Invirase

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



 

2 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INVIRASE 500 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One film-coated tablet contains 500 mg of saquinavir as saquinavir mesilate. 
 
Excipient with known effect: Lactose monohydrate: 38.5 mg. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Light orange to greyish or brownish orange film-coated tablet of oval cylindrical biconvex shape with 
the marking "SQV 500" on the one side and "ROCHE" on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Invirase is indicated for the treatment of HIV-1 infected adult patients. Invirase should only be given 
in combination with ritonavir and other antiretroviral medicinal products (see section 4.2). 
 
4.2 Posology and method of administration 
 
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, except rilpivirine (see section 4.5), without a wash-out period, should however initiate 
and continue Invirase at the standard recommended dose of 1000 mg two times daily with ritonavir 
100 mg two times daily. 
 
Renal impairment: 
No dosage adjustment is necessary for patients with mild to moderate renal impairment. Caution 
should be exercised in patients with severe renal impairment (see section 4.4). 
 
Hepatic impairment: 
No dosage adjustment is necessary for HIV-infected patients with mild hepatic impairment. No dosage 
adjustment seems warranted for patients with moderate hepatic impairment based on limited data. 



 

3 

Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is 
recommended due to increased variability of the exposure in this population. Invirase/ritonavir is 
contraindicated in patients with decompensated hepatic impairment (see sections 4.3 and 4.4). 
 
Paediatric population: 
The safety and activity of saquinavir boosted with ritonavir in HIV-infected patients less than 2 years 
have not been established. No dose recommendations for paediatric patients ≥2 years of age could be 
established that are both effective and below thresholds of concern for QT and PR interval 
prolongation. 
 
Adults over 60 years: 
The experience with Invirase in adults over 60 years is limited. 
 
Method of administration 
Invirase film-coated tablets should be swallowed whole and taken at the same time as ritonavir with or 
after food (see section 5.2).  
 
4.3 Contraindications 
 
Invirase is contraindicated in patients with: 

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

potentially life-threatening undesirable effects (see sections 4.4, 4.5 and 4.8): 
- drugs that prolong the QT and/or PR interval (see sections 4.4 and 4.5) 
- midazolam administered orally (for caution on parenterally administered midazolam, see 

section 4.5), triazolam (potential for prolonged or increased sedation, respiratory 
depression) 

- simvastatin, lovastatin (increased risk of myopathy including rhabdomyolysis) 
- ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine) 

(potential for acute ergot toxicity) 
- rifampicin (risk of severe hepatocellular toxicity) (see sections 4.4, 4.5, and 4.8) 
- quetiapine (risk of coma, see section 4.5).  
- lurasidone (potential for serious and/or life-threatening reactions, see section 4.5) 

 
4.4 Special warnings and precautions for use 
 
Considerations when initiating Invirase therapy: Invirase should not be given as the sole protease 
inhibitor. Invirase should only be given in combination with ritonavir (see section 4.2). Invirase is not 
recommended for use in combination with cobicistat as dosing recommendations for this combination 
have not been established. 
 
Patients should be informed that saquinavir is not a cure for HIV infection and that they may continue 
to acquire illnesses associated with advanced HIV infection, including opportunistic infections. While 
effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk 
of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should 
be taken in accordance with national guidelines. 
 
Patients should also be advised that they might experience undesirable effects associated with co-
administered medications.  
 



 

4 

Cardiac conduction and repolarisation abnormalities:  
Dose-dependent prolongations of QT and PR intervals have been observed in healthy volunteers 
receiving ritonavir-boosted Invirase (see section 5.1). Concomitant use of ritonavir-boosted 
Invirase with other medicinal products that prolong the QT and/or PR interval is therefore 
contraindicated (see section 4.3). 
 
Since the magnitude of QT and PR prolongation increases with increasing concentrations of 
saquinavir, the recommended dose of ritonavir-boosted Invirase should not be exceeded. Ritonavir-
boosted Invirase at a dose of 2000 mg once daily with ritonavir 100 mg once daily has not been 
studied with regard to the risk of QT prolongation and is not recommended. Other medicinal products 
known to increase the plasma concentration of ritonavir-boosted Invirase should be used with caution. 
 
Women and elderly patients may be more susceptible to drug-associated effects on the QT and/or PR 
interval. 
 
• Clinical Management: 
Consideration should be given for performing baseline and follow-up electrocardiograms after 
initiation of treatment, e.g. in patients taking concomitant medication known to increase the exposure 
of saquinavir (see section 4.5). If signs or symptoms suggesting cardiac arrhythmia occur, continuous 
monitoring of ECG should be performed. Ritonavir-boosted Invirase should be discontinued if 
arrhythmias are demonstrated, or if prolongation occurs in the QT or PR interval. 
 
Patients initiating therapy with ritonavir-boosted Invirase: 

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

- For treatment-naïve patients initiating treatment with Invirase/ritonavir 500/100 mg two 
times daily for the first 7 days of treatment followed by Invirase 1000 mg two times daily 
with ritonavir 100 mg two times daily after 7 days and with a baseline QT interval < 450 
msec, an on-treatment ECG is suggested after approximately 10 days of therapy. 

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

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

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

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

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

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

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

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



 

5 

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

 
Liver disease: The safety and efficacy of saquinavir/ritonavir has not been established in patients with 
significant underlying liver disorders, therefore saquinavir/ritonavir should be used cautiously in this 
patient population. Invirase/ritonavir is contraindicated in patients with decompensated liver disease 
(see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral 
therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of 
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information 
for these medicinal products. 
 
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy and should be 
monitored according to standard practice. If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 
 
No dosage adjustment seems warranted for patients with moderate hepatic impairment based on 
limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic 
response is recommended due to increased variability of the exposure in this population (see sections 
4.2 and 5.2). There have been reports of exacerbation of chronic liver dysfunction, including portal 
hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver 
abnormalities. 
 
Renal impairment: Renal clearance is only a minor elimination pathway, the principal route of 
metabolism and excretion for saquinavir being via the liver. Therefore, no initial dose adjustment is 
necessary for patients with renal impairment. However, patients with severe renal impairment have not 
been studied and caution should be exercised when prescribing saquinavir/ritonavir in this population.  
 
Patients with chronic diarrhoea or malabsorption: No information on boosted saquinavir and only 
limited information on the safety and efficacy of unboosted saquinavir is available for patients 
suffering from chronic diarrhoea or malabsorption. It is unknown whether patients with such 
conditions could receive subtherapeutic saquinavir levels. 
 
Paediatric population: The safety and activity of saquinavir boosted with ritonavir in HIV-infected 
patients less than 2 years have not been established. No dose recommendations for paediatric patients 
≥2 years of age could be established that are both effective and below thresholds of concern for QT 
and PR interval prolongation. Therefore, use in this population is not recommended. 
 
Adults over 60 years: The experience with Invirase in adults over 60 years is limited. Elderly patients 
may be more susceptible to drug-associated effects on the QT and/or PR interval. 
 
Lactose intolerance: Invirase 500 mg film-coated tablets contain lactose. Patients with rare hereditary 
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption 
should not take this medicine. 
 
Patients with haemophilia: There have been reports of increased bleeding, including spontaneous skin 
haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. 
In some patients additional factor VIII was given. In more than half of the reported cases, treatment 
with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal 
relationship has been evoked, although the mechanism of action has not been elucidated. 
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. 
 
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose 
may occur during antiretroviral therapy. Such changes may in part be linked to disease control and 
lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there 
is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and 



 

6 

glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed 
as clinically appropriate. 
 
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, 
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis 
have been reported particularly in patients with advanced HIV–disease and/or long-term exposure to 
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they 
experience joint aches and pain, joint stiffness or difficulty in movement. 
 
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time 
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to 
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or 
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or 
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or 
focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms 
should be evaluated and treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 
CYP3A4 Interactions: Saquinavir could interact and modify the pharmacokinetics of other drugs that 
are substrates for CYP3A4 and/or P-gp and should be used with caution. Conversely, other drugs that 
induce CYP3A4 may also reduce saquinavir plasma concentrations. Monitoring of saquinavir plasma 
concentration might be indicated. See table 1, section 4.5, for drugs known and/or having the potential 
to interact with saquinavir and specific recommendations. 
 
Interaction with ritonavir: The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 
100 mg ritonavir twice daily. Higher doses of ritonavir have been shown to be associated with an 
increased incidence of adverse events. Co-administration of saquinavir and ritonavir has led to severe 
adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-
existing liver disease.  
 
Interaction with tipranavir: Concomitant use of boosted saquinavir and tipranavir, co-administered 
with low dose ritonavir in a dual-boosted regimen, results in a significant decrease in saquinavir 
plasma concentrations (see section 4.5). Therefore, the co-administration of boosted saquinavir and 
tipranavir, co-administered with low dose ritonavir, is not recommended. 
 
