Last Updated on eMC 12-12-2016 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:10-11-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

 

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 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.

 

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).

 

4.4       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.

 

[…]

 

4.5       Interaction with other medicinal products and other forms of interaction

[…]

Cobicistat containing medicinal products

Cobicistat

Interaction with Invirase/ritonavir not studied. Cobicistat is not recommended in combination with regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

It is not recommended to coadminister Invirase/ritonavir with cobicistat containing products (see section 4.4).

Other medicinal products
 Alpha-1 adrenoreceptor antagonist

 

 

 

[…]

 

10.       DATE OF REVISION OF THE TEXT

10 November 2016

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects - how to report a side effect

Date of revision of text on the SPC:28-01-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

SPC republished to correct the link to the Maltese website for ADR reporting as the link did not work

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:28-01-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

 

Strike through text = deleted text

 

 

4.       CLINICAL PARTICULARS

 

 

4.4     Special warnings and precautions for use

 

[ … ]

 

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.

 

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 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).

 

[ … ]

 

4.5     Interaction with other medicinal products and other forms of interaction

 

[ … ]

 

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.

Use of unboosted saquinavir with zalcitabine and/or zidovudine has been studied in adults. Absorption, distribution and elimination of each of the drugs are unchanged when they are used together.

 

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
«

 

[ … ]

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

 

[ … ]

 

 

 

Efavirenz 600 mg qd
(
saquinavir/ritonavir 1600/200 mg qd, or
saquinavir/ritonavir 1000/100 mg bid, or
s
aquinavir/ritonavir 1200/100 mg qd)

Saquinavir «
Efavirenz
«

No dose adjustment required. Liver function should be monitored (see section 4.4).

[ … ]

 

HIV protease inhibitors (PIs)

 

 

[ … ]

 

-  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.

[ … ]

 

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 (see section 4.4).

[ … ]

 

Anticoagulant

 

 

Warfarin

(saquinavir/ritonavir)

Concentrations of warfarin may be affected when co-administered with Invirase/ritonavir.

INR (international normalised ratio) monitoring recommended.

Anticonvulsants

 

 

-  Carbamazepine Phenobarbital
Phenytoin
(saquinavir/ritonavir)

-           Interaction with Invirase/ritonavir not studied.

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

Use with caution.

 

Monitoring of saquinavir plasma concentration is recommended (see section 4.4)

-  Carbamazepine Phenobarbital
Phenytoin
(unboosted saquinavir)

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

 

Antidepressants

 

 

Tricyclic antidepressants
(e.g. amitriptyline, imipramine, clomipramine) (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).

 

Maprotiline

Maprotiline’s metabolism appears to involve the cytochrome P450 isozymes CYP2D6 and CYP 1A2

Associated with a prolongation of QTc intervals.

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

-  Nefazodone
(saquinavir/ritonavir)

-           Interaction with saquinavir/ritonavir not evaluated.

Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.

Combination not recommended. Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended (see section 4.4).Monitoring for saquinavir toxicity is recommended.

-  Nefazodone
(unboosted saquinavir)

-  Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.

-  Combination not recommended.

Trazodone
(saquinavir/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).

 [ … ]

 

Antihistamines

 

 

Terfenadine
Astemizole
(saquinavir/ritonavir)

Terfenadine AUC ↑, associated with a prolongation of QTc intervals.
A similar interaction with astemizole is likely.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).Terfenadine and astemizole are contraindicated with boosted or unboosted saquinavir (see section 4.3).

[ … ]

 

Anti-infectives

 

 

-  Clarithromycin
(saquinavir/ritonavir)

-  Interaction with Invirase/ritonavir not studied.

Clarithromycin is a CYP3A4 substrate and is associated with QT prolongation.

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

-  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.

Erythromycin is a CYP3A4 substrate and is associated with QT prolongation.

-           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 %

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).-   No dose adjustment required.

[ … ]

 

-  Streptogramin antibiotics
(saquinavir/ritonavir)

-           Interaction with Invirase/ritonavir not studied.

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

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended (see section 4.4).

Use with caution due to possible cardiac arrhythmias.

-  Streptogramin antibiotics
(unboosted saquinavir)

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

-  Monitoring for saquinavir toxicity recommended.

