Invirase^® (Tablets) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Labeled By

ORTAT, JSC (Russia)

Manufactured By

ROCHE FARMA, S.A. (Spain)

ATC Code

J05AE01 (Saquinavir)

Active Substance

Saquinavir (Rec.INN registered by WHO)

Dosage Form

Invirase®

Film-coated tablets, 500 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light orange to grayish or brownish-orange in color, oval, cylindrical, biconvex; engraved with “SQV 500” on one side and “ROCHE” on the other.

Excipients: povidone K30 – 40 mg, lactose monohydrate – 38.5 mg, croscarmellose sodium – 45 mg, microcrystalline cellulose – 95 mg, magnesium stearate – 10 mg.

Shell composition hypromellose – 7.929 mg, titanium dioxide – 4.887 mg, talc – 4.61 mg, iron oxide yellow dye – 0.645 mg, iron oxide red dye – 0.369 mg, triacetin – 1.559 mg.

120 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Antiretroviral drug, HIV protease inhibitor.

HIV protease is a key viral enzyme necessary for the process of specific cleavage of viral structural polypeptides Gag and Gag-Pol. These viral polypeptides contain a cleavage site that is recognized only by HIV protease and closely related viral proteases.

Saquinavir is a peptide-like structural analog of these cleavage sites and is a selective and reversible inhibitor of HIV protease, preventing the formation of mature infectious viral particles.

Antiviral activity in vitro

Saquinavir exhibits antiviral activity against both laboratory strains and clinical isolates of HIV-1 with typical EC₅₀ and EC₉₀ values (concentrations inhibiting 50% and 90% of HIV protease activity) ranging from 1 to 10 nmol/ml and from 5 to 50 nmol/ml, respectively. The antiviral activity of saquinavir in vitro was evaluated in an infected T-cell line and primary human lymphocyte and monocyte cultures. Antiviral activity in vitro was observed against a panel of HIV-1 group M isolates, except clade B (A, AE, C, D, G, H) and HIV-2 with EC₅₀ values of 0.3-2.5 nmol/ml. In the presence of 50% human serum or alpha1-acid glycoprotein (1 mg/ml), the antiviral activity of saquinavir decreases on average by 25 and 14 times, respectively.

Resistance to saquinavir

Antiviral activity relative to baseline genotype and phenotype

Genotypic and phenotypic clinical criteria predicting the clinical efficacy of ritonavir-boosted saquinavir were obtained from retrospective analyses of clinical trials and analysis of a large cohort of hospitalized patients.

It was shown that the baseline phenotype to saquinavir (fold change in susceptibility relative to reference; PhenoSense test) is a predictive factor for virological response. The first decrease in virological response was observed with a decrease in susceptibility of more than 2.3-fold. A positive virological response was not observed with a decrease in susceptibility of more than 12-fold.

Nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) were identified as associated with a reduced virological response to saquinavir therapy in combination with ritonavir (1000/100 mg twice daily) in patients not previously treated with Saquinavir. The presence of 3 or more mutations resulted in a reduced response to saquinavir/ritonavir therapy.

The relationship between the number of these saquinavir resistance-associated mutations and virological response was confirmed in an independent clinical trial including a population of patients who had previously received more intensive therapy, including 54% of patients previously treated with Saquinavir ( p=0.0133, see Table 1 ).The mutation G48V, which was previously identified in vitro as a saquinavir-specific mutation, was present at baseline in 3 patients. None of these patients achieved a response to therapy.

Table 1. Virological response to Saquinavir/ritonavir, stratified by the number of baseline saquinavir resistance-associated mutations

^†Data obtained from clinical trial report

Table 3. Therapy outcomes in conducted studies ^† (at 48 weeks).

* For both studies: for patients enrolled in the study with viral load <200 copies/ml, virological failure was defined as >200 copies/ml. Study 1: for patients enrolled in the study with viral load >200 copies/ml, virological failure was defined as any increase >0.5 log and/or viral load >50,000 copies/ml at 4 weeks, >5000 copies/ml at 12 weeks, or viral load >200 copies/ml at 24 weeks, etc. Study 2: any increase >0.5 log at a single visit; 0.5 log decrease if viral load >200 copies/ml at 4 weeks; 1.0 log decrease from baseline if viral load >200 copies/ml at 12 weeks; and viral load >200 copies/ml at 24 weeks.

^#ITT/e = all patients enrolled in the study/exposed to treatment.

^†Data obtained from clinical trial report.

^‡Data from publication of study 1.

Effect on ECG parameters

The effect of the drug Invirase^® in combination with ritonavir at doses of 1000/100 mg twice daily (therapeutic doses) and 1500/100 mg twice daily (supratherapeutic doses) on the QT interval at 20 h on day 3 of drug administration was studied in a double-blind, four-period crossover design study with placebo and active control (moxifloxacin 400 mg daily) involving healthy volunteers (male and female) aged 18 to 55 years (N=59).

Based on data from a previous 14-day multiple-dose pharmacokinetic study in which maximum pharmacokinetic exposure was achieved on day 3 of drug administration, day 3 was selected as the assessment point. The mean C_maxvalues for Invirase^® in combination with ritonavir at doses of 1000/100 mg twice daily and 1500/100 mg twice daily on day 3 of the study in healthy volunteers were approximately 3 and 4 times higher, respectively, than the mean C_maxvalues at steady state for Invirase^® in combination with ritonavir at a dose of 1000/100 mg twice daily in HIV-infected patients.

In this study, a study-specific QTcS measure (QT interval corrected for baseline values obtained prior to drug administration (dense predose-baseline correction) and depending on heart rate (similar to Fridericia’s correction)) was used to adequately assess QT interval changes in the different groups.

On day 3, the upper bound of the one-sided 95% confidence interval for the maximum mean difference in QTcS values between both active substance groups (Invirase^® in combination with ritonavir at therapeutic and supratherapeutic doses) and the placebo group was >10 milliseconds (msec) (see Table 4). It was found that Invirase^® in combination with ritonavir at supratherapeutic doses has a more significant effect on the QT interval compared to therapeutic doses. In the majority of study participants (89% of patients on therapeutic doses and 80% of patients receiving drugs at supratherapeutic doses) QTcS was <450 msec, and no participant had a QTc interval >500 msec (see also the “Precautions” section).

Table 4. Maximum mean ddQTcS^†(msec) value on day 3 for therapy with Invirase^® in combination with ritonavir at therapeutic doses, supratherapeutic doses, and for active control (moxifloxacin) in healthy volunteers.

^† Derived difference between QTcS values (QT interval corrected for baseline values obtained prior to drug administration, study-specific) in the active treatment group and the placebo group.

^ Administration of 400 mg only on day 3.

Note in the study, the QTcS value for men was calculated using the formula QT/RR^0.319, and for women – QT/RR^0.337, which corresponds to Fridericia’s correction (QTcF=QT/RR^0.333).

In this study, on day 3, PR interval prolongation >200 msec was observed in 40% of patients receiving Invirase^®/ritonavir at a dose of 1000/100 mg twice daily, and in 47% of patients receiving Invirase^®/ritonavir at a dose of 1500/100 mg twice daily. PR prolongation >200 msec was observed in 3% of patients receiving moxifloxacin as active control and in 5% of patients in the placebo group. The maximum mean change in PR interval compared to pre-dose values was 25 msec in the group receiving Invirase^®/ritonavir at a dose of 1000/100 mg twice daily, and 34 msec in the group receiving Invirase^®/ritonavir at a dose of 1500/100 mg twice daily (see also the “Precautions” section).

No cases of torsade de pointes or QT interval prolongation >500 msec were observed in the study. In some patients, a connection between the development of syncope or presyncope and PR interval prolongation cannot be ruled out. The clinical significance of these changes observed in healthy volunteers is not known for HIV-infected patients receiving Invirase^®/ritonavir, but an increase in the dose of Invirase^®/ritonavir beyond 1000/100 mg twice daily should be avoided.

