Invirase: Indications, Dosage, Precautions, Adverse Effects
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Invirase - Product Information

Manufacture: Roche
Country: Australia
Condition: HIV Infection, Nonoccupational Exposure, Occupational Exposure
Class: Protease inhibitors
Form: Tablets
Ingredients: saquinavir as saquinavir mesylate, lactose, microcrystalline cellulose (460), croscarmellose sodium, povidone, magnesium stearate (470), hypromellose, talc (553), water, triacetin, colourants, iron oxide red (172), iron oxide yellow (172) and titanium dioxide (171).

Saquinavir mesylate



The chemical name for saquinavir mesylate is cis-N-tert-Butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)- L-asparginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxyamide methanesulfonate. The molecular formula is C38H50N6O5 • CH4O3S. Saquinavir mesylate has a molecular weight of 766.96.

Description

INVIRASE is available as film-coated tablets containing 571.5 mg of saquinavir mesylate equivalent to 500 mg saquinavir free base.

INVIRASE (saquinavir mesylate) is a highly selective inhibitor of the Human Immunodeficiency Virus enzyme, HIV proteinase (HIV protease).

Saquinavir mesylate is a white to off-white, fine powder with an aqueous solubility of 220 mg/100 mL at 25°C.

Each 500 mg film-coated tablet also contains the inactive ingredients: lactose, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, talc, iron oxide yellow CI 77492, iron oxide red CI 77491 and triacetin.

Pharmacology

Pharmacodynamics

Mechanism of action: The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins. These viral polyproteins contain a type of cleavage site, which is only recognised by HIV and closely related viral proteases. Saquinavir has been designed as a peptide-like structural mimetic of the viral cleavage site. Saquinavir is a selective and reversible inhibitor of the HIV protease that prevents the creation of mature infectious virus particles.

Antiviral activity in vitro: Saquinavir demonstrates antiviral activity against both 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, using acutely infected T cell lines or primary human lymphocytes / monocytes. In vitro antiviral activity was observed against a panel of HIV-1 group M non-clade B isolates (A, AE, C, D, F, G and H) and HIV-2 with EC50 values ranging from 0.3-2.4 nM. In the presence of 50% human serum or alpha-1 acid glycoprotein (1 mg/ml), the antiviral activity of saquinavir decreases by an average factor of 25-fold and 14-fold, respectively.

Resistance

In vitro resistance:

In vitro selection of resistance from wild-type HIV-1 virus: The most commonly reported mutations, G48V and L90M, were observed to develop during in vitro passage of HIV-1 wild-type virus in the presence of increasing concentrations of saquinavir. Recombinant virus harbouring the G48V and L90M mutations exhibited 7.9-fold and 3.4-fold reductions in viral susceptibility to saquinavir, respectively. Protease mutations such as M36I, I54V, K57R, and L63V developed less frequently in the presence of saquinavir.

In vivo resistance:

Treatment naïve patients: Four studies have investigated boosted saquinavir regimens in antiretroviral therapy (ART) naïve patients [(saquinavir/ritonavir (1600 mg/100 mg) daily, n=349; (1000 mg/100 mg) bd, n=92]. Baseline resistance analyses were conducted on 26 patients experiencing virological rebound. Data from 2 patients was excluded either because protease inhibitor (PI) mutations were present at baseline or a signature protease mutation (D30N) associated with another PI subsequently developed. Virus from 2 patients (2/24) developed protease mutations (M36I and M46i/m, respectively). These mutations are not typically associated with saquinavir resistance. No specific saquinavir-associated protease mutations were observed to develop following virological failure.

Treatment experienced patients: Baseline and on-therapy genotype was evaluated for 22 previously PI-experienced patients who experienced virological failure after receiving a boosted saquinavir regimen (MaxCmin 1 and 2 studies; 1000/100 mg bd, n=171). Virus from 8 patients (8/22; 36%) developed additional protease mutations following virological failure. The relative incidence of each mutation was: I84V (n=4, 18%); F53L, A71V or G73S (n=2, 9%); L10V, M46I, I54V, V82A or L90M (n=1, 4.5%).

Antiviral activity according to baseline genotype and phenotype: Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of boosted saquinavir have been derived from retrospective analyses of 2 open-label randomised clinical studies (RESIST 1 and 2) and a large independent hospital cohort study.

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.

A clinical hospital cohort study (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) bd in 138 saquinavir-naïve patients. The presence of 3 or more mutations was associated with reduced response to saquinavir/ritonavir.

To confirm the association between the number of these saquinavir-associated resistance mutations and virological response using an independent dataset, the association was investigated using data for patients receiving boosted saquinavir in the RESIST 1 and 2 clinical studies. The RESIST 1 and 2 studies enrolled a more heavily treatment experienced patient population, including 54% who had received prior saquinavir. This analysis confirmed the association between the number of saquinavir-associated mutations (p=0.0133, see Table 1). In addition, 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.

Virological response to HAART relies upon the activity of the individual antiretroviral components. The association between the number of saquinavir mutations at baseline and the activity of the concomitant antiretroviral components of the regimen was assessed using baseline phenotypic susceptibility data. The association between the number of baseline saquinavir resistance-associated mutations and response was highly significant when the activity of the optimized background was taken into account (p=0.0011, see Table 2). Patients receiving saquinavir in the presence of active concomitant ART and having fewer saquinavir-associated mutations had an improved response compared to patients receiving fewer active co-medication and higher numbers of saquinavir-associated mutations.

Table 1: Virological response to boosted saquinavir stratified by the number of baseline saquinavir-associated resistance mutations
Number of
Saquinavir
Associated
Resistance
Mutations
at Baseline*
Marcelin et al (2007)
SQV Naive Population**
RESIST 1 & 2
SQV Naive/Experienced Population**
n=138 Log10 Change in Baseline
Plasma HIV-1 RNA at
Weeks 12-20
n=114 Log10 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

SQV = saquinavir

* 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

** Saquinavir naïve is defined as the patient who had never previously received a saquinavir-based regimen. Saquinavir-experienced patients had received prior saquinavir-based therapy (with or without boosting with ritonavir). Consequently, saquinavir-experienced patients were being retreated with a saquinavir-based therapy. Of note, patients receiving a saquinavir-based therapy at study entry (i.e. continuing a failing saquinavir based regimen) were excluded from the analysis.

Table 2: Virological response (log10 change in viral load) at week 4 stratified by the activity of concomitant antiretrovirals and the number of saquinavir-associated mutations
PSS
of OBT
Number of Saquinavir-Associated Resistance Mutations at Baseline (n=114)
0 1 2 3 4 5 6 7 Total
0 - - -2.62 -0.32 -0.38 0.06 -0.51 0.24 -0.32
1 - - -1.44 -1.09 -0.32 -0.38 0.12 - -0.44
2 -1.45 -0.92 -1.44 -1.58 -0.92 -0.79 0.16 - -1.34
>2 -2.64 -1.78 - -1.97 -2.05 -2.21 -0.94 - -2.01
Total -2.04 -1.69 -1.57 -1.41 -0.75 -0.44 0.08 0.24 -1.17

p-value = 0.0011 (model including PSS and saquinavir-associated resistance mutations)

PSS = Phenotypic Sensitivity Score (zero = no active background antiretroviral co-medication);

OBT = Optimised Background Treatment

Hypersusceptibility to Mutant Virus:

Hypersusceptibility of some resistant viruses to inhibition with saquinavir has been described, for example in the presence of the 30N substitution (with or without additional substitutions at residues 46, 71 or 88). This was also observed in complexes of substitutions showing resistance to amprenavir including 50V in presence or absence of 46I and 47V. A high proportion of viruses with substitutions at residue 82 either retain susceptibility (37%) or show enhanced activity (8%) to saquinavir. The clinical significance of hypersusceptibility to saquinavir has not been established.

Pharmacokinetics

Absorption and Bioavailability: The absolute bioavailability of saquinavir 200 mg capsules is very low: following administration of a 600 mg oral dose to healthy volunteers, in the presence of food, the mean absolute bioavailability was 4% (range: 1% - 9%). The low bioavailability is thought to be due to a combination of incomplete absorption (approximately 30%) and extensive first pass metabolism. Gastric pH has been shown not to play a major role in the large increase in bioavailability when given with food.

