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Invirase 500mg Film-Coated Tablets

Last Updated on eMC 13-May-2014 View changes  | Roche Products Limited Contact details

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 particulars
4.1 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

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 x 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 x 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, 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.

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

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.

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).

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).

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 co-administered 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-naïve 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.

Diabetes mellitus and hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these patients, the hyperglycaemia was severe and in some cases was also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

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), 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.

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 pre-existing 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 (see section 4.5).

Oral contraceptives: Because concentration of ethinyl estradiol may be decreased when co-administered 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

Medicinal product by therapeutic area (dose of Invirase used in study)

Interaction

Recommendations concerning co-administration

Antiretroviral agents

Nucleoside reverse transcriptase inhibitors (NRTIs)

- Zalcitabine and/or Zidovudine

(saquinavir/ritonavir)

- No pharmacokinetic interaction studies have been completed. Interaction with zalcitabine is unlikely due to different routes of metabolism and excretion.

For zidovudine (200 mg every 8 hours) a 25 % decrease in AUC was reported when combined with ritonavir (300 mg every 6 hours). The pharmacokinetics of ritonavir remained unchanged.

- No dose adjustment required.

- Zalcitabine and/or Zidovudine

(unboosted saquinavir)

- Saquinavir ↔

Zalcitabine ↔

Zidovudine ↔

 

Didanosine 400 mg single dose

(saquinavir/ritonavir 1600/100 mg qd)

Saquinavir AUC ↓ 30%

Saquinavir Cmax ↓ 25%

Saquinavir Cmin

No dose adjustment required.

Tenofovir disoproxil fumarate 300 mg qd

(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir AUC ↓ 1%

Saquinavir Cmax ↓ 7%

Saquinavir Cmin

No dose adjustment required.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

- Delavirdine

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Delavirdine

(unboosted saquinavir)

- Saquinavir AUC ↑ 348%.

There are limited safety and no efficacy data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in 13 % of subjects during the first several weeks of the delavirdine and saquinavir combination (6 % Grade 3 or 4).

- Hepatocellular changes should be monitored frequently if this combination is prescribed.

Efavirenz 600 mg qd

(saquinavir/ritonavir 1600/200 mg qd, or saquinavir/ritonavir 1000/100 mg bid, or saquinavir/ritonavir 1200/100 mg qd)

Saquinavir ↔

Efavirenz ↔

No dose adjustment required.

- Nevirapine

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Nevirapine

(unboosted saquinavir)

- Saquinavir AUC ↓ 24%

Nevirapine AUC ↔

- No dose adjustment required.

HIV protease inhibitors (PIs)

Atazanavir 300 mg qd

(saquinavir/ritonavir 1600/100 mg qd)

Saquinavir AUC ↑ 60%

Saquinavir Cmax ↑ 42%

Ritonavir AUC ↑ 41%

Ritonavir Cmax ↑ 34%

Atazanavir ↔

No clinical data available for the combination of saquinavir/ritonavir 1000/100 mg bid and atazanavir.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Fosamprenavir 700 mg bid

(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir AUC ↓ 15%

Saquinavir Cmax ↓ 9%

Saquinavir Cmin ↓ 24% (remained above the target threshold for effective therapy.)

No dose adjustment required for Invirase/ritonavir.

- Indinavir

(saquinavir/ritonavir)

- Low dose ritonavir increases the concentration of indinavir.

Increased concentrations of indinavir may result in nephrolithiasis.

- Indinavir 800 mg tid

(saquinavir 600-1200 mg single dose)

- Saquinavir AUC ↑ 4.6-7.2 fold

Indinavir ↔

No safety and efficacy data available for this combination. Appropriate doses of combination not established.

 

Lopinavir/ritonavir 400/100 mg bid

(saquinavir 1000 mg bid in combination with 2 or 3 NRTIs)

Saquinavir ↔

Ritonavir ↓ (effectiveness as boosting agent not modified).