Interaction with HMG-CoA reductase inhibitors: Caution must be exercised if Invirase/ritonavir is 
used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this 
situation a reduced dose of atorvastatin should be considered. If treatment with a HMG-CoA reductase 
inhibitor is indicated, pravastatin or fluvastatin is recommended with careful monitoring (see section 
4.5). 
 
Oral contraceptives: Because concentration of ethinyl estradiol may be decreased when co-
administered with Invirase/ritonavir, alternative or additional contraceptive measures should be used 
when oestrogen-based oral contraceptives are co-administered (see section 4.5). 
 
Glucocorticoids: Concomitant use of boosted saquinavir and fluticasone or other glucocorticoids that 
are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs 
the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see 
section 4.5). 
 
Interaction with efavirenz: The combination of saquinavir and ritonavir with efavirenz has been 
shown to be associated with an increased risk of liver toxicity; liver function should be monitored 
when saquinavir and ritonavir are co-administered with efavirenz. No clinically significant alterations 



 

7 

of either saquinavir or efavirenz concentration were noted in studies in healthy volunteers or in HIV-
infected patients (see section 4.5). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Most drug interaction studies with saquinavir have been completed with unboosted Invirase or 
unboosted saquinavir soft capsules. A limited number of studies have been completed with ritonavir 
boosted Invirase or ritonavir boosted saquinavir soft capsules. 
 
Observations from drug interaction studies done with unboosted saquinavir might not be 
representative of the effects seen with saquinavir/ritonavir therapy. Furthermore, results seen with 
saquinavir soft capsules may not predict the magnitude of these interactions with Invirase/ritonavir. 
 
The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 
responsible for 90 % of the hepatic metabolism. Additionally, in vitro studies have shown that 
saquinavir is a substrate and an inhibitor for P-glycoprotein (P-gp). Therefore, medicinal products that 
either share this metabolic pathway or modify CYP3A4 and/or P-gp activity (see "Other potential 
interactions") may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also 
modify the pharmacokinetics of other medicinal products that are substrates for CYP3A4 or P-gp. 
 
Ritonavir can affect the pharmacokinetics of other medicinal products because it is a potent inhibitor 
of CYP3A4 and P-gp. Therefore, when saquinavir is co-administered with ritonavir, consideration 
should be given to the potential effects of ritonavir on other medicinal products (see the Summary of 
Product Characteristics for Norvir). 
 
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers 
receiving Invirase/ritonavir (see sections 4.3, 4.4 and 5.1), additive effects on QT and PR interval 
prolongation may occur. Therefore, concomitant use of ritonavir-boosted Invirase with other 
medicinal products that prolong the QT and/or PR interval is contraindicated. The combination of 
Invirase/ritonavir with drugs known to increase the exposure of saquinavir is not recommended and 
should be avoided when alternative treatment options are available. If concomitant use is deemed 
necessary because the potential benefit to the patient outweighs the risk, particular caution is 
warranted (see section 4.4; for information on individual drugs, see Table 1). 
 



 

8 

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 
 

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. 

Didanosine 
400 mg single dose 
(saquinavir/ritonavir 
1600/100 mg qd) 

Saquinavir AUC ↓ 30% 
Saquinavir Cmax ↓ 25% 
Saquinavir Cmin ↔ 

No dose adjustment required. 

Tenofovir disoproxil 
fumarate 300 mg qd 
(saquinavir/ritonavir 
1000/100 mg bid) 

Saquinavir AUC ↓ 1% 
Saquinavir Cmax ↓ 7% 
Saquinavir Cmin ↔ 

No dose adjustment required. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)   
- Delavirdine 

(saquinavir/ritonavir) 
Interaction with Invirase/ritonavir not 
studied. 

 

- Delavirdine 
(unboosted saquinavir) 

Saquinavir AUC ↑ 348%. 
There are limited safety and no 
efficacy data available from the use of 
this combination. In a small, 
preliminary study, hepatocellular 
enzyme elevations occurred in 13 % 
of subjects during the first several 
weeks of the delavirdine and 
saquinavir combination (6 % Grade 3 
or 4). 

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

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

Saquinavir ↔ 
Efavirenz ↔ 

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



 

9 

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

Interaction Recommendations concerning co-
administration 

Rilpivirine  Switching directly from a rilpivirine 
containing regimen to 
Invirase/ritonavir is contraindicated 
as is concomitant use due to the 
potential for life threatening cardiac 
arrhythmia (see sections 4.3 and 4.4). 

- Nevirapine 
(saquinavir/ritonavir) 

Interaction with Invirase/ritonavir not 
studied. 

 

- Nevirapine 
(unboosted saquinavir) 

Saquinavir AUC ↓ 24% 
Nevirapine AUC ↔ 

No dose adjustment required. 

HIV protease inhibitors (PIs)   
Atazanavir 300 mg qd 
(saquinavir/ritonavir 
1600/100 mg qd) 

Saquinavir AUC ↑ 60% 
Saquinavir Cmax ↑ 42% 
Ritonavir AUC ↑ 41% 
Ritonavir Cmax ↑ 34% 
Atazanavir ↔ 
No clinical data available for the 
combination of saquinavir/ritonavir 
1000/100 mg bid and atazanavir. 

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

Fosamprenavir 
700 mg bid 
(saquinavir/ritonavir 
1000/100 mg bid) 

Saquinavir AUC ↓ 15% 
Saquinavir Cmax ↓ 9% 
Saquinavir Cmin ↓ 24% (remained 
above the target threshold for 
effective therapy.) 

No dose adjustment required for 
Invirase/ritonavir. 
 

- Indinavir 
(saquinavir/ritonavir) 

Low dose ritonavir increases the 
concentration of indinavir. 

Increased concentrations of indinavir 
may result in nephrolithiasis. 

- Indinavir 800 mg tid 
(saquinavir 600-1200 mg 
single dose) 

Saquinavir AUC ↑ 4.6-7.2 fold 
Indinavir ↔ 
No safety and efficacy data available 
for this combination. Appropriate 
doses of combination not established. 

 

Lopinavir/ritonavir 
400/100 mg bid 
(saquinavir 1000 mg bid in 
combination with 2 or 3 
NRTIs) 

Saquinavir ↔ 
Ritonavir ↓ (effectiveness as boosting 
agent not modified). 
Lopinavir ↔ (based on historical 
comparison with unboosted lopinavir) 

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



 

10 

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

Interaction Recommendations concerning co-
administration 

- Nelfinavir 1250 mg bid 
(saquinavir/ritonavir 
1000/100 mg bid) 

Saquinavir AUC ↑ 13% 
(90% CI: 27↓ - 74↑) 
Saquinavir Cmax ↑ 9% 
(90% CI: 27↓ - 61↑ ) 
Nelfinavir AUC ↓ 6% 
(90% CI: 28↓ - 22↑) 
Nelfinavir Cmax ↓ 5% 
(90% CI: 23↓ - 16↑) 

Combination not recommended. 

Ritonavir 100 mg bid 
(saquinavir 1000 mg bid) 

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

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

Tipranavir/ritonavir 
(saquinavir/ritonavir) 

Saquinavir Cmin ↓ 78% 
Dual-boosted protease inhibitor 
combination therapy in multiple-
treatment experienced HIV-positive 
adults. 

Concomitant administration of 
tipranavir, co-administered with low 
dose ritonavir, with 
saquinavir/ritonavir, is not 
recommended. If the combination is 
considered necessary, monitoring of 
the saquinavir plasma levels is 
strongly encouraged (see section 
4.4). 

HIV fusion inhibitor   
Enfuvirtide 
(saquinavir/ritonavir 
1000/100 mg bid) 

Saquinavir ↔ 
Enfuvirtide ↔ 
No clinically significant interaction 
was noted. 

No dose adjustment required. 



 

11 

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

Interaction Recommendations concerning co-
administration 

HIV CCR5 antagonist 
Maraviroc 100 mg bid 
(saquinavir/ritonavir 
1000/100 mg bid) 

Maraviroc AUC12 ↑ 8.77 
Maraviroc Cmax: ↑ 3.78 
Saquinavir/ritonavir concentrations 
not measured, no effect is expected. 

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

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 

  

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

Contraindicated in combination with 
Invirase/ritonavir due to potential 
increase in alfuzosin concentration 
which can result in hypotension and 
potentially life-threatening cardiac 
arrhythmia. 

Antiarrhythmics 
Bepridil 
Lidocaine (systemic) 
Quinidine 
Hydroquinidine 
(saquinavir/ritonavir) 

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

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

Amiodarone 
flecainide 
propafenone 
(saquinavir/ritonavir) 

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

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

Dofetilide 
(saquinavir/ritonavir) 

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

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

Ibutilide 
Sotalol 
(saquinavir/ritonavir) 

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



 

12 

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

Interaction Recommendations concerning co-
administration 

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) 

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). 