[ … ]

 

Antifungals

 

 

[ … ]

 

-  Itraconazole
(saquinavir/ritonavir)

-  Itraconazole
(unboosted saquinavir)

-  Interaction with Invirase/ritonavir not studied.

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

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended (see section 4.4).Monitoring for saquinavir toxicity recommended.

Fluconazole/miconazole
(saquinavir/ritonavir)

Interaction with Invirase/ritonavir not studied. Both drugs are CYP3A4 inhibitors and may increase the plasma concentration of saquinavir.

Use with caution due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity recommended (see section 4.4).Clinical monitoring for saquinavir toxicity recommended.

[ … ]

 

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 (see sectin 4.3).

[ … ]

 

Corticosteroids

 

 

-  Dexamethasone
(saquinavir/ritonavir)

-  Dexamethasone
(unboosted saquinavir)

-           Interaction with Invirase/ritonavir not studied.

-           Dexamethasone induces CYP3A4 and may decrease saquinavir concentrations.

Use with caution. Monitoring of saquinavir plasma concentration is recommended (see section 4.4).

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

[ … ]

 

 

 

 

 

Histamine H2-receptor antagonist

 

 

-  Ranitidine
(saquinavir/ritonavir)

-  Ranitidine
(unboosted saquinavir)

-           Interaction with Invirase/ritonavir not studied.

-           Saquinavir AUC 67 % (unboosted saquinavr)


 

 

-           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 (see section 4.4).

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, see section 4.4).

Immunosuppressants

 

 

Tacrolimus

Tacrolimus is a substrate of CYP3A4 and P-glycoprotein. Concomitant use of tacrolimus and saquinavir/ritonavir is expected to increase plasma levels of tacrolimus.

Tacrolimus may be associated with torsades de pointes.

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

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 these 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 (see section 4,4).

 [ … ]

 

Neuroleptics

 

 

Pimozide
(
saquinavir/ritonavir)

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

Pimozide is a CYP3A4 substrate and is associated with QT prolongation.

Contraindicated in combination with Invirase/ritonavir due to the potential for life threatening cardiac arrhythmia (see sections 4.3 and 4.4).Due to a potential for life threatening cardiac arrhythmias, Invirase/ritonavir is contra-indicated in combination with pimozide (see section 4.3).

Clozapine
Haloperidol

Chlorpromazine
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 (see section 4.4).

Phosphodiesterase type 5 (PDE5) inhibitors

 

 

- Sildenafil

(saquinavir/ritonavir)         Sildenafil 100 mg
(single dose)
(unboosted saquinavir 1200 mg tid)

-          Interaction with Invirase/ritonavir not studied.

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).

 [ … ]

 

 

Others

 

 

[ … ]

 

 

-  St. John’s wort
(saquinavir/ritonavir)

-          Interaction with Invirase/ritonavir not studied.

 

-  St. John’s wort
(unboosted saquinavir)

-          Plasma levels of unboosted 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).

[ … ]

 

 

 

 

Key: ¯ reduced, ↑ increased, « unchanged, ↑↑ markedly increased

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

28 January 2016

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:05-01-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined Text = New Text

Strike Through Text = deleted text

 

4.4     Special warnings and precautions for use

 

[ … ]

 

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.

 

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).

 

[ … ]

 

 

4.8     Undesirable effects

 

a. Summary of the safety profile

 

[ … ]

 

 

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

 

[ … ]



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

[ … ]

 

Skin and subcutaneous tissue disorders

Common

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

Uncommon

Stevens Johnson syndrome, dermatitis bullous

[ … ]

 

 

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)

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).

 

[ … ]

 

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 HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.iewww.hpra.ie/

e-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie

 

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mtwww.medicinesauthority.gov.mt/portal

e-mail: postlicensing.medicinesauthority@gov.mt

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

05 January 2016

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Removal of black triangle

Date of revision of text on the SPC:02-05-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underline text = new text
Strike through text = deleted text

 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.


4.4     Special warnings and precautions for use

 

[…]

 

·    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.

-     For patients with a baseline QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 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.

 

[…]

 

 

5.1     Pharmacodynamic properties

 

[…]

 

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).