Lopinavir ↔ (based on historical comparison with unboosted lopinavir)

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

- Nelfinavir 1250 mg bid

(saquinavir/ritonavir 1000/100 mg bid)

- Saquinavir AUC ↑ 13%

(90% CI: 27↓ - 74↑)

Saquinavir Cmax ↑ 9%

(90% CI: 27↓ - 61↑ )

Nelfinavir AUC ↓ 6%

(90% CI: 28↓ - 22↑)

Nelfinavir Cmax ↓ 5%

(90% CI: 23↓ - 16↑)

Combination not recommended.

- Nelfinavir 750 mg tid

(unboosted saquinavir 1200 mg tid)

- Saquinavir AUC ↑ 392%

Saquinavir Cmax ↑ 179%

Nelfinavir AUC ↑ 18%

Nelfinavir Cmax ↔

- Quadruple therapy, including saquinavir soft capsules and nelfinavir in addition to two nucleoside reverse transcriptase inhibitors gave a more durable response (prolongation of time to virological relapse) than triple therapy with either single protease inhibitor. Concomitant administration of nelfinavir and saquinavir soft capsules resulted in a moderate increase in the incidence of diarrhoea.

Ritonavir 100 mg bid

(saquinavir 1000 mg bid)

Saquinavir ↑

Ritonavir ↔

In HIV-infected patients, Invirase or saquinavir soft capsules in combination with ritonavir at doses of 1000/100 mg twice daily provide a systemic exposure of saquinavir over a 24 hour period similar to or greater than that achieved with saquinavir soft capsules 1200 mg three times daily (see section 5.2).

This is the approved combination regimen. No dose adjustment is recommended.

Tipranavir/ritonavir

(saquinavir/ritonavir)

Saquinavir Cmin ↓ 78%

Dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults.

Concomitant administration of tipranavir, co-administered with low dose ritonavir, with saquinavir/ritonavir, is not recommended. If the combination is considered necessary, monitoring of the saquinavir plasma levels is strongly encouraged.

HIV fusion inhibitor

Enfuvirtide

(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir ↔

Enfuvirtide ↔

No clinically significant interaction was noted.

No dose adjustment required.

HIV CCR5 antagonist

Maraviroc 100 mg bid

(saquinavir/ritonavir 1000/100 mg bid)

Maraviroc AUC12 ↑ 9.77

Maraviroc Cmax: ↑ 4.78

Saquinavir/ritonavir concentrations not measured, no effect is expected.

No dose adjustment of saquinavir/ritonavir is required. Dose of maraviroc should be decreased to 150 mg bid with monitoring.

Other medicinal products

Alpha-1 adrenoreceptor antagonist

Alfuzosin

Concomitant use of alfuzosin and saquinavir/ritonavir is expected to increase plasma levels of alfuzosin.

Contraindicated in combination with Invirase/ritonavir due to potential increase in alfuzosin concentration which can result in hypotension.

Antiarrhythmics

Bepridil

Lidocaine (systemic)

Quinidine

Hydroquinidine

(saquinavir/ritonavir)

Concentrations of bepridil, systemic lidocaine, quinidine or hydroquinidine may be increased when co-administered with Invirase/ritonavir.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Amiodarone

flecainide

propafenone

(saquinavir/ritonavir)

Concentrations of amiodarone, flecainide or propafenone may be increased when co-administered with Invirase/ritonavir.

Contraindicated in combination with saquinavir/ritonavir due to potentially life threatening cardiac arrhythmia (see section 4.3).

Dofetilide

(saquinavir/ritonavir)

Although specific studies have not been performed, co-administration of Invirase/ritonavir with medicinal products that are mainly metabolised by CYP3A4 pathway may result in elevated plasma concentrations of these medicinal products.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Ibutilide

Sotalol

(saquinavir/ritonavir)

 

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Anticoagulant

Warfarin

(saquinavir/ritonavir)

Concentrations of warfarin may be affected.

INR (international normalised ratio) monitoring recommended.

Anticonvulsants

- Carbamazepine

Phenobarbital

Phenytoin

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Carbamazepine

Phenobarbital

Phenytoin

(unboosted saquinavir)

- These medicinal products will induce CYP3A4 and may therefore decrease saquinavir concentrations.

