Invirase - instructions for use, dose, side effects, contraindications

Active substanceSaquinavirSaquinavir

Similar drugsTo uncover

Invirase®

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Hoffmann-La Roche Ltd. Switzerland

Interfast®

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FARMASINTEZ, JSC (Irkutsk) Russia

Dosage form: & nbspThe tablets covered with a cover.

Composition:

One tablet contains:

active substance: saquinavir 500 mg (in the form of saquinavir mesylate 571.5 mg): excipients: povidone K30 40 mg, lactose monohydrate 38.5 mg, croscarmellose sodium 45 mg, microcrystalline cellulose 95 mg, magnesium stearate 10 mg;

shell material: Hypromellose 7.929 mg, titanium dioxide 4.887 mg, talc 4.61 mg, iron oxide oxide yellow 0.645 mg, iron oxide red oxide 0.369 mg, triacetin 1.559 mg.

Description:Oval, cylindrical, biconvex tablets covered with a film coat, from light orange to grayish or brownish-orange; on one side of the tablet the engraving "SQV 500", on the other side - "ROCHE".

Pharmacotherapeutic group:An antiviral [HIV] agent.

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.01 Saquinavir

Pharmacodynamics:

Mechanism of action

An antiretroviral drug, an HIV protease inhibitor.

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

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

Antiviral activity in vitro

Saquinavir exhibits antiviral activity in both laboratory strains and clinical isolates of HIV-1 with typical EC50 and EC90 values (concentrations that inhibit 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 on the infected T cell line and in primary human cultures of lymphocytes and monocytes. Antiviral activity in vitro was observed with respect to a set of isolates of HIV-1 group M, except clades 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 alpha 1-acid glycoprotein (1 mg / ml), the antiviral activity of saquin-vir decreases on average 25 and 14 times, respectively.

Resistance to saquinavir

Antiviral activity relative to the initial genotype and phenotype

Genotypic and phenotypic clinical criteria predicting the clinical efficacy of saquinavir enhanced with ritonavir,were obtained after retrospective analyzes of clinical studies, as well as analysis of a large group of hospitalized patients.

It was shown that the initial phenotype with respect to saquinavir (change in sensitivity relative to the reference, PhenoSense test) is a prognostic factor of the virologic response. The first decrease in the virologic response was observed with a decrease in sensitivity of more than 2.3 times. A positive virologic response was not observed with a decrease in sensitivity of more than 12 times. 9 protease codons have been identified (L10F / I / M / R / V, I15A / V, K20I / M / R / T, L24I, I62V, G73S / T, V82A / F / S / T, I84V, L90M) associated with a decrease in the virologic response to saquinavir in combination with ritonavir (1000/100 mg twice daily), in patients who had not previously taken saquinavir. The presence of 3 or more mutations caused a reduced response to saquinavir / ritonavir therapy.

The relationship between the number of these saquinavir-resistant mutations and the virologic response was confirmed in an independent clinical trial involving a population of patients who previously received more intensive therapy, including 54% of patients previously receiving saquinavir (p = 0.0133, see Table 1).The G48V mutation, which was previously determined in vitro as a mutation specific for saquinavir, was present initially in 3 patients. All these patients received no response to therapy.

Table 1. Virological response to saquinavir / ritonavir, stratified by the number of initial mutations causing resistance to saquinavir.

The number of initial mutations causing resistance to saquinavir *	Hospitalized patients Number of patients not previously treated with saquinavir		Retrospective analysis of CI Number of patients not receiving / previously treated with saquinavir
	N = 138	The change in the concentration of HIV-1 RNA in blood plasma at 12-20 weeks compared with the initial	N = 114	The change in the concentration of HIV-1 RNA in blood plasma at week 4 compared with the baseline
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

* Scale of mutations associated with saquinavir: L10F / I / M / R / V, I15A / V, K20I / M / R / T, L241,162V, G73S / T, V82A / F / S / T, I84V, L90M

Efficiency

Comparison of efficacy and safety of saquinavir in soft gelatin capsules in combination with ritonavir (1000 mg / 100 mg twice daily) and two nucleoside (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) and indinavir in combination with ritonavir (800 mg / 100 mg twice daily) andtwo NRTIs / NNRTIs in more than 300 patients (who received / did not receive HIV protease inhibitor treatment earlier). The combination of saquinavir with ritonavir was characterized by greater virologic activity compared with the combination of indinavir and ritonavir, while a change in the prescribed treatment was considered a virological failure (study 1).