Preclinical safety data

Carcinogenicity

No carcinogenic activity of saquinavir was detected when the drug was administered to rats and mice for 2 years. The plasma exposure (AUC) of saquinavir in these species was approximately 37% and 85% of the saquinavir exposure in humans when taking Invirase^® and ritonavir at doses of 1000/100 mg twice daily.

Mutagenicity

In in vitro mutagenicity and genotoxicity studies (with metabolic activation if necessary), Saquinavir was shown to have no mutagenic activity in either bacterial cells (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test with hypoxanthine-guanine phosphoribosyltransferase). Saquinavir does not cause chromosomal mutations in vivo (mouse micronucleus test) or in vitro in human lymphocytes, and does not cause primary DNA damage in vitro (DNA repair synthesis).

Effect on fertility

Studies in rats revealed no adverse effects on reproductive performance and fertility at exposure (AUC) values approximately 33% of the exposure in humans when taking Invirase^® in combination with ritonavir at the recommended doses of 1000/100 mg twice daily.

Teratogenicity

Studies in rats and rabbits revealed no embryotoxic or teratogenic effects of saquinavir at exposure (AUC) values approximately 32% of the exposure in humans when taking Invirase^® in combination with ritonavir at the recommended doses of 1000/100 mg twice daily.

Pharmacokinetics

Absorption

When taking a single 600 mg dose of the drug after a high-calorie meal, the absolute bioavailability of saquinavir is 4%, ranging from 1% to 9%. The bioavailability is most likely limited by a combination of incomplete absorption and significant first-pass metabolism in the liver. It has been shown that pH does not play a major role in the significant increase in bioavailability observed after food intake.

With multiple doses after meals (25-600 mg three times daily), a greater increase in saquinavir exposure (50-fold) was noted than with a proportional increase in dose (24-fold). After multiple doses of saquinavir (600 mg three times daily) in HIV-infected patients, the steady-state area under the concentration-time curve (AUC) is 2.5 times higher (95% confidence interval (CI), 1.6-3.8) than after a single dose.

In healthy volunteers, the AUC after taking 600 mg of saquinavir on an empty stomach was 24 ng _* h/ml (coefficient of variation 33%), after a meal (48 g protein, 60 g carbohydrates, 57 g fat, 1006 kcal) – 161 ng x h/ml (coefficient of variation 35%).

Food intake increases the maximum concentration of saquinavir from 3.0 ng/ml to 35.5 ng/ml and the time to reach it from 2.4 to 3.8 h. This effect of food continues for up to 2 hours after a meal. Therefore, Invirase^® should be taken no later than 2 hours after a meal.

In a crossover study in HIV-infected patients receiving Invirase^® in combination with ritonavir 1000/100 mg twice daily, first on an empty stomach (three consecutive doses) and then after a high-calorie meal (46 g fat, 1091 kcal) (three consecutive doses), the AUC_0-12of saquinavir was 10320 ng x h/ml and 34926 ng x h/ml, respectively. In all patients (except one), the minimum steady-state drug concentration (Cssmin) was above the lower limits of the therapeutic range when taken on an empty stomach. Nevertheless, Invirase^® in combination with ritonavir should be taken within 2 hours after a meal.

In HIV-infected patients receiving Saquinavir 600 mg three times daily after meals, the AUC and maximum plasma concentration (C_max) were approximately twice as high as in healthy volunteers with a similar dosing regimen.

Saquinavir in 200 mg soft gelatin capsules or Saquinavir in 500 mg film-coated tablets in combination with ritonavir at doses of 400/400 mg or 1000/100 mg twice daily provide similar or greater systemic exposure to saquinavir over 24 hours than increasing the dose of saquinavir in 200 mg soft gelatin capsules to 1200 mg/three times daily.

Diarrhea does not affect the absorption of saquinavir, nor does the drug itself affect gastrointestinal absorption parameters.

Saquinavir is a substrate for the MDR1 (P-glycoprotein) multidrug resistance protein.

Distribution

Well distributed in tissues. The mean V_d at steady state after IV administration of 12 mg is 700 L (coefficient of variation 39%). Plasma protein binding is 98%, independent of drug concentration (15-700 ng/ml). Saquinavir (when taken 600 mg three times daily) is not detected in the cerebrospinal fluid.

Metabolism

Undergoes significant hepatic metabolism. Rapid metabolism to mono- and dihydroxylated inactive derivatives is mediated by the cytochrome P450 system and is carried out by the CYP3A4 isoenzyme, which accounts for more than 90% of hepatic metabolism (in vitro studies). After IV administration, 66% of circulating saquinavir is found unchanged, the rest is in the form of metabolites, which corresponds to extensive first-pass metabolism in the liver.

The systemic clearance following intravenous infusion of 6, 36, and 72 mg of saquinavir is high and amounts to 1.14 L/h/kg (coefficient of variation 12%), which slightly exceeds hepatic blood flow.

The elimination half-life (T_1/2) of the drug from the body is 7 hours.

Elimination

Four days after oral administration of ¹⁴C-saquinavir (600 mg), 88% and 1% of radioactivity are detected in feces and urine, respectively.

Four days after intravenous administration of ¹⁴C-saquinavir (10.5 mg), 81% and 3% of radioactivity are detected in feces and urine, respectively.

After oral administration, 13% of the circulating plasma saquinavir was present in unchanged form, the remainder was in the form of metabolites.

Pharmacokinetics in special clinical groups

The pharmacokinetics of Invirase^® in patients with renal impairment has not been studied.

The effect of hepatic impairment on the steady-state pharmacokinetics of saquinavir in combination with ritonavir was studied in HIV-infected patients (N=7) with moderate hepatic impairment (Child-Pugh class B (score 7-9)). This study included a control group of HIV-infected patients (N=7) with normal liver function, matched to the study patients by age, sex, body weight, and tobacco use. In HIV-infected patients with moderate hepatic impairment, the mean (% coefficient of variation) values for AUC_0-12 and C_max of saquinavir were 24.3 (102%) mg × h/mL and 3.6 (83%) mg/mL, respectively. The corresponding values in the control group were 28.5 (71%) mg × h/mL and 4.3 (68%) mg/mL. For AUC_0-12 and C_max, the geometric mean ratio of pharmacokinetic parameters in patients with hepatic impairment to those in patients with normal liver function (90% CI) was 0.7 (0.3-1.6), suggesting an approximately 30% decrease in pharmacokinetic exposure in patients with moderate hepatic impairment. No dose adjustment of saquinavir is required in HIV-infected patients with moderate hepatic impairment (see sections “Use in Pregnancy and Lactation, Children, and Adults with Chronic Diseases” and “Special Precautions”).

No effect of sex on the pharmacokinetics of Invirase^® was identified after a single oral dose of 600 mg in healthy volunteers. In a bioequivalence study of saquinavir 200 mg capsules and 500 mg film-coated tablets in combination with ritonavir, higher saquinavir exposure was found in women (AUC by 56%, C_max by 26%), independent of body weight and age. No clinically significant differences in the efficacy and safety of the registered dosing regimen of saquinavir were found between men and women. Therapy with saquinavir in combination with ritonavir at doses of 1000/100 mg was found to be safe and effective in both sexes.

The effect of race on the pharmacokinetics of saquinavir has not been studied.

Studies of pharmacokinetic parameters in children under 16 years of age and adults over 65 years of age have not been conducted.

Indications

• As part of combination therapy with ritonavir and other antiretroviral agents for the treatment of adult patients infected with HIV-1.

ICD codes

Dosage Regimen

Invirase^® is prescribed only in combination with ritonavir!

It is recommended to strictly adhere to the prescribed drug regimen.

Orally, during or no later than 2 hours after a meal.

Standard dosing regimen

Adults and adolescents over 16 years:in combination with ritonavir (boosted regimen) Invirase^® 1000 mg twice daily and ritonavir 100 mg twice daily in combination with other antiretroviral drugs; Invirase^® and ritonavir are taken orally simultaneously and no later than 2 hours after a meal; in combination with other HIV protease inhibitors to familiarize with the recommended doses and possible side effects of other antiretroviral drugs, their prescribing information should be consulted.