In healthy volunteers the extent of absorption (as reflected by AUC) after a 600 mg oral dose of saquinavir given 30 minutes before food to fasted subjects, was substantially increased when the same dose was given following a full breakfast (including eggs, bacon, cereal, toast, coffee or tea) from 110 ng.h/mL to 390 ng.h/mL. The presence of food also increased the time taken to achieve maximum concentration from 1.7 hours to 2.5 hours and substantially increased the mean maximum plasma concentrations (Cmax) from 41 ng/mL to 173 ng/mL. This effect of food has been shown to be present for up to 2 hours after food intake (systemic exposure (AUC) was similar for doses given 5 minutes and 2 hours after a standardised meal). Therefore, INVIRASE should be taken within 2 hours after a meal.

In another study in healthy volunteers, it was shown that the increased extent of absorption of a 600 mg oral dose of saquinavir following a full breakfast was approximately double the absorption after a light breakfast (only cereal, toast, coffee or tea).

In a cross-over study, 22 HIV-infected patients treated with INVIRASE/ritonavir (1000/100 mg) bd and receiving 3 consecutive dosings under fasting conditions or after a high-fat meal (46 g fat, 1091 kcal), the AUC0-12 of saquinavir was 10320 ng·h/mL and 34926 ng·h/mL, respectively. All but 1 of the patients achieved Ctrough above the therapeutic threshold in the fasted state. Nevertheless, INVIRASE should be administered within 2 hours following a meal.

In HIV-infected patients, boosted saquinavir (FORTOVASE (soft gel capsules) or INVIRASE) at doses of 400/400 mg bd or 1000/100 mg bd provides saquinavir systemic exposures over a 24-hour period similar to, or greater than those achieved with FORTOVASE 1200 mg tds (see Table 3).

Table 3: Pharmacokinetic Parameters of Saquinavir at Steady-state after Administration of Different Regimens in HIV-infected Patients
Dosing regimen N AUCτ
(ng·h/mL)
AUC24h
(ng·h/mL)
Cmin
(ng/mL)
INVIRASE 600 mg tds 10 866 2598 79
FORTOVASE 1200 mg tds 31 7249 21747 216
INVIRASE 400 mg bd + ritonavir 400 mg bd 7 16000 32000 480
INVIRASE 1000 mg bd + ritonavir 100 mg bd 24 14607 29214 371
FORTOVASE 1000 mg bd + ritonavir 100 mg
bd
24 19085 38170 433
INVIRASE 1000 mg bd + ritonavir 100 mg bd
Fasting conditions
22 10320 20640 313
INVIRASE 1000 mg bd + ritonavir 100 mg bd
High fat meal
22 34926 69852 1179

FORTOVASE: saquinavir soft gel capsules; τ: dosing interval (8 hrs if tds, 12 hrs if bd);

In treatment-naïve HIV-1 infected patients initiating INVIRASE/ritonavir treatment with a modified INVIRASE/ritonavir dosing regimen of INVIRASE 500 mg bd with ritonavir 100 mg bd for the first 7 days of treatment and increased to INVIRASE 1000 mg bd with ritonavir 100 mg bd in the subsequent 7 days, INVIRASE systemic exposures generally approached or exceeded the range of historical steady-state values with the standard INVIRASE/ritonavir 1000 mg/100 mg bd dosing regimen across study days (see Tables 3 and 4).

Table 4 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)
AUCτ
(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)

No differences in gastrointestinal absorption were noted between HIV-positive subjects with and without diarrhoea, and administration of saquinavir had no effect on these parameters.

Saquinavir is a substrate for the MDR1 Multidrug Transporter (P-glycoprotein, P-gp).

Bioequivalence of INVIRASE 500 mg film-coated tablets and INVIRASE 200 mg capsules was demonstrated in 94 healthy male and female volunteers who received 1000 mg (either as two 500 mg tablets or five 200 mg capsules) under fed conditions in combination with 100 mg ritonavir bd. Mean exposure ratios were estimated to be 1.10 for AUC0-∞ and 1.19 for Cmax of saquinavir with corresponding 90% CI of 1.04 - 1.16 and 1.14 - 1.25, respectively.

Distribution: 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.

Saquinavir shows a high degree of protein binding (approximately 98%) which is independent of concentrations over the range 15 - 700 ng/mL. Saquinavir does not enter the cerebrospinal fluid readily and concentrations are low compared with plasma, as would be expected from saquinavir’s high protein binding.

Metabolism and Elimination: Saquinavir is metabolised extensively via the hepatic route. Values >96% of a radiolabelled intravenous dose appeared in the faeces after 4 days. In vitro studies identified that the metabolism of saquinavir is cytochrome P450-mediated, with the specific isoenzyme CYP3A4 responsible for more than 90% of the hepatic metabolism. Renal excretion is a very minor route of elimination for saquinavir (< 4%). The metabolic profile of saquinavir has been investigated in bile, plasma and microsomes in rats and in microsomes from other species, including man. Saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds.

Systemic clearance is rapid, 80 L/hr; which is close to hepatic plasma flow. Systemic clearance was constant after intravenous doses of 6, 36 and 72 mg infused over 3 hours. The mean residence time of saquinavir was found to be 7 hours.

After single and multiple oral doses of capsules (25 - 600 mg tds) in the presence of food, the increase in exposure (50-fold) was greater than directly proportional to the increase in dose (24-fold). Accumulation following multiple dosing (25 - 600 mg tds) in HIV-infected patients is modest. AUC was increased by 150% at steady-state compared to single doses.

Pharmacokinetics in Special Populations

Patients with renal impairment: No pharmacokinetic investigations of INVIRASE in patients with renal insufficiency have been performed.

Patients with hepatic impairment: The effect of hepatic impairment on the steady-state pharmacokinetics of INVIRASE/ritonavir (1000 /100 mg) bd for 14 days, was investigated in 7 HIV-infected patients with moderate liver impairment (Child Pugh Grade B score 7 - 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% CI) was 0.7 (0.3 - 1.6) for both AUC0-12 and Cmax, which suggests approximately 30% reduction in the pharmacokinetic exposure in patients with moderate hepatic impairment. No dose adjustment is warranted for saquinavir in HIV-infected patients with moderate hepatic impairment (see PRECAUTIONS: Hepatic Impairment).

Effect of gender, race and age:

Gender: No effect of gender was observed on the pharmacokinetics of INVIRASE 200 mg capsule administered as a 600 mg single dose in 71 healthy volunteers. A gender difference was observed with females showing higher saquinavir exposure than males (AUC 56%, Cmax 26%) in the bioequivalence study comparing INVIRASE 500 mg film-coated tablets with INVIRASE 200 mg capsules (boosted therapies). There was no evidence that age and body-weight explained the gender difference in this study. A clinically significant difference in safety profile and efficacy between men and women has not been reported with the approved dosage regimen. Treatment with INVIRASE/ritonavir (1000/100 mg) bd in male and female patients is found to be well-tolerated and effective.

Race: The influence of race on the pharmacokinetics of INVIRASE has not been determined.

Elderly: INVIRASE pharmacokinetics have not been investigated in elderly patients (> 65 years).

Paediatric: INVIRASE pharmacokinetics have not been investigated in paediatric patients (< 12 years) (see PRECAUTIONS: Paediatric Use).

Clinical Trials

Advanced Patients without Prior Zidovudine Therapy

A dose-ranging study (Italy, V13330) conducted in 92 zidovudine-naïve patients (mean baseline CD4 = 179) studied saquinavir at doses of 75 mg, 200 mg and 600 mg tds in combination with zidovudine 200 mg tds compared to saquinavir 600 mg tds alone and zidovudine alone. In analyses of average CD4 changes over 16 weeks, treatment with the combination of saquinavir 600 mg tds + zidovudine (n = 14) produced greater CD4 cell increases than zidovudine monotherapy (see Fig 1). The CD4 changes of zidovudine in combination with doses of saquinavir lower than 600 mg tds were no greater than that of zidovudine alone. The number of patients studied was too limited to permit adequate comparison of the efficacies of saquinavir 1800 mg daily versus recommended doses of zidovudine as monotherapy.



Advanced Patients with Prior Zidovudine Therapy

In ACTG229/NV14255, 295 patients (mean baseline CD4 = 165) with a history of prolonged zidovudine treatment (median 713 days) were randomised to receive either saquinavir 600 mg tds + zalcitabine + zidovudine (triple combination), saquinavir 600 mg tds + zidovudine or zalcitabine + zidovudine. In analyses of average CD4 changes over 24 weeks, the triple combination (n = 89) produced greater increases in CD4 cell counts (see Fig 2) compared with that of zalcitabine + zidovudine. There were no significant differences in CD4 changes among patients receiving saquinavir + zidovudine and zalcitabine + zidovudine. Based on surrogate markers, including CD4 count and plasma HIV-RNA response but not quality of life measures, the combination of saquinavir 1800 mg daily with zidovudine and zalcitabine was superior to saquinavir + zidovudine and zidovudine + zalcitabine but longer term follow-up information including morbidity and mortality information are lacking.