The effectiveness and safety of saquinavir in soft gelatin capsules in combination with ritonavir (1000 mg / 100 mg twice daily) and two NRTIs / NNRTIs and lopinavir in combination with ritonavir (400 mg / 100 mg twice daily) and saquinavir two NRTIs / NNRTIs in 324 patients (who received / did not receive HIV protease inhibitor treatment earlier). No patient in the lopinavir / ritonavir therapy group took lopinavir before randomization, while 16 patients from the saquinavir / ritonavir group took saquinavir earlier (study 2).

Table 2. Demographic characteristics of patients from the studies.

	Saquinavir /	Indinavir /	Saquinavir /	Lopinavir /
	ritonavir	ritonavir	ritonavir	ritonavir
	N = 148	N = 158	N = 161	N = 163
Sex (male)	82%	74%	81%	76%
Race (Europoid / Negroid / Mongoloid) (%)	86/9/1	82/12/4	75/19/1	74/19/2
Age, median, years	39	40	40	40
Stage C (classification CDC) (%)	32%	28%	32%	31%
Patients who did not previously take antiretroviral drugs (%)	28%	22%	31%	34%
Patients who did not previously take HIV protease inhibitors (%)	41%	38%	48%	48%
The median of the initial value of HIV-1 RNA, log₁_o copies / ml (scatter)	4.0 (1.7-5.1)	3.9 (1.7-5.2)	4.4 (3.1-5.1)	4.6 (3.5-5.3)
Median initial number of cells Cd4⁺, cells / mm³ (scatter)	272 (135-420)	280 (139-453)	241 (86-100)	239 (95-420)

Data are from a clinical trial report

Table 3. Results of therapy in the conducted studies + (after 48 weeks).

results	Saquinavir /	Indinavir /	Saquinavir /	Lopinavir /
	ritonavir	ritonavir	ritonavir	ritonavir
Initiated treatment, n (%)	148 (94%)	158 (99%)	161 (94%)	163 (98%)
The appointed treatment was canceled, n (%)	40 (27%)	64 (41%)	48 (30%)	23 (14%)
	P = 0.01		P = 0.001
Virological failure in patients ITT / e *^#	36/148 (24%)	41/158 (26%)	53/161 (33%)	29/163 (18%)
	P = 0.76		P = 0.002
The rate of patients with viral load <50 copies / ml at 48 weeks, ITT / e^#	97/144 (67%)	106/154 (69%)	90/158 (57%)	106/162 (65%)
	P> 0.05 ⁺ ⁺		Р = 0.12
The rate of patients with viral load <50 copies / ml at 48 weeks, patients under treatment	82/104 (79%)	73/93 (78%)	84/113 (74%)	97/138 (70%)
	P> 0.05⁺ ⁺		P = 0.48
The median increase in the number Cd4 cells after 48 weeks (cells / mm)³)	85	73	110	106

* For both studies: for patients included in the study with a viral load <200 copies / ml, the virologic failure was defined as> 200 copies / ml.Study 1: for patients enrolled in a study with a viral load> 200 copies / ml, virologic 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 after 24 weeks, etc. Study 2: any increase> 0.5 log on a separate visit; <0.5 log decrease if viral load> 200 copies / ml after 4 weeks; <1.0 log decrease from the initial value if the viral load> 200 copies / ml after 12 weeks; and a viral load> 200 copies / ml after 24 weeks.

# ITT / e = all patients included in the study / treated.

+ Data are from a clinical trial report.

⁺ Study publication data 1.

Influence on ECG parameters

The effect of Invirase ® in combination with ritonavir in doses of 1000/100 mg twice a day (therapeutic doses) and 1500/100 mg twice a day (doses exceeding the therapeutic dose) per QT interval at 20 h on the 3rd day of drug administration was studied in a double-blind study with a 4-component cross-over design, placebo and active control (moxifloxacin 400 mg daily) with the participation of healthy volunteers (male and female) aged 18 to 55 years (N = 59).

Considering the data of the previous 14-day pharmacokinetic study using multiple doses, in which the maximum pharmacokinetic exposure was achieved on the 3rd day of the drug, the third day was chosen as the point of evaluation. The mean Cmax values when taking Invirase ® in combination with ritonavir at doses of 1000/100 mg twice a day and 1500/100 mg twice a day on the 3rd day of the study in healthy volunteers were approximately 3 and 4 times higher, respectively than the mean Cmax values in the equilibrium state when taking Invirase ® in combination with ritonavir at a dose of 1000/100 mg twice daily for HIV-infected patients.