Dosing in special cases

In case of severe toxicity, treatment with saquinavir should be interrupted. Due to the possible increase in plasma concentrations during combination therapy with other antiretroviral drugs (e.g., ritonavir), dose adjustments of HIV protease inhibitors may be required.

In HIV-infected patients with moderate hepatic impairment, no dose adjustment of saquinavir is required. Severe hepatic failure is a contraindication for the use of Invirase^®.

In patients with mild to moderate renal impairment, no dose adjustment of saquinavir is required. Caution should be exercised when using Invirase^® in patients with severe renal impairment.

The efficacy and safety of saquinavir in children under 16 years of age have not been established. There is limited information on the use of saquinavir in soft gelatin capsules (unboosted regimen) in children. There is no information on the use of Invirase^® without ritonavir (unboosted regimen) in children. Given the significantly lower serum concentration of saquinavir compared to adults, children should not be prescribed Invirase^® without ritonavir. Preliminary data in children suggest that when saquinavir in soft gelatin capsules is used in combination with ritonavir, the plasma concentration of saquinavir exceeds that when saquinavir in soft gelatin capsules is used without ritonavir.

Experience in patients over 60 years of age is limited. There are no data to recommend a dosing regimen.

Adverse Reactions

Data from clinical studies

The most frequent adverse events with at least a possible relationship to the ritonavir-boosted regimen were diarrhea, nausea, fatigue, vomiting, flatulence, and abdominal pain.

The following categories are used to describe the frequency of adverse reactions occurring with ritonavir-boosted saquinavir: very common (≥10%) and common (≥1%, <10%).

Below are the adverse reactions observed with the unboosted regimen of Invirase^®.

Nervous system disorders: hypesthesia, impaired coordination, intracranial hemorrhage.

Psychiatric disorders : confusion, depression, anxiety, suicide attempt, insomnia, libido disorder.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, bullous dermatitis, drug rash, severe skin reactions associated with impaired liver function.

Hepatobiliary disorders: jaundice, portal hypertension, exacerbation of chronic liver disease (with grade 4 liver function impairment).

General disorders and administration site conditions: fever, mucosal ulceration, chest pain.

Musculoskeletal and connective tissue disorders: muscle weakness and polyarthritis.

Blood and lymphatic system disorders: hemolytic anemia and neutropenia.

Gastrointestinal disorders: ascites, pancreatitis, and intestinal obstruction.

Metabolism and nutrition disorders: decreased appetite.

Benign and malignant neoplasms (including cysts and polyps): skin papillomas, acute myeloid leukemia.

Renal and urinary disorders: nephrolithiasis.

Cardiac disorders: peripheral vasospasm.

Laboratory abnormalities: increased creatine phosphokinase (CPK) activity, hyperglycemia, hypoglycemia.

Post-marketing surveillance

Immune system disorders: hypersensitivity reactions.

Metabolism and nutrition disorders diabetes mellitus or hyperglycemia, sometimes accompanied by ketoacidosis; lipodystrophy: in HIV-infected patients, combined antiretroviral therapy is associated with the redistribution of adipose tissue – lipodystrophy, including atrophy of subcutaneous fat on the face and limbs, increase in visceral and intra-abdominal fat, breast enlargement, and fat deposition on the dorsocervical and dorsal area (“buffalo hump”); hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia.

Nervous system disorders: drowsiness, convulsions.

Blood and lymphatic system disorders: increased bleeding, including spontaneous formation of subcutaneous hematomas and hemarthrosis in patients with hemophilia A and B receiving treatment with HIV protease inhibitors.

Hepatobiliary disorders: hepatitis.

Musculoskeletal and connective tissue disorders: with the use of HIV protease inhibitors, especially in combination with nucleoside analogues, increased CPK activity, myalgia, myositis, and rarely rhabdomyolysis have been reported. Cases of osteonecrosis have been reported, especially in patients with generally accepted risk factors, advanced HIV infection, or long-term combined antiretroviral therapy. Frequency unknown.

Renal and urinary disorders: impaired renal function.

In HIV-infected patients with severe immunodeficiency at the time of initiation of combined antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections (immune reconstitution syndrome) may develop.

Contraindications

• Hypersensitivity to saquinavir or any other component of the drug, ritonavir;
• Concomitant use of terfenadine, astemizole, cisapride, pimozide, amiodarone, flecainide, propafenone (life-threatening arrhythmias); rifampicin (severe hepatocellular toxicity); dihydroergotamine, ergometrine, ergotamine, methylergometrine (acute toxicity); simvastatin, lovastatin (rhabdomyolysis); triazolam, orally administered midazolam (prolonged/excessive sedation);
• Severe hepatic failure;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

Invirase^® in combination with ritonavir is contraindicated in patients with:

• Congenital or documented acquired QT interval prolongation;
• Electrolyte disturbances, especially uncorrected hypokalemia;
• When used with certain drugs that have both pharmacokinetic interaction and the ability to prolong QT and/or PR intervals (see section “Interaction with other medicinal products and food”).

Use in Pregnancy and Lactation

Animal experiments do not indicate a direct or indirect damaging effect of saquinavir on embryonic or fetal development, the course of pregnancy, or peri- and postnatal development. Clinical experience with the drug in pregnant women is limited. When saquinavir was used in combination with other antiretroviral drugs in pregnant women, rare reports of congenital malformations, congenital anomalies, and other disorders not accompanied by congenital anomalies were received.

During pregnancy, Saquinavir should be used only if the potential benefit to the mother justifies the potential risk to the fetus.

There are no data from animals or humans regarding the possible passage of saquinavir into breast milk. It is not possible to assess the possible adverse effects of saquinavir in breastfed infants; therefore, breastfeeding should be discontinued before starting treatment with saquinavir. HIV-infected women are not recommended to breastfeed to avoid transmitting HIV to the child.

Use in Hepatic Impairment

In HIV-infected patients with moderate hepatic impairment, no dose adjustment of saquinavir is required. Severe hepatic failure is a contraindication for the use of Invirase^®.

Use in Renal Impairment

In patients with mild to moderate renal impairment, no dose adjustment of saquinavir is required. Caution should be exercised when using Invirase^® in patients with severe renal impairment.

Pediatric Use

The efficacy and safety of saquinavir in children under 16 years of age have not been established. There is limited information on the use of saquinavir in soft gelatin capsules (unboosted regimen) in children. There is no information on the use of Invirase^® without ritonavir (unboosted regimen) in children. Given the significantly lower serum concentration of saquinavir compared to adults, children should not be prescribed Invirase^® without ritonavir. Preliminary data in children suggest that when saquinavir in soft gelatin capsules is used in combination with ritonavir, the plasma concentration of saquinavir exceeds that when saquinavir in soft gelatin capsules is used without ritonavir.

Geriatric Use

Experience in patients over 60 years of age is limited. There are no data to recommend a dosing regimen.

Special Precautions

Before starting therapy

Invirase^® is prescribed only in combination with ritonavir.

Patients should be informed that Saquinavir does not cure HIV infection and that they may develop associated diseases, including opportunistic infections. It is also necessary to inform about the possibility of adverse events when several drugs are used in combination.

Cardiac conduction and repolarization disorders

A dose-dependent prolongation of the QT and PR intervals was observed in healthy volunteers receiving Invirase^® in combination with ritonavir.

Invirase^® in combination with ritonavir is contraindicated in patients with congenital or documented acquired QT interval prolongation, electrolyte disturbances, especially uncorrected hypokalemia. A family history of sudden death at a young age may suggest congenital QT prolongation.

Invirase^® in combination with ritonavir is contraindicated when used with certain drugs that have both pharmacokinetic interaction and the ability to prolong QT and/or PR intervals (see sections “Contraindications” and “Interaction with other medicinal products and food”).