Only limited and transient antiviral activity has been demonstrated with INVIRASE monotherapy. Therefore, INVIRASE must be given in combination with other antiretrovirals.

Saquinavir in Combination with Ritonavir

MaxCmin1 study

In the MaxCmin1 study, the safety and efficacy of saquinavir soft gel capsules (FORTOVASE) / ritonavir (1000/100 mg) bd in combination with 2 NRTIs/NNRTIs was compared with indinavir/ritonavir (800/100 mg) bd in combination with 2 NRTIs/NNRTIs. Median baseline CD4 cell count was 272 cells/mm3 and median baseline plasma HIV-RNA was 4.0 log10 copies/mL in the FORTOVASE/ritonavir arm. Median baseline CD4 cell count was 280 cells/mm3 and median baseline plasma HIV-RNA was 3.9 log10 copies/mL in the indinavir/ritonavir arm. At 48 weeks, the median increases in CD4 cell counts were 85 and 73 cells/mm3 for the FORTOVASE and indinavir arms, respectively. For the intent-to-treat (ITT) analysis at week 48 (switch = failure) the proportion of patients in the saquinavir containing arm with viral load below the limit of detection (< 400 copies/mL) was 69% (n = 102) compared with 53% in the indinavir containing arm.

MaxCmin2 study

In the MaxCmin2 study, the safety and efficacy of saquinavir soft gel capsules (FORTOVASE) / ritonavir (1000/100 mg) bd in combination with 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir (400/100 mg) bd in combination with 2 NRTIs/NNRTIs in over 324 subjects. Values for median baseline CD4 count and median baseline plasma HIV-RNA were 241 cells/mm3 and 4.4 log10 copies/mL in the FORTOVASE/ritonavir arm, and 239 cells/mm3 and 4.6 log10 copies/mL in the lopinavir/ritonavir arm, respectively.

In the primary efficacy analysis, incidence of virological failure, including all subjects that took at least one dose of the study medication (ITT/exposed population) 29 failures were observed in the lopinavir/ritonavir arm and 53 failures in the FORTOVASE/ritonavir arm (hazard ratio HR: 0.5; 95% CI: 0.3 – 0.8). The better outcome in the lopinavir/ritonavir arm was associated with lower failure rates among subjects no longer taking their assigned treatment and better compliance with the protocols intention to use ART strategies aimed at suppressing viral replication at all times. Comparable findings were made in the analysis where discontinuation of the assigned treatment was regarded as virological failure (ITT/exposed population/discontinuation = failure; HR: 0.6; 95% CI: 0.4 – 0.9). In this analysis the better outcome in the lopinavir/ritonavir arm was associated with a reduced risk of discontinuation of the assigned treatment due to factors not linked to antiviral activity.

At 48 weeks, the proportion of subjects with HIV-RNA below the limit of detection (< 50 copies/mL) was 53% (n = 161) for the FORTOVASE arm versus 60% (n = 163) for the lopinavir arm in the ITT, switch equals failure analysis, and 74% (n = 114) for the FORTOVASE arm versus 70% (n = 141) for the lopinavir arm in the on-treatment analysis (p = ns for both comparisons). At the cut off level of HIV-RNA < 400 copies/mL, the probability of viral suppression was lower in the FORTOVASE/ritonavir arm from week 24 and onwards in the ITT/exposed population analysis and from week 36 in the ITT/exposed population/discontinuation analysis. No statistical differences were observed in the on-treatment analysis.

Over 48 weeks a similar strong immunological response was seen in both arms with median increases in CD4 count of 106 cells/mm3 for the lopinavir/ritonavir arm, and 110 cells/mm3 for the FORTOVASE/ritonavir arm.

More subjects in the FORTOVASE/ritonavir arm (30%) than in the lopinavir/ritonavir arm (14%) prematurely discontinued the assigned treatment (p = 0.001). The primary reasons for premature discontinuation were non-fatal adverse events and subject’s choice.

No difference in the incidence of adverse events of Grade 3 and/or 4 was seen between the two arms.

Effects on Electrocardiogram

The effect of 1000/100 mg bd (therapeutic dose) and 1500/100 mg bd (supra-therapeutic dose) of INVIRASE/ritonavir on the QT interval was evaluated over 20 hours on day 3 of dosing 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). The day 3 time point was chosen since the pharmacokinetic exposure was maximum on that day in a previous 14-day multiple dose pharmacokinetic study. These doses of INVIRASE/ritonavir on day 3 in this study resulted in a mean Cmax of approximately 3-fold and 4-fold, respectively, higher than the mean Cmax observed with INVIRASE/ritonavir 1000/100 mg bd in HIV patient population at steady-state. On day 3, the upper 1-sided 95% CI 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 INVIRASE/ritonavir treatment groups (see results in Table 5). The supra-therapeutic dose of INVIRASE/ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of INVIRASE/ritonavir. Majority (89% and 80% in therapeutic dose and supra-therapeutic dose, respectively) of subjects had the QTcS of < 450 msec and none had the QTc interval of > 500 msec. (Also see PRECAUTIONS: Cardiac Conduction and Repolarisation Abnormalities)

Table 5 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
Treatment Post-Dose
Time Point
Maximum Mean
ddQTcS
Standard
Error
Upper 95%-CI
of ddQTcS
INVIRASE/ritonavir
1000/100 mg bd
12 hours 18.86 1.91 22.01
INVIRASE/ritonavir
1500/100 mg bd
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 prolongation of > 200 msec was also observed in 40% and 47% of subjects receiving INVIRASE/ritonavir 1000/100 mg bd and 1500/100 mg bd, respectively, on day 3.Three percent of subjects in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of > 200 msec. The maximum mean PR interval changes relative to the pre-dose baseline value were 25 msec and 34 msec in the two INVIRASE/ritonavir treatment groups, 1000/100 mg bd and 1500/100 mg bd, respectively. (Also see PRECAUTIONS: Cardiac Conduction and Repolarisation Abnormalities).

There was no torsade de pointes and no QT prolongation >500 msec in the study. In several subjects, association of syncope or presyncope with PR prolongation could not be ruled out. The clinical significance 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/ritonavir1000/100 mg bd should be avoided.

The effect of treatment initiation with a dosing regimen of INVIRASE/ritonavir 500 /100 mg bd in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) for the first 7 days of treatment followed by INVIRASE/ritonavir 1000/100 mg bd 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 pre-dose 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 6) based on cross-study comparison in a different population. Only 2/21 (9%) patients across all study days had maximum QTcF change from dense pre-dose baseline ≥ 30 msec following administration of the modified INVIRASE/ritonavir regimen in the treatment-naïve HIV-1 infected patient population; and the maximum mean change from dense pre-dose baseline in QTcF was < 10 msec 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 6). The proportion of patients with a reported PR interval prolongation > 200 msec in this study ranged from 3/22 (14%) (day 3) to 8/21 (38%) (day14).

Following the modified INVIRASE/ritonavir regimen, SQV exposure during the first week peaked on Day 3 and declined to the lowest exposure on Day 7 with RTV induction effects, while Day 14 SQV PK parameters (following full doses of INVIRASE/ritonavir in the second week) approached the range of historical mean values for SQV steady-state values in HIV-1 infected patients (Table 6). 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 6 Summary of electrocardiogram parameters following administration of the modified INVIRASE/ritonavir regimen in treatment naïve HIV-1 infected patients initiating treatment with INVIRASE/ritonavir
Parameter Day 3
500/100
mg
(n=22)
Day 4
500/100
mg
(n=21)
Day 7
500/100
mg
(n=21)
Day 10
1000/100
mg
(n=21)
Day 14
1000/100
mg
(n=21)
TQT Study
Day 3*
(n=57)
Mean Maximal
ΔQTcFdense msec (SD)
3.26 ±
7.01
0.52 ±
9.25
7.13 ±
7.36
11.97 ±
11.55
7.48 ±
8.46
32.2 ± 13.4
Patients with maximal
ΔQTcFdense ≥ 30 msec (%)
0 0 0 2/21
(9%)
0 29/57
(51%)

*Historical data from the thorough QT study conducted in healthy volunteers

Indications

INVIRASE (saquinavir) is indicated for the treatment of HIV/AIDS in adults. Saquinavir must be used only in combination with ritonavir and other antiretroviral therapies (see CLINICAL TRIALS).