In the study, a QTcS-specific QTcS (QT interval adjusted for baseline pre-dose baseline correction) was used to adequately assess QT interval changes in different groups and depending on heart rate (similar to the Fridericia amendment )).

On day 3, the upper limit of the one-sided 95% confidence interval for the maximum value of the mean difference in QTcS between both active substance intake groups (Invirase® in combination with ritonavir in therapeutic doses anddoses exceeding therapeutic) and the placebo group was> 10 milliseconds (msec) (see Table 4). It was found that the drug Invirase ® in combination with ritonavir in doses exceeding therapeutic, has a more significant effect on the QT interval compared with therapeutic doses. In the majority of study participants (89% of patients receiving therapeutic doses and 80% of patients receiving drugs at doses higher than therapeutic ones), QTcS was <450 msec, and no participant had a QTc interval> 500 msec (see also "Special instructions ").

Table 4. The mean maximum ddQTcS + (ms) for the 3rd day for therapy with Invirase® in combination with ritonavir in therapeutic doses at doses above therapeutic and for active control (moxifloxacin) in healthy volunteers.

Treatment	Temporary	Poppy indicator	Standard	Upper
	assessment point	of the	error	border
	after taking	its meanings		95% CI for
	preparation	ddQTcS		ddQTcS
Invirase® / ritonavir	12 h	18.86	1.91	22.01
1000/100 mg 2 times in
day
Invirase® / ritonavir	20 h	30.22	1.91	33.36
1500/100 mg 2 times in
day
Moxifloxacin ^	4h	12.18	1.93	15.36

The derived difference between the QTcS values (QT interval, corrected for the initial values,received before the start of the drug, specific for this study) in the group receiving active treatment, and in the placebo group.

Admission 400 mg only on the third day.

Note: in the study, the QTcS for men was calculated using the formula

QT / RR 0.319, and for women QT / RR0.337, which corresponds to the Fridericia correction (QTcF = QT / RR0.333).

In this study, on day 3, an extension of the PR interval> 200 msec was observed in 40% of patients receiving Invirase ® / ritonavir at a dose of 1000/100 mg twice daily, and 47% of patients receiving Invirase ® / ritonavir in dose 1500/100 mg 2 times a day. In 3% of patients who received moxifloxacin as an active control, and in 5% of patients in the placebo group, an extension of PR> 200 msec was observed. The maximum value of the mean change in the PR interval compared to the pre-treatment score was 25 msec in the group receiving Invirase® / ritonavir at a dose of 1000/100 mg twice daily and 34 msec for the Invirase® / ritonavir dose 1500/100 mg twice a day (see also section "Special instructions").

The cases of "pirouette" tachycardia (torsade des pointes) and prolongation of the QT interval> 500 msec were not observed in the study. In some patients, the relationship between the development of syncope or the presynopal state and the extension of the PR interval can not be ruled out.The clinical significance of these changes observed in healthy volunteers is not known for HIV-infected patients receiving Invirase ® / ritonavir, however, an increase in the dose of Invirase ® / ritonavir more than 1000/100 mg 2 times a day.

Results of the study of the effect of Invirase® on the QT interval, pharmacokinetics and viral load in HIV-infected patients who had not previously received therapy and who are starting treatment with Invirase® / ritonavir using a modified dosing regimen (Invirase® / ritonavir 500/100 mg 2 once a day in combination with two nucleoside reverse transcriptase inhibitors for 7 days followed by a dose increase of up to 1000/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors for the next 7 days) showed that an increase in QT interval is less pronounced with a modified dosing regimen. The proportion of patients with an interval of PR> 200 ms varied from 14% on day 3 of therapy to 38% on day 14 of therapy. When taking Invirase ® with ritonavir in a modified dosing regimen due to the effectimproving the pharmacokinetics of saquinavir in the first week the exposure of saquinavir reached a maximum on day 3 of therapy and decreased to a minimum value on day 7. A consistent decrease in the level of HIV-RNA was observed in all patients receiving Invirase® / ritonavir in a modified dosing regimen during the 2-week treatment period and previously untreated, indicating a suppression of the virus. Long-term effectiveness with a modified dosing regimen has not been studied.