The use of Invirase^® in combination with ritonavir is not recommended in patients simultaneously receiving other medicinal products with the ability to prolong the QT interval. If concomitant use is necessary, caution should be exercised and an electrocardiogram should be performed if symptoms of arrhythmia occur. Caution should be exercised when using Invirase^® in combination with ritonavir in patients with concomitant structural heart disease, cardiac conduction disorders, coronary artery disease, or cardiomyopathy, as such patients have an increased risk of developing cardiac conduction disorders.

Therapy with Invirase^® in combination with ritonavir should be discontinued in case of significant arrhythmias, QT or PR interval prolongation. Drug-induced QT interval changes are most likely to occur in women and the elderly.

The recommended doses of Invirase^® in combination with ritonavir should not be exceeded, as the degree of QT and PR interval prolongation may increase with increasing drug concentration.

The use of Invirase^® in combination with ritonavir at a dose of 2000 mg once daily/100 mg once daily is not recommended, as the effect of such a combination on the risk of QT interval prolongation has not been studied.

Patients starting therapy with Invirase^® in combination with ritonavir: an electrocardiogram should be performed before starting therapy. Invirase^® in combination with ritonavir should not be prescribed if the QT interval is >450 msec. Patients with a QT interval <450 msec should have a repeat electrocardiogram 3-4 days after starting therapy. Therapy with Invirase^® in combination with ritonavir should be discontinued if the QT interval is >480 msec, or if the QT interval has increased by more than 20 msec compared to the baseline value.

Patients continuing therapy with Invirase^® in combination with ritonavir, if concomitant therapy with drugs that can prolong the QT interval is necessary; or patients receiving therapy with drugs that can prolong the QT interval, if therapy with Invirase^® in combination with ritonavir is necessary, and if alternative therapy is not available, and the benefit outweighs the risk: an electrocardiogram must be performed before starting concomitant therapy. Concomitant therapy should not be prescribed if the QT interval is >450 msec (see section “Interaction with other medicinal products and/or food”). A repeat electrocardiogram should be performed if the baseline QT interval is <450 msec. If the QT interval is >480 msec or the QT interval has increased by more than 20 msec after adding concomitant therapy, the treating physician, depending on the clinical situation, should decide to discontinue Invirase^® in combination with ritonavir and/or concomitant therapy.

In HIV-infected patients with mild to moderate hepatic impairment, no dose adjustment is required (data are limited). After initiation of saquinavir therapy, cases of worsening liver disease or development of portal hypertension accompanied by jaundice, ascites, edema, and esophageal varices (with fatal outcome in several patients) have been observed in patients with hepatitis B or C, cirrhosis, chronic alcoholism, and/or other liver diseases. A causal relationship between the development of portal hypertension and saquinavir therapy has not been established. Symptoms and signs of hepatotoxicity should be carefully monitored.

Only a small portion of the drug is excreted through the kidneys, so initial dose adjustment in patients with renal impairment is not necessary. However, studies have not been conducted in patients with severe renal failure, therefore caution should be exercised when using saquinavir in such patients.

Pediatric and Geriatric Use

The efficacy and safety of saquinavir in HIV-infected children (under 16 years of age) have not been established. There is no information on the use of Invirase^® without ritonavir (unboosted regimen) in children; there is only limited information on the use of saquinavir in soft gelatin capsules (unboosted regimen) in children. Given the significantly lower serum concentration of saquinavir compared to adults, children should not use Invirase^® without ritonavir. When saquinavir in soft gelatin capsules (50 mg/kg twice daily) was used concomitantly with nelfinavir or ritonavir in children, the exposure to saquinavir increased significantly. When used concomitantly with ritonavir, the exposure to saquinavir can be up to 2 times greater than the exposure in adults taking Saquinavir in soft gelatin capsules 1200 mg three times daily. Experience in patients over 60 years of age is limited.

Cases of newly diagnosed diabetes mellitus, hyperglycemia, or decompensation of pre-existing diabetes mellitus have been reported in patients receiving HIV protease inhibitors. In some cases, hyperglycemia was severe and sometimes accompanied by ketoacidosis. Many of these patients had concomitant diseases, sometimes requiring the administration of drugs known to increase blood glucose levels and cause diabetes mellitus or hyperglycemia. A causal relationship between HIV protease inhibitor therapy and the development of hyperglycemia and diabetes mellitus has not been established.

Cases of increased bleeding, including spontaneous formation of subcutaneous hematomas and hemarthrosis, have been reported in patients with hemophilia type A and B treated with HIV protease inhibitors. Some patients required an increased dose of coagulation factor VIII. In more than half of the cases, treatment with the HIV protease inhibitor was continued or resumed. A causal relationship between these adverse events and the use of HIV protease inhibitors can be assumed, although the mechanism of this effect is not understood. Patients with hemophilia should be informed about the possibility of increased bleeding.

Fat Redistribution

Fat redistribution or accumulation, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral fat wasting, breast enlargement due to fat accumulation, and “cushingoid appearance” (moon face, facial redness, truncal obesity, fat deposition in the supraclavicular fossae) have been observed in patients receiving combination antiretroviral therapy. Redistribution of body fat is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, and hyperglycemia. The severity of these disorders varies both within and between classes of antiretroviral drugs (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors). Factors that increase the risk of developing lipodystrophy include: older age, longer duration of therapy, use of stavudine, hypertriglyceridemia, hyperlactatemia. Diagnosis involves assessment of physical signs of fat redistribution and testing of blood glucose and lipids. If such changes are detected, consideration should be given to modifying the antiretroviral therapy and/or taking measures to correct these deviations (e.g., prescribing lipid-lowering agents). Currently, the mechanism of development of these metabolic disorders and their long-term consequences, such as an increased risk of cardiovascular disease, are unknown.

The use of Invirase^® in combination with ritonavir at doses higher than 1000/100 mg twice daily is usually associated with an increased frequency of adverse events, as plasma concentrations of saquinavir increase in the presence of ritonavir. In some cases, the concomitant use of saquinavir and ritonavir has led to serious adverse events, primarily the development of diabetic ketoacidosis and impaired liver function, especially in patients with pre-existing liver disease.

Drug and Food Interactions

Concomitant use of Invirase^® (unboosted regimen), taken in combination with other antiretroviral drugs, with rifabutin, rifampicin, or efavirenz leads to a significant decrease in plasma concentrations of saquinavir; therefore, concomitant use of these drugs is not recommended. The recommended dose of rifabutin, taken in combination with Invirase^® and ritonavir, is 150 mg once every 4 days. Information on the concomitant use of saquinavir, ritonavir, and efavirenz is limited. Rifampicin should not be administered to patients taking Invirase^® with ritonavir, in combination with other antiretroviral drugs, due to the risk of severe hepatocellular toxicity.

Herbal preparations containing St. John’s wort (Hypericum perforatum) and garlic extract should not be used in combination with Invirase^® (unboosted regimen), due to the possible decrease in plasma concentrations and clinical efficacy of Invirase^®.

When Invirase^® in combination with ritonavir is used concomitantly with HMG-CoA reductase inhibitors, primarily those metabolized by cytochrome P450 3A4 (e.g., simvastatin and lovastatin), an increase in plasma concentrations of the HMG-CoA reductase inhibitors may occur. In rare cases, increased concentrations of simvastatin and lovastatin can lead to serious adverse events, such as myalgia and rhabdomyolysis. Concomitant use of these drugs should be avoided. Caution is recommended when using Invirase^® in combination with ritonavir concomitantly with atorvastatin and cerivastatin (which are less metabolized by cytochrome P450 3A4). In this case, the dose of atorvastatin and cerivastatin should be reduced. If HMG-CoA reductase inhibitors are necessary, fluvastatin or pravastatin are recommended.

The use of Invirase^® in combination with ritonavir reduces the concentration of ethinyl estradiol. Therefore, other or additional methods of contraception should be used when taking Invirase^® in combination with ritonavir and estrogen-containing oral contraceptives concomitantly.