This indication is based on changes in surrogate markers. At present there are no results from controlled clinical trials evaluating the effect of regimens containing saquinavir on HIV disease progression or survival (see CLINICAL TRIALS).

Contraindications

Please also refer to the full product information for ritonavir which is used in combination with Invirase.

INVIRASE is contraindicated in patients with hypersensitivity to saquinavir or to any of the excipients in the film-coated tablet.

INVIRASE is contraindicated in patients with severe hepatic impairment (see Precautions).

INVIRASE is contraindicated with other medicines that may interact and result in potentially life threatening side effects associated with concomitantly administered medicines. Examples of medicines which are contraindicated with INVIRASE are included in Table7.

INVIRASE is contraindicated in patients with congenital or documented acquired QT prolongation, and electrolyte disturbances particularly uncorrected hypokalaemia. Familial history of sudden death at a young age may be suggestive of congenital QT prolongation.

Table 7: Medicines that are Contraindicated with INVIRASE/ritonavir
Medicine class Medicines within class that are
contraindicated with INVIRASE / ritonavir
Side effect
Alpha 1-adrenoreceptor
antagonist
Alfuzosin Potentially increased alfuzosin
concentrations can result in
hypotension
Antiarrhythmics Class IA: (e.g. Quinidine)
Class IB (e.g. Lidocaine (systemic))
Class IC (e.g. Amiodarone, flecainide,
propafenone, bepridil, dofetilide)
Life-threatening cardiac
arrhythmia
Antidepressant Trazodone Increased Trazodone
concentrations can result in
potentially life-threatening
cardiac arrhythmia.
Hypotension, nausea,
dizziness and syncope have
been observed.
Antihistamines Astemizole, terfenadine, mizolastine Potentially life-threatening
cardiac arrhythmia
Antiinfectives Clarithromycin
Erythromycin
Halofantrine
Potentially life- threatening
cardiac arrhythmia.
Antimycobacterial Agents Rifampicin Severe hepatocellular toxicity
Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine,
methylergonovine
Acute ergot toxicity
GI Motility Agents Cisapride Potentially life-threatening
cardiac arrhythmia
HIV protease inhibitors (PIs) Atazanavir Potentially life- threatening
cardiac arrhythmia.
HMG-CoA Reductase Inhibitors Simvastatin, lovastatin Rhabdomyolysis
Immunosupressant Tacrolimus Potentially life-threatening
cardiac arrhythmia.
Neuroleptics Pimozide, clozapine, haloperidol,
chlorpromazine, sertindole, thioridazine,
ziprasidone
Potentially life-threatening
cardiac arrhythmia
Quetiapine Increased quetiapine-related
toxicity
Sedatives/Hypnotics Triazolam, oral midazolam Prolonged/increased sedation
Other medicinal products that
are substrate of CYP3A4
Dapsone
Disopyramide
Quinine
Potentially life- threatening
cardiac arrhythmia.

Precautions

Information for Patients

INVIRASE must be given only in combination with ritonavir (see Dosage and Administration).

INVIRASE should NOT be given without ritonavir.

INVIRASE may interact with other medicines, therefore, patients should consult their doctor before taking other medications (prescription or non-prescription).

Alternative or additional contraceptive measures should be used when oestrogen-based oral contraceptives are co-administered (see INTERACTIONS WITH OTHER MEDICINES).

Patients should also be advised that they may experience toxicities associated with co-administered medications.

Patients should be informed that INVIRASE is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.

Patients should be advised that INVIRASE does not reduce the risk of transmitting HIV to others through sexual contact or contamination through blood.

Patients should have regular visits with their doctor for blood tests and monitoring of blood glucose concentrations.

Hepatic Impairment

INVIRASE is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).

No dosage adjustment is necessary for HIV-infected patients with moderate hepatic impairment based on limited data (see PHARMACOLOGY: Pharmacokinetics in Special Population and DOSAGE AND ADMINISTRATION: Special Dosage Instructions). In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease and development of portal hypertension while on treatment with INVIRASE. Associated symptoms include jaundice, ascites, oedema and, in some cases oesophageal varices. Several of these patients died. A causal relationship between INVIRASE therapy and development of portal hypertension has not been established. Careful monitoring for signs and symptoms of liver toxicity, and tests of liver function (including transaminases) are recommended.

Renal Impairment

Clinical studies with saquinavir included patients with a range of renal impairment from mild to moderate (highest creatinine value measured: 143 μmol/L). In these patients, exposure to saquinavir was not correlated with laboratory markers of renal impairment. No data are available in patients with more severe renal impairment. Although renal clearance is only a minor elimination pathway for saquinavir, clinical judgment should be exercised when administering INVIRASE to patients with renal insufficiency.

Diabetes and Hyperglycaemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycaemia have been reported during post-marketing surveillance in HIV-infected patients receiving PI therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made.

Fat Redistribution

Redistribution and/or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump) and breast enlargement, “cushingoid appearance” and loss of body fat from the face, limbs and upper trunk (peripheral lipodystrophy) have been reported in HIV positive patients receiving ART. It has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, and hyperglycaemia. The severity of these metabolic abnormalities differs within and between the three classes of antiretrovirals (PIs, NRTIs, and NNRTIs). A higher risk of lipodystrophy has been associated with older age, longer duration of ART, stavudine use, hypertriglyceridaemia and hyperlactaemia. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of serum lipids and blood glucose is recommended. In case of such metabolic abnormalities, a switch in ART may be considered, and/or the addition of treatments designed to directly correct these abnormalities (e.g. lipid lowering agents). The mechanisms of these events and long-term consequences, such as an increased risk of cardiovascular disease, are currently unknown.

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE. During the initial phase of combination antiretroviral treatment in patients with severe immune deficiency, a systemic inflammatory reaction to asymptomatic or residual opportunistic pathogens or self-antigens may arise and cause serious clinical conditions or aggravation of symptoms, which may necessitate further evaluation and treatment.

Autoimmune disorders have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

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. A causal relationship has been suggested. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Patients with Diarrhoea

The effects of diarrhoea on the absorption and clinical efficacy of saquinavir have not been studied systematically. The possibility that severe or prolonged diarrhoea may impair the efficacy of INVIRASE should be kept in mind.

Cardiac Conduction and Repolarisation Abnormalities

Dose-dependent prolongations of QT and PR intervals have been observed in healthy volunteers receiving INVIRASE/ritonavir (see CONTRAINDICATIONS).

It is not recommended to administer INVIRASE/ritonavir to patients concurrently with other medicinal products that prolong the QT interval. Caution is advised if concomitant use is considered necessary and an ECG performed if signs of cardiac arrhythmias occur. INVIRASE/ritonavir should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, and ischemic heart disease or cardiomyopathies as they may be at increased risk for developing cardiac conduction abnormalities.

INVIRASE/ritonavir should be discontinued if significant arrhythmias, QT or PR prolongations occur. Generally, women and elderly patients may be more susceptible to drug-associated effects on the QT interval. The magnitude of QT and PR prolongation may increase with increasing concentrations of saquinavir. Therefore, the recommended dose of INVIRASE/ritonavir should not be exceeded. 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.

Patients initiating therapy with INVIRASE/ritonavir: An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not initiate treatment with INVIRASE/ritonavir. For patients with a QT interval < 450 msec, an on-treatment ECG is recommended.

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

Patients with a QT interval increased to > 480 msec or prolongation over pre-treatment by > 20 msec should discontinue INVIRASE/ritonavir (see CLINICAL TRIALS, Effects on Electrocardiogram).

Patients stable on INVIRASE/ritonavir and requiring concomitant medication with potential to increase the QT interval or patients on medication with potential to increase the QT interval and requiring concomitant INVIRASE/ritonavir where no alternative therapy is available and the benefits outweigh the risks: An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy (see INTERACTIONS WITH OTHER MEDICINES). If baseline QT interval < 450 msec, an on-treatment ECGs 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 INVIRASE/ritonavir or the concomitant therapy or both.

Lactose Intolerance

Each 500mg film-coated tablet contains 38.5 mg lactose (monohydrate). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder) should not take INVIRASE.

Effects on Fertility

Fertility and reproductive performance were not affected in rats at plasma exposures (AUC values) approximately 33% of those achieved in humans at the recommended clinical dose of INVIRASE/ritonavir (1000/100 mg) bd.