 

[…]

 

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

 

[…]

 



5.2     Pharmacokinetic properties

 

[…]

 

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)

AUC0-12τ (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).


[…]

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

2 May 2014

 

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:24-03-2014

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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.

 

[…]

10.       DATE OF REVISION OF THE TEXT

 

24 March 2014

 

 

Reasons for adding or updating:

  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

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4.3     Contraindications

 

Invirase is contraindicated in patients with:

 

[ … ]

 

-    quetiapine (risk of coma, see section 4.5)

 

4.5     Interaction with other medicinal products and other forms of interaction

 

[ … ]

 

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

[ … ]

 

 

 

 

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.

 

[ … ]

 

 

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

25 July 201318 October 2013

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.2 - Posology and method of administration

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SUMMARY OF PRODUCT CHARACTERISTICS

 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

4.2     Posology and method of administration

 

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

 

Adults and adolescents over the age of 16 years:

 

[ … ]

 

Paediatric populationChildren under the age of 16 and adults over 60 years:


The experience with Invirase in children below the age of 16 and adults over 60 years is limited. In children, as in adults, Invirase should only be given in combination with ritonavir.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.

 

 

4.4     Special warnings and precautions for use

 

[ … ]

 

Paediatric populationChildren under the age of 16 and adults over 60 years: The experience with Invirase in children below the age of 16 and adults over 60 years is limited. In children, as in adults, Invirase should only be given in combination with ritonavir.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.

 

[ … ]

 

4.8     Undesirable effects

 

[ … ]

 

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 Appendix V (see details below).

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

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

Website: www.mhra.gov.uk/yellowcard

 

 

 

5.2     Pharmacokinetic properties

 

[ … ]

 

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).

 

 

10.     DATE OF REVISION OF THE TEXT

 

25 May25 July 2013

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.4     Special warnings and precautions for use

 

[ … ]

 

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.

 

[ … ]

 

 

4.8     Undesirable effects

 

[ … ]

 

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 (see section 4.4). 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).

 

[ … ]

 

 

10.     DATE OF REVISION OF THE TEXT

 

17 January 201325 May 2013

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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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 were reported with the highest severity (grades 3 and 4): anaemia, diabetes mellitus, diarrhoea, nausea, vomiting, acquired lipodystrophy and fatigue.

 

 

[ … ]

 

b. Tabulated list of adverse reactions

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Adverse reactions from clinical trials where saquinavir was boosted with ritonavir

 

Limited data is available from two 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. Adverse reactions in thesefrom 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. The list also includes marked laboratory abnormalities that have been observed with the saquinavir soft capsule in combination with ritonavir (at 48 weeks). 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 from the MaxCmin1 and MaxCmin2 study in clinical studies and post-marketing experience in adult patients. (Very common (³ 10 %); common (³ 1 % and < 10 %))

 

Body System

Frequency of Reaction

Adverse Reactions

 

Grades 3&4

All Grades

Blood and the lymphatic system disorders

Common

Anaemia

Anaemia

Immune system disorders

Common

 

Hypersensitivity

Metabolism and nutrition disorders

Common

Diabetes mellitus

Diabetes mellitus, anorexia, increased appetite

Psychiatric disorders

Common

 

Decreased libido, sleep disorder

Nervous System Disorders

Common

 

Paraesthesia, peripheral neuropathy, dizziness, dysgeusia, headache

Respiratory, thoracic and mediastinal disorders

Common

 

Dyspnoea

Gastrointestinal disorders

Very common

 

Diarrhoea, nausea

Common

Diarrhoea, nausea, vomiting

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

Skin and subcutaneous tissue disorders

Common

Acquired lipodystrophy

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

Musculoskeletal and connective tissue disorders

Common

 

Muscle spasms

General disorders and administration site conditions

Common

Fatigue

Asthenia, fatigue, increased fat tissue, malaise

Investigations

Very common

 

Increased alanine aminotransferase, increased aspartate aminotransferase, increased blood cholesterol, increased blood triglycerides, increased low density lipoprotein, decreased platelet count

Common

 

Increased blood amylase, increased blood bilirubin, increased blood creatinine, decreased haemoglobin, decreased lymphocyte count, decreased white blood cell count

 

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

 

 

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.