Concomitant use of saquinavir in combination with ritonavir and tipranavir (double-boosted regimen) leads to a significant decrease in plasma concentrations of saquinavir. Therefore, concomitant therapy with these drugs is not recommended.

Concomitant administration of digoxin and saquinavir in combination with ritonavir leads to a significant increase in plasma concentrations of digoxin. These drugs should be used with caution. The dose of digoxin should be reduced and its plasma concentrations monitored.

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV infection and/or on long-term combination antiretroviral therapy. Patients should be advised to seek medical attention if they experience joint pain, joint stiffness, or difficulty moving.

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immunodeficiency at the initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections, or an exacerbation of symptoms, may occur. Typically, these reactions were observed within the first few weeks or months after starting combination antiretroviral therapy. Characteristic examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any symptoms of inflammation should be evaluated and treated accordingly.

Chronic Diarrhea or Malabsorption

There is no information on the use of saquinavir in a boosted regimen in patients suffering from chronic diarrhea or malabsorption.

Data on the efficacy and safety of saquinavir in an unboosted regimen in such patients are limited and do not allow for assessment of the possibility of subtherapeutic saquinavir levels.

Effect on Ability to Drive and Use Machines

No specific studies have been conducted. There are no data on the ability of Invirase^® to affect driving or operating machinery. However, the drug’s safety profile should be considered when operating machinery.

Overdose

Current clinical experience with saquinavir overdose in humans is limited.

Acute or chronic overdose with saquinavir monotherapy does not lead to serious complications.

In combination with other HIV protease inhibitors, the following symptoms may occur: general weakness, fatigue, diarrhea, nausea, vomiting, hair loss, dry mouth, hyponatremia, weight loss, orthostatic hypotension.

Treatment: There is no specific antidote. Supportive measures should be instituted, including monitoring of vital signs, ECG, and clinical status of the patient. Further absorption of the drug should be prevented. Since Saquinavir is highly bound to plasma proteins, dialysis is not advisable.

Drug Interactions

Most drug interaction studies have investigated the use of Invirase^® in an unboosted regimen. Information on the use of Invirase^® in combination with ritonavir (boosted regimen) is limited. Results obtained from studies with Invirase^® in an unboosted regimen may not fully reflect the effects of using Invirase^® in combination with ritonavir. This section provides complete information on drug interactions, including data from studies conducted with saquinavir in soft gelatin capsules, previously marketed.

Saquinavir is metabolized by the cytochrome P450 isoenzyme CYP3A4 and is a substrate for P-glycoprotein (P-gp).

Drugs that are metabolized by the CYP3A4 isoenzyme or affect the activity of the CYP3A4 isoenzyme and/or P-glycoprotein may alter the pharmacokinetics of saquinavir. Similarly, Saquinavir may alter the pharmacokinetics of other drugs that are substrates of the CYP3A4 isoenzyme or P-glycoprotein.

Ritonavir, as a potent inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, may affect the pharmacokinetics of other drugs. Possible interactions with ritonavir should be considered when prescribing combination therapy.

Given the results obtained with Invirase^® in combination with ritonavir in healthy volunteers regarding dose-dependent prolongation of the QT and PR intervals (see sections “Contraindications”, “Precautions”, “Pharmacotherapeutic Group”), additive effects on QT and PR interval prolongation may occur when used with drugs of the following classes: Class IA or III antiarrhythmics, neuroleptics, tricyclic antidepressants, phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), certain antibacterial and antihistamine drugs, as well as other medicinal products (see below). These additive effects may lead to an increased risk of ventricular arrhythmias, particularly torsade de pointes. Therefore, concomitant administration of Invirase^® in combination with ritonavir and the listed drugs should be avoided if other therapeutic alternatives are available. Drugs that have both a pharmacokinetic interaction with Invirase^® in combination with ritonavir and the ability to prolong the QT and PR intervals are strictly contraindicated. Combining Invirase^® and ritonavir with other drugs known to prolong the QT and PR intervals is not recommended. Consequently, if such a combination is absolutely necessary, it should be used with caution.

Nucleoside Reverse Transcriptase Inhibitors

Didanosine

Saquinavir/ritonavir (boosted regimen): A single dose of didanosine 400 mg led to a decrease in the AUC and C_max of saquinavir, taken in combination with ritonavir (1600 mg/100 mg once daily for 2 weeks) in healthy volunteers, by approximately 30% and 25%, respectively, but did not affect the minimum concentration (C_min) of saquinavir. These changes are probably not of definite clinical significance.

Saquinavir monotherapy (unboosted regimen): Interaction between saquinavir and didanosine has not been studied.

Tenofovir

Saquinavir/ritonavir: Concomitant administration of tenofovir disoproxil fumarate with Invirase^® in combination with ritonavir did not have a clinically significant effect on saquinavir exposure. Administration of tenofovir disoproxil fumarate 300 mg once daily led to a 1% and 7% decrease in the AUC and C_max of saquinavir (Invirase^® in combination with ritonavir 1000/100 mg twice daily), respectively. However, these changes are not clinically significant. Dose adjustment is not required in such cases.

Zalcitabine and/or Zidovudine

Saquinavir monotherapy: Concomitant administration of zalcitabine and/or zidovudine with saquinavir does not affect the pharmacokinetic parameters of these drugs.

Saquinavir/ritonavir: There are currently no completed studies investigating changes in pharmacokinetic parameters with concomitant administration of these drugs.

Non-Nucleoside Reverse Transcriptase Inhibitors

Delavirdine

Saquinavir monotherapy: Concomitant administration leads to an increase in the AUC of saquinavir by 348%, which in some cases may be accompanied by an increase in hepatic transaminases. Currently, information on the safety of such a drug combination is limited, and efficacy data are lacking. Liver function monitoring is recommended during combination therapy with delavirdine.

Saquinavir/ritonavir: Interaction between Invirase^® in combination with ritonavir and delavirdine has not been studied.

Efavirenz

Saquinavir monotherapy: Concomitant administration of efavirenz (600 mg) and saquinavir (1200 mg three times daily) decreased the AUC of saquinavir by 62% and the C_max of saquinavir by 50%. Efavirenz concentrations also decreased by 10%, but this decrease is not clinically significant. Based on these results, Saquinavir should be used in combination with efavirenz only if the blood concentration of saquinavir is increased by the intake of other antiretroviral drugs, for example, ritonavir.

Saquinavir/ritonavir: No clinically significant deviations in saquinavir or efavirenz concentrations were noted.

Nevirapine

Saquinavir monotherapy: Concomitant administration of nevirapine and Invirase^® decreased the AUC of saquinavir by 24% but did not affect the AUC of nevirapine. These changes are not clinically significant. Dose adjustment is not required in such cases.

Saquinavir/ritonavir: Interaction between Invirase^® in combination with ritonavir and nevirapine has not been studied.

HIV Protease Inhibitors

Fosamprenavir

Saquinavir/ritonavir: Concomitant administration of fosamprenavir and Invirase^® in combination with ritonavir (1000/100 mg) did not cause clinically significant changes in saquinavir exposure (AUC and C_max of saquinavir decreased by 15% and 9%, respectively, and C_min of saquinavir decreased by 24%, but nevertheless remained above the therapeutic efficacy threshold). Dose adjustment is not required.

Indinavir

Saquinavir monotherapy: Concomitant use of indinavir (800 mg three times daily) and a single dose of Invirase^® or saquinavir (600-1200 mg) led to a 4.6-7.2-fold increase in the plasma AUC_0-24 of saquinavir. The plasma concentration of indinavir did not change. Currently, there are no data on the safety and efficacy of such a drug combination. Appropriate doses for this drug combination have not been established.

Saquinavir/ritonavir: Administration of low doses of ritonavir leads to an increase in the concentration of indinavir, which may lead to the development of nephrolithiasis.