Preclinical safety data

Carcinogenicity

There was no evidence of carcinogenic activity of saquinavir when administered to rats and mice for 2 years. The exposure of saquinavir in plasma (AUC) in these individuals was approximately 37% and 85% of saquinavir exposure in humans when taking Invirase ® and ritonavir at doses of 1000/100 mg 2 times a day.

Mutagenicity

In in vitro studies on mutagenicity and genotoxicity (if necessary with metabolic activation), it was shown that saquinavir does not have mutagenic activity on both bacterial cells (Ames test) and mammalian cells (Chinese hamster lung cells V79 / HPRT test with hypoxanthine guanine phosphoribosyltransferase).Saquinavir does not induce chromosomal mutations in vivo (micronucleated mice in mice) or in vitro in human lymphocytes, nor does it cause primary DNA damage in vitro (reparative DNA synthesis).

Influence on Fertility

In studies on rats, there was no adverse effect on reproductive function and fertility at exposure values (AUC) of approximately 33% of the exposure in humans when taking Invirase ® in combination with ritonavir at recommended doses of 1000/100 mg twice daily .

Teratogenicity

In studies on rats and rabbits, there was no embryotoxic or teratogenic effect of saquinavir at exposure values (AUC) of approximately 32% of exposure in humans when taking Invirase ® in combination with ritonavir at recommended doses of 1000/100 mg twice daily.

Pharmacokinetics:

Suction

When taking a single dose of 600 mg after taking high-calorie food, the absolute bioavailability of saquinavir is 4%, varying from 1% to 9%. Most likely bioavailability is limited by a combination of the effect of incomplete absorption and a pronounced metabolism of the "first passage" through the liver.It has been shown that pH does not play a big role in a significant increase in bioavailability after eating.

When taking multiple doses after meals (25-600 mg 3 times a day), there was a greater increase in saquinavir exposure (50 times) than with a proportional increase in the dose (24 times). Following multiple administration of Saquinavir (600 mg 3 times daily) in HIV-infected patients, the area under the curve "concentration-time" in the equilibrium state (AUC) in 2.5-fold higher (95% confidence interval (CI) 1.6-3.8) than after a single dose.

In healthy volunteers, AUC after taking 600 mg saquinavir on an empty stomach was 24 ng * h / ml (coefficient of variation 33%), after eating (48 g protein, 60 g carbohydrates, 57 g fat, 1006 kcal) - 161 ng * h / ml (coefficient of variation of 35%). Food intake increases the maximum concentration of saquinavir from 3.0 ng / ml to 35.5 ng / ml and the time it reaches from 2.4 to 3.8 hours. This effect of food continues for 2 hours after eating. Therefore, taking Invirase ® should be done no later than 2 hours after eating.

In a crossover study in HIV-infected patients treated Inviraza® drug in combination with ritonavir 1000/100 mg 2 times a day on an empty stomach first (three consecutive times)and then after intake of high-calorie food (46 g fat, 1091 kcal) (three consecutive doses), AUCo-12 saquinavir was 10320 ng * h / ml and 34,926 ng * h / ml, respectively. All patients (except one) had the achievement of the minimum equilibrium concentration of the drug (Cssmin) above the lower values of the therapeutic range for fasting. Nevertheless, the drug Invirase ® in combination with ritonavir should be taken within 2 hours after meals. In HIV-infected patients who received saquinavir 600 mg 3 times in the soft after meal, the AUC and the maximum plasma concentration (Cmax) were approximately twice as high as those in healthy volunteers with a similar dosing regimen.

Saquinavir in soft gelatin capsules 200 mg or saquinavir in coated tablets, 500 mg in combination with ritonavir at doses of 400/400 mg or 1000/100 mg twice daily provide a similar or greater systemic exposure of saquinavir for 24 hours than with an increase in the dose of saquinavir in soft gelatin capsules of 200 mg to 1200 mg / three times a day.

In HIV-infected patients who have not previously received therapy and who are beginning treatment with Invirase® / ritonavir in a modified dosing regimen (500/100 mg twice daily forthe first 7 days of therapy followed by a dose increase of up to 1000/100 mg twice a day for the next 7 days of therapy), the system exposure of Invirase® generally reached or exceeded the values observed in the equilibrium state with the standard dosage regimen of Invariase® / ritonavir in a dose of 1000 / 100mg twice daily.