- 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). 

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). 

Anti-gout preparation 
Colchicine Concomitant use of colchicine and 

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

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

Antihistamines   
Terfenadine 
Astemizole 
(saquinavir/ritonavir) 

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

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

Mizolastine 
(saquinavir/ritonavir) 

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



 

13 

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 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). 

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 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). 
 

 Halofantrine 
Pentamidine 
Sparfloxacin 
(saquinavir/ritonavir) 

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

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

Saquinavir AUC ↔ 
Saquinavir Cmax ↔ 
Ritonavir AUC ↔ 
Ritonavir Cmax ↔ 
Ketoconazole AUC ↑ 168% 
(90% CI 146%-193%) 
Ketoconazole Cmax ↑ 45% 
(90% CI 32%-59%) 

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



 

14 

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

Interaction Recommendations concerning co-
administration 

 Itraconazole 
(saquinavir/ritonavir) 

  

 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). 

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). 

Antimycobacterials   
Rifampicin 600 mg qd 
(saquinavir/ritonavir 
1000/100 mg bid) 

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

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

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

Saquinavir AUC0-12 ↓ 13% 
(90% CI: 31↓ - 9↑) 
Saquinavir Cmax ↓ 15% 
(90% CI: 32↓ - 7↑) 
Ritonavir AUC0-12 ↔ 
(90% CI: 10↓ - 9↑) 
Ritonavir Cmax ↔ 
(90% CI: 8↓ - 7↑) 
 
Rifabutin active moiety* 
AUC0-72 ↑ 134% 
(90% CI 109%-162%) 
Rifabutin active moiety* 
Cmax ↑ 130% 
(90% CI 98%-167%) 
Rifabutin AUC0-72 ↑ 53% 
(90% CI 36%-73%) 
Rifabutin Cmax ↑ 86% 
(90% CI 57%-119%) 
 
* Sum of rifabutin + 25-O-desacetyl 

rifabutin metabolite  

 
To prevent possible development of 
rifabutin resistance in TB and HIV 
co-infected patients, the 
recommended dose of rifabutin is 
150 mg every other day or three 
times per week, with the dose of 
saquinavir/ritonavir unchanged 
(1000/100 mg bid).  
 
Monitoring of neutropenia and liver 
enzyme levels is recommended due 
to an expected increase in exposure 
to rifabutin. 
 

Antipsychotics   
Lurasidone Due to CYP3A inhibition by 

saquinavir/ritonavir, concentrations of 
lurasidone are expected to increase. 

Concomitant administration of 
Invirase and lurasidone is contra-
indicated as it may increase 
lurasidone-related toxicity (see 
section 4.3). 

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). 



 

15 

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

Interaction Recommendations concerning co-
administration 

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). 

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). 

Benzodiazepines   
Midazolam 7.5 mg 
single dose (oral) 
(saquinavir/ritonavir 
1000/100 mg bid) 

Midazolam AUC ↑ 12.4 fold 
Midazolam Cmax ↑ 4.3 fold 
Midazolam t1/2 ↑ from 4.7 h to 14.9 h 
No data are available on concomitant 
use of ritonavir boosted saquinavir 
with intravenous midazolam. Studies 
of other CYP3A modulators and 
i.v. midazolam suggest a possible 3-
4 fold increase in midazolam plasma 
levels. 

Co-administration of 
Invirase/ritonavir with orally 
administered midazolam is 
contraindicated (see section 4.3). 
Caution should be used with co-
administration of Invirase and 
parenteral midazolam. 
If Invirase is co-administered with 
parenteral midazolam it should be 
done in an intensive care unit (ICU) 
or similar setting which ensures close 
clinical monitoring and appropriate 
medical management in case of 
respiratory depression and/or 
prolonged sedation. Dosage 
adjustment should be considered, 
especially if more than a single dose 
of midazolam is administered. 

Alprazolam 
Clorazepate 
Diazepam 
Flurazepam 
(saquinavir/ritonavir) 

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

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

Triazolam 
(saquinavir/ritonavir) 

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

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

Calcium channel blockers   
Felodipine, nifedipine, 
nicardipine, diltiazem, 
nimodipine, verapamil, 
amlodipine, nisoldipine, 
isradipine 
(saquinavir/ritonavir) 

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

Caution is warranted and clinical 
monitoring of patients is 
recommended. 



 

16 

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

Interaction Recommendations concerning co-
administration 

Corticosteroids   
- Dexamethasone 

(saquinavir/ritonavir) 
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). 
 

Fluticasone propionate 
50 mcg qid, intranasal 
(ritonavir 100 mg bid) 

Fluticasone propionate ↑ 
Intrinsic cortisol ↓ 86% 
(90% CI 82%-89%) 
Greater effects may be expected when 
fluticasone propionate is inhaled. 
Systemic corticosteroid effects 
including Cushing’s syndrome and 
adrenal suppression have been 
reported in patients receiving 
ritonavir and inhaled or intranasally 
administered fluticasone propionate; 
this could also occur with other 
corticosteroids metabolised via the 
P450 3A pathway e.g. budesonide. 
 
Effects of high fluticasone systemic 
exposure on ritonavir plasma levels 
yet unknown. 

Concomitant administration of 
boosted saquinavir and fluticasone 
propionate and other corticosteroids 
metabolised via the P450 3A 
pathway (e.g. budesonide) is not 
recommended unless the potential 
benefit of treatment outweighs the 
risk of systemic corticosteroid effects 
(see section 4.4). 
Dose reduction of the glucocorticoid 
should be considered with close 
monitoring of local and systemic 
effects or a switch to a 
glucocorticoid, which is not a 
substrate for CYP3A4 (e.g. 
beclomethasone). 
In case of withdrawal of 
glucocorticoids progressive dose 
reduction may have to be performed 
over a longer period. 

Endothelin receptor antagonist 
Bosentan  Not studied. Concomitant use of 

bosentan and saquinavir/ritonavir 
may increase plasma levels of 
bosentan and may decrease plasma 
levels of saquinavir/ritonavir. 

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

Medicinal products that are substrates of P-glycoprotein 
Digitalis glycosides 

  

Digoxin 0.5 mg 
single dose 
(saquinavir/ritonavir 
1000/100 mg bid) 

Digoxin AUC0-72 ↑ 49% 
Digoxin Cmax ↑ 27% 
Digoxin levels may differ over time. 
Large increments of digoxin may be 
expected when saquinavir/ritonavir is 
introduced in patients already treated 
with digoxin. 

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



 

17 

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

Interaction Recommendations concerning co-
administration 

Histamine H2-receptor antagonist   
- Ranitidine 

(saquinavir/ritonavir) 
- Ranitidine 

(unboosted saquinavir) 

Interaction with Invirase/ritonavir not 
studied. 
Saquinavir AUC ↑ 67 %  
 

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

HMG-CoA reductase inhibitors   
Pravastatin 
Fluvastatin 
(saquinavir/ritonavir) 

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

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



 

18 

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

Interaction Recommendations concerning co-
administration 

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).  

Narcotic analgesics   
Methadone 60-120 mg qd 
(saquinavir/ritonavir 
1000/100 mg bid) 

Methadone AUC ↓ 19 % 
(90 % CI 9 % to 29 %) 
None of the 12 patients experienced 
withdrawal symptoms. 

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

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). 

Vardenafil 
(saquinavir/ritonavir) 

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

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

Tadalafil 
(saquinavir/ritonavir) 

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

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



 

19 

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

Interaction Recommendations concerning co-
administration 

Proton pump inhibitors   
Omeprazole 40 mg qd 
(saquinavir/ritonavir 
1000/100 mg bid) 
 

Saquinavir AUC ↑ 82% 
(90 % CI 44-131 %) 
Saquinavir Cmax ↑ 75% 
(90 % CI 38-123 %) 
Ritonavir ↔ 

Combination not recommended. 

Other proton pump 
inhibitors 
(saquinavir/ritonavir 
1000/100 mg bid) 

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

Combination not recommended. 

Tyrosine kinase inhibitors   
All tyrosine kinase 
inhibitors with a risk of 
QT prolongation  
e.g. dasatinib,  
sunitinib 

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). 

Others   
Ergot alkaloids (e.g. 
ergotamine, 
dihydroergotamine, 
ergonovine, and 
methylergonovine) 
(saquinavir/ritonavir) 

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

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

- Grapefruit juice 
(saquinavir/ritonavir) 

Interaction with Invirase/ritonavir not 
studied. 