Use in Pregnancy: Category B1

Reproduction studies conducted with saquinavir in rats and rabbits have shown no embryotoxicity or teratogenicity at plasma exposures (based on AUC) approximately 32% of those achieved in humans at the recommended clinical dose of INVIRASE/ritonavir (1000/100 mg) bd. Only small amounts of saquinavir were shown to cross the placental barrier in these species. In a perinatal and postnatal study in rats, at plasma exposures similar to those in the teratogenicity study, there was no effect on the survival, growth and development of offspring to weaning.

Because animal reproduction studies are not always predictive of human response and clinical experience in pregnant women is limited, caution should be exercised before INVIRASE is prescribed during pregnancy.

Use in Lactation

It is not known whether saquinavir is excreted in animal or human milk. Because many medicines are excreted in human milk, and because of the potential for serious adverse reactions to saquinavir in nursing infants, breast feeding should be stopped during treatment with INVIRASE.

Paediatric Use

The safety and efficacy of INVIRASE/ritonavir in HIV-infected patients younger than 2 years have not been established. No dose recommendation for children 2 to < 16 years of age could be established that are both reliably effective and below thresholds of concern for QT and PR interval prolongation.

Limited information is available in children. Unboosted INVIRASE should not be used in children due to the significantly lower saquinavir plasma levels in children compared with adults.

Use in the Elderly

Only limited experience is available in patients older than 60 years. No data are available to establish a dose recommendation in elderly patients.

Carcinogenicity

Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir 125 – 1000 mg/kg/d and 200 – 2500 mg/kg/d, respectively, for approximately 2 years. The plasma exposures (area under the curve [AUC] values) in the respective species were up to approximately 37% and 85% of those obtained in humans at the recommended clinical dose of INVIRASE/ritonavir (1000/100 mg) bd.

Genotoxicity

Saquinavir, with and without metabolic activation as appropriate, was not mutagenic in the Salmonella typhimurium reverse-mutation assay or in the chinese hamster lung V79/HPRT test, was not clastogenic in the mouse micronucleus assay in vivo or in human peripheral blood leucocytes in vitro, and did not induce DNA damage in primary rat hepatocytes.

Effects on Ability to Drive and Use Machines

No studies have been conducted on the ability to drive and to use machines whilst using INVIRASE. There is no evidence that INVIRASE may alter the patient's ability to drive and use machines, however, the adverse event profile of INVIRASE should be taken into account (see ADVERSE EFFECTS).

Drug Interactions

Saquinavir could interact and modify the pharmacokinetics of other drugs that are substrates for CYP3A4 and/or P-glycoprotein and should be used with caution. The drugs which are known to or have potential to interact with saquinavir are listed in INTERACTIONS WITH OTHER MEDICINES.

Interactions with Other Medicines

Most medicine interaction studies with saquinavir have been completed without the administration of ritonavir (i.e. unboosted) with saquinavir soft gel capsules (FORTOVASE). Observations from medicine interaction studies conducted with unboosted saquinavir might not be representative of the effects seen with the boosted saquinavir therapy. Furthermore, results seen with FORTOVASE may not be predictive for INVIRASE and vice versa.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme, CYP3A4, responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-glycoprotein (P-gp). Therefore, medicines that either share or modify CYP3A4 and/or P-gp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other medicines that are substrates for CYP3A4 or P-gp.

Ritonavir can affect the pharmacokinetics of other medicines because it is a potent inhibitor of CYP3A4 and P-gp and is also an enzyme inducer of several cytochrome P450 isozymes (see Table 7: Medicines that are Contraindicated with INVIRASE/ritonavir and the Product Information for ritonavir).

Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving INVIRASE/ritonavir (see CONTRAINDICATIONS; PRECAUTIONS: Cardiac Conduction and Repolarisation Abnormalities and CLINICAL TRIALS: Effects on Electrocardiogram) additive effects on QT and PR interval prolongation may occur with the following medicinal classes: Anti-arrhythmics class IA or class III, neuroleptics, tricyclic anti-depressive agents, PDE5 inhibitors, certain antimicrobials and anti-histaminics and medicines which affect cardiac conduction (see also below under individual medicine interactions). This effect might lead to an increased risk of ventricular arrhythmias, notably torsade de pointes. Therefore, concurrent administration of these agents with INVIRASE/ritonavir should be avoided when alternative treatment options are available. Medicines showing both pharmacokinetic interactions with INVIRASE/ritonavir and additive effects on QT and PR interval prolongation are strictly contraindicated. The combination of INVIRASE/ritonavir with other medicines known to prolong the QT and PR interval is not recommended and should be used with caution if concomitant use is deemed necessary (see CONTRAINDICATIONS and PRECAUTIONS: Cardiac Conduction and Repolarisation Abnormalities).

Inhibitors of CYP3A4: An increase in plasma concentrations of saquinavir could occur with other compounds that are inhibitors of the CYP3A4 isoenzyme. In a clinical study, ketoconazole (a potent CYP 3A4 inhibitor) did not increase PK exposure of saquinavir when it was co-administered with ritonavir,suggesting that a second CYP3A4 inhibitor in a therapy may not further elevate the plasma levels of saquinavir. However, clinical monitoring of patients is recommended when Invirase is coadministered with CYP 3A4 inibitors (see Table 8: Examples of known and predicted Drug-Drug Interactions -Antifungals). If such medicines are used concomitantly with INVIRASE, monitoring for saquinavir toxicity may be necessary.

Inducers of CYP3A4 or P-gp: Other medicines that induce CYP3A4 may also reduce saquinavir plasma concentrations.

Medicines reducing gastrointestinal transit time: It is unknown whether medicines that reduce the gastrointestinal transit time could lead to lower saquinavir plasma concentrations.

Table 8 Examples of known and predicted Drug-Drug Interactions
Medicinal product by
therapeutic area (dose of
Invirase used in study)
InteractionRecommendations concerning co-
administration
Antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTIs)
Zalcitabine and/or
Zidovudine
- No pharmacokinetic interaction
studies have been completed with
Invirase/ritonavir.

- 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.

- No dose adjustment required.
Didanosine
400 mg single dose
(saquinavir soft gel capsules
/ritonavir 1600/100 mg qd
for 2 weeks, in eight healthy
subjects
- Saquinavir AUC ↓ 30 %
Saquinavir Cmax ↓ 25 %
Saquinavir Cmin
- Clinical significance not known

- No dose adjustment required.
Tenofovir disoproxil
fumarate 300 mg qd
(saquinavir/ritonavir
1000/100 mg bid) 18 HIV-
infected patients
- Saquinavir AUC ↓ 1 %
Saquinavir Cmax ↓ 7 %
Saquinavir Cmin
- No clinically significant effect on
saquinavir exposure.

- No dose adjustment required.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Delavirdine- The interaction with
Invirase/ritonavir has not been
evaluated.

- There are limited safety and no
efficacy data available from the use
of this combination.

- With saquinavir AUC ↑ 348 %.

- 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.

- Concomitant use only if the
benefit outweighs the risk
Efavirenz 600 mg qd
saquinavir/ritonavir
1000/100 mg bid (n=32)

Efavirenz 600mg and
unboosted saquinavir
1200mg tds to 12 subjects
Boosted saquinavir:
- Saquinavir ↔
- Efavirenz ↔

Unboosted saquinavir:
- Saquinavir AUC ↓
62% and Cmax by 50%. The
concentrations of efavirenz
were also decreased by about
10%, but this was not suggested
to be clinically significant.
- No dose adjustment required.
Nevirapine- The interaction with
Invirase/ritonavir has not been
evaluated.

- Unboosted saquinavir:
Saquinavir AUC ↓ 24 %
Nevirapin AUC ↔
- Clinical significance not known
- No dose adjustment required.
HIV protease inhibitors (PIs)
Fosamprenavir
700 mg bid
(saquinavir/ritonavir
1000/100 mg bid, in 18
HIV-infected patients)
- 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/ritonavir

Indinavir 800 mg tid
(saquinavir 600-1200 mg
soft gel capsules single dose)
six healthy volunteers
- Low dose ritonavir increases the
concentration of indinavir.

- Unboosted saquinavir Saquinavir
AUC ↑ 4.6-7.2 fold
Indinavir plasma concentration ↔
- Increased concentrations of
indinavir may result in urological
complaints e.g. haematuria, flank
pain, dysuria, passing urinary
calculi. Adequate fluid intake (≥
1.5L daily) is recommended as a
potential preventative measure,
and reduction of indinavir dose is
appropriate if nephrolithiasis
develops.