Diarrhea does not affect the absorption of saquinavir, and also the drug itself does not affect the parameters of gastrointestinal absorption.

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

Distribution

Well distributed in tissues. The average volume of distribution in the equilibrium state after intravenous administration of 12 mg is 700 L (coefficient of variation is 39%). The connection with plasma proteins is -98%, does not depend on the concentration of the drug (15-700 ng / ml). Saquinavir (when taken 600 mg 3 times a day) is not detected in the cerebrospinal fluid.

Metabolism

Exposed to significant hepatic metabolism. Rapid metabolism to mono- and dihydroxylated inactive derivatives is mediated through the cytochrome P450 system and is performed by the CYP3A4 isoenzyme, which accounts for more than 90% of hepatic metabolism (in vitro studies).After iv introduction, 66% of circulating saquinavir is found unchanged, the rest is metabolites, which corresponds to the extensive metabolism of the "first passage" in the liver. Systemic clearance after IV infusion of 6, 36 and 72 mg saquinavir is high and is 1.14 l / h / kg (coefficient of variation of 12%), slightly exceeding the hepatic blood flow. The half-life of the drug from the body is 7 hours.

Excretion

Four days after taking 14C-saquinavir, inside (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 faeces and urine, respectively.

After ingestion of 13% of the circulating plasma saquinavir was presented unchanged, the rest - in the form of metabolites.

Pharmacokinetics in special clinical groups

The pharmacokinetics of Invirase® in patients with renal insufficiency not studied.

Liver failure

The effect of liver dysfunction on the equilibrium pharmacokinetics of saquinavir in combination with ritonavir was studied with the participation of HIV-infected patients (N = 7) with moderate impaired hepatic function (grade B (7-9 points) on the Child-Pugh scale).This study included a control group of HIV-infected patients (N = 7) with normal liver function, corresponding to the patients studied by age, sex, body weight and tobacco consumption. In HIV-infected patients with moderate impaired hepatic function, the mean (% coefficient of variation) of AUCo-12 and Cmax saquinavir was 24.3 (102%) mg / hr 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. Concerning AUC0-12 and Cmax, the geometric mean of the pharmacokinetic parameters in patients with impaired hepatic function to the pharmacokinetic parameters of 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 a violation of the liver. In HIV-infected patients with moderate violations of the function of the liver, dosage adjustment of saquinavir is not required (see the sections "Dosing and Administration", "Special instructions").

No effect sex on the pharmacokinetics of the drug Invirase ® with a single oral intake of 600 mg in healthy volunteers.In a study of the bioequivalence of saquinavir in 200 mg capsules and coated tablets, 500 mg in combination with ritonavir, a higher exposure of saquinavir in women (AUC by 56%, Cmax by 26%) was found, regardless of body weight and age. Clinically significant differences in the efficacy and safety of the registered dosage regimen of saquinavir in men and women have not been identified. Therapy with saquinavir in combination with ritonavir in doses of 1000/100 mg was found to be safe and effective in both sexes. The influence of the race on the pharmacokinetics of saquinavir has not been studied.

Study of pharmacokinetic parameters in children under 16 years and adults over 65 years not carried out.

Equilibrium exposure of saquinavir, observed in pediatric studies, was significantly higher compared with previous data obtained in adults (who observed a dose-dependent and exposure-dependent lengthening of QT and PR intervals).

Indications:Treatment of HIV-1 infected adults in combination therapy with ritonavir and other antiretroviral drugs.

Contraindications:

Hypersensitivity to saquinavir or any other component of the drug, ritovirus.

Simultaneous reception of terfenadine, astemizole, cisapride, pimozide, amiodarone, fl-kainide, propafenone, atazanavir, lopinavir, bepridil, lidocaine, quinidine, ibutyl, sotalol, amitriptyline, imipramine, trazodone, clarithromycin, pentamidine, sparfloxacin, methadone, sildenafil, tadalafil, vardenafil, clozapine, haloperidol, mesoridazine, phenothiazine, sertindole, sultopride, thioridazine, vincomamine, dapsone, disopyramide, quinine, fentanyl, alfentanil (life-threatening arrhythmias); rifampicin (severe hepatocellular toxicity); ergot alkaloids (eg, dihydroergotamine, ergometrine, ergotamine, methylergometrine (acute toxicity)); simvastatin, lovastatin (rhabdomyolysis); triazolam, midazolam oral use (prolonged / excessive sedation); quetiapine (increased toxicity of quetiapine), alfuzion (arterial hypotension).

