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Saquinavir Sandoz 500 mg, filmomhulde tabletten

RegistratienummerRVG 114370
ProcedurenummerNL/H/3050/001
Farmaceutische vormFilmomhulde tablet
ToedieningswegOraal gebruik
ATCJ05AE01 - Saquinavir
AfleverstatusUitsluitend recept
Registratiedatum08 mei 2015
RegistratiehouderSandoz B.V.
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1327 AH ALMERE
Werkzame stof(fen)SAQUINAVIRMESILAAT
SAMENSTELLING
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SAQUINAVIR
Hulpstof(fen)CELLULOSE, MICROKRISTALLIJN (E 460)
CROSCARMELLOSE NATRIUM (E 468)
GLYCEROLTRIACETAAT (E 1518)
HYPROMELLOSE, Type 2910 (3 - 15 mPa.s) (E 464)
IJZEROXIDE GEEL (E 172)
IJZEROXIDE ROOD (E 172)
LACTOSE 1-WATER
MAGNESIUMSTEARAAT (E 572)
POVIDON K 30 (E 1201)
TALK (E 553 B)
TITAANDIOXIDE (E 171)
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Saquinavir Sandoz 500 mg, filmomhulde tabletten 
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1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
 
2. QUALITATIVE 
AND 
QUANTITATIVE 
COMPOSITION 
 
One film-coated tablet contains 500 mg of saquinavir (as saquinavir mesilate).  
 
Excipients with known effect:  
One film-coated tablet contains 32.5 mg lactose monohydrate.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL 
FORM 
 
Film-coated tablet.  
 
Light orange to brownish orange, oval cylindrical, biconvex film-coated tablets debossed with “H” on 
one side and “165” on the other side.  
 
 
4. CLINICAL 
PARTICULARS 
 
4.1 Therapeutic 
indications 
 
Saquinavir Sandoz is indicated for the treatment of HIV-1 infected adult patients. Saquinavir Sandoz 
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 Saquinavir Sandoz should be initiated by a physician experienced in the 
management of HIV infection.  
 
In combination with ritonavir 
 
The recommended dose of Saquinavir Sandoz is 1000 mg (2 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 saquinavir/ritonavir, the recommended starting 
dose of Saquinavir Sandoz is 500 mg (1 film-coated tablet) two times daily with ritonavir 100 mg two 
 
 

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times daily in combination with other antiretroviral agents for the first 7 days of treatment. After 
7 days, the recommended dose of Saquinavir Sandoz 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 Saquinavir Sandoz at the standard recommended dose of 
1000 mg two times daily with ritonavir 100 mg two times daily.  
 
Renal impairment: 
 
No dosage adjustment is necessary for patients with mild to moderate renal impairment. 
Caution should be exercised in patients with severe renal impairment (see section 4.4).  
 
Hepatic impairment: 
 
No dosage adjustment is necessary for HIV-infected patients with mild hepatic impairment. No dosage 
adjustment seems warranted for patients with moderate hepatic impairment based on limited data. 
Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is 
recommended due to increased variability of the exposure in this population. Saquinavir 
Sandoz/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 Saquinavir Sandoz in adults over 60 years is limited. 
 
Method of administration 
Saquinavir Sandoz film-coated tablets should be swallowed whole and taken at the same time as 
ritonavir with or after food (see section 5.2).  
 
4.3 Contraindications 
 
Saquinavir Sandoz 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 medicinal products, which may interact and result 
 
 

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in potentially life-threatening undesirable effects (see sections 4.4, 4.5 and 4.8):  
 
medicinal products 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 Saquinavir Sandoz therapy: Saquinavir Sandoz should not be 
given as the sole protease inhibitor. Saquinavir Sandoz 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. 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 saquinavir (see section 5.1). Concomitant use of ritonavir-boosted 
Saquinavir Sandoz 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 Saquinavir Sandoz should not be exceeded. 
Ritonavir-boosted saquinavir 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 saquinavir 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 Saquinavir Sandoz should be 
discontinued if arrhythmias are demonstrated, or if prolongation occurs in the QT or PR interval.  
 