Lopinavir/ritonavir

Saquinavir/ritonavir: Administration of lopinavir 400 mg did not alter the pharmacokinetic parameters of saquinavir taken in combination with ritonavir (steady-state AUC_0-12 of saquinavir – 15130 and 16977 ng·h/mL, C_max 2410 and 2300 ng/mL and C_min 427 and 543 ng/mL with and without lopinavir, respectively) but significantly decreased ritonavir exposure. However, the efficacy of ritonavir remained the same. Plasma concentrations of lopinavir were unchanged (compared to data from previous studies of the lopinavir/ritonavir combination). Dose adjustment is not required.

Lopinavir/ritonavir should be used with caution due to the possible additive effect on QT and/or PR interval prolongation when used with Invirase^® in combination with ritonavir (see sections “Contraindications” and “Precautions”).

Nelfinavir

Unboosted Saquinavir: A treatment regimen including Saquinavir (1200 mg three times daily) and nelfinavir (750 mg three times daily) in addition to 2 nucleoside reverse transcriptase inhibitors led to a longer response (prolongation of time to virological relapse). A 392% and 179% increase in the AUC and C_max of saquinavir, respectively, was observed. The AUC of nelfinavir increased by 18%, C_max was unchanged. Concomitant use of nelfinavir and saquinavir moderately increased the frequency of diarrhea.

Saquinavir/ritonavir: The geometric mean ratio of AUC_0-12 and C_max of nelfinavir (1250 mg twice daily) in the presence or absence of saquinavir in combination with ritonavir (1000 mg/100 mg twice daily) was 0.94 (90% CI: 0.72-1.22) and 0.95 (90% CI: 0.77-1.16), respectively. In the presence of saquinavir in combination with ritonavir, the AUC_0-12 and C_max of the nelfinavir metabolite M8 decreased by 2.25-fold (90% CI: 1.47-3.44) and 1.74-fold (90% CI: 1.25-2.4), respectively. However, the safety profile of nelfinavir was unchanged.

The geometric mean ratio of AUC_0-12 and C_max of saquinavir in combination with ritonavir (1000 mg/100 mg twice daily) in the presence or absence of nelfinavir (1250 mg twice daily) was 1.13 (90% CI: 0.73-1.74) and 1.09 (90% CI: 0.73-1.61), respectively. Patients tolerated this drug combination well.

Ritonavir

Saquinavir does not affect the pharmacokinetics of ritonavir after single or multiple doses in healthy volunteers.

Ritonavir significantly inhibits the metabolism of saquinavir, leading to higher plasma concentrations of saquinavir. The steady-state values of AUC_0-24 and C_max of saquinavir in patients after taking Invirase^® at a dose of 600 mg three times a day were 2598 ng x h/ml and 197 ng/ml, respectively.

When taking 1000 mg of Invirase^® in combination with 100 mg of ritonavir twice daily, the steady-state values of AUC_0-24, C_max, and C_min were 29214 ng x h/ml, 2623 ng/ml, and 371 ng/ml, respectively.

When taking saquinavir or Invirase^® in combination with ritonavir at a dose of 1000 mg/100 mg twice daily, the systemic exposure of saquinavir over a 24-hour period was similar to or exceeded its exposure when taking saquinavir at a dose of 1200 mg three times a day.

Tipranavir

Saquinavir/ritonavir: combination therapy is not recommended because tipranavir boosted with low doses of ritonavir reduces the C_min of saquinavir by 78% (the clinical significance of this reduction has not been established). If, nevertheless, a decision is made on the need to prescribe this drug combination, it is strongly recommended to monitor saquinavir plasma concentrations.

Fusion inhibitors

Enfuvirtide

Saquinavir/ritonavir: simultaneous use of enfuvirtide and saquinavir in combination with ritonavir (1000 mg/100 mg twice daily) did not lead to clinically significant changes in the pharmacokinetics of these drugs.

Saquinavir monotherapy : interaction between saquinavir and enfuvirtide has not been studied.

Other medicinal products

Antiarrhythmic agents (bepridil, lidocaine, quinidine)

Saquinavir/ritonavir: concentrations of bepridil, lidocaine, quinidine may increase. These antiarrhythmic agents are contraindicated for concomitant use with Invirase^® in combination with ritonavir due to the possible development of life-threatening cardiac arrhythmias (see sections “Contraindications” and “Precautions”).

Anticoagulant (warfarin)

Saquinavir/ritonavir : warfarin concentrations may change; it is necessary to monitor the international normalized ratio (INR).

Antiepileptic agents (carbamazepine, phenobarbital, phenytoin)

Saquinavir monotherapy: carbamazepine, phenobarbital, phenytoin – inducers of hepatic microsomal enzymes (CYP3A4 isoenzyme) may reduce the plasma concentration of saquinavir.

Saquinavir/ritonavir: interaction with Invirase^® in combination with ritonavir and these drugs has not been studied.

Antidepressants

Tricyclic antidepressants (amitriptyline, imipramine)

Saquinavir/ritonavir: ritonavir may increase the concentration of tricyclic antidepressants; monitoring of tricyclic antidepressant blood concentrations is recommended during concomitant use.

Nefazodone

Nefazodone, as an inhibitor of the CYP3A4 isoenzyme, may increase the concentration of saquinavir. When using Nefazodone and Invirase^® concomitantly, it is recommended to monitor the patient’s condition for signs of saquinavir toxicity.

Trazodone

Saquinavir/ritonavir: simultaneous intake of trazodone and Invirase^® in combination with ritonavir may lead to increased plasma concentrations of trazodone. Adverse reactions such as nausea, dizziness, hypotension, and syncope have been observed with concomitant use of trazodone and ritonavir. Trazodone is contraindicated for use with Invirase^® in combination with ritonavir due to the possible development of life-threatening arrhythmias (see sections “Contraindications” and “Precautions”).

Antihistamines (terfenadine, astemizole)

Simultaneous intake of terfenadine and saquinavir leads to an increase in the AUC of terfenadine in plasma, which is associated with QTc interval prolongation. Terfenadine is contraindicated in patients taking Saquinavir in combination with ritonavir.

Due to the high likelihood of a similar interaction, Saquinavir in combination with ritonavir should also not be prescribed together with astemizole.

Medicines for the prevention and treatment of infections

Clarithromycin

Saquinavir monotherapy : with simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (1200 mg three times daily), an increase in the AUC and C_max of saquinavir by 177% and 187%, respectively, was noted. The AUC and C_max values of clarithromycin increased by approximately 40% compared to clarithromycin monotherapy. No dose adjustments are required when these drugs are used concomitantly at the studied doses for a limited time.

Saquinavir/ritonavir interaction between saquinavir in combination with ritonavir and clarithromycin has not been studied.

Erythromycin

Saquinavir monotherapy: with simultaneous use of erythromycin (250 mg four times a day) and saquinavir (1200 mg three times a day), an increase in the AUC and C_max of saquinavir by 99% and 106% was noted. No dose adjustment is required when these drugs are used concomitantly.

Saquinavir/ritonavir interaction between saquinavir in combination with ritonavir and erythromycin has not been studied. Erythromycin should be used with caution due to a possible additive effect on QT and/or PR interval prolongation when used with Invirase^® in combination with ritonavir (see sections “Contraindications” and “Precautions”).

Streptogramins (quinupristin/dalfopristin)

Saquinavir/ritonavir : inhibit the CYP3A4 isoenzyme, may increase the concentration of saquinavir. When these drugs are used concomitantly, it is recommended to monitor the patient’s condition for signs of saquinavir toxicity.

Antifungal agents

Ketoconazole

Saquinavir monotherapy : with simultaneous use of ketoconazole (200 mg daily) and Invirase^®, the plasma concentration of saquinavir increases by 1.5 times. No increase in half-life or change in absorption rate was noted. Taking saquinavir at a dose of 600 mg three times a day does not affect the pharmacokinetics of ketoconazole. No dose adjustment is required when these two drugs are used concomitantly at the studied doses.