Decompensated liver disease.

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Congenital or documented acquired interval elongation.

Electrolyte disturbances, especially uncorrected hypokalemia.

Clinically significant bradycardia.

Clinically significant heart failure with a reduced fraction of left ventricular ejection.

Symptomatic arrhythmia in the anamnesis.

Simultaneous use with drugs that can extend the intervals of QT and / or PR (see section "Interaction with other drugs").

Children under 18 years.

Carefully:

Precautions: simultaneous reception of colchicine (rhabdomyolysis), nefazodone, omeprazole (increasing the concentration of saquinavir), fusidic acid (increased toxicity), rifabutin, dexamethasone, herbal, containing St. John's wort (Hypericum perforatum), drugs and biologically active additive (BAA), containing garlic extract (reduced concentration saquinavir), alprazolam, klorazepama dipotassium, diazepam, flurozepama (increase sedation), felodipine, nifedipine, nicardipine, diltiazem, nimodipine, ve rapamila, amlodipine, nisoldipine, isradipine (increasing drug concentration), digoxin (digoxin concentration increase) ethinyl estradiol (decrease in drug concentration).

Pregnancy and lactation:

Animal experiments do not indicate direct or indirect harmful effects of saquinavir in the development of the embryo or fetus during pregnancy, peri- and postnatal development. The experience of clinical use of the drug in pregnant women is limited. When saquinavir was used in combination with other antiretroviral drugs in pregnant women, seldom reported congenital malformations, congenital anomalies, and other disorders not accompanied by congenital anomalies.

During pregnancy saquinavir Should be used only if the possible benefit to the mother exceeds the potential risk to the fetus.

Data obtained on animals and in humans regarding the possible penetration of saquinavir into breast milk, no. Assess the possible side effects of saquinavir in infants is not possible, therefore, breastfeeding should be discontinued before treatment with saquinavir. HIV-infected women are not recommended to breast-feed to avoid transmission of the HIV virus to the child.

Dosing and Administration:

The drug Invirase® is prescribed only in combination with ritonavir!

It is recommended to strictly follow the prescribed regimen of taking medications.

Inside, during or no later than 2 hours after eating.

Standard dosing regimen

Adults

In combination with ritonavir (enhanced regimen)

The drug Invirase® 1000 mg 2 times a day and ritonavir 100 mg 2 times a day in combination with other antiretroviral drugs. In patients who have not received therapy and begin treatment with Invirase®, the recommended initial dose of Invirase® is 500 mg twice daily in combination with ritonavir 100 mg twice daily for the first 7 days of therapy. After 7 days from the start of therapy, it is recommended that the dose of Invirase ® / ritonavir is increased to 1000/100 mg twice a day.

When switching from therapy with other HIV protease inhibitors in combination with ritonavir or non-nucleoside reverse transcriptase inhibitors, it is recommended to initiate therapy with Invirase® at a standard recommended dose of 1000 mg twice daily in combination with ritonavir at a dose of 100 mg twice daily without a washout period.

The drug Invirase® and ritonavir taken inside at the same time and no later than 2 hours after eating.

In combination with other HIV protease inhibitors

To familiarize yourself with recommended doses and possible side effects of other antiretroviral drugs, instructions for their use should be studied.

Dosing in special cases

If severe toxic effects occur, treatment with saquinavir should be discontinued. Due to the possible increase in plasma concentrations in combination therapy with other antiretroviral drugs (eg with ritonavir), the dose of HIV protease inhibitors may need to be changed.

Dosing in special patient groups

Patients with hepatic insufficiency

In HIV-infected patients with moderate impairment of liver function, dose adjustment of saquinavir is not required. Decompensated liver disease is a contraindication to the use of the drug Invirase®.

Patients with renal insufficiency

In patients with mild to moderate renal failure, dose adjustment of saquinavir is not required. When using Invirase ® in patients with severe renal failure should be showncaution.

Childhood

The effectiveness and safety of saquinavir in children under 18 years of age have not been established. For this population there are no doses of saquinavir that do not cause prolongation of the QT and PR intervals and simultaneously correspond to the efficacy parameters. There is limited information on the use of saquinavir in soft gelatin capsules (unresponsive regimen) in children. Information on the use of the drug Invirase® without ritonavir (unresponsive regimen) in children is absent.