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

Saquinavir soft gel
capsules/ritonavir
1000/100 mg bid in
combination with 2 or 3
NRTIs in 32 HIV-infected
patients)

Saquinavir soft gel capsules
1000 mg bid and the fixed
combination of
lopinavir/ritonavir
400/100 mg bid in 45 HIV-
nfected patients)
Saquinavir ↔

Ritonavir ↓ (effectiveness as boosting
agent not modified).
Lopinavir ↔ (based on historical
comparison with unboosted lopinavir).
- Use lopinavir/ritonavir with
caution as additive effects on QT
and/or PR interval prolongation
may occur with Invirase.(See
Precautions: Cardiac Conduction
and Repolarisation
Abnormalities
).

- For patients already taking
ritonavir as part of their
antiretroviral regimen, no
additional ritonavir is needed.
Nelfinavir 1250 mg bid
(saquinavir/ritonavir
1000/100 mg bid)
Multiple dose saquinavir/
ritonavir 1000 mg / 100mg
bid) nelfinavir (1250 mg
bid) in 12 HIV-infected
patients.
- Saquinavir AUC ↑ 13 %
(90 % CI: 27↓ - 74↑)
Saquinavir Cmax ↑ 9 %
(90 % CI: 27↓ - 61↑)
- Combination not recommended.
Ritonavir 100 mg bid
(saquinavir 1000 mg bid)
- Saquinavir ↑
Ritonavir ↔
(see Pharmacokinetics).
- The approved combination
regimen is saquinavir 1000 mg bid
with ritonavir 100 mg bid.

- Higher doses of ritonavir have
been shown to be associated with
an increased incidence of adverse
events.

- In some cases, 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
Tipranavir/ritonavir

Dual-boosted protease
inhibitor combination
therapy in multiple-
treatment experienced HIV-
positive adults
- Saquinavir Cmin ↓ 78 %- Concomitant administration of
tipranavir, co-administered with
low dose ritonavir, with
saquinavir/ritonavir, is not
recommended as the clinical
relevance of this reduction has not
been established.

- If the combination is nevertheless
considered necessary, monitoring
of the saquinavir plasma levels is
strongly encouraged.
HIV fusion inhibitor
Enfuvirtide
(saquinavir soft gel capsules
/ritonavir 1000/100 mg bid)
12 HIV patients.
- Saquinavir ↔
Enfuvirtide ↔
- No clinically significant
interaction was noted.

- No dose adjustment required.
HIV CCR5 antagonist
Maraviroc 100 mg bid
(saquinavir/ritonavir
1000/100 mg bid)
- Maraviroc AUC12 ↑ approx 10 fold
Maraviroc Cmax: ↑ approx 5 fold
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.
Antiarrhythmics
Ibutilide
Sotalol
- No studies performed however no
pk interaction expected.
- Use with caution due to possible
cardiac arrhythmias
Anticoagulant
Warfarin- Concentrations of warfarin may be
affected.
- INR (international normalised
ratio) monitoring recommended.
Anticonvulsants
Carbamazepine
Phenobarbital
Phenytoin
- Interaction with Invirase/ritonavir
has not been studied. However,
these medicinal products will induce
CYP3A4 if unboosted Invirase is
taken, and may therefore decrease
saquinavir concentrations.
- Use with caution.

- Monitoring of saquinavir plasma
concentration is encouraged.
Antidepressants
Tricyclic antidepressants
(e.g. amitriptyline imipramine)

Clomipramine
Maprotiline
- Invirase/ritonavir may increase
concentrations of tricyclic
antidepressants.
- Therapeutic concentration
monitoring is recommended for
tricyclic antidepressants.

- Use with caution due to possible
cardiac arrhythmias
Nefazodone- Interaction with Invirase/ritonavir
not evaluated.

- Nefazodone inhibits CYP3A4.
Saquinavir concentrations may be
increased.
- Monitoring for saquinavir toxicity
is recommended.
Anti-gout preparation
Colchicine- Concomitant use of colchicine and
Invirase/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 Invirase/ritonavir is not
recommended, especially in the
case of renal or hepatic
impairment
Fusidic acid- The interaction with Invirase has not
been evaluated.

- Co-administration of fusidic acid
and Invirase/ritonavir can cause
increased plasma concentration of
both fusidic acid and
saquinavir/ritonavir.
- Concomitant use of fusidic acid
and saquinavir/ritonavir is not
recommended due to potential for
increased mutual toxicity.
Streptogramin antibiotics
(quinupristin/dalfopristin)






Pentamidine
Sparfloxacin
- Interaction with Invirase/ritonavir
has not been evaluated.

- Streptogramin antibiotics such as
quinupristin/dalfopristin will inhibit
CYP3A4 and may increase
saquinavir concentrations.

- Interaction with Invirase/ritonavir
not studied
- Clinical monitoring for saquinavir
toxicity recommended.
- Use with caution due to possible
cardiac arrhythmias.
- Use with caution due to possible
cardiac arrhythmias.
Antifungals
Ketoconazole 200 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
- Saquinavir AUC ↔
Saquinavir Cmax
Ritonavir AUC ↔
Ritonavir Cmax
Ketoconazole AUC ↑ 168 %
(90 % CI 146%-193%)
Ketoconazole Cmax ↑ 45 %
(90 % CI 32 %-59 %)
- No dose adjustment required
when saquinavir/ritonavir
combined with ≤ 200 mg/day
ketoconazole.
- High doses of ketoconazole
(> 200 mg/day) are not
recommended
Itraconazole- The interaction with
Invirase/ritonavir has not been
evaluated .
- Itraconazole is a moderately potent
inhibitor of CYP3A4. An interaction
is possible
- Clinical monitoring for saquinavir
toxicity recommended.
Fluconazole/miconazole- Interaction with Invirase/ritonavir
has not been evaluated.
- Both drugs are CYP3A4 inhibitors
and may increase the plasma
concentration of saquinavir.
Clinical monitoring for saquinavir
toxicity recommended.
Antimycobacterials
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
- Dose adjustment of rifabutin
(150 mg qod) is recommended
when used in combination with
Invirase.

- Monitoring of neutropenia and
liver enzyme levels is
recommended due to an expected
increase in exposure to rifabutin.
Limited data support the use of
saquinavir with efavirenz when
co-administered with ritonavir.
Benzodiazepines
Midazolam parenteral- No data are available on concomitant
use of Invirase/ritonavir with
intravenous midazolam

- Studies of other CYP3A modulators
and intravenous midazolam suggest a
possible 3 to 4-fold increase in
midazolam plasma levels.
- 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 a 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
- Concentrations of these medicinal
products may be increased when co-
dministered with Invirase/ritonavir.
- Careful monitoring of patients with
regard to the benzodiazepam
effects is warranted.

- A decrease in the dose of the
benzodiazepine may be required.
Calcium channel blockers
Felodipine, nifedipine,
nicardipine, diltiazem,
nimodipine, verapamil,
amlodipine, nisoldipine,
isradipine
- Concentrations of these medicinal
products may be increased when co-
administered with Invirase.
- Caution is warranted and clinical
monitoring of patients is
recommended.
Corticosteroids
Dexamethasone- Interaction with Invirase/ritonavir has
not been evaluated.

- Dexamethasone induces CYP3A4
and may decrease saquinavir
concentrations.
- Use with caution. Saquinavir may
be less effective in patients taking
these products concomitantly.
Fluticasone propionate
50 mcg qid, intranasal
(ritonavir 100 mg bid)
budesonide
Fluticasone propionate ↑
- Intrinsic cortisol ↓ 86 %
(90 % CI 82 %-89 %)
Greater effects may be expected
when fluticasone propionate is
inhaled.

- Systemic exposure to fluticasone and
budesonide has been reported when
either of these products is
administered via oral inhalation or
intranasal application with low dose
ritonavir.

- Several cases of Cushings disease
associated with this interaction have
been reported in the literature.

- Consideration should be given to
switching subjects requiring
inhaled/intranasal corticosteroid
therapy to beclomethasone.
- Concomitant administration of
Invirase/ritonavir and fluticasone
propionate and other
corticosteroids is not recommended
unless the potential benefit of
treatment outweighs the risk of
systemic corticosteroid effects.

- 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- Interaction has not been evaluated.

- Concomitant use of bosentan and
Invirase/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
Invirase/ritonavir, the patient’s
tolerability of bosentan should be
monitored.