 

Antidepressants

Tricyclic antidepressants (e.g. amitriptyline, imipramine)

(saquinavir/ritonavir)

Invirase/ritonavir may increase concentrations of tricyclic antidepressants.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

- Nefazodone

(saquinavir/ritonavir)

- Interaction with saquinavir/ritonavir not evaluated.

 

- Nefazodone

(unboosted saquinavir)

- Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.

- Combination not recommended.

Trazodone

(ritonavir)

Plasma concentrations of trazodone may increase.

Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Anti-gout preparation

Colchicine

Concomitant use of colchicine and saquinavir/ritonavir is expected to increase plasma levels of colchicine due to P-gp and/or CYP3A4 inhibition by the protease inhibitor.

Because of a potential increase of colchicine-related toxicity (neuromuscular events including rhabdomyolysis), its concomitant use with saquinavir/ritonavir is not recommended, especially in the case of renal or hepatic impairment (see section 4.4).

Antihistamines

Terfenadine

Astemizole

(saquinavir/ritonavir)

Terfenadine AUC ↑, associated with a prolongation of QTc intervals.

A similar interaction with astemizole is likely.

Terfenadine and astemizole are contraindicated with boosted or unboosted saquinavir (see section 4.3).

Mizolastine

(saquinavir/ritonavir)

 

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Anti-infectives

Clarithromycin

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

 

Clarithromycin 500 mg bid

(unboosted saquinavir 1200 mg tid)

Saquinavir AUC ↑ 177 %

Saquinavir Cmax↑ 187 %

Clarithromycin AUC ↑ 40 %

Clarithromycin Cmax↑ 40 %

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Erythromycin

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Erythromycin 250 mg qid

(unboosted saquinavir 1200 mg tid)

Saquinavir AUC ↑ 99 %

Saquinavir Cmax↑ 106 %

No dose adjustment required.

Fusidic acid

(saquinavir/ritonavir)

Not studied. Co-administration of fusidic acid and Invirase/ritonavir can cause increased plasma concentration of both fusidic acid and saquinavir/ritonavir.

 

Streptogramin antibiotics

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

 

Streptogramin antibiotics

(unboosted saquinavir)

Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4. Saquinavir concentrations may be increased.

Monitoring for saquinavir toxicity recommended.

Halofantrine

Pentamidine

Sparfloxacin

(saquinavir/ritonavir)

 

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Antifungals

Ketoconazole 200 mg qd

(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir AUC ↔

Saquinavir Cmax

Ritonavir AUC ↔

Ritonavir Cmax

Ketoconazole AUC ↑ 168%

(90% CI 146%-193%)

Ketoconazole Cmax ↑ 45%

(90% CI 32%-59%)

No dose adjustment required when saquinavir/ritonavir combined with ≤ 200 mg/day ketoconazole. High doses of ketoconazole (> 200 mg/day) are not recommended.

Itraconazole

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

 

Itraconazole

(unboosted saquinavir)

Itraconazole is a moderately potent inhibitor of CYP3A4. An interaction is possible.

Monitoring for saquinavir toxicity recommended.

Fluconazole/miconazole

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

 

Antimycobacterials

Rifampicin 600 mg qd

(saquinavir/ritonavir 1000/100 mg bid)

In a clinical study 11 of 17 (65 %) healthy volunteers developed severe hepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of co-administration.

Rifampicin is contraindicated in combination with Invirase/ritonavir (see section 4.3).

Rifabutin 150 mg q3d

(saquinavir/ritonavir 1000/100 mg bid) in healthy volunteers

Saquinavir AUC0-12 ↓ 13%

(90% CI: 31↓ - 9↑)

Saquinavir Cmax ↓ 15%

(90% CI: 32↓ - 7↑)

Ritonavir AUC0-12

(90% CI: 10↓ - 9↑)

Ritonavir Cmax

(90% CI: 8↓ - 7↑)

Rifabutin active moiety*

AUC0-72 ↑ 134%

(90% CI 109%-162%)

Rifabutin active moiety*

Cmax ↑ 130%

(90% CI 98%-167%)

Rifabutin AUC0-72 ↑ 53%

(90% CI 36%-73%)

Rifabutin Cmax ↑ 86%

(90% CI 57%-119%)

* Sum of rifabutin + 25-O-desacetyl rifabutin metabolite

To prevent possible development of rifabutin resistance in TB and HIV co-infected patients, the recommended dose of rifabutin is 150 mg every other day or three times per week, with the dose of saquinavir/ritonavir unchanged (1000/100 mg bid).