 

Post-marketing experience with saquinavir

 

Serious and non-serious adverse reactions from post-marketing spontaneous reports (where saquinavir was taken as the sole protease inhibitor or in combination with ritonavir), not mentioned previously in section 4.8, for which a causal relationship to saquinavir cannot be excluded, are summarised below. As these data come from the spontaneous reporting system, the frequency of the adverse reactions is unknown.

c. Description of selected adverse reactions

·        Immune system disorders: Hypersensitivity.

 

·        Metabolism and nutrition disorders:

 

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

 

-           Lipodystrophy: 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).

 

 

·          Nervous system disorders: Somnolence, convulsions.

 

·          Vascular disorders: 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).

 

·          Hepato-biliary disorders: Hepatitis.

 

·          Musculoskeletal, connective tissue and bone disorders: 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).

 

 

·          Renal and urinary disorders: Renal impairment.

 

·          Eye disorders: Visual impairment.

 

·         

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 (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.

 

 

10.     DATE OF REVISION OF THE TEXT

 

24 October 201217 January 2013

 

 

Reasons for adding or updating:

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:24-10-2012

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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 (Fortovase). A limited number of studies have been completed with ritonavir boosted Invirase or ritonavir boosted saquinavir soft capsules.

 

[ … ]

 

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

 

[ …]

 

 

 

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).

 

[ …]

 

 

 

Key: ¯ reduced, ↑ increased, « unchanged, ↑↑ markedly increased

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

27 June 24 October2012

 

 

 

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 6. 6 - Instructions for use, handling and disposal
  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text
  • Change to separate SPCs covering individual presentations

Date of revision of text on the SPC:27-06-2012

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

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

 

Excipient with known effect: Contains lLactose monohydrate: 38.5 mg mg.

 

For a the full list of excipients, see section 6.1.

 

 

 

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

 

[…]

 

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

[…]


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

 

Rifabutin 150 mg mg q3d
(saquinavir/ritonavir 1000/100 mg 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

No dose adjustment of saquinavir/ritonavir 1000/100 mg bid is required if ritonavir-boosted Invirase is administered in combination with rifabutin.

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

 

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

 

Rifabutin 150 mg q4d
(
saquinavir/ritonavir 1000/100 mg bid)

Rifabutin active moiety*
AUC
0-96 ↑ 60%
(90% CI 43%-79%)

Rifabutin active moiety*

C
max ↑ 111%
(90% CI 75%-153%)

Rifabutin AUC0-96 «

(90% CI 10¯ - 13↑)

Rifabutin Cmax ↑ 68%

(90% CI 38%-105%)

 

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

The recommended dose of rifabutin is 150 mg twice weekly on set days (for example Mondays and Thursdays), with the dose of Invirase/ritonavir unchanged (1000/100 mg bid).

 

Monitoring of neutropenia and the liver enzyme levels is recommended. Tapering the rifabutin dose to 150 mg every four days could be justified in cases of marked neutropenia.

 

[…]

 

4.6     Fertility, pregnancy and lactation

 

[…]

 

LactationBreast-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.

 

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 and bioavailability in adults: 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 7). The pharmacokinetics of saquinavir is stable during long-term treatment.

 

[…]

 

Metabolism 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 mg/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).

 

[…]

 

6.6     Special precautions for disposal

 

No special requirements for disposal.

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 04 October 1996

Date of last latest renewal: 04 October 2006

 

 

10.     DATE OF REVISION OF THE TEXT

 

2 March 201227 June 2012

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 5.2 - Pharmacokinetic Properties
  • Individual presentations superseded by joint SPC

Date of revision of text on the SPC:26-03-2010

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4.2     Posology and method of administration

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).

 

Renal and hHepatic impairment:
No dosage adjustment is necessary for HIV-infected patients with mild hepatic impairment.No dosage adjustment is necessary for HIV-infected patients with mild to moderate renal or mild hepatic impairment based on limited data Caution should be exercised in patients with severe renal or moderate 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).