- Monitoring the plasma levels of
Invirase and concomitant HIV
medications is recommended.
Medicinal products that are substrates of P-glycoprotein
Digitalis glycosides
Digoxin 0.5 mg
single dose after 2 weeks of
Invirase/ritonavir 1000/100
mg twice daily to 16 healthy
volunteers in a cross-over
study
- Digoxin AUC0-72 ↑ 49 %
Digoxin Cmax ↑ 27 %
Digoxin levels may differ over time.

- Large increments of digoxin may be
expected when saquinavir/ritonavir is
introduced in patients already treated
with digoxin
- Caution should be exercised when
Invirase/ritonavir and digoxin are
co-administered.

- The serum concentration of
digoxin should be monitored and a
dose reduction of digoxin should
be considered if necessary.
Histamine H2-receptor antagonist
Ranitidine- Interaction with Invirase/ritonavir has
not been evaluated.

- With unboosted saquinavir there was
an increase in exposure of saquinavir
when Invirase was dosed in the
presence of both ranitidine and food,
relative to Invirase dosed with food
alone. This resulted in AUC values of
saquinavir, which were 67 % higher.
This increase is not thought to be
clinically relevant
- No dose adjustment is
recommended as a clinically
relevant interaction would not be
anticipated with Invirase/ritonavir.
HMG-CoA reductase inhibitors
Pravastatin
Fluvastatin
- Interaction not studied.

- Pravastatin, fluvastatin are not
metabolized by CYP3A4, and
interactions are not expected with
protease inhibitors including
ritonavir.

- Interaction via effects on transport
proteins cannot be excluded.
- Interaction unknown.
- If no alternative treatment is
available, use with careful
monitoring.

- If treatment with a HMG-CoA
reductase inhibitor is indicated,
either pravastatin or fluvastatin are
recommended
Atorvastatin, cerivastatin- Atorvastatin / cerivastatin are less
dependent on CYP3A4 for
metabolism.
- When used with Invirase, the
lowest possible dose of atorvastatin
and cerivastatin should be
administered and the patient should
be carefully monitored for
signs/symptoms of myopathy
(muscle weakness, muscle pain,
rising plasma creatinine kinase).
Immunosuppressants
Cyclosporin
Rapamycin
- Concentrations of these medicinal
products may increase several fold
when co-administered with Invirase.
- Careful therapeutic drug
monitoring is necessary for
immunosuppressants when co
-administered with Invirase.
Long-acting beta2-adrenergic agonist
Salmeterol- Concomitant use of salmeterol and
saquinavir/ritonavir is expected to
increase plasma levels of salmeterol.
- Combination not recommended as
may result in increased risk of
cardiovascular adverse events
associated with salmeterol,
including QT prolongation,
palpitations, and sinus tachycardia.
Narcotic analgesics
Methadone 60-120 mg qd
(saquinavir/ritonavir
1000/100 mg bid) once a day
in 12 HIV negative
methadone maintenance
patients
- Methadone AUC ↓ 19 %
(90 % CI 9 % to 29 %)
None of the 12 patients experienced
withdrawal symptoms.
- No dosage adjustment is required
when Invirase is combined with
methadone.

- Use with caution as additive effects
on QT and/or PR interval
prolongation may occur.
Oral contraceptives
Ethinyl estradiol- Concentration of ethinyl estradiol
may be decreased when co-
administered with Invirase/ritonavir.
- Alternative or additional
contraceptive measures should be
used when oestrogen-based oral
contraceptives are co-administered.
Phosphodiesterase type 5 (PDE5) inhibitors
Sildenafil- Interaction with Invirase/ritonavir has
not been evaluated.

- However sildenafil is a substrate of
CYP3A4 and co administration of
sildenafil 100mg single dose with
unboosted saquinavir (1200 mg tid)
lead to:
Saquinavir ↔
Sildenafil Cmax ↑ 140 %
Sildenafil AUC ↑ 210 %
Sildenafil had no effect on saquinavir
pharmacokinetic.
- Use sildenafil with caution at
reduced doses of no more than
25 mg every 48 hours with
increased monitoring of adverse
events.
Vardenafil- Interaction with Invirase/ritonavir has
not been evaluated.

- Concentrations of vardenafil may be
increased when co-administered with
Invirase.
- Use vardenafil with caution at
reduced doses of no more than
2.5 mg every 72 hours with
increased monitoring of adverse
events
Tadalafil- Interaction with Invirase/ritonavir has
not been evaluated.

- Concentrations of tadalafil may be
increased when co-administered with
Invirase.
- Use tadalafil with caution at
reduced doses of no more than
10 mg every 72 hours with
increased monitoring of adverse
events
Proton pump inhibitors
Omeprazole 40 mg qd
(saquinavir/ritonavir
1000/100 mg bid in 8 healthy
volunteers)


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

- No data are available on the
concomitant administration of
Invirase/ritonavir and other proton
pump inhibitors.
- If omeprazole is taken
concomitantly with Invirase,
monitoring for potential saquinavir
toxicities is recommended.

- If other proton pump inhibitors are
taken concomitantly with Invirase,
monitoring for potential saquinavir
toxicities is recommended
Others
Grapefruit juice- Interaction with Invirase/ritonavir has
not been evaluated.

- Co-administration of unboosted
saquinavir and grapefruit juice as
single administration in healthy
volunteers resulted in:
Saquinavir ↑ 50 % (normal strength
grapefruit juice)
Saquinavir ↑ 100 % (double strength
grapefruit juice)
- No dose adjustment is
recommended as a clinically
relevant interaction would not be
anticipated with Invirase/ritonavir
Garlic capsules- Interaction with Invirase/ritonavir has
not been evaluated.

- With unboosted saquinavir resulted
in:
Saquinavir AUC ↓ 51 %
Saquinavir Ctrough ↓ 49 % (8 hours
post dose)
Saquinavir Cmax ↓ 54 %
- Patients on saquinavir treatment
should not take garlic capsules due
to the risk of decreased plasma
concentrations and loss of
virological response and possible
resistance to one or more
components of the antiretroviral
regimen.
St. John’s wort- Interaction with Invirase/ritonavir has
not been evaluated.

- Plasma levels of saquinavir can be
reduced by concomitant use of the
herbal preparation St. John’s wort
(Hypericum perforatum). This is due
to induction of drug metabolising
enzymes and/or transport proteins by
St. John’s wort induce CYP3A4 or P-
glycoprotein.
- Herbal preparations containing St.
John’s wort (hypericum
perforatum
) should not be used
concomitantly with Invirase due to
the risk of decreased plasma
concentrations and loss of virologic
responses and possible resistance to
one or more components of the
antiretroviral regimen.
Other potential interactions
Medicinal products that are substrates of CYP3A4
e.g. 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.
- Combinations should be given with
caution
Gastroenterological medicinal products
Metoclopramide- It is unknown whether medicinal
products which reduce the
gastrointestinal transit time could
lead to lower saquinavir plasma
concentrations.
Vasodilators (peripheral)
Vincamine i.v- Use with caution due to potential
cardiac arrhythmias

Key: ↓ reduced, ↑ increased, ↔ unchanged, ↑↑ markedly increased

Adverse Effects

Clinical Trial Data

The most frequently reported adverse effects, with at least a possible relationship to boosted INVIRASE (i.e. adverse reactions) were nausea, diarrhoea, fatigue, vomiting, flatulence, and abdominal pain.

Adverse Reactions from Clinical Trials with Boosted Saquinavir

Limited data are available from 2 studies where the safety of saquinavir soft gel capsules (FORTOVASE) (1000 mg bd) used in combination with low dose ritonavir (100 mg bd) for at least 48 weeks was studied in 311 patients. Adverse reactions (including marked laboratory abnormalities) from these pivotal studies are summarized in Table 9.

Adverse effects from clinical trials with saquinavir soft gel capsules (FORTOVASE) are given for completeness, however, due to the higher bioavailability of FORTOVASE, these adverse effects might not be predictive of the safety profile of INVIRASE.

Table 9: Incidences of Adverse Reactions and Marked Laboratory Abnormalities from MaxCmin1 and MaxCmin2 Studies (FORTOVASE).

The following descriptors are used to describe the frequency of adverse reactions tabulated below; Very Common (≥ 10%), Common (≥ 1% and < 10%). Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.