Monitoring of neutropenia and liver enzyme levels is recommended due to an expected increase in exposure to rifabutin.

Antipsychotics

Quetiapine

Due to CYP3A inhibition by saquinavir/ritonavir, concentrations of quetiapine are expected to increase.

Concomitant administration of Invirase and quetiapine is contra-indicated as it may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma.

Benzodiazepines

Midazolam 7.5 mg single dose (oral)

(saquinavir/ritonavir 1000/100 mg bid)

Midazolam AUC ↑ 12.4 fold

Midazolam Cmax ↑ 4.3 fold

Midazolam t1/2 ↑ from 4.7 h to 14.9 h

No data are available on concomitant use of ritonavir boosted saquinavir with intravenous midazolam. Studies of other CYP3A modulators and i.v. midazolam suggest a possible 3-4 fold increase in midazolam plasma levels.

Co-administration of Invirase/ritonavir with orally administered midazolam is contraindicated (see section 4.3). Caution should be used with co-administration of Invirase and parenteral midazolam.

If Invirase is co-administered with parenteral midazolam it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment should be considered, especially if more than a single dose of midazolam is administered.

Alprazolam

Clorazepate

Diazepam

Flurazepam

(saquinavir/ritonavir)

Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir.

Careful monitoring of patients with regard to sedative effects is warranted. A decrease in the dose of the benzodiazepine may be required.

Triazolam

(saquinavir/ritonavir)

Concentrations of triazolam may be increased when co-administered with Invirase/ritonavir.

Contraindicated in combination with saquinavir/ritonavir, due to the risk of potentially prolonged or increased sedation and respiratory depression (see section 4.3).

Calcium channel blockers

Felodipine, nifedipine, nicardipine, diltiazem, nimodipine, verapamil, amlodipine, nisoldipine, isradipine

(saquinavir/ritonavir)

Concentrations of these medicinal products may be increased when co-administered with Invirase/ritonavir.

Caution is warranted and clinical monitoring of patients is recommended.

Corticosteroids

- Dexamethasone

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Dexamethasone

(unboosted saquinavir)

- Dexamethasone induces CYP3A4 and may decrease saquinavir concentrations.

- Use with caution. Saquinavir may be less effective in patients taking dexamethasone.

Fluticasone propionate 50 mcg qid, intranasal

(ritonavir 100 mg bid)

Fluticasone propionate ↑

Intrinsic cortisol ↓ 86%

(90% CI 82%-89%)

Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide.

Effects of high fluticasone systemic exposure on ritonavir plasma levels yet unknown.

Concomitant administration of boosted saquinavir and fluticasone propionate and other corticosteroids metabolised via the P450 3A pathway (e.g. budesonide) is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).

Dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone).

In case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Endothelin receptor antagonist

Bosentan

Not studied. Concomitant use of bosentan and saquinavir/ritonavir may increase plasma levels of bosentan and may decrease plasma levels of saquinavir/ritonavir.

Dose adjustment of bosentan may be required. When bosentan is administered concomitantly with saquinavir/ritonavir, the patient's tolerability of bosentan should be monitored. Monitoring of the patient's HIV therapy is also recommended.

Medicinal products that are substrates of P-glycoprotein

Digitalis glycosides

Digoxin 0.5 mg single dose

(saquinavir/ritonavir 1000/100 mg bid)

Digoxin AUC0-72 ↑ 49%

Digoxin Cmax ↑ 27%

Digoxin levels may differ over time. Large increments of digoxin may be expected when saquinavir/ritonavir is introduced in patients already treated with digoxin.

Caution should be exercised when Invirase/ritonavir and digoxin are co-administered. The serum concentration of digoxin should be monitored and a dose reduction of digoxin should be considered if necessary.

Histamine H2-receptor antagonist

- Ranitidine

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Ranitidine

(unboosted saquinavir)

- Saquinavir AUC ↑ 67 %

- Increase not thought to be clinically relevant. No dose adjustment of saquinavir recommended.