 

- Grapefruit juice 
(single dose) 
(unboosted saquinavir) 

Saquinavir ↑ 50% (normal strength 
grapefruit juice) 
Saquinavir ↑ 100% (double strength 
grapefruit juice) 

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

- Garlic capsules 
(saquinavir/ritonavir) 

Interaction with Invirase/ritonavir not 
studied. 

 

- Garlic capsules 
(dose approx. equivalent 
to two 4 g cloves of 
garlic daily) 
(unboosted saquinavir 
1200 mg tid) 

Saquinavir AUC ↓ 51 % 
Saquinavir Ctrough ↓ 49 % (8 hours 
post dose) 
Saquinavir Cmax ↓ 54 %. 

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



 

20 

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

Interaction Recommendations concerning co-
administration 

 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 
 

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

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

Gastroenterological medicinal products   
Metoclopramide It is unknown whether medicinal 

products which reduce the 
gastrointestinal transit time could lead 
to lower saquinavir plasma 
concentrations. 

 

Cisapride 
(saquinavir/ritonavir) 

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

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

Diphemanil 
(saquinavir/ritonavir) 

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

Vasodilators (peripheral)   
Vincamine i.v.  Contraindicated in combination with 

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

Key: ↓ reduced, ↑ increased, ↔ unchanged, ↑↑ markedly increased 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy: Evaluation of experimental animal studies does not indicate direct or indirect harmful 
effects with respect to the development of the embryo or foetus, the course of gestation and peri- and 
post-natal development. Clinical experience in pregnant women is limited: Congenital malformations, 
birth defects and other disorders (without a congenital malformation) have been reported rarely in 
pregnant women who had received saquinavir in combination with other antiretroviral agents. 



 

21 

However, so far the available data are insufficient and do not identify specific risks for the unborn 
child. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential 
risk to the foetus (see section 5.3). 
 
Breast-feeding: There are no laboratory animal or human data available on secretion of saquinavir in 
breast milk. The potential for adverse reactions to saquinavir in nursing infants cannot be assessed, 
and therefore, breast-feeding should be discontinued prior to receiving saquinavir. It is recommended 
that HIV-infected women do not breast feed their infants under any circumstances in order to avoid 
transmission of HIV. 
 
4.7 Effects on ability to drive and use machines 
 
Invirase may have a minor influence on the ability to drive and use machines. Dizziness, fatigue and 
visual impairment have been reported during treatment with Invirase. No studies on the effects on the 
ability to drive and use machines have been performed. 
 
4.8 Undesirable effects 
 
a. Summary of the safety profile 
 
Limited data is available from two clinical studies where the safety of saquinavir soft capsule 
(1000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 
weeks was studied in 311 patients.  
 
The following adverse events with an at least possible relationship to ritonavir boosted saquinavir (i.e. 
adverse reactions) were reported most frequently: nausea, diarrhoea, fatigue, vomiting, flatulence, and 
abdominal pain. 
 
The following adverse events were reported with the highest severity (grades 3 and 4): anaemia, 
diabetes mellitus, diarrhoea, nausea, vomiting and fatigue.  
 
For comprehensive dose adjustment recommendations and drug-associated adverse reactions for 
ritonavir and other medicinal products used in combination with saquinavir, physicians should refer to 
the Summary of Product Characteristics for each of these medicinal products. 
 
b. Tabulated list of adverse reactions 
 
Adverse reactions from two pivotal studies of saquinavir soft capsule (1000 mg twice daily) used in 
combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks are summarised in 
Table 2.  Also included are serious and non-serious adverse reactions from post-marketing 
spontaneous reports for which a causal relationship to saquinavir cannot be excluded.  
Adverse reactions are presented according to the MedDRA system organ classification. The frequency 
groupings according to MedDRA convention are: Very common (≥ 1/10); common (≥ 1/100 to 
<1/10); uncommon (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not 
known (frequency cannot be estimated from the available data). 
 



 

22 

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

Body System 
Frequency of reaction 

Adverse reactions 

Blood and the lymphatic system disorders 
Very common Decreased platelet count 
Common Anaemia, decreased haemoglobin, decreased 

lymphocyte count, decreased white blood cell 
count 

Uncommon Neutropenia 
Eye Disorders 
Uncommon Visual impairment 
Immune System Disorders 
Common Hypersensitivity   
Metabolism and nutrition disorders 
Very common Increased blood cholesterol, increased blood 

triglycerides 
Common Diabetes mellitus, anorexia, increased appetite 
Uncommon Decreased appetite 
Psychiatric Disorders 
Common Decreased libido, sleep disorder 
Nervous System Disorder 
Common Paraesthesia, peripheral neuropathy, dizziness, 

dysgeusia, headache 
Uncommon Somnolence, convulsions 
Respiratory, thoracic and mediastinal disorders 
Common Dyspnoea 
Gastrointestinal disorders 
Very common Diarrhoea, nausea 
Common Vomiting, abdominal distension, abdominal pain, 

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

Uncommon Pancreatitis 
Hepato-biliary disorders 
Very common Increased alanine aminotransferase, increased 

aspartate aminotransferase, increased low density 
lipoprotein 

Common Increased blood bilirubin, increased blood 
amylase 

Uncommon Hepatitis, jaundice 
Renal and urinary disorders 
Common Increased blood creatinine 
Uncommon Renal impairment 
Skin and subcutaneous tissue disorders 
Common 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 
 



 

23 

c. Description of selected adverse reactions 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 
 
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthroses, in haemophilic patients type A and B treated with protease inhibitors (see section 4.4). 
 
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with protease 
inhibitors, particularly in combination with nucleoside analogues. Cases of osteonecrosis have been 
reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or 
long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown 
(see section 4.4).  
 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves’disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). 
 
d. Paediatric population 
 
Limited safety data are available from a paediatric study (NV20911, n=18) in which the safety of 
saquinavir hard capsules (50 mg/kg bid, not to exceed 1000 mg bid) used in combination with low 
dose ritonavir oral solution (3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body 
weight from 15 to 40 kg and 100 mg bid for body weight >40 kg) has been studied in paediatric 
patients aged 4 months to 6 years old. 
 
Four patients in the study experienced five adverse events that were considered related to trial 
treatment. These events were vomiting (3 patients), abdominal pain (1 patient) and diarrhoea (1 
patient). No unexpected adverse events were observed in this study. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is limited experience of overdose with saquinavir. Whereas acute or chronic overdose of 
saquinavir alone did not result in major complications, in combination with other protease inhibitors, 
overdose symptoms and signs such as general weakness, fatigue, diarrhoea, nausea, vomiting, hair loss, 
dry mouth, hyponatraemia, weight loss and orthostatic hypotension have been observed. There is no 
specific antidote for overdose with saquinavir. Treatment of overdose with saquinavir should consist 
of general supportive measures, including monitoring of vital signs and ECG, and observations of the 
patient’s clinical status. If indicated, prevention of further absorption can be considered. Since 
saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the 
active substance. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

24 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: Antiviral agent, ATC code J05A E01 
 
Mechanism of action: The HIV protease is an essential viral enzyme required for the specific 
cleavage of viral gag and gag-pol polyproteins. Saquinavir selectively inhibits the HIV protease, 
thereby preventing the creation of mature infectious virus particles. 
 
QT and PR prolongation on electrocardiogram: The effects of therapeutic (1000/100 mg twice daily) 
and supra-therapeutic (1500/100 mg twice daily) doses of Invirase/ritonavir on the QT interval were 
evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg) 
study in healthy male and female volunteers aged 18 to 55 years old (N=59). On Day 3 of dosing, 
ECG measurements were done over a period of 20 hours. The Day 3 timepoint was chosen since the 
pharmacokinetic exposure was maximum on that day in a previous 14-day multiple dose 
pharmacokinetic study. On Day 3, mean Cmax values were approximately 3-fold and 4-fold higher with 
the therapeutic and supra-therapeutic doses, respectively, relative to the mean Cmax observed at steady 
state with the therapeutic dose administered to HIV patients. On Day 3, the upper 1-sided 95% 
confidence interval of the maximum mean difference in pre-dose baseline-corrected QTcS (study 
specific heart rate corrected QT) between the active drug and placebo arms was > 10 msec for the two 
ritonavir-boosted Invirase treatment groups (see results in Table 3). While the supra-therapeutic dose 
of Invirase/ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of 
Invirase/ritonavir, it is not sure if maximum effect for both doses has been observed. In the therapeutic 
and the supra-therapeutic arm 11% and 18% of subjects, respectively, had a QTcS between 450 and 
480 msec. There was no QT prolongation > 500 msec and no torsade de pointes in the study (see also 
section 4.4). 
 