 

4.4     Special warnings and precautions for use

In cases ofFor HIV-infected patients with mild moderate hepatic impairment no initial dosage adjustment is necessary based on limited data. at the recommended dose. The use of Invirase in combination with ritonavir in patients with moderate hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur.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.

 

5.1     Pharmacodynamic properties

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. No dose adjustment is warranted for saquinavir in HIV-infected 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).

 

Reasons for adding or updating:

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:15-03-2010

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4.5     Interaction with other medicinal products and other forms of interaction

 

 

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.

Caution is warranted.
A lower dose of trazodone should be considered.

 

Rifabutin 150 mg q3d
(
saquinavir/ritonavir 1000/100 mg bid)

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

No dose adjustment of saquinavir/ritonavir 1000/100 mg bid is required if ritonavir-boosted Invirase is administered in combination with rifabutin.

Rifabutin 150 mg q4d
(
saquinavir/ritonavir 1000/100 mg bid)

Rifabutin active moiety*
AUC0-96 ↑ 60%
(90% CI 43%-79%)
Rifabutin active moiety*
Cmax ↑ 111%
(90% CI 75%-153%)

Rifabutin AUC0-96 «

(90% CI 10¯ - 13↑)

Rifabutin Cmax ↑ 68%

(90% CI 38%-105%)

 

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

The recommended dose of rifabutin is 150 mg twice weekly on set days (for example Mondays and Thursdays), with the dose of Invirase/ritonavir unchanged (1000/100 mg bid).

 

Monitoring of neutropenia and the liver enzyme levels is recommended. Tapering the rifabutin dose to 150 mg every four days could be justified in cases of marked neutropenia.

 

Reasons for adding or updating:

  • Change to section 5.3 - Preclinical Safety Data

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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.

 

 at dose levels that gave maximum plasma exposures (AUC values) approximately 1.5-, 1.0-, 4 to 9- and 3 fold greater, respectively, than those achieved in humans at the recommended dose.

 

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.Studies with and without metabolic activation (as appropriate) have shown that saquinavir has no mutagenic or genotoxic activity.

 

Carcinogenesis: There was no evidence of carcinogenic activity after the administration of saquinavir mesilate for 96 to 104 weeks to rats (maximum dose 1000 mg/kg/day) and mice (maximum dose 2500 mg/kg/day). The plasma exposures (AUC values) in the respective speciesrats (maximum dose 1000 mg/kg/day) were up to approximately 60 37%, and the plasma exposures inand in mice (maximum dose 2500 mg/kg/day) were lower thanup to approximately 85%of those the expected plasma exposures obtained in humans at the recommended clinical dose of saquinavir ritonavir boosted Invirasesoft capsules or equivalent to them.

 

Reproductive toxicityImpairment of fertility: (see section 4.6). Fertility, peri- and reproductive performancepostnatal development were not affected in rats at plasma exposures (AUC values) approximately 50 % of those achieved in humans at the recommended dose., and

 

Teratogenicity: embryotoxic / teratogenic effects were not observed in rats or rabbits at. The plasma exposures (AUC values) lower than those achieved(AUC values) 32 in humans at the recommended clinical dose of ritonavir boosted Invirase.Reproduction studies conducted with saquinavir in rats have shown no embryotoxicity or teratogenicity at plasma exposures (AUC values) approximately 50 % of those achieved in humans at the recommended dose or in rabbits at plasma exposures approximately 40 % of those achieved at the recommended clinical dose. Distribution studies in these speciesrats  showed that the placental transfer of saquinavir is low (less than 5 % of maternal plasma concentrations).

Studies in rats indicated that exposure to saquinavir from late pregnancy through lactation at plasma concentrations (AUC values) approximately 50 % of those achieved in humans at the recommended dose had no effect on the survival, growth and development of offspring to weaning.

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

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4.2     Posology and method of administration

In combination with other protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors
Dose reduction may be required when Invirase/ritonavir is administered with some other HIV protease inhibitors (e.g. nelfinavir, indinavir and delavirdine), since these medicinal products may increase saquinavir plasma levels (see section 4.5).

 

4.5     Interaction with other medicinal products and other forms of interaction

-Nelfinavir 1250 mg bid (saquinavir/ritonavir 1000/100 mg bid)    No dose adjustment required

 

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)

 

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:07-07-2008

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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 differential 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 when zidovudine is co-administered with ritonavir.