Body System
Frequency of Reaction
Adverse Reactions
Grades 3 & 4 All Grades
Blood and the lymphatic system disorders
Common Anaemia Anaemia
Immune system disorders
Common Hypersensitivity
Metabolism and nutrition disorders
Common Diabetes mellitus Diabetes mellitus, anorexia, increased appetite
Psychiatric disorders
Common Decreased libido, sleep disorder
Nervous System Disorders
Common Paresthesia, peripheral neuropathy, dizziness,
dysgeusia, headache
Respiratory, thoracic and mediastinal disorders
Common Dyspnoea
Gastrointestinal disorders
Very common Diarrhoea, nausea
Common Diarrhoea, nausea,
vomiting
Vomiting, abdominal distension, abdominal pain,
upper abdominal pain, constipation, dry mouth,
dyspepsia, eructation, flatulence, lip dry, loose
stools
Skin and subcutaneous tissue disorders
Common Acquired
lipodystrophy
Acquired lipodystrophy, alopecia, dry skin, eczema,
lipoatrophy, pruritus, rash
Musculoskeletal and connective tissue disorders
Common Muscle spasms
General disorders and administration site conditions
Common Fatigue Asthenia, fatigue, increased fat tissue, malaise
Investigations
Very common Increased alanine aminotransferase, increased
aspartate aminotransferase, increased blood
cholesterol, increased blood triglycerides, increased
low density lipoprotein, decreased platelet count
Common Increased blood amylase, increased blood bilirubin,
increased blood creatinine, decreased haemoglobin,
decreased lymphocyte count, decreased white blood
cell count

Additionally, for completeness, the following adverse reactions reported in clinical trials with unboosted saquinavir and not mentioned in the table above are listed below by body system.

General disorders and administration site conditions: chest pain, fever, intoxication, mucosal damage, oedema, pyrexia, retrosternal pain, shivering, wasting syndrome, weight decrease.

Cardiovascular disorders: Cyanosis, heart murmur, heart valve disorder, hypertension, hypotension, syncope, thrombophlebitis, distended vein.

Endocrine/Metabolic disorders: Appetite decrease, appetite disturbance, dehydration, hyperglycaemia, weight increase, xerophthalmia.

Gastrointestinal disorders: Ascites, bucca mucosa ulceration, cheilitis, dysphagia, eructation, faeces bloodstained, faeces discoloured, gastralgia, gastritis, gastrointestinal inflammation, intestinal obstruction, gingivitis, glossitis, haemorrhage rectum, haemorrhoids, hepatomegaly, hepatosplenomegaly, melaena, pelvic pain, painful defecation, pancreatitis, parotid disorder, salivary gland disorders, stomatitis, tooth disorder, vomiting.

Hepatobiliary disorders: Jaundice, portal hypertension, exacerbation of chronic liver disease with Grade 4 elevated liver function test.

Investigations: Blood creatinine phosphokinase increased, blood glucose increased, blood glucose decreased, raised transaminase values.

Blood and the lymphatic system: Anaemia, haemolytic anaemia, microhaemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.

Musculoskeletal and connective tissue disorders: Arthralgia, arthritis, back pain, muscle cramps, musculoskeletal disorders, musculoskeletal pain, myalgia, polyarthritis, stiffness, tissue changes, trauma.

Nervous system disorders: Ataxia, frequent bowel movements, confusion, convulsions, coordination abnormal, dysarthria, dysesthesia, extremity numbness, heart rate disorder, hyperaesthesia, hyperreflexia, hypoaesthesia, hyporeflexia, intracranial haemorrhage, dry mouth, face numbness (facial pain), paresis, poliomyelitis, progressive multifocal leukoencephalopathy, seizures, spasms, tremor.

Neoplasms benign, malignant and unspecified (including cysts and polyps): Skin papilloma, acute myeloid leukaemia.

Psychiatric disorders: Agitation, amnesia, anxiety, confusional state, depression, excessive dreaming, euphoria, hallucination, insomnia, intellectual ability reduced, irritability, lethargy, libido disorder, overdose effect, psychic disorder, somnolence, speech disorder, suicide attempt.

Reproductive system: Enlarged prostate, vaginal discharge.

Resistance mechanism: Abscess, angina tonsillaris, candidiasis, herpes simplex, herpes zoster, staphylococcal infection, other bacterial infections, mycotic infections, influenza, lymphadenopathy, tumour.

Respiratory: Bronchitis, cough, epistaxis, haemoptysis, laryngitis, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection.

Skin and cutaneous tissue disorders: Acne, dermatitis, dermatitis bullous skin eruption, drug eruption, seborrheic dermatitis, erythema, folliculitis, furunculosis, hair changes, hot flushes, photosensitivity reaction, skin pigment changes, maculopapular rash, severe cutaneous reaction associated with increased liver function tests, skin disorder, skin nodule, skin ulceration, Stevens-Johnson syndrome, increased sweating, urticaria, verruca, xeroderma.

Special senses: Blepharitis, earache, ear pressure, eye irritation, dry eye syndrome, decreased hearing, otitis, taste alteration, tinnitus, visual disturbance.

Renal and urinary disorders: Micturition disorder, urinary tract infection, nephrolithiasis.

Vascular disorders: Vasoconstriction.

Post-Marketing Experience with Saquinavir

Serious and non-serious adverse effects from post-marketing spontaneous reports (where saquinavir was taken as the sole protease inhibitor or in combination with ritonavir), not mentioned in any section above, for which a causal relationship to saquinavir cannot be excluded, are listed below:

Nervous system disorders: Somnolence; convulsions.

Immune system disorders: Hypersensitivity.

Hepato-bilary disorders: Hepatitis.

Metabolism and nutrition disorders:

  • Diabetes mellitus or hyperglycaemia, sometimes associated with ketoacidosis;
  • Metabolic abnormalities such as hypertriglyceridemia; hypercholesterolemia; insulin resistance; hyperlactatemia;
  • Lipodystrophy (including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsicervical fat accumulation (buffalo hump)).

Vascular disorders: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors.

Dosage and Administration

INVIRASE must be given in combination with ritonavir (ritonavir-boosted Invirase). Please also see the complete product information for ritonavir.

The recommended dose of INVIRASE is 1000 mg bd (2000 mg daily total dose) with ritonavir 100 mg bd in combination with other antiretroviral agents.

For treatment-naïve patients initiating treatment with INVIRASE, the recommended starting dose of INVIRASE is 500 mg bd with ritonavir 100 mg bd for the first 7 days of treatment. After 7 days, the recommended dose of INVIRASE is 1000 mg bd with ritonavir 100 mg bd.

Patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from a non-nucleoside reverse transcriptase inhibitor based regimen, without a wash-out period, should initiate and continue INVIRASE at the standard recommended dose of 1000 mg bd with ritonavir 100 mg bd.

Ritonavir should be taken at the same time as INVIRASE and within 2 hours after a meal. Note that food increases the bioavailability of INVIRASE and that in particular, a full meal has a greater effect than a light meal (see PHARMACOKINETICS).

For the recommended dose and possible adverse effects of other antiretroviral agents used in combination therapy, please see the complete product information for these medicines. For patients already taking ritonavir as part of their antiretroviral regimen, no additional ritonavir is needed.

As with all antiretroviral therapies, adherence to the prescribed regimen is strongly recommended.

Special Dosage Instructions

For serious toxicities that may be associated with INVIRASE, the treatment should be interrupted. INVIRASE should not be administered at less than the recommended dose (see DOSAGE AND ADMINISTRATION). For combination treatment involving some other antiretrovirals dose modifications of the protease inhibitors may be required since plasma levels might increase (see INTERACTIONS WITH OTHER MEDICINES).

For dosage instructions in special populations, please refer to PRECAUTIONS: Hepatic Impairment, Renal Impairment, Paediatric Use and Use in the Elderly.

Overdosage

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 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.

Contact the Poisons Information Centre for advice on management of overdosage.

Presentation and Storage Conditions

INVIRASE 500 mg film-coated tablets are light orange to brownish orange, oval, cylindrical and biconvex. The tablets are marked “SQV 500” on one side and “ROCHE” on the other side. INVIRASE tablets are available in bottles of 120.

INVIRASE tablets should be stored below 30oC.

Note: Saquinavir soft gel capsules (FORTOVASE) are no longer marketed in Australia.

Disposal of Medicines

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

Name and Address of the Sponsor

Roche Products Pty Limited

ABN 70 000 132 865

4-10 Inman Road

Dee Why NSW 2099


Medical enquiries: 1800 233 950

Poison Schedule of the Medicine

Schedule 4 – Prescription only medicine

Date of First Inclusion in the Australian Register of Therapeutic Good (the ARTG)

7 July 2006

Date of Most Recent Amendment

30 October 2015