Table 3: Maximum mean of ddQTcS† (msec) on day 3 for therapeutic dose of Invirase/ritonavir, 

supra-therapeutic dose of Invirase/ritonavir and active control moxifloxacin in healthy 
volunteers in Thorough QT (TQT) Study 

 
Treatment Post-Dose 

Time Point 
Mean  

ddQTcS 
Standard 

Error 
Upper 95%-CI of 

ddQTcS 
Invirase/ritonavir 
1000/100 mg BID 

12 hours 18.86 1.91 22.01 

Invirase/ritonavir 
1500/100 mg BID 

20 hours 30.22 1.91 33.36 

Moxifloxacin  ̂ 4 hours 12.18 1.93 15.36 
† Derived difference of pre-dose baseline corrected QTcS between active treatment and placebo 
arms 
 ̂ 400 mg was administered only on Day 3 

Note: QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for females, which are similar to 
Fridericia’s correction (QTcF=QT/RR0.333). 
 
In this study, PR interval of > 200 msec was also observed in 40% and 47% of subjects receiving 
Invirase/ritonavir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3. PR 
intervals of > 200 msec were seen in 3% of subjects in the active control group (moxifloxacin) and 5% 
in the placebo arm. The maximum mean PR interval changes relative to the pre-dose baseline value 
were 25 msec and 34 msec in the two ritonavir-boosted Invirase treatment groups, 1000/100 mg twice 
daily and 1500/100 mg twice daily, respectively (also see section 4.4). 
 
Events of syncope/presyncope occurred at a higher than expected rate and were seen more frequently 
under treatment with saquinavir (11 of 13). The clinical relevance of these findings from this study in 
healthy volunteers to the use of Invirase/ritonavir in HIV-infected patients is unclear, but doses 
exceeding Invirase/ritonavir 1000/100 mg twice daily should be avoided. 



 

25 

 
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 
ΔQTcF

dense
 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 
ΔQTcF

dense
 ≥ 30 ms (%) 

0 0 0 2/21 (9%) 0 29/57 
(51%) 

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



 

26 

Resistance 
 
Antiviral activity according to baseline genotype and phenotype: 
 
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted 
saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and 
analysis of a large hospital cohort (Marcelin et al 2007).  
 
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was 
shown to be a predictive factor of virological outcome. Virological response was first observed to 
decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the 
fold shift exceeded 12-fold. 
 
Marcelin et al (2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, 
I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to 
saquinavir/ritonavir (1000/100 mg twice daily) in 138 saquinavir naive patients. The presence of 3 or 
more mutations was associated with reduced response to saquinavir/ritonavir. The association between 
the number of these saquinavir-associated resistance mutations and virological response was 
confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment 
experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see 
Table 5). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was 
present at baseline in virus from three patients, none of whom responded to therapy. 
 
Table 5: Virological response to saquinavir/ritonavir stratified by the number of baseline saquinavir-

associated resistance mutations 
 
Number of 
Saquinavir 
Associated 
Resistance 
Mutations 

at Baseline* 

Marcelin et al (2007) RESIST 1 & 2 
SQV Naive Population SQV Naive/Experienced Population 

N=138 
Change in Baseline 

Plasma HIV-1 RNA at 
Weeks 12-20 

N=114 
Change in Baseline 

Plasma HIV-1 RNA at 
Week 4 

0 35 -2.24 2 -2.04 
1 29 -1.88 3 -1.69 
2 24 -1.43 14 -1.57 
3 30 -0.52 28 -1.41 
4 9 -0.18 40 -0.75 
5 6 -0.11 17 -0.44 
6 5 -0.30 9 0.08 
7 0 - 1 0.24 

* Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, 
V82A/F/S/T, I84V, L90M 

 
Clinical results from studies with treatment naïve and experienced patients 
 
In the MaxCmin1 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg 
twice daily plus 2 NRTIs/Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) was compared 
to indinavir/ritonavir 800/100 mg twice daily plus 2 NRTIs/NNRTIs in over 300 (both protease 
inhibitor treatment naïve and experienced) subjects. The combination of saquinavir and ritonavir 
exhibited a superior virological activity compared with the indinavir and ritonavir arm when switch 
from the assigned treatment was counted as virological failure.  
 
In the MaxCmin2 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg 
twice daily plus 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir 400/100 mg twice daily plus 
2 NRTIs/NNRTIs in 324 (both protease inhibitor treatment naïve and experienced) subjects. None of 



 

27 

the subjects in the lopinavir/ritonavir arm had been exposed to lopinavir prior to randomisation 
whereas 16 of the subjects in the saquinavir/ritonavir arm had previously been exposed to saquinavir. 
 
Table 6: Subject Demographics MaxCmin1 and MaxCmin2† 
 
 MaxCmin1 MaxCmin2 
 SQV/r IDV/r SQV/r LPV/r 
 N=148 N=158 N=161 N=163 
Sex 
Male 

 
82% 

 
74% 

 
81% 

 
76% 

Race (White/Black/Asian) % 86/9/1 82/12/4 75/19/1 74/19/2 
Age, median, yrs 39 40 40 40 
CDC Category C (%) 32% 28% 32% 31% 
Antiretroviral naïve (%) 28% 22% 31% 34% 
PI naïve (%) 41% 38% 48% 48% 
Median Baseline HIV-1 RNA, 
log10 copies/ml (IQR) 

4.0 
(1.7-5.1) 

3.9 
(1.7-5.2) 

4.4  
(3.1-5.1) 

4.6 
(3.5-5.3) 

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

272 
(135-420)  

280 
(139-453) 

241 
(86-400) 

239 
(95-420) 

† data from clinical study report 
 
Table 7: Outcomes at Week 48 MaxCmin1 and MaxCmin2† 
 
Outcomes MaxCmin1 MaxCmin2 
 SQV/r IDV/r SQV/r LPV/r 
Initiated assigned treatment,  
n (%) 

148 
(94%) 

158 
(99%) 

161 
(94%) 

163 
(98%) 

Discontinued assigned 
treatment, n (%) 

40 
(27%) 

64 
(41%) 

48 
(30%) 

23 
(14%) 

 P=0.01 P=0.001 
Virological failure ITT/e*# 36/148 (24%) 41/158 (26%) 53/161 (33%) 29/163 (18%) 
 P=0.76 P=0.002 
Proportion with VL < 50 
copies/ml at week 48, ITT/e# 

97/144 
(67%) 

106/154 
(69%) 

90/158 
(57%) 

106/162 
(65%) 

 P >0.05‡ P=0.12 
Proportion with VL < 50 
copies/ml at week 48, 
On Treatment 

82/104 
(79%) 

73/93 
(78%) 

84/113 
(74%) 

97/138 
(70%) 

 P>0.05‡ P=0.48 
Median increase in CD4 cell 
count at week 48 (cells/mm3) 

85 73 110 106 

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

# ITT/e = Intent-to-treat/exposed 
† Data from clinical study report 
‡ Data from MaxCmin1 publication 
 
Clinical results from paediatric studies 
 
The pharmacokinetics, safety and activity of saquinavir have been evaluated in an open label, 
multicenter study in 18 children aged 4 months to less than 6 years old in which saquinavir (50 mg/kg 



 

28 

bid up to the adult dose of 1000 mg bid) was administered in combination with ritonavir oral solution 
(3 mg/kg bid for body weight from 5 to <15 kg, 2.5 mg/kg bid for body weight from 15 to 40 kg and 
100 mg bid for body weight >40 kg) plus ≥2 background ARVs. The infants and young children were 
stratified into 2 groups: Group A “Low Age Group” 4 months to less than 2 years old (n=5) and Group 
B “High Age Group” children 2 years to less than 6 years old (n=13).  
 
In the “High Age Group”, the number of patients with a viral load <400 copies/mL at week 48 was 11 
of 13.  The number of patients with viral load <50 copies/mL was 9 of 13 for the same period.  The 
CD4 lymphocyte count expressed as percentage mean CD4 increased by a mean of 2.97% over the 
same 48 week period. The size of the study was too small to allow conclusions on clinical benefit. 
 
5.2 Pharmacokinetic properties 
 
Saquinavir is essentially completely metabolised by CYP3A4. Ritonavir inhibits the metabolism of 
saquinavir, thereby increasing ("boosting") the plasma levels of saquinavir.  
 
Absorption: In HIV-infected adult patients, Invirase in combination with ritonavir at doses of 
1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period similar to or 
greater than those achieved with saquinavir soft capsules 1200 mg tid (see Table 8). The 
pharmacokinetics of saquinavir is stable during long-term treatment. 
 