Elderly age

Experience in patients over 60 years of age is limited. Data for the recommended dosage regimen are not available.

Side effects:

Clinical Trials Data

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

To describe the incidence of adverse reactions that occur with saquinavir supplemented with ritonavir, the following categories are used: very often (>10%), often (>1%, <10%) and infrequently (>0.1%, <1%).

Body System		Undesirable reactions
From the skin and subcutaneous fat	Often	Acquired lipodystrophy, alopecia, dry skin, eczema, lipoatrophy, rash, itching.
From the skin and subcutaneous fat	Infrequently	Stevens-Johnson syndrome, bullous dermatitis.
From the nervous system	Often	Headache, peripheral neuropathy, paresthesia, dizziness, change in taste sensations.
From the nervous system	Infrequently	Drowsiness, convulsions.
From the psychic sphere	Often	Decreased libido, sleep disturbance.
From the gastrointestinal tract	Often	Diarrhea, nausea.
	Often	Vomiting, bloating, flatulence, abdominal pain, pain in the upper abdomen, constipation, dry mouth, indigestion, belching, dry lips, unformed stool.
	Infrequently	Pancreatitis.
From the side of the liver and bile excretory ways	Infrequently	Hepatitis, jaundice.
From the side of the musculoskeletal system	Often	Muscle spasm.
From the side of the musculoskeletal system	Frequency unknown	Myalgia, myositis, rhabdomyolysis.
From the side of the kidneys and urinary tract	Infrequently	Impaired renal function.
From the immune system	Often	Hypersensitivity reactions.
Disorders of nutrition and metabolism	Often	Hypercholesterolemia, hypertriglyceridemia.
	Often	Diabetes mellitus, anorexia, increased appetite.
	Infrequently	Decreased appetite.
	Frequency unknown	Insulin resistance, hyperlactatemia, hyperglycemia, sometimes accompanied by ketoacidosis.
From the respiratory system	Often	Dyspnea.
From the blood system and hematopoiesis	Often	Decrease in the number of platelets.
	Often	Anemia, hemoglobinemia, a decrease in the number of lymphocytes, a decrease in the number of leukocytes.
	Infrequently	Neutropenia.
	Frequency unknown	Increased bleeding, including spontaneous formation of subcutaneous hematomas and hemarthrosis in patients with hemophilia type A and B receiving treatment with HIV protease inhibitors.
From the laboratory indicators	Often	Increase of AJIT and ACT activity; increased cholesterol concentration; low-density lipoproteins and triglycerides; thrombocytopenia.
From the laboratory indicators	Often	Increased activity of amylase, bilirubin concentration, creatinine; decreased hemoglobin; limfocytopenia; leukocytopenia.
Other	Often	General weakness (asthenia), fatigue, malaise, fatty tissue increase.
Other	Infrequently	Ulceration of the mucosa.

Below are the undesirable reactions observed when taking Invirase ® in unresponsive mode.

From the nervous system: hypoesthesia, impaired coordination, intracranial hemorrhage.

From the psychic sphere: confusion, depression, anxiety, attempted suicide, insomnia, violation of libido.

From the skin and subcutaneous fat: Stevens-Johnson syndrome, bullous dermatitis, drug rash, severe skin reactions associated with impaired liver function.

On the part of the organs of the hepatobiliary system: jaundice, portal hypertension, exacerbation of chronic liver diseases (with a violation of liver function of the 4th degree). On the part of the body as a whole: fever, ulceration of the mucous membrane, pain in the chest.

From the musculoskeletal system: muscle weakness and polyarthritis.

On the part of the blood system and hemopoiesis: hemolytic anemia and neutropenia.

On the part of the organs of the gastrointestinal tract: ascites, pancreatitis and intestinal obstruction.

Disorders of nutrition and metabolism: decreased appetite.

Benign and malignant neoplasms (including cysts and polyps): papilloma of the skin, acute myelogenous leukemia.

From the urinary system: nephrolithiasis.

From the cardiovascular system: spasm of peripheral vessels.

From the laboratory indicators: increased activity of creatinine phosphokinase (CK), hyperglycemia, hypoglycemia.

Postmarketing surveillance

On the part of the immune system: hypersensitivity reactions.

Disorders of nutrition and metabolism:

- 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 extremities, an increase in visceral and intra-abdominal fat, an increase in mammary glands and fat deposition on the dorsal surface of the neck and back ("bull hump" );

- hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

From the nervous system: drowsiness, convulsions.