Saquinavir/ritonavir: simultaneous use of ketoconazole (200 mg daily) and Invirase^® in combination with ritonavir (1000 mg/100 mg twice daily) did not lead to changes in the steady-state values of AUC_0-12 and C_max of saquinavir and ritonavir. No dose adjustment is required when these drugs are used concomitantly with ketoconazole at a dose less than or equal to 200 mg. However, such use (ketoconazole 200 mg daily and Invirase^® in combination with ritonavir 1000 mg/100 mg twice daily) led to an increase in the steady-state values of C_max and AUC_0-24 of ketoconazole by 45% (90% CI: 32-59%) and 168% (90% CI:146-193%), respectively. These data should be taken into account when deciding on the dose of ketoconazole in this drug combination. The use of ketoconazole in doses greater than 200 mg per day is not recommended.

Itraconazole

Saquinavir monotherapy: itraconazole, like ketoconazole, is a relatively potent inhibitor of the CYP3A4 isoenzyme, therefore a similar interaction may be observed. When itraconazole and saquinavir are taken concomitantly, it is recommended to monitor the patient’s condition for signs of saquinavir toxicity.

Saquinavir/ritonavir: interaction between Invirase^®, boosted with ritonavir, and itraconazole has not been studied.

Fluconazole/miconazole

Fluconazole and miconazole are inhibitors of the CYP3A4 isoenzyme and may increase the plasma concentrations of saquinavir. Special studies of this drug combination have not been conducted.

Antimycobacterial drugs

Rifabutin

Saquinavir monotherapy : rifabutin reduces the plasma concentration of saquinavir by 40%. Saquinavir monotherapy should not be used concomitantly with rifabutin.

Saquinavir/ritonavir: with a multiple dosing regimen of rifabutin (150 mg once every 3 days) in combination with Invirase^® ritonavir (1000/100 mg twice daily), the values of AUC_0-12 and C_max of saquinavir were slightly reduced by 13% (90% CI: -31% – 9%) and by 15% (90% CI: -32% – 7%), respectively, in healthy volunteers. However, rifabutin did not affect the AUC_0-12 (90% CI: -10% – 9%) and C_max (90% CI: -8% – 7%) of ritonavir. No dose adjustment is required.

The effect of the multiple dosing regimen of Invirase^® in combination with ritonavir (1000/100 mg twice daily) on the pharmacokinetics of rifabutin when used at a dose of 150 mg once every 3 days or at a dose of 150 mg once every 4 days compared with rifabutin monotherapy 150 mg daily was evaluated. When rifabutin was used at a dose of 150 mg once every 3 days in combination with Invirase^® and ritonavir, the values of AUC_0-72 and C_max of the active substance (rifabutin + 25-O-desacetyl-rifabutin) increased by 134% (90% CI: 109% – 162%) and by 130% (90% CI: 98% – 167%), respectively. The exposure of rifabutin increased by 53% (90% CI: 36% – 73%) for AUC_0-72 and by 86% (90% CI: 57% – 119%) for C_max. When rifabutin was used at a dose of 150 mg once every 4 days in combination with Invirase^® and ritonavir, the values of AUC_0-96 and C_max of the active substance (rifabutin + 25-O-desacetyl-rifabutin) increased by 60% (90% CI: 43% – 79%) and by 111% (90% CI: 75% – 153%), respectively. With this dosing regimen, the exposure of rifabutin did not change for AUC_0-96 (90% CI: -10% – 13%) and increased by 68% (90% CI: 38% – 105%) for C_max.

The recommended dose of rifabutin when used in combination with Invirase^® and ritonavir (1000/100 mg twice daily) is 150 mg once every 4 days. With this dosing regimen of these drugs, monitoring of liver enzyme activity and neutrophil count (to detect neutropenia) in the blood is recommended.

Based on available data, the use of rifabutin twice a week in combination with Invirase^® and ritonavir (1000/100 mg twice daily) is not recommended. This dosing regimen may lead to an increase in the exposure of rifabutin and its metabolites to levels achieved with daily intake of the drug at a dose of 300 mg, which may lead to an increase in the frequency and severity of adverse events associated with rifabutin (see section “Precautions”).

Rifampicin

Saquinavir monotherapy : simultaneous intake of rifampicin (600 mg once daily) reduces the plasma concentration of saquinavir by 80%. Simultaneous intake of rifampicin and saquinavir is not recommended, as this may lead to a decrease in saquinavir concentration below the therapeutic level.

Saquinavir/ritonavir: simultaneous intake of rifampicin in patients with tuberculosis taking Saquinavir in combination with ritonavir (1600 mg/200 mg daily) reduced the AUC of saquinavir by 50%, but the concentration of saquinavir remained within the therapeutic range. Also, the concentration of saquinavir remained within the therapeutic range in patients with tuberculosis taking Invirase^®, boosted with ritonavir, 1000/100 mg twice daily, and 450 mg rifampicin daily, or Invirase^® in combination with ritonavir, 400/400 mg twice daily, and rifampicin 600 mg daily. When using such a drug combination, there is a possibility of developing acute hepatocellular toxicity, therefore, rifampicin should not be used in patients taking Invirase^® in combination with ritonavir as part of antiretroviral therapy.

Benzodiazepines

Midazolam

Saquinavir monotherapy : with simultaneous oral intake of midazolam (7.5 mg) Saquinavir (1200 mg three times daily) increased the C_max and AUC of midazolam by 235% and 514% respectively. Saquinavir increased the half-life of midazolam from 4.3 to 10.9 h and the absolute bioavailability of midazolam from 41 to 90%, which was accompanied by impaired psychomotor activity and enhanced sedative effect. When midazolam and saquinavir are used concomitantly, the dose of midazolam should be significantly reduced and this combination should be used with caution. With intravenous administration of midazolam (0.05 mg/kg) and intake of saquinavir, the clearance of midazolam decreased by 56%, and the half-life increased from 4.1 to 9.5 h, with only a subjective sensation of the effect of midazolam being enhanced.

Saquinavir/ritonavir: with simultaneous single oral intake of midazolam (7.5 mg) after 2 weeks of taking Invirase^®/ritonavir (1000/100 mg twice daily), an increase in the C_max of midazolam by 4.3 times and the AUC of midazolam by 12.4 times was observed. Invirase^®/ritonavir increased the half-life of midazolam from 4.7 to 14.9 h. Oral intake of midazolam is contraindicated in patients taking Saquinavir in combination with ritonavir. Caution should be exercised when administering midazolam parenterally to patients taking Invirase^®. Data on simultaneous intake of saquinavir in combination with ritonavir and intravenous administration of midazolam are not available. Based on data from studies on the combined use of CYP3A4 isoenzyme modulators and midazolam with intravenous administration, a possible increase in plasma concentrations of midazolam by 3-4 times can be assumed. Simultaneous use of Invirase^® and intravenous administration of midazolam should be carried out in intensive care units or in departments with the possibility of timely clinical monitoring and adequate treatment in case of respiratory depression and/or prolonged sedation. Dose adjustment is necessary, especially in cases of repeated administration of midazolam.

Alprazolam, clorazepate dipotassium, diazepam and flurazepam

Saquinavir/ritonavir possible increase in the concentration of benzodiazepines and the risk of enhanced sedative effect. These drugs are recommended to be used with caution; if necessary, the dose of benzodiazepines should be reduced.

Slow calcium channel blockers

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

Saquinavir/ritonavir: possible increase in the concentration of these drugs. These drugs in combination with Invirase^® and ritonavir should be used with caution; clinical monitoring of the patients’ condition is recommended.

Glucocorticosteroids

Dexamethasone

It is an inducer of the CYP3A4 isoenzyme and may reduce the concentrations of saquinavir. With simultaneous intake, the effectiveness of saquinavir may decrease. These drugs are recommended to be used with caution.

Interaction between Invirase^® in combination with ritonavir and dexamethasone has not been studied.

Fluticasone, budesonide

Several cases of Cushing’s syndrome have been described with simultaneous use of these glucocorticosteroids (inhaled or intranasal route of administration) and a low dose of ritonavir. If combination therapy is necessary, the possibility of switching patients to beclomethasone inhalations should be considered.