HMG-CoA reductase inhibitors

Pravastatin

Fluvastatin

(saquinavir/ritonavir)

Interaction not studied. Metabolism of pravastatin and fluvastatin is not dependent on CYP3A4. Interaction via effects on transport proteins cannot be excluded.

Interaction unknown. If no alternative treatment is available, use with careful monitoring.

Simvastatin

Lovastatin

(saquinavir/ritonavir)

Simvastatin ↑↑

Lovastatin ↑↑

Plasma concentrations highly dependent on CYP3A4 metabolism.

Increased concentrations of simvastatin and lovastatin have been associated with rhabdomyolysis. These medicinal products are contraindicated for use with Invirase/ritonavir (see section 4.3).

Atorvastatin

(saquinavir/ritonavir)

Atorvastatin is less dependent on CYP3A4 for metabolism.

When used with Invirase/ritonavir, the lowest possible dose of atorvastatin should be administered and the patient should be carefully monitored for signs/symptoms of myopathy (muscle weakness, muscle pain, rising plasma creatinine kinase).

Immunosuppressants

Ciclosporin

Tacrolimus

Rapamycin

(saquinavir/ritonavir)

Concentrations of these medicinal products increase several fold when co-administered with Invirase/ritonavir.

Careful therapeutic drug monitoring is necessary for immunosuppressants when co-administered with Invirase/ritonavir.

Long-acting beta2-adrenergic agonist

Salmeterol

Concomitant use of salmeterol and saquinavir/ritonavir is expected to increase plasma levels of salmeterol.

Combination not recommended as may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Narcotic analgesics

Methadone 60-120 mg qd

(saquinavir/ritonavir 1000/100 mg bid)

Methadone AUC ↓ 19 %

(90 % CI 9 % to 29 %)

None of the 12 patients experienced withdrawal symptoms.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Neuroleptics

Pimozide

(saquinavir/ritonavir)

Concentrations of pimozide may be increased when co-administered with Invirase/ritonavir.

Due to a potential for life threatening cardiac arrhythmias, Invirase/ritonavir is contra-indicated in combination with pimozide (see section 4.3).

Clozapine

Haloperidol

Mesoridazine

Phenothiazines

Sertindole

Sultopride

Thioridazine

Ziprasidone

(saquinavir/ritonavir)

 

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Oral contraceptives

Ethinyl estradiol

(saquinavir/ritonavir)

Concentration of ethinyl estradiol may be decreased when co-administered with Invirase/ritonavir.

Alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered.

Phosphodiesterase type 5 (PDE5) inhibitors

- Sildenafil

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Sildenafil 100 mg

(single dose)

(unboosted saquinavir 1200 mg tid)

- Saquinavir ↔

Sildenafil Cmax ↑ 140 %

Sildenafil AUC ↑ 210 %

- Sildenafil is a substrate of CYP3A4.

- Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Vardenafil

(saquinavir/ritonavir)

Concentrations of vardenafil may be increased when co-administered with Invirase/ritonavir.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Tadalafil

(saquinavir/ritonavir)

Concentrations of tadalafil may be increased when co-administered with Invirase/ritonavir.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Proton pump inhibitors

Omeprazole 40 mg qd

(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir AUC ↑ 82%

(90 % CI 44-131 %)

Saquinavir Cmax ↑ 75%

(90 % CI 38-123 %)

Ritonavir ↔

Combination not recommended.

Other proton pump inhibitors

(saquinavir/ritonavir 1000/100 mg bid)

No data are available on the concomitant administration of Invirase/ritonavir and other proton pump inhibitors.

Combination not recommended.

Others

Ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine)

(saquinavir/ritonavir)

Invirase/ritonavir may increase ergot alkaloids exposure, and consequently, increase the potential for acute ergot toxicity.

The concomitant use of Invirase/ritonavir and ergot alkaloids is contra-indicated (see section 4.3).

- Grapefruit juice

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Grapefruit juice

(single dose)

(unboosted saquinavir)

- Saquinavir ↑ 50% (normal strength grapefruit juice)

- Saquinavir ↑ 100% (double strength grapefruit juice)

- Increase not thought to be clinically relevant. No dose adjustment required.