On the part of the blood system and hemopoiesis: increased bleeding, including spontaneous formation of subcutaneous hematomas and hemarthrosis in patients with hemophilia type A and B receiving treatment with HIV protease inhibitors.

On the part of the organs of the hepatobiliary system: hepatitis.

From the osteomuscular and connective tissue: the application of HIV protease inhibitors, particularly in combination with nucleoside analogues reported increase of CPK activity, myalgia, myositis and rhabdomyolysis infrequently. Cases of osteonecrosis, especially in patients with generally accepted risk factors for patients with HIV infection or prolonged combined antiretro virus term therapy. The frequency is unknown.

From the side of the kidneys and urinary tract: 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 reactivation syndrome) may develop. Immune reactivation syndrome may also present the development of autoimmune disorders (such as Graves' disease), which are developed in different periods of therapy. The development of autoimmune disorders is also possible many months after the initiation of therapy.

Overdose:

At present, the clinical experience of the overdose of saquinavir in humans is limited.An acute or chronic overdose with monotherapy with saquinavir does not lead to serious complications.

In combination with other HIV protease inhibitors, the following symptoms are possible:

general weakness, fatigue, diarrhea, nausea, vomiting, hair loss, dry mouth, hyponatraemia, weight loss, orthostatic hypotension.

Treatment: there is no specific antidote. Activities aimed at maintaining vital functions, including monitoring of vital signs, ECG, monitoring the clinical condition of the patient. It is necessary to prevent the subsequent absorption of the drug. As saquinavir is highly associated with plasma proteins, the use of dialysis is not appropriate.

Interaction:

In most of the studies conducted on drug interaction, the use of Invirase® in unresponsive regimens was studied. Information on the use of the drug Invirase ® in combination with ritonavir (enhanced regimen) is limited. The results obtained during studies on the use of Invirase® in non-stimulated regimens may not completely reflect the effects of Invirase® in combination with ritonavir.This section provides complete information on drug interactions, including studies using saquinavir in soft gelatin capsules previously marketed.

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

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

Ritonavir, as a potent inhibitor of the isoenzyme CYP3A4 and P-glycoprotein, may affect the pharmacokinetics of other drugs. When prescribing combination therapy, possible interactions with ritonavir should be considered. Taking into account the results obtained with the use of the preparation Invirase® in combination with ritonavir in healthy volunteers with respect to the dose-dependent lengthening of QT and PR intervals (see the sections "Contraindications", "Special instructions", "Pharmacotherapeutic group"),additive effects on the prolongation of QT and PR intervals can occur with the use of drugs of the following classes: antiarrhythmic agents of IA or III class, neuroleptics, tricyclic antidepressants, type 5 phosphodiesterase inhibitors (IFE-5), individual antibacterial and antihistamines, and also other medications (see below). These additive effects can lead to an increased risk of ventricular arrhythmias, especially arrhythmias of the ventricular tachysystolic type "pirouette" (torsade des pointes). Thus, joint ingestion of Invirase® in combination with ritonavir and listed drugs should be avoided, if other alternative therapeutic options are available. Strictly contraindicated are medications that simultaneously have a pharmacokinetic interaction with the drug Invirase ® in combination with ritonavir and the ability to extend the intervals of QT and PR. It is not recommended to combine Invirase® and ritonavir with other drugs having a known prolonging action with respect to the QT and PR intervals.Therefore, in case of emergency, such a combination should be used with caution.

Nucleoside reverse transcriptase inhibitors

Didanosine

Saquinavir / ritonavir (enhanced regimen): a single dose of didanosine at a dose of 400 mg led to a decrease in AUC and Cmax of saquinavir taken in combination with ritonavir (1600 mg / 100 mg 4 times a day for 2 weeks) by healthy volunteers, approximately 30% and 25%, respectively, but not influenced the minimum concentration (Cmjn) of saquinavir. These changes probably do not have a certain clinical significance. Correction of the dose in such cases is not required.

Monotherapy with saquinavir (unresponsive regimen): the interaction between saquinavir and didanosine has not been studied.

Tenofovir

Saquinavir / ritonavir: simultaneous administration of tenofovir disoproxil fumarate with the preparation Invirase ® in combination with ritonavir did not exert a clinically significant effect on the exposure of saquinavir. The use