Table 8: Mean (% CV) AUC, Cmax and Cmin of saquinavir in patients following multiple dosing of 

Invirase, saquinavir soft capsules, Invirase/ritonavir, and saquinavir soft capsules/ritonavir 
 
Treatment N AUCτ (ng·h/ml) AUC0-24 

(ng·h/ml) † 
Cmax 

(ng/ml) 
Cmin 

(ng/ml) 
Invirase (hard capsule) 
600 mg tid 

10 866 (62) 2,598 197 (75) 75 (82) 

saquinavir soft capsule 
1200 mg tid 

31 7,249 (85) 21,747 2,181 (74) 216 (84) 

Invirase (tablet) 
1000 mg bid plus 
ritonavir 100 mg bid* 
(fasting condition) 

22 10,320 
(2,530-30,327) 

20,640 1,509 
(355-4,101) 

313 
(70-1,725) †† 

Invirase (tablet) 
1000 mg bid plus 
ritonavir 100 mg bid* 
(high fat meal) 

22 34,926 
(11,826-105,992) 

69,852 5,208 
(1,536-
14,369) 

1,179 
(334-5,176) †† 

τ = dosing interval, i.e. 8 hour for tid and 12 h for bid dosing. 
Cmin = the observed plasma concentration at the end of the dose interval. 
bid = twice daily 
tid = three times daily 
* results are geometric mean (min - max)  
† derived from tid or bid dosing schedule 
†† Ctrough values 
 
Absolute bioavailability averaged 4 % (CV 73 %, range: 1 % to 9 %) in 8 healthy volunteers who 
received a single 600 mg dose (3 x 200 mg hard capsule) of Invirase following a heavy breakfast. The 
low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-
pass metabolism. Gastric pH has been shown to be only a minor component in the large increase in 
bioavailability seen when given with food. The absolute bioavailability of saquinavir co-administered 
with ritonavir has not been established in humans. 
 
In combination with ritonavir, bioequivalence of Invirase hard capsules and film-coated tablets was 
demonstrated under fed conditions. 
 



 

29 

Effective therapy in treatment naïve patients is associated with a Cmin of approximately 50 ng/ml and 
an AUC0-24 of about 20,000 ng·h/ml. Effective therapy in treatment experienced patients is associated 
with a Cmin of approximately 100 ng/ml and an AUC0-24 of about 20,000 ng·h/ml. 
 
In treatment-naïve HIV-1 infected patients initiating Invirase/ritonavir treatment with a modified 
Invirase/ritonavir dosing regimen of Invirase 500 mg two times daily with ritonavir 100 mg two times 
daily for the first 7 days of treatment and increased to Invirase 1000 mg two times daily with ritonavir 
100 mg two times daily in the subsequent 7 days, saquinavir systemic exposures generally approached 
or exceeded the range of historical steady-state values with the standard Invirase/ritonavir 
1000 mg/100 mg bid dosing regimen across study days (see Tables 9 and 8).  
 
Table 9: Mean (CV%) PK Parameters following administration of the Modified Invirase/ritonavir 
Regimen in Treatment Naïve HIV-1 infected Patients initiating treatment with Invirase/ritonavir 
Parameter Day 3 

500/100 mg 
(n=22) 

Day 4 
500/100 mg 
(n=21) 

Day 7 
500/100 mg 
(n=21) 

Day 10 
1000/100 mg 
(n=21) 

Day 14 
1000/100 mg 
(n=21) 

AUC0-12 
(ng*hr/ml) 

27100 (35.7) 20300 (39.9) 12600 (54.5) 34200 (48.4) 31100 (49.6) 

Cmax (ng/ml) 4030 (29.1) 2960 (40.2) 1960 (53.3) 5300 (36.0) 4860 (46.8) 

C12 (ng/ml) 899 (64.9) 782 (62.4) 416 (98.5) 1220 (91.6) 1120 (80.9) 
 
In vitro studies have shown that saquinavir is a substrate for P-glycoprotein (P-gp). 
 
Effect of food: In a cross-over study in 22 HIV-infected patients treated with Invirase/ritonavir 
1000 mg/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a 
high-fat, high-calorie meal (46 g fat, 1,091 Kcal), the AUC0-12, Cmax and Ctrough values of saquinavir 
under fasting conditions were about 70 per cent lower than with a high-fat meal. All but one of the 
patients achieved Ctrough values of saquinavir above the therapeutic threshold (100 ng/ml) in the fasted 
state. There were no clinically significant differences in the pharmacokinetic profile of ritonavir in 
fasting and fed conditions but the ritonavir Ctrough (geometric mean 245 vs. 348 ng/ml) was lower in 
the fasting state compared to the administration with a meal. Invirase/ritonavir should be administered 
with or after food. 
 
Distribution in adults: Saquinavir partitions extensively into the tissues. The mean steady-state 
volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 l 
(CV 39 %). It has been shown that saquinavir is approximately 97 % bound to plasma proteins up to 
30 µg/ml. In two patients receiving Invirase 600 mg three times daily, cerebrospinal fluid 
concentrations of saquinavir were negligible when compared to concentrations from matching plasma 
samples. 
 
Biotransformation and elimination in adults: In vitro studies using human liver microsomes have 
shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, 
CYP3A4, responsible for more than 90 % of the hepatic metabolism. Based on in vitro studies, 
saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds. In a 
mass balance study using 600 mg 14C-saquinavir (n = 8), 88 % and 1 % of the orally administered 
radioactivity, was recovered in faeces and urine, respectively, within 4 days of dosing. In an additional 
four subjects administered 10.5 mg 14C-saquinavir intravenously, 81 % and 3 % of the intravenously 
administered radioactivity was recovered in faeces and urine, respectively, within 4 days of dosing. 
13 % of circulating saquinavir in plasma was present as unchanged compound after oral administration 
and the remainder as metabolites. Following intravenous administration 66 % of circulating saquinavir 
was present as unchanged compound and the remainder as metabolites, suggesting that saquinavir 
undergoes extensive first pass metabolism. In vitro experiments have shown that the hepatic 
metabolism of saquinavir becomes saturable at concentrations above 2 µg/ml. 



 

30 

Systemic clearance of saquinavir was high, 1.14 l/h/kg (CV 12 %), slightly above the hepatic plasma 
flow, and constant after intravenous doses of 6, 36 and 72 mg. The mean residence time of saquinavir 
was 7 hours (n = 8). 
 
Special populations 
 
Effect of gender following treatment with Invirase/ritonavir: A gender difference was observed with 
females showing higher saquinavir exposure than males (AUC on average 56 % higher and Cmax on 
average 26 % higher) in the bioequivalence study comparing Invirase 500 mg film coated tablets with 
Invirase 200 mg hard capsules both in combination with ritonavir. There was no evidence that age and 
body-weight explained the gender difference in this study. Limited data from controlled clinical 
studies with the approved dosage regimen do not indicate a major difference in the efficacy and safety 
profile between men and women. 
 
Patients with hepatic impairment: The effect of hepatic impairment on the steady state 
pharmacokinetics of saquinavir/ritonavir (1000 mg/100 mg twice daily for 14 days) was investigated 
in 7 HIV-infected patients with moderate liver impairment (Child Pugh Grade B score 7 to 9). The 
study included a control group consisting of 7 HIV-infected patients with normal hepatic function 
matched with the hepatically impaired patients for age, gender, weight and tobacco use. The mean 
(% coefficient of variation in parentheses) values for saquinavir AUC0-12 and Cmax were 24.3 
(102%) µg·hr/ml and 3.6 (83%) µg/ml, respectively, for HIV-infected patients with moderate hepatic 
impairment. The corresponding values in the control group were 28.5 (71%) µg·hr/ml and 4.3 
(68%) µg/ml. The geometric mean ratio (ratio of pharmacokinetic parameters in hepatically impaired 
patients to patients with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both 
AUC0-12 and Cmax, which suggests approximately 30% reduction in the pharmacokinetic exposure in 
patients with moderate hepatic impairment. Results are based on total concentrations (protein-bound 
and unbound). Concentrations unbound at steady-state were not assessed. No dosage adjustment seems 
warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of 
safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to 
increased variability of the exposure in this population (see sections 4.2 and 4.4). 
 
Paediatric Patients: Steady state pharmacokinetic information is available from HIV-infected 
paediatric patients from study NV20911. In this study, 5 patients were <2 years and 13 between 2 to 
<6 years and received 50 mg/kg saquinavir bid (not to exceed 1000 mg bid) boosted with ritonavir at 
3 mg/kg for patients with body weight ranging from 5 to <15 kg or 2.5 mg/kg for patients with body 
weight ranging from 15 to 40 kg (not to exceed 100 mg bid). Sixteen of 18 children could not swallow 
Invirase hard capsules and received medication by opening the capsules and mixing the contents with 
different vehicles. The pharmacokinetic exposure parameters for the “High Age Group” are listed in 
Table 10. Results of the “Low Age Group” are not shown as data are limited due to the small size of 
the group. 
 
