavailability averaged 4 % (CV 73 %, range: 1 % to 9 %) in 8 healthy volunteers who received a single 600 mg dose (3 × 200 mg hard capsule) of Invirase following a heavy breakfast. The low bioavailability is thought to be due to a combination of incomplete absorption and extensive firstpass metabolism. Gastric pH has been shown to be only a minor component in the large increase in bioavailability seen when given with food. The absolute bioavailability of saquinavir co-administered with ritonavir has not been established in humans.

In combination with ritonavir, bioequivalence of Invirase hard capsules and film-coated tablets was demonstrated under fed conditions.

Effective therapy in treatment naïve patients is associated with a Cmin of approximately 50 ng/ml and an AUC0–24 of about 20,000 nyh ml. Effective therapy in treatment experienced patients is associated with a Cmin of approximately 100 ng/ml and an AUC0–24 of about 20,000 nyh ml.

In treatment-naïve HIV-1 infected patients initiating Invirase.ritonavir treatment with a modified Invirase/ritonavir dosing regimen of Invirase 500 mg two times daily with ritonavir 100 mg two times daily for the first 7 days of treatment and increased to Invirase 1000 mg two times daily with ritonavir 100 mg two times daily in the subsequent 7 days, saquinavir systemic exposures generally approached or exceeded the range of historical steady-state values with the standard Invirase/ritonavir 1000 mg/100 mg bid dosing regimen across study days (see Tables 9 and 8).

Table 9: Mean (CV%) PK Parameters following administration of the Modified Invirase/ritonavir Regimen in Treatment Naïve HIV-1 infected Patients initiating treatment with Invirase/ritonavir

In vitro studies have shown that saquinavir is a substrate for P-glycoprotein (P-gp).

Effect of food: In a cross-over study in 22 HIV-infected patients treated with Invirase/ritonavir 1000 mg/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a high-fat, high-calorie meal (46 g fat, 1,091 Kcal), the AUC0–12, Cmax and Ctrough values of saquinavir under fasting conditions were about 70 per cent lower than with a high-fat meal. All but one of the patients achieved Ctrough values of saquinavir above the therapeutic threshold (100 ng/ml) in the fasted state. There were no clinically significant differences in the pharmacokinetic profile of ritonavir in fasting and fed conditions but the ritonavir Ctrough (geometric mean 245 vs. 348 ng/ml) was lower in the fasting state compared to the administration with a meal. Invirase/ritonavir should be administered with or after food.

Distribution in adults: Saquinavir partitions extensively into the tissues. The mean steady-state volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 l (CV 39 %). It has been shown that saquinavir is approximately 97 % bound to plasma proteins up to 30 pg/ml. In two patients receiving Invirase 600 mg three times daily, cerebrospinal fluid concentrations of saquinavir were negligible when compared to concentrations from matching plasma samples.

Biotransformation and elimination in adults: In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90 % of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mg 14C-saquinavir (n = 8), 88 % and 1 % of the orally administered radioactivity, was recovered in faeces and urine, respectively, within 4 days of dosing. In an additional four subjects administered 10.5 mg 14C-saquinavir intravenously, 81 % and 3 % of the intravenously administered radioactivity was recovered in faeces and urine, respectively, within 4 days of dosing. 13 % of circulating saquinavir in plasma was present as unchanged compound after oral administration and the remainder as metabolites. Following intravenous administration 66 % of circulating saquinavir was present as unchanged compound and the remainder as metabolites, suggesting that saquinavir undergoes extensive first pass metabolism. In vitro experiments have shown that the hepatic metabolism of saquinavir becomes saturable at concentrations above 2 pg/ml.

Systemic clearance of saquinavir was high, 1.14 l/h/kg (CV 12 %), slightly above the hepatic plasma flow, and constant after intravenous doses of 6, 36 and 72 mg. The mean residence time of saquinavir was 7 hours (n = 8).

Special populations

Effect of gender following treatment with Invirase/rito­navir: A gender difference was observed with females showing higher saquinavir exposure than males (AUC on average 56 % higher and Cmax on average 26 % higher) in the bioequivalence study comparing Invirase 500 mg film coated tablets with Invirase 200 mg hard capsules both in combination with ritonavir. There was no evidence that age and body-weight explained the gender difference in this study. Limited data from controlled clinical studies with the approved dosage regimen do not indicate a major difference in the efficacy and safety profile between men and women.