Cardiac glycosides

Digoxin

Simultaneous intake of a single dose of digoxin (0.5 mg) after two weeks of taking Invirase^® in combination with ritonavir (1000/100 mg twice daily) led to an increase in the C_max and AUC_0-12 of digoxin by 27% and 49%, respectively. These drugs are recommended to be used with caution. It is necessary to reduce the dose of digoxin and monitor its plasma concentrations.

Ergot alkaloids and their derivatives

Dihydroergotamine, ergometrine, ergotamine, methylergometrine

Simultaneous use of these drugs with Invirase^® in combination with ritonavir is contraindicated due to the possibility of acute toxicity.

H₂-histamine receptor blockers

Ranitidine

Saquinavir monotherapy : with simultaneous intake of Invirase^®, ranitidine and food, the exposure of saquinavir (AUC by 67%) increased compared to taking only Invirase^® and food. These changes are not clinically significant. No dose adjustment is required.

Saquinavir/ritonavir: interaction between Invirase^® in combination with ritonavir and ranitidine has not been studied.

Immunosuppressants

Cyclosporine, tacrolimus, sirolimus

Saquinavir/ritonavir: the concentration of immunosuppressants may increase. Monitoring of therapeutic concentrations of cyclosporine, tacrolimus, sirolimus is recommended during concomitant use.

HMG-CoA reductase inhibitors

Saquinavir/ritonavir : a significant increase in the concentration of simvastatin and lovastatin is observed, leading to rhabdomyolysis. Simvastatin and lovastatin should not be used in combination with saquinavir/ritonavir.

The metabolism of atorvastatin and cerivastatin is less dependent on the activity of the CYP3A4 isoenzyme; in combination, they should be used in lower doses, and patients should be carefully monitored for the development of myopathy (muscle weakness, muscle pain, increased CPK activity).

Pravastatin and fluvastatin are not metabolized by the CYP3A4 isoenzyme. If the use of HMG-CoA reductase inhibitors is indicated, it is recommended to use pravastatin or fluvastatin.

Narcotic analgesics

Methadone

Saquinavir/ritonavir : simultaneous intake of saquinavir in combination with ritonavir (1000/100 mg twice daily) and methadone (60-120 mg once daily) led to a decrease in the AUC of methadone by 19%. No dose adjustment is required. However, it should be used with caution due to a possible additive effect on QT and/or PR interval prolongation when used with Invirase^® in combination with ritonavir (see sections “Contraindications” and “Precautions”).

Oral contraceptives (ethinyl estradiol)

Saquinavir/ritonavir : reduces the concentration of ethinyl estradiol. Other or additional methods of contraception should be used.

Phosphodiesterase type 5 inhibitors (PDE-5 inhibitors)

Sildenafil

Simultaneous use of saquinavir (1200 mg three times daily) and sildenafil (single dose of 100 mg), which is a substrate of the CYP3A4 isoenzyme, led to an increase in the C_max and AUC of sildenafil by 140% and 210% respectively. Sildenafil did not affect the pharmacokinetic parameters of saquinavir. These drugs are recommended to be used with caution. The dose of sildenafil should be reduced (no more than 25 mg every 48 hours). When taken concomitantly with Invirase^® in combination with ritonavir, the patient should be recommended to carefully monitor their condition for the development of adverse events.

Tadalafil

Saquinavir/ritonavir: with simultaneous intake, an increase in tadalafil concentrations is possible. These drugs are recommended to be used with caution. The dose of tadalafil should be reduced (no more than 10 mg every 72 hours). When taken concomitantly with Invirase^® in combination with ritonavir, the patient should be recommended to carefully monitor their condition for the development of adverse events.

Vardenafil

Saquinavir/ritonavir: concomitant use may increase vardenafil concentrations. These drugs should be used with caution. The dose of vardenafil should be reduced (no more than 2.5 mg every 72 hours). When used concomitantly with Invirase^® in combination with ritonavir, the patient should be recommended to carefully monitor their condition for the development of adverse events.

Drugs that increase gastrointestinal motility

Cisapride

Saquinavir/ritonavir : increased cisapride exposure (AUC) and prolongation of the QTc interval. Cisapride is contraindicated in patients taking Saquinavir in combination with ritonavir due to the potential for life-threatening arrhythmias (see sections “Contraindications” and “Precautions”).

Antipsychotic agents (neuroleptics)

Pimozide

Saquinavir/ritonavir : increased pimozide exposure (AUC), associated with an additive effect on QT and/or PR interval prolongation (see sections “Contraindications” and “Precautions”). Pimozide is contraindicated in patients taking Saquinavir in combination with ritonavir (see section “Contraindications”).

Proton pump inhibitors (omeprazole)

Saquinavir/ritonavir : concomitant administration of omeprazole (40 mg daily) and Invirase^®in combination with ritonavir (1000/100 mg twice daily) resulted in an 82% (90% CI: 44% – 131%) and 75% (90% CI: 38% – 123%) increase in steady-state AUC and C_maxof saquinavir, respectively. Ritonavir plasma concentrations did not change significantly. Data on the concomitant use of Invirase^®in combination with ritonavir and other proton pump inhibitors are not available. In combination with omeprazole or other proton pump inhibitors, it is recommended to use with caution, monitoring the patient’s condition for the possibility of saquinavir toxicity.

Grapefruit juice

Saquinavir monotherapy : saquinavir exposure increased by 50% in healthy volunteers after a single dose of grapefruit juice and by 100% with double-strength juice, which is not clinically significant and does not require saquinavir dose adjustment.

Saquinavir/ritonavir interaction has not been studied.

Herbal preparations containing St. John’s wort (Hypericum perforatum)

Saquinavir monotherapy: some herbal preparations may contain components that are inhibitors or inducers of the CYP3A4 isoenzyme or P-glycoprotein and may lead to changes in the pharmacokinetics of saquinavir. A decrease in saquinavir plasma concentration, loss of virological response, and development of resistance to one of the components of antiretroviral therapy are possible. Herbal preparations containing St. John’s wort (Hypericum perforatum) should not be used in patients taking Invirase^®.

Saquinavir/ritonavir: interaction has not been studied.

Medicinal products and dietary supplements containing garlic extract

Saquinavir monotherapy: a decrease in saquinavir plasma concentration, loss of virological response, and development of resistance to one of the components of antiretroviral therapy are possible. When medicinal products or dietary supplements containing garlic extract (a dose approximately equal to two 4-gram cloves of garlic) and saquinavir (1200 mg three times daily) were taken concomitantly by healthy volunteers, a 51% decrease in saquinavir AUC, a 49% decrease in mean minimum saquinavir concentration (8 hours after dose), and a 54% decrease in C_maxwere observed. Medicinal products and dietary supplements containing garlic extract should not be used in patients taking Saquinavir.

Saquinavir/ritonavir: interaction has not been studied.

Other possible interactions

Although specific studies have not been conducted, concomitant administration of saquinavir/ritonavir and other drugs that are substrates of the CYP3A4 isoenzyme (dapsone, disopyramide, quinine, fentanyl, alfentanil) may increase the plasma concentrations of these drugs, so such combinations should be used with caution (see sections “Contraindications” and “Precautions”).

Concomitant use of Invirase^® in combination with ritonavir with drugs that are substrates of P-glycoprotein (e.g., azithromycin) may lead to increased plasma concentrations of these drugs, so when using such combinations, the patient should be monitored for symptoms of toxicity.

Administration of combinations with inhibitors of the CYP3A4 isoenzyme also leads to increased saquinavir plasma concentrations. In such cases, it is recommended to monitor the patient’s condition for symptoms of toxicity.

Conversely, concomitant use with drugs that are inducers of the CYP3A4 isoenzyme or P-glycoprotein may reduce saquinavir plasma concentrations.

There is no information on decreased saquinavir plasma concentrations when co-administered with drugs that reduce gastrointestinal transit time (e.g., metoclopramide).

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F), in a place inaccessible to children.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.