 

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1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
 
Patients initiating therapy with ritonavir-boosted Saquinavir Sandoz
:  
-  An ECG should be performed prior to initiation of treatment: patients with a QT interval 
> 450 msec should not use ritonavir-boosted Saquinavir Sandoz.  
-  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 Saquinavir Sandoz.  
 
Patients stable on ritonavir-boosted Saquinavir Sandoz 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 Saquinavir 
Sandoz 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 Saquinavir Sandoz 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 Saquinavir Sandoz 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 Saquinavir Sandoz 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. Saquinavir Sandoz/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.  
 
 

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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 [nationally completed name 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:
 Saquinavir Sandoz 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 
 
 

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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 saquinavir and ritonavir is 1000 mg saquinavir 
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 saquinavir/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 saquinavir/ritonavir, alternative or additional contraceptive measures should be 
used when oestrogen-based oral contraceptives are co-administered (see section 4.5).  
 
 
 

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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).  
 
Sexual transmission: 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. 
 
4.5  Interaction with other medicinal products and other forms of interaction 
 
Most drug interaction studies with saquinavir have been completed with unboosted saquinavir film-
coated tablets or unboosted saquinavir soft capsules. A limited number of studies have been completed 
with ritonavir boosted saquinavir film-coated tablets 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 saquinavir film-
coated tablets/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, active ingredients 
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 the ritonavir containing medicinal product).  
 
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers 
receiving saquinavir/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 Saquinavir Sandoz with 
other medicinal products that prolong the QT and/or PR interval is contraindicated. The combination 
of Saquinavir Sandoz/ritonavir with medicinal products 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, 
 
 

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particular caution is warranted (see section 4.4; for information on individual medicinal products, see 
Table 1).  
 
Table 1: Interactions and dose recommendations with other medicinal products  
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Antiretroviral agents  
 
Nucleoside reverse transcriptase inhibitors (NRTIs)  
 Zidovudine 
 No pharmacokinetic interaction 
 No dose adjustment required.  
(saquinavir/ritonavir)  
studies have been completed.  
 
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.  
 
 Zidovudine  
 Saquinavir ↔  
 
(unboosted saquinavir) 
 
Zidovudine ↔ 
Didanosine  
Saquinavir AUC ↓ 30%  
No dose adjustment required.  
400 mg single dose  
Saquinavir Cmax ↓ 25%  
(saquinavir/ritonavir 
Saquinavir Cmin ↔  
1600/100 mg qd)  
Tenofovir disoproxil 
Saquinavir AUC ↓ 1%  
No dose adjustment required.  
fumarate 300 mg qd 
Saquinavir Cmax ↓ 7%  
(saquinavir/ritonavir 
Saquinavir Cmin ↔  
1000/100 mg bid)  
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  
 
-Delavirdine 
 Interaction with saquinavir/ritonavir 
 
(saquinavir/ritonavir)  
not studied.  
 
 

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Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
 Delavirdine  
 Saquinavir AUC ↑ 348%.  
 Hepatocellular changes should be 
(unboosted saquinavir) 
There are limited safety and no 
monitored frequently if this 
efficacy data available from the use 
combination is prescribed. 
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). 
Efavirenz 600 mg qd 
Saquinavir ↔  
No dose adjustment required.  
(saquinavir/ritonavir 
Efavirenz ↔  
1600/200 mg qd, or 
saquinavir/ritonavir 
1000/100 mg bid, or 
saquinavir/ritonavir 
1200/100 mg qd)  
 Nevirapine  
 Interaction with saquinavir/ritonavir 
 
(saquinavir/ritonavir)  
not studied.   
 Nevirapine (unboosted 
 Saquinavir AUC ↓ 24%  
 No dose adjustment required. 
saquinavir) 
Nevirapine AUC ↔  
HIV protease inhibitors (PIs)  
 
Atazanavir 300 mg qd 
Saquinavir AUC ↑ 60%  
Contraindicated in combination with 
(saquinavir/ritonavir 
Saquinavir Cmax ↑ 42%  
Saquinavir Sandoz/ritonavir due to 
1600/100 mg qd)  
Ritonavir AUC ↑ 41%  
the potential for life threatening 
Ritonavir Cmax ↑ 34%  
cardiac arrhythmia (see sections 4.3 
Atazanavir ↔  
and 4.4).  
No clinical data available for the 
combination of saquinavir/ritonavir 
1000/100 mg bid and atazanavir.  
Fosamprenavir 700 mg bid  Saquinavir AUC ↓ 15%  
No dose adjustment required for 
(saquinavir/ritonavir 
Saquinavir Cmax ↓ 9%  
Saquinavir Sandoz/ritonavir.  
1000/100 mg bid)  
Saquinavir Cmin ↓ 24% (remained 
above the target threshold for 
effective therapy.)  
 Indinavir 
 Low dose ritonavir increases the 
 Increased concentrations of indinavir 
(saquinavir/ritonavir)  
concentration of indinavir.  
may result in nephrolithiasis.  
 
 

Sandoz B.V. 
 
Page 10/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
 Indinavir 800 mg tid 
 Saquinavir AUC ↑ 4.6-7.2 fold 
 
(saquinavir 600-1200 mg 
Indinavir ↔  
single dose) 
No safety and efficacy data available 
for this combination. Appropriate 
doses of combination not 
established. 
Lopinavir/ritonavir 
Saquinavir ↔  
Contraindicated in combination with 
400/100 mg bid 
Ritonavir ↓ (effectiveness as boosting  Saquinavir Sandoz/ritonavir due to 
(saquinavir 1000 mg bid in  agent not modified).  
the potential for life threatening 
combination with 2 or 3 
Lopinavir ↔ (based on historical 
cardiac arrhythmia (see sections 4.3 
NRTIs)  
comparison with unboosted 
and 4.4).  
lopinavir) 
Ritonavir 100 mg bid 
Saquinavir ↑  
This is the approved combination 
(saquinavir 1000 mg bid)  
Ritonavir ↔  
regimen. No dose adjustment is 
In HIV-infected patients, saquinavir 
recommended.  
film-coated tablets 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).  
Tipranavir/ritonavir 
Saquinavir Cmin ↓ 78%  
Concomitant administration of 
(saquinavir/ritonavir)  
Dual-boosted protease inhibitor 
tipranavir, co-administered with low 
combination therapy in multiple-
dose ritonavir, with 
treatment experienced HIV-positive 
saquinavir/ritonavir, is not 
adults.  
recommended. If the combination is 
considered necessary, monitoring of 
the saquinavir plasma levels is 
strongly encouraged.  
HIV fusion inhibitor  
 
Enfuvirtide 
Saquinavir ↔  
No dose adjustment required.  
(saquinavir/ritonavir 
Enfuvirtide ↔  
1000/100 mg bid)  
No clinically significant interaction 
was noted.  
HIV CCR5 antagonist  
 
 
 

Sandoz B.V. 
 
Page 11/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Maraviroc 100 mg bid 
Maraviroc AUC12 ↑ 9.77  
No dose adjustment of 
(saquinavir/ritonavir 
Maraviroc Cmax: ↑ 4.78 
saquinavir/ritonavir is required. Dose 
1000/100 mg bid)  
Saquinavir/ritonavir concentrations 
of maraviroc should be decreased to 
not measured, no effect is expected.  
150 mg bid with monitoring.  
Other medicinal products  
 
Alpha-1 adrenoreceptor antagonist  
Alfuzosin  
Concomitant use of alfuzosin and 
Contraindicated in combination with 
saquinavir/ritonavir is expected to 
Saquinavir Sandoz/ritonavir due to 
increase plasma levels of alfuzosin.  
potential increase in alfuzosin 
concentration which can result in 
hypotension.  
Antiarrhythmics  
 
 
Bepridil  
Concentrations of bepridil, systemic 
Contraindicated in combination with 
Lidocaine (systemic) 
lidocaine, quinidine or 
Saquinavir Sandoz/ritonavir due to 
Quinidine  
hydroquinidine may be increased 
potentially life threatening cardiac 
Hydroquinidine 
when co-administered with 
arrhythmia (see sections 4.3 and 4.4). 
(saquinavir/ritonavir)  
saquinavir/ritonavir.  
Amiodarone  
Concentrations of amiodarone, 
Contraindicated in combination with 
flecainide  
flecainide or propafenone may be 
saquinavir/ritonavir due to 
propafenone 
increased when co-administered with 
potentially life threatening cardiac 
(saquinavir/ritonavir)  
saquinavir/ritonavir.  
arrhythmia (see section 4.3).  
Dofetilide 
Although specific studies have not 
Contraindicated in combination with 
(saquinavir/ritonavir)  
been performed, co-administration of 
Saquinavir Sandoz/ritonavir due to 
saquinavir/ritonavir with medicinal 
potentially life threatening cardiac 
products that are mainly metabolised 
arrhythmia (see sections 4.3 and 4.4). 
by CYP3A4 pathway may result in 
elevated plasma concentrations of 
these medicinal products.  
Ibutilide  
 
Contraindicated in combination with 
Sotalol 
Saquinavir Sandoz/ritonavir due to 
(saquinavir/ritonavir)  
the potential for life threatening 
cardiac arrhythmia (see sections 4.3 
and 4.4).  
Anticoagulant  
 
 
Warfarin 
Concentrations of warfarin may be 
INR (international normalised ratio) 
(saquinavir/ritonavir)  
affected.  
monitoring recommended.  
Anticonvulsants  
 
 
 
 

Sandoz B.V. 
 
Page 12/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
 Carbamazepine 
 Interaction with saquinavir/ritonavir 
 
Phenobarbital  
not studied.  
Phenytoin 
 
(saquinavir/ritonavir)  
 Carbamazepine 
 These medicinal products will induce   
Phenobarbital  
CYP3A4 and may therefore decrease 
Phenytoin (unboosted 
saquinavir concentrations. 
saquinavir) 
Antidepressants  
 
 
Tricyclic antidepressants 
saquinavir/ritonavir may increase 
Contraindicated in combination with 
(e.g. amitriptyline, 
concentrations of tricyclic 
Saquinavir Sandoz/ritonavir due to 
imipramine) 
antidepressants.  
potentially life threatening cardiac 
(saquinavir/ritonavir)  
arrhythmia (see sections 4.3 and 4.4). 
 Nefazodone 
 Interaction with saquinavir/ritonavir 
 
(saquinavir/ritonavir)  
not evaluated.  
 Nefazodone (unboosted   Nefazodone inhibits CYP3A4. 
 Combination not recommended. 
saquinavir) 
Saquinavir concentrations may be 
increased. 
Trazodone (ritonavir)  
Plasma concentrations of trazodone 
Contraindicated in combination with 
may increase.  
Saquinavir Sandoz/ritonavir due to 
Adverse events of nausea, dizziness, 
potentially life threatening cardiac 
hypotension and syncope have been 
arrhythmia (see sections 4.3 and 4.4). 
observed following co-administration 
of trazodone and ritonavir.  
Anti-gout preparation  
 
 
Colchicine  
Concomitant use of colchicine and 
Because of a potential increase of 
saquinavir/ritonavir is expected to 
colchicine-related toxicity 
increase plasma levels of colchicine 
(neuromuscular events including 
due to P-gp and/or CYP3A4 
rhabdomyolysis), its concomitant use 
inhibition by the protease inhibitor.  
with saquinavir/ritonavir is not 
recommended, especially in the case 
of renal or hepatic impairment (see 
section 4.4).  
Antihistamines  
 
 
Terfenadine  
Terfenadine AUC ↑, associated with 
Terfenadine and astemizole are 
Astemizole 
a prolongation of QTc intervals.  
contraindicated with boosted or 
(saquinavir/ritonavir)  
A similar interaction with astemizole  unboosted saquinavir (see section 
is likely.  
4.3).  
 
 

Sandoz B.V. 
 
Page 13/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Mizolastine 
 
Contraindicated in combination with 
(saquinavir/ritonavir)  
Saquinavir Sandoz/ritonavir due to 
the potential for life threatening 
cardiac arrhythmia (see sections 4.3 
and 4.4).  
Anti-infectives  
 
 
 Clarithromycin 
 Interaction with saquinavir/ritonavir   
(saquinavir/ritonavir) 
not studied.  
 
 Clarithromycin 500 mg 
 Saquinavir AUC ↑ 177%  
 Contraindicated in combination 
bid (unboosted 
Saquinavir Cmax ↑ 187% 
with Saquinavir Sandoz/ritonavir 
saquinavir 1200 mg tid) 
Clarithromycin AUC ↑ 40% 
due to the potential for life 
Clarithromycin Cmax ↑ 40% 
threatening cardiac arrhythmia (see 
sections 4.3 and 4.4). 
 Erythromycin 
 Interaction with saquinavir/ritonavir   Contraindicated in combination 
(saquinavir/ritonavir)  
not studied.  
with Saquinavir Sandoz/ritonavir 
 
 
due to the potential for life 
 
 
threatening cardiac arrhythmia (see 
sections 4.3 and 4.4).   
 Erythromycin 250 mg 
 Saquinavir AUC ↑ 99%  
 No dose adjustment required. 
qid (unboosted 
Saquinavir Cmax ↑ 106% 
saquinavir 1200 mg tid) 
 Fusidic acid 
 Not studied. Co-administration of 
 
(saquinavir/ritonavir) 
fusidic acid and Saquinavir 
Sandoz/ritonavir can cause 
increased plasma concentration of 
both fusidic acid and 
saquinavir/ritonavir. 
 Streptogramin antibiotics   Interaction with saquinavir/ritonavir   
(saquinavir/ritonavir)  
not studied.  
 Streptogramin antibiotics   Streptogramin antibiotics such as 
 Monitoring for saquinavir toxicity 
(unboosted saquinavir) 
quinupristin/dalfopristin inhibit 
recommended. 
CYP3A4. Saquinavir concentrations 
may be increased. 
 Halofantrine  
 
 Contraindicated in combination 
Pentamidine  
with Saquinavir Sandoz/ritonavir 
Sparfloxacin 
due to the potential for life 
(saquinavir/ritonavir)  
threatening cardiac arrhythmia (see 
sections 4.3 and 4.4).  
 
 

Sandoz B.V. 
 
Page 14/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Antifungals  
 
 
Ketoconazole 200 mg qd 
Saquinavir AUC ↔  
No dose adjustment required when 
(saquinavir/ritonavir 
Saquinavir Cmax ↔  
saquinavir/ritonavir combined with 
1000/100 mg bid)  
Ritonavir AUC ↔  
≤ 200 mg/day ketoconazole. High 
Ritonavir Cmax ↔  
doses of ketoconazole 
Ketoconazole AUC ↑ 168%  
(> 200 mg/day) are not 
(90% CI 146%-193%)  
recommended.  
Ketoconazole Cmax ↑ 45%  
(90% CI 32%-59%)  
 Itraconazole 
 Interaction with saquinavir/ritonavir 
(saquinavir/ritonavir)  
not studied.  
 
 Itraconazole (unboosted   Itraconazole is a moderately potent   Monitoring for saquinavir toxicity 
saquinavir) 
inhibitor of CYP3A4. An interaction 
recommended. 
is possible. 
Fluconazole/miconazole 
Interaction with saquinavir/ritonavir 
 
(saquinavir/ritonavir)  
not studied.  
Antimycobacterials  
 
 
Rifampicin 600 mg qd 
In a clinical study 11 of 17 (65%) 
Rifampicin is contraindicated in 
(saquinavir/ritonavir 
healthy volunteers developed severe 
combination with Saquinavir 
1000/100 mg bid)  
hepatocellular toxicity with 
Sandoz/ritonavir (see section 4.3).  
transaminase elevations up to > 20-
fold the upper limit of normal after 1 
to 5 days of co-administration.  
 
 

Sandoz B.V. 
 
Page 15/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Rifabutin 150 mg q3d 
Saquinavir AUC0-12 ↓ 13%  
To prevent possible development of 
(saquinavir/ritonavir 
(90% CI: 31↓ - 9↑)  
rifabutin resistance in TB and HIV 
1000/100 mg bid) in 
Saquinavir Cmax ↓ 15%  
co-infected patients, the 
healthy volunteers 
(90% CI: 32↓ - 7↑)  
recommended dose of rifabutin is 
Ritonavir AUC0-12 ↔  
150 mg every other day or three 
(90% CI: 10↓ - 9↑)  
times per week, with the dose of 
Ritonavir Cmax ↔  
saquinavir/ritonavir unchanged 
(90% CI: 8↓ - 7↑)  
(1000/100 mg bid). Monitoring of 
 
neutropenia and liver enzyme levels 
Rifabutin active moiety*  
is recommended due to an expected 
AUC0-72 ↑ 134%  
increase in exposure to rifabutin. 
(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   
Antipsychotics 
Quetiapine 
Due to CYP3A inhibition by 
Concomitant administration of 
saquinavir/ritonavir, concentrations of  Invirase and quetiapine is contra- 
quetiapine are expected to increase 
indicated as it may increase 
quetiapine-related toxicity. Increased 
plasma concentrations of quetiapine 
may lead to coma. 
Benzodiazepines  
 
 
 
 

Sandoz B.V. 
 
Page 16/35 
Saquinavir Sandoz 500 mg, filmomhulde tabletten 
1311-V1 
RVG 114370 
1.3.1.1 Samenvatting van de Productkenmerken 
November 2014 
 
 
Medicinal product by 
Interaction  
Recommendations concerning co-
therapeutic area (dose of 
administration  
saquinavir used in study)  
Midazolam 7.5 mg single 
Midazolam AUC ↑ 12.4 fold 
Co-administration of Saquinavir 
dose (oral) 
Midazolam Cmax ↑ 4.3 fold 
Sandoz/ritonavir with orally 
(saquinavir/ritonavir 
Midazolam t1/2 ↑ from 4.7 h to 14.9 h 
administered midazolam is 
1000/100 mg bid)  
No data are available on concomitant 
contraindicated (see section 4.3). 
use of ritonavir boosted saquinavir 
Caution should be used with co-
with intravenous midazolam. Studies 
administration of Saquinavir Sandoz 
of other CYP3A modulators and i.v. 
and parenteral midazolam.  
midazolam suggest a possible 34 fold  If Saquinavir Sandoz is co-
increase in midazolam plasma levels.   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  
Concentrations of these medicinal 
Careful monitoring of patients with 
Clorazepate  
products may be increased when co-
regard to sedative effects is 
Diazepam  
administered with 
warranted. A decrease in the dose of 
Flurazepam 
saquinavir/ritonavir.   
the benzodiazepine may be required.  
(saquinavir/ritonavir)  
Triazolam 
Concentrations of triazolam may be 
Contraindicated in combination with 
(saquinavir/ritonavir)  
increased when co-administered with 
saquinavir/ritonavir, due to the risk 
saquinavir/ritonavir.  
of potentially prolonged or increased 
sedation and respiratory depression 
(see section 4.3).  
Calcium channel blockers    
 
Felodipine, nifedipine, 
Concentrations of these medicinal 
Caution is warranted and clinical 
nicardipine, diltiazem, 
products may be increased when co-
monitoring of patients is 
nimodipine, verapamil, 



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