Patients with hepatic impairment: The effect of hepatic impairment on the steady state pharmacokinetics of saquinavir/ri­tonavir (1000 mg/100 mg twice daily for 14 days) was investigated in 7 HIV-infected patients with moderate liver impairment (Child Pugh Grade B score 7 to 9). The study included a control group consisting of 7 HIV-infected patients with normal hepatic function matched with the hepatically impaired patients for age, gender, weight and tobacco use. The mean (% coefficient of variation in parentheses) values for saquinavir AUC0–12 and Cmax were 24.3 (102%) iigJir. ml and 3.6 (83%) ug. ml, respectively, for HIV-infected patients with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) iigJir. ml and 4.3 (68%) Lg.ml. The geometric mean ratio (ratio of pharmacokinetic parameters in hepatically impaired patients to patients with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both AUC0–12 and Cmax, which suggests approximately 30% reduction in the pharmacokinetic exposure in patients with moderate hepatic impairment. Results are based on total concentrations (protein-bound and unbound). Concentrations unbound at steady-state were not assessed. No dosage adjustment seems warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to increased variability of the exposure in this population (see sections 4.2 and 4.4).

Paediatric Patients : Steady state pharmacokinetic information is available from HIV-infected paediatric patients from study NV20911. In this study, 5 patients were <2 years and 13 between 2 to <6 years and received 50 mg.kg saquinavir bid (not to exceed 1000 mg bid) boosted with ritonavir at 3 mg.kg for patients with body weight ranging from 5 to <15 kg or 2.5 mg.kg for patients with body weight ranging from 15 to 40 kg (not to exceed 100 mg bid). Sixteen of 18 children could not swallow Invirase hard capsules and received medication by opening the capsules and mixing the contents with different vehicles. The pharmacokinetic exposure parameters for the “High Age Group” are listed in Table 10. Results of the “Low Age Group” are not shown as data are limited due to the small size of the group.

Table 10: Pharmacokinetic parameters of saquinavir at steady-state in HIV-infected pediatric patients

* All parameters normalized to a 50 mg.kg dose

Steady state saquinavir exposures observed in paediatric trials were substantially higher than historical data in adults where dose- and exposure-dependent QTc and PR prolongation were observed (see section 4.4).

5.3 Preclinical safety data

A cute and chronic toxicity: Saquinavir was well tolerated in oral acute and chronic toxicity studies in mice, rats, dogs and marmosets.

Mutagenesis: Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.

Carcinogenesis: There was no evidence of carcinogenic activity after the administration of saquinavir mesilate for 96 to 104 weeks to rats and mice. The plasma exposures (AUC values) in rats (maximum dose 1000 mg/kg/day) and in mice (maximum dose 2500 mg/kg/day) were lower than the expected plasma exposures obtained in humans at the recommended clinical dose of ritonavir boosted Invirase.

Reproductive toxicity: Fertility, peri- and postnatal development were not affected, and embryotoxic / teratogenic effects were not observed in rats or rabbits at plasma exposures lower than those achieved in humans at the recommended clinical dose of ritonavir boosted Invirase. Distribution studies in these species showed that the placental transfer of saquinavir is low (less than 5% of maternal plasma concentrations).

Safety pharmacology: Cloned human cardiac potassium channel (hERG) trafficking in vitro was inhibited by 75% at 30p.M of saquinavir. Saquinavir inhibited both hERG current and L-type Ca++ channel current with respective IC50s of 4.7 and 6.3 uM. In a myocardial distribution study in the rat an approximately 2-fold accumulation of saquinavir was observed in the heart compared to plasma after coadministration of saquinavir and ritonavir. The clinical relevance of these preclinical results are unknown, however cardiac conduction and repolarisation abnormalities in humans have been observed with saquinavir and ritonavir combination therapy (see section 4.4 and 5.1).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core:

Microcrystalline cellulose,

Croscarmellose sodium,

Povidone,

Lactose (monohydrate),

Magnesium stearate.

Tablet coat:

Hypromellose,

Titanium dioxide (E 171),

Talc,

Glycerol triacetate,

Iron oxide yellow and red (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Plastic bottles (HDPE) containing 120 tablets.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

8. MARKETING AUTHORISATION NUMBER

EU/1/96/026/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04 October 1996

Date of latest renewal: 04 October 2006