- Garlic capsules

(saquinavir/ritonavir)

- Interaction with Invirase/ritonavir not studied.

 

- Garlic capsules

(dose approx. equivalent to two 4 g cloves of garlic daily)

(unboosted saquinavir 1200 mg tid)

- Saquinavir AUC ↓ 51 %

Saquinavir Ctrough ↓ 49 % (8 hours post dose)

Saquinavir Cmax ↓ 54 %.

- Patients on saquinavir treatment must not take garlic capsules due to the risk of decreased plasma concentrations and loss of virological response and possible resistance to one or more components of the antiretroviral regimen.

St. John's wort

(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied.

 

St. John's wort

(unboosted saquinavir)

Plasma levels of saquinavir can be reduced by concomitant use of the herbal preparation St. John's wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or transport proteins by St. John's wort.

Herbal preparations containing St. John's wort must not be used concomitantly with Invirase. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible saquinavir levels. Saquinavir levels may increase on stopping St. John's wort, and the dose of saquinavir may need adjusting. The inducing effect of St. John's wort may persist for at least 2 weeks after cessation of treatment.

Other potential interactions

Medicinal products that are substrates of CYP3A4

e.g. dapsone, disopyramide, quinine, fentanyl, and alfentanyl

(unboosted saquinavir)

Although specific studies have not been performed, co-administration of Invirase/ritonavir with medicinal products that are mainly metabolised by CYP3A4 pathway may result in elevated plasma concentrations of these medicinal products.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Gastroenterological medicinal products

Metoclopramide

It is unknown whether medicinal products which reduce the gastrointestinal transit time could lead to lower saquinavir plasma concentrations.

 

Cisapride

(saquinavir/ritonavir)

Although specific studies have not been performed, co-administration of Invirase/ritonavir with medicinal products that are mainly metabolised by CYP3A4 pathway may result in elevated plasma concentrations of these medicinal products.

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Diphemanil

(saquinavir/ritonavir)

 

Contraindicated in combination with Invirase/ritonavir due to potentially life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Vasodilators (peripheral)

Vincamine i.v.

 

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).

Key: ↓ reduced, ↑ increased, ↔ unchanged, ↑↑ 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, acquired lipodystrophy 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.

Body System

Frequency of reaction

Adverse reactions

Blood and the lymphatic system disorders

Very common

Decreased platelet count

Common

Anaemia, decreased haemoglobin, decreased lymphocyte count, decreased white blood cell count

Uncommon

Neutropenia

Eye Disorders

Uncommon

Visual impairment

Immune System Disorders

Common

Hypersensitivity

Metabolism and nutrition disorders

Very common

Increased blood cholesterol, increased blood triglycerides

Common

Diabetes mellitus, anorexia, increased appetite

Uncommon

Decreased appetite

Psychiatric Disorders

Common

Decreased libido, sleep disorder

Nervous System Disorder

Common

Paraesthesia, peripheral neuropathy, dizziness, dysgeusia, headache

Uncommon

Somnolence, convulsions

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Gastrointestinal disorders

Very common

Diarrhoea, nausea

Common

Vomiting, abdominal distension, abdominal pain, upper abdominal pain, constipation, dry mouth, dyspepsia, eructation, flatulence, lip dry, loose stools

Uncommon

Pancreatitis

Hepato-biliary disorders

Very common

Increased alanine aminotransferase, increased aspartate aminotransferase, increased low density lipoprotein

Common

Increased blood bilirubin, increased blood amylase

Uncommon

Hepatitis, jaundice

Renal and urinary disorders

Common

Increased blood creatinine

Uncommon

Renal impairment

Skin and subcutaneous tissue disorders

Common

Acquired lipodystrophy, alopecia, dry skin, eczema, lipoatrophy, pruritus, rash

Uncommon

Stevens Johnson syndrome, dermatitis bullous

Musculoskeletal and connective tissue disorders

Common

Muscle spasms

General disorders and administration site conditions

Common

Asthenia, fatigue, increased fat tissue, malaise

Uncommon

Mucosal ulceration

c. Description of selected adverse reactions

Diabetes mellitus or hyperglycaemia sometimes associated with ketoacidosis have been reported in patients receiving protease inhibitors (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsicervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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) 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 (see details below).