-    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.The changes are of doubtful clinical significance.

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
s
aquinavir/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.No dose adjustment for Invirase or nevirapine recommended.

Key: ¯ reduced, ↑ increased, « unchanged, ↑↑ markedly increased


Table 1 (continued): Interactions and dose recommendations with other medicinal products

 

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

Interaction

Recommendations concerning co-administration

HIV protease inhibitors (NNRTIPIs)

 

 

Atazanavir 300 mg qd
(
saquinavir/ritonavir 1600/100 mg qd)

Saquinavir AUC 60%
Saquinavir C
max 42%

Ritonavir AUC ↑ 41%
Ritonavir C
max ↑ 34%
Atazanavir
«

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

 

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/ritonavir 1000/100 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)

No dose adjustment required.

-    Nelfinavir
(
saquinavir/ritonavir)

-      Interaction with Invirase/ritonavir not studied.

 

-    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.

 

 


Table 1 (continued): Interactions and dose recommendations with other medicinal products

 

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

Interaction

Recommendations concerning co-administration

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 saquinavir a systemic exposure of saquinavir over a 24 hour period similar to or greater than thosethat 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 nevertheless 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.

Other medicinal products
Antiarrhythmics

 

 

Bepridil
Lidocaine (systemic) Quinidine
(saquinavir/ritonavir)

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

Caution is warranted.
Therapeutic concentration monitoring is recommended
, if available.

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).

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 evaluatedstudied.

 

-    Carbamazepine Phenobarbital
Phenytoin
(unboosted saquinavir)

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

 

 


Table 1 (continued): Interactions and dose recommendations with other medicinal products

 

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

Interaction

Recommendations concerning co-administration

Antidepressants

 

 

Tricyclic antidepressants
(e.g. amitriptyline, imipramine) (saquinavir/ritonavir)

Invirase/ritonavir may increase concentrations of tricyclic antidepressants.

Therapeutic concentration monitoring recommended.

-    Nefazodone
(saquinavir/ritonavir)

-      Interaction with saquinavir/ritonavir not evaluated.

 

-    Nefazodone
(unboosted saquinavir)

-      Nefazodone inhibits CYP3A4. Saquinavir concentrations may be increased.

-      Monitoring for saquinavir toxicity recommended.

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).

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 %

-      No dose adjustment is required when co-administered for a limited time at the doses studied.

-    Erythromycin
(saquinavir/ritonavir)

-      Interaction with Invirase/ritonavir not studied.

 

-    Erythromycin
250 mg qid
(unboosted saquinavir 1200 mg tid)

-      Saquinavir AUC 99 %
Saquinavir Cmax
106
%

-      No dose adjustment required.

-    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.

Antifungals

 

 

Ketoconazole 200 mg qd
(saquinavir/ritonavir 1000/100 mg bid)

Saquinavir AUC «
Saquinavir C
max «
Ritonavir AUC
«
Ritonavir C
max «
Ketoconazole AUC ↑
168%
(90% CI
146%-1
93%)
Ketoconazole C
max
↑ 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 like ketoconazole. An interaction of similar magnitude is possible.

Monitoring for saquinavir toxicity recommended.

 


Table 1 (continued): Interactions and dose recommendations with other medicinal products

 

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

Interaction

Recommendations concerning co-administration

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
(
saquinavir/ritonavir 1000/100 mg bid)

Interaction with saquinavir/ritonavir 1000/100 mg not studied.

A dosage reduction to rifabutin

150 mg every three days is recommended based on experience with low dose ritonavir boosted protease inhibitors. Patients receiving rifabutin with Invirase/ritonavir should be closely monitored for liver function test elevations and emergence of adverse events associated with rifabutin therapy. Further dosage reduction of rifabutin may be necessary. Therapeutic concentration monitoring for saquinavir is recommended.

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.

 


Table 1 (continued): Interactions and dose recommendations with other medicinal products

 

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

Interaction

Recommendations concerning co-administration

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.

Medicinal products that are substrates of P-glycoprotein

Digitalis glycosides

 

 

Digoxin 0.5 mg
single dose

(