Table 10: Pharmacokinetic parameters of saquinavir at steady-state in HIV-infected pediatric patients 
 
 Mean ± SD Saquinavir (%CV) 

Pharmacokinetic Parameters* 

Study Age 
Group 
(Years) 

N AUC0-12h 
(ng•h/mL) 

Ctrough 
(ng/mL) 

Cmax (ng/mL) 

NV20911 2 to < 6 years 13 38000 ± 
18100 

(48%) 

1860 ± 1060 

(57%) 

5570 ± 2780 

(50%) 

* All parameters normalized to a 50 mg/kg dose 
 



 

31 

Steady state saquinavir exposures observed in paediatric trials were substantially higher than historical 
data in adults where dose- and exposure-dependent QTc and PR prolongation were observed (see 
section 4.4). 
 
5.3 Preclinical safety data 
 
Acute and chronic toxicity: Saquinavir was well tolerated in oral acute and chronic toxicity studies in 
mice, rats, dogs and marmosets. 
 
Mutagenesis: Mutagenicity and genotoxicity studies, with and without metabolic activation where 
appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames 
test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce 
chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood 
lymphocytes and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis 
test. 
 
Carcinogenesis: There was no evidence of carcinogenic activity after the administration of saquinavir 
mesilate for 96 to 104 weeks to rats and mice. The plasma exposures (AUC values) in rats (maximum 
dose 1000 mg/kg/day) and in mice (maximum dose 2500 mg/kg/day) were lower than the expected 
plasma exposures obtained in humans at the recommended clinical dose of ritonavir boosted Invirase.  
 
Reproductive toxicity: Fertility, peri- and postnatal development were not affected, and embryotoxic / 
teratogenic effects were not observed in rats or rabbits at plasma exposures lower than those achieved 
in humans at the recommended clinical dose of ritonavir boosted Invirase. Distribution studies in these 
species showed that the placental transfer of saquinavir is low (less than 5% of maternal plasma 
concentrations). 
 
Safety pharmacology: Cloned human cardiac potassium channel (hERG) trafficking in vitro was 
inhibited by 75% at 30μM of saquinavir. Saquinavir inhibited both hERG current and L-type Ca++ 
channel current with respective IC50s of 4.7 and 6.3 μM. In a myocardial distribution study in the rat 
an approximately 2-fold accumulation of saquinavir was observed in the heart compared to plasma 
after coadministration of saquinavir and ritonavir. The clinical relevance of these preclinical results are 
unknown, however cardiac conduction and repolarisation abnormalities in humans have been observed 
with saquinavir and ritonavir combination therapy (see section 4.4 and 5.1). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core:  
Microcrystalline cellulose, 
Croscarmellose sodium, 
Povidone, 
Lactose (monohydrate), 
Magnesium stearate. 
 
Tablet coat: 
Hypromellose, 
Titanium dioxide (E 171), 
Talc, 
Glycerol triacetate, 
Iron oxide yellow and red (E172). 
 
6.2 Incompatibilities 
 
Not applicable. 



 

32 

 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Plastic bottles (HDPE) containing 120 tablets. 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER  
 
EU/1/96/026/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 October 1996 
Date of latest renewal: 04 October 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 

http://www.ema.europa.eu/


 

33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING 
 SUPPLY AND USE 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE 
 MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



 

34 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Str. 1, 
79639 Grenzach-Wyhlen, 
Germany. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

- At the request of the European Medicines Agency; 
- Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
 



 

35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



 

36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

37 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
TEXT FOR THE OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Invirase 500 mg film-coated tablets 
Saquinavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg of saquinavir as saquinavir mesilate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose (monohydrate) 38.5 mg, colourants (titanium dioxide E 171, iron oxide E 172) 
and other constituents. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
The film-coated tablets should be swallowed whole 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



 

38 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/026/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
invirase 500 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



 

39 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
TEXT FOR THE BOTTLE LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Invirase 500 mg film-coated tablets 
Saquinavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg of saquinavir as saquinavir mesilate. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose (monohydrate) 38.5 mg, colourants (titanium dioxide E 171, iron oxide E 172) 
and other constituents. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
The film-coated tablets should be swallowed whole 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



 

40 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/026/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
 
 
 



 

41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

42 

 
Package Leaflet: Information for the user 

 
Invirase 500 mg film-coated tablets 

Saquinavir 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Invirase is and what it is used for 
2. What you need to know before you take Invirase 
3. How to take Invirase 
4. Possible side effects 
5. How to store Invirase 
6. Contents of the pack and other information 
 
 
1. What Invirase is and what it is used for 
 
Invirase contains the active substance saquinavir which is an antiviral agent. It is a member of a class 
of medicines called protease inhibitors. It is for the treatment of infection with the human 
immunodeficiency virus (HIV). 
 
Invirase is used by HIV-1-infected adults. Invirase is prescribed for use in combination with ritonavir 
(Norvir) and other antiretroviral medicines. 
 
 
2. What you need to know before you take Invirase 
 
Do not take Invirase if you have: 
• an allergy to saquinavir, ritonavir or any of the other ingredients (see “Invirase contains lactose” 

later in this section and “What Invirase contains” in Section 6) 
• any heart problems that show on an electrocardiogram (ECG, electrical recording of the heart) - 

you may have been born with that 
• a very slow heart rate (bradycardia) 
• a weak heart (heart failure) 
• a history of an irregular heart beat (arrhythmias) 
• a salt imbalance in your blood, especially low blood concentrations of potassium (hypokalaemia), 

which is not currently controlled by treatment 
• severe liver problems such as jaundice, hepatitis or liver failure - where your belly fills with fluid, 

you get confused or your oesophagus (the tube that runs from your mouth to your stomach) 
bleeds 

• recently taken the HIV medicine rilpivirine. 
Do not take Invirase if any of the above applies to you. If you are not sure, talk to your doctor or 
pharmacist before taking Invirase. 



 

43 

Do not take Invirase if you are taking any of the following medicines: 
Any medicine that can change your heart beat, such as: 
• certain medicines for HIV - such as atazanavir, lopinavir, rilpivirine 
• certain heart medicines - amiodarone, bepridil, disopyramide, dofetilide, flecainide, 

hydroquinidine, ibutilide, lidocaine, propafenone, quinidine, sotalol 
• certain medicines for depression - amitriptyline, imipramine, trazodone, maprotiline 
• medicines for other severe mental health problems - such as clozapine, haloperidol, 

mesoridazine, phenothiazines, sertindole, sultopride, thioridazine, ziprasidone 
• certain medicines for infection - such as clarithromycin, dapsone, erythromycin, halofantrine, 

pentamidine, sparfloxacin 
• certain strong pain killers (narcotics) - such as alfentanyl, fentanyl, methadone 
• medicines for erectile dysfunction - sildenafil, vardenafil, tadalafil 
• certain medicines that may be used for a variety of things: cisapride, diphemanil, mizolastine, 

quinine, vincamine. 
• certain medicines used to prevent rejection of new organs after a transplant operation such as 

tacrolimus 
• certain medicines used to treat the symptoms of Benign Prostatic Hyperplasia (an increase in size 

of the prostate) such as alfuzosin 
• certain medicines commonly used for allergy symptoms such as terfenadine and astemizole 
• certain medicines for severe mental health problems such as pimozide  
• certain medicines (so called tyrosine kinase inhibitors) used to treat different types of cancer such 

as dasatinib and sunitinib. 
 
Any of these other medicines: 
• ergot alkaloids - for migraine attacks 
• triazolam and midazolam (taken by mouth) - to help you sleep or for anxiety 
• rifampicin - for preventing or treating tuberculosis 
• simvastatin and lovastatin - for lowering blood cholesterol 
• quetiapine – used to treat schizophrenia, bipolar disorder and major depressive disorder 
• lurasidone – used to treat schizophrenia. 
 
Do not take Invirase with any other drug unless you have talked to your doctor first.  The drugs listed 
above might cause serious side effects if you take them together with Invirase. 
 
Do not take Invirase if any of the above applies to you. If you are not sure, talk to your doctor or 
pharmacist before taking Invirase. 
 
Warnings and precautions 
You should know that Invirase/ritonavir is not a cure for HIV infection and that you may continue to 
develop infections or other illnesses associated with HIV disease. You should, therefore, remain under 
the care of your doctor while taking Invirase/ritonavir. 
 
You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting other 
people. 
 
At present, there is only limited information on the use of Invirase/ritonavir in children and in adults 
over the age of 60 years. 
 
Abnormal heart rhythms (arrhythmias): 
Invirase can change how your heart beats - this can be serious. This can happen especially if you are 
female or elderly.  
• If you are taking any medicine that decreases your blood potassium levels talk to your doctor 

before taking Invirase.  
• Contact your doctor immediately, if you get palpitations or an irregular heart beat during 

treatment. Your doctor may wish to do an ECG to check your heart beat. 