Ireland

IMB Pharmacovigilance

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IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

United Kingdom

Yellow Card Scheme

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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 Cmax values 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

Treatment

Post-Dose

Time Point

Mean

ddQTcS

Standard Error

Upper 95%-CI of ddQTcS

Invirase/ritonavir

1000/100 mg BID

12 hours

18.86

1.91

22.01

Invirase/ritonavir

1500/100 mg BID

20 hours

30.22

1.91

33.36

Moxifloxacin^

4 hours

12.18

1.93

15.36

Derived difference of pre-dose baseline corrected QTcS between active treatment and placebo arms

^ 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, treatment-naïve 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 (ΔQTcFdense). The modified Invirase/ritonavir regimen reduced mean maximum ΔQTcFdense 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-naïve 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-naïve 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

Parameter

Day 3

500/100 mg

(n=22)

Day 4

500/100 mg

(n=21)

Day 7

500/100 mg

(n=21)

Day 10

1000/100 mg

(n=21)

Day 14

1000/100 mg

(n=21)

TQT Study

Day 3*

(n=57)

Mean Maximal ΔQTcFdense ms (SD)

3.26 ± 7.01

0.52 ± 9.25

7.13 ± 7.36

11.97 ± 11.55

7.48 ± 8.46

32.2 ± 13.4

Patients with maximal ΔQTcFdense≥ 30 ms (%)

0

0

0

2/21 (9%)

0

29/57 (51%)

*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

Number of Saquinavir Associated Resistance Mutations at Baseline*

Marcelin et al (2007)

RESIST 1 & 2

SQV Naive Population

SQV Naive/Experienced Population

N=138

Change in Baseline Plasma HIV-1 RNA at Weeks 12-20

N=114

Change in Baseline Plasma HIV-1 RNA at Week 4

0

35

-2.24

2

-2.04

1

29

-1.88

3

-1.69

2

24

-1.43

14

-1.57

3

30

-0.52

28

-1.41

4

9

-0.18

40

-0.75

5

6

-0.11

17

-0.44

6

5

-0.30

9

0.08

7

0

-

1

0.24

* 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 MaxCmin1 and MaxCmin2

 

MaxCmin1

MaxCmin2

SQV/r

IDV/r

SQV/r

LPV/r

N=148

N=158

N=161

N=163

Sex

Male

 

82%

 

74%

 

81%

 

76%

Race (White/Black/Asian) %

86/9/1

82/12/4

75/19/1

74/19/2

Age, median, yrs

39

40

40

40

CDC Category C (%)

32%

28%

32%

31%

Antiretroviral naïve (%)

28%

22%

31%

34%

PI naïve (%)

41%

38%

48%

48%

Median Baseline HIV-1 RNA, log10 copies/ml (IQR)

4.0

(1.7-5.1)

3.9

(1.7-5.2)

4.4

(3.1-5.1)

4.6

(3.5-5.3)

Median Baseline CD4+ Cell Count, cells/mm3 (IQR)

272

(135-420)

280

(139-453)

241

(86-400)

239

(95-420)

 data from clinical study report

Table 7: Outcomes at Week 48 MaxCmin1 and MaxCmin2

Outcomes

MaxCmin1

MaxCmin2

SQV/r

IDV/r

SQV/r

LPV/r

Initiated assigned treatment,

n (%)

148

(94%)

158

(99%)

161

(94%)

163

(98%)

Discontinued assigned treatment,

n (%)

40

(27%)

64

(41%)

48

(30%)

23

(14%)

 

P=0.01

P=0.001

Virological failure ITT/e*#

36/148 (24%)

41/158 (26%)

53/161 (33%)

29/163 (18%)

 

P=0.76

P=0.002

Proportion with VL < 50 copies/ml at week 48, ITT/e#

97/144

(67%)

106/154

(69%)

90/158

(57%)

106/162

(65%)

 

P >0.05

P=0.12

Proportion with VL < 50 copies/ml at week 48,

On Treatment

82/104

(79%)

73/93

(78%)

84/113

(74%)

97/138

(70%)

 

P>0.05

P=0.48

Median increase in CD4 cell count at week 48 (cells/mm3)

85

73

110

106

* For both studies: For patients entering study with VL < 200 copies/ml, VF defined as > 200 copies/ml. MaxCmin1: For those entering with VL > 200 copies/ml, VF defined as any increase > 0.5 logs and/or VL > 50,000 copies/ml at week 4, > 5,000 copies/ml at week 12, or > 200 copies/ml at week 24 or thereafter. MaxCmin2: any rise > 0.5 log at a specific visit; < 0.5 log reduction if VL > 200 copies/ml at week 4; < 1.0 log reduction from base line if VL > 200 copies/ml at week 12; and a VL > 200 copies/ml at week 24.

# ITT/e = Intent-to-treat/exposed

 Data from clinical study report

 Data from MaxCmin1 publication

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

Treatment

N

AUC (ng·h/ml)

AUC0-24

(ng·h/ml)

Cmax

(ng/ml)

Cmin

(ng/ml)

Invirase (hard capsule)

600 mg tid

10

866 (62)

2,598

197 (75)

75 (82)

saquinavir soft capsule

1200 mg tid

31

7,249 (85)

21,747

2,181 (74)

216 (84)

Invirase (tablet)

1000 mg bid plus ritonavir 100 mg bid*

(fasting condition)

22

10,320

(2,530-30,327)

20,640

1,509

(355-4,101)

313

(70-1,725) ††

Invirase (tablet)

1000 mg bid plus ritonavir 100 mg bid*

(high fat meal)

22

34,926

(11,826-105,992)

69,852

5,208

(1,536-14,369)

1,179

(334-5,176) ††

= 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)

 derived from tid or bid dosing schedule

†† Ctrough values

Absolute bioavailability averaged 4 % (CV 73 %, range: 1 % to 9 %) in 8 healthy volunteers who received a single 600 mg dose (3 x 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 first-pass 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 ng·h/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 ng·h/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

Parameter

Day 3

500/100 mg

(n=22)

Day 4

500/100 mg

(n=21)

Day 7

500/100 mg

(n=21)

Day 10

1000/100 mg

(n=21)

Day 14

1000/100 mg

(n=21)

AUC0-12

(ng*hr/ml)

27100 (35.7)

20300 (39.9)

12600 (54.5)

34200 (48.4)

31100 (49.6)

Cmax(ng/ml)

4030 (29.1)

2960 (40.2)

1960 (53.3)

5300 (36.0)

4860 (46.8)

C12 (ng/ml)

899 (64.9)

782 (62.4)

416 (98.5)

1220 (91.6)

1120 (80.9)

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 μg/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 μg/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%) µg·hr/ml and 3.6 (83%) µg/ml, respectively, for HIV-infected patients with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) µg·hr/ml and 4.3 (68%) µg/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

 

Mean ± SD Saquinavir (%CV) Pharmacokinetic Parameters*

Study

Age Group

(Years)

N

AUC0-12h (ng•h/mL)

Ctrough (ng/mL)

Cmax (ng/mL)

NV20911

2 to < 6 years

13

38000 ± 18100

(48%)

1860 ± 1060

(57%)

5570 ± 2780

(50%)

* 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

Acute 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 30μM of saquinavir. Saquinavir inhibited both hERG current and L-type Ca++ channel current with respective IC50s of 4.7 and 6.3 μM. 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 particulars
6.1 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

3 years.

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 and other handling

No special requirements for disposal.

7. Marketing authorisation holder

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. Marketing authorisation number(s)

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

10. Date of revision of the text

2 May 2014

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Company contact details

Roche Products Limited

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Address

Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW

Fax

+44 (0)1707 338 297

Medical Information e-mail
Medical Information Fax

+44 (0)1707 384555

Telephone

+44 (0)1707 366 000

Medical Information Direct Line

+44 (0)800 328 1629

Customer Care direct line

+44 (0)800 731 5711

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Active ingredients

saquinavir mesilate

Legal categories

POM - Prescription Only Medicine

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