 

44 

 
Other conditions 
There are certain conditions, which you may have, or have had, which require special care before or 
while taking Invirase/ritonavir. Therefore, before taking this medicine, you should have told your 
doctor if you suffer from diarrhoea, or if you have allergies (see Section 4) or if you have an 
intolerance to some sugars (see section “Invirase contains lactose”). 
 
Kidney disease: Consult your doctor if you have a history of kidney disease. 
 
Liver disease: Please speak with your doctor if you have a history of liver disease. Patients with 
chronic hepatitis B or C and treated with antiretroviral agents are at increased risk of severe and 
potentially fatal liver adverse events and may require blood tests for control of liver function. 
 
Infection: In some patients with advanced HIV infection (AIDS) and a history of opportunistic 
infection, signs and symptoms of inflammation from previous infections may occur soon after anti-
HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s 
immune response, enabling the body to fight infections that may have been present with no obvious 
symptoms. If you notice any symptoms of infection, please inform your doctor immediately (see 
Section 4). 
 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment. 
 
Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease 
called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression, higher body mass index, among others, may be some of the many risk factors for 
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the 
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.  
 
Other medicines and Invirase 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.  
 
Invirase/ritonavir may be taken with a number of other medications that are commonly used in HIV 
infection. 
 
There are some medications that must not be taken with Invirase/ritonavir (see section "Do not take 
Invirase if you are taking any of the following medicines:" above). There are also some medicines that 
require dosage reduction of that medicine or Invirase or ritonavir (see section “Medicines that can 
interact with saquinavir or ritonavir include:” below). Ask your doctor or pharmacist for more 
information about taking Invirase/ritonavir with other medicines. 
 
Medicines that can interact with saquinavir or ritonavir include: 
• other HIV medicines - such as nelfinavir, indinavir, nevirapine, delavirdine, efavirenz, maraviroc, 

cobicistat 
• some medicines affecting the immune system - such as ciclosporin, sirolimus (rapamycin), 

tacrolimus 
• various steroids - such as dexamethasone, ethinyl estradiol, fluticasone 
• certain heart medicines - such as calcium channel blockers, quinidine, digoxin 
• medicines used to lower blood cholesterol - such as statins 
• antifungals - ketoconazole, itraconazole, fluconazole, miconazole 
• anticonvulsants - such as phenobarbital, phenytoin, carbamazepine 



 

45 

• sedative agents - such as midazolam administered by injection 
• certain antibiotics - such as quinupristin/dalfopristin, rifabutin, fusidic acid 
• medicines to treat depression - such as nefazodone, tricyclic antidepressants 
• medicines for anticoagulation - warfarin 
• herbal preparations containing St. John’s wort or garlic capsules 
• some medicines that treat diseases related to the acid in the stomach - such as omeprazole or other 

proton pump inhibitors 
• medicines used to treat asthma or other chest illness such as Chronic Obstructive Pulmonary 

Disease (COPD) such as salmeterol 
• medicines for gout, such as colchicine 
• medicines used to treat high blood pressure in the arteries of the lungs (a disease known as 

pulmonary arterial hypertension) such as bosentan. 
 
Therefore you should not take Invirase/ritonavir with other medicines without your doctor’s consent.  
 
If you are taking an oral contraceptive to prevent pregnancy, you should use an additional or different 
type of contraception since ritonavir may reduce the effectiveness of oral contraceptives. 
 
Invirase with food and drink  
Invirase must be taken together with ritonavir and with or after food.  
 
Pregnancy and breast-feeding 
Ask your doctor or pharmacist for advice before taking any medicine. Inform your doctor if you are 
pregnant or planning to become pregnant. This medicine should be taken during pregnancy only after 
consultation with your doctor. 
 
You should not breast-feed your baby if you are taking Invirase/ritonavir. 
 
Driving and using machines 
Invirase has not been tested for its effect on your ability to drive a car or operate machinery. However, 
dizziness, fatigue and visual impairment have been reported during treatment with Invirase. Do not 
drive or operate machines if you experience these symptoms. 
 
Invirase contains lactose 
Each film-coated tablet contains lactose (monohydrate) 38.5 mg. If you have been told by your doctor 
that you have an intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Invirase 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. Invirase comes as a 500 mg film-coated tablet. Your doctor will prescribe Invirase 
in combination with ritonavir (Norvir) and other HIV medicines. 
 
How to take 
• Take Invirase at the same time as your ritonavir (Norvir) capsules. 
• Take your Invirase film-coated tablets with or after food. 
• Swallow them whole with water. 
 
How much to take 
 
Standard dose 

• Take two 500 mg film-coated tablets of Invirase twice a day. 
• Take one 100 mg capsule of ritonavir (Norvir) twice a day.  
 



 

46 

If this is your first medicine for HIV or the first time you are taking ritonavir (Norvir) 
You need to take a lower dose of Invirase for your first week.  
Week 1: 
• Take one 500 mg film-coated tablet of Invirase twice a day. 
• Take one 100 mg capsule of ritonavir (Norvir) twice a day.  
 
Week 2 onwards: 
• Continue with the standard dose. 
 
If you take more Invirase than you should  
If you have taken more than the prescribed dose of Invirase/ritonavir you must contact your doctor or 
pharmacist. 
 
If you forget to take Invirase 
Do not take a double dose to make up for a forgotten individual dose. If you forget to take one dose, 
take this dose as soon as you remember together with some food. Then go on with the regular schedule 
as prescribed. Do not change the prescribed dose yourself. 
 
If you stop taking Invirase  
Continue to take this medicine until your doctor tells you otherwise. 
If you have any further questions on the use of this medicine, ask your doctor or pharmascist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and lifestyle, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.  
 
When treating HIV infection it is not always possible to differentiate between unwanted effects caused 
by Invirase or by any other medicines you take at the same time or by the complications of the 
infection. For these reasons it is very important to inform your doctor of any change in your condition. 
 
The most frequently (in more than ten in a hundred persons) reported side effects of saquinavir taken 
with ritonavir concern the gastrointestinal tract, with feeling sick, diarrhoea, tiredness, vomiting, wind 
and abdominal pain being the most common. Also, changes in laboratory markers (e.g., blood or urine 
tests) have been reported very commonly. 
 
Other reported side effects (in more than one in a hundred but less than one in ten persons), which 
may occur are: rash, itching, eczema and dry skin, hair loss, dry mouth, headache, peripheral 
neuropathy (a disturbance of the nerves in the feet and hands that may take the form of numbness, pins 
and needles, shooting or burning pain), weakness, dizziness, libido problems, taste alteration, mouth 
ulcers, dry lips, abdominal discomfort, indigestion, weight loss,constipation, increased appetite,  
muscle spasms and shortness of breath.  
 
 Other less frequently reported side effects (in more than one in one thousand persons but less than 
one in a hundred persons) include: decreased appetite, visual disturbance, inflammation of the liver, 
fits, allergic reactions, blisters, sleepiness, abnormal renal function, inflammation of the pancreas, 
yellowing of the skin or whites of the eyes caused by liver problems and Steven’s Johnson syndrome 
(a serious illness with blistering of the skin, eyes, mouth and genitals).  
 
In patients with haemophilia type A and B, there have been reports of increased bleeding while taking 
this treatment or another protease inhibitor. Should this happen to you, seek immediate advice from 
your doctor. 
 



 

47 

There have been reports of muscle pain, tenderness or weakness, particularly with combination 
antiretroviral therapy including protease inhibitors and nucleoside analogues. On rare occasions these 
muscle disorders have been serious (rhabdomyolysis). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse.  This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Invirase 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date (EXP) which is stated on the bottle and carton. The 
expiry date refers to the last day of that month. 
 
Invirase does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Invirase contains 
 
• The active substance is saquinavir. One film-coated tablet of Invirase contains 500 mg of 

saquinavir as saquinavir mesilate. 
• The other ingredients (excipients) are microcrystalline cellulose, croscarmellose sodium, 

povidone, lactose (monohydrate) 38.5 mg, magnesium stearate, hypromellose, titanium dioxide 
(E171), talc, glycerol triacetate, iron oxide yellow (E172) and iron oxide red (E172). 

 
What Invirase looks like and contents of the pack 
 
Invirase 500 mg film-coated tablets are light orange to greyish or brownish orange tablets of oval 
shape with the marking "SQV 500" on one side and "ROCHE" on the other side. One plastic (HDPE) 
bottle contains 120 tablets. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer  
Roche Pharma AG,  
Emil-Barell-Strasse 1, 
79639 Grenzach-Wyhlen, 
Germany. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

48 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark  
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33 (0) 1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 



 

49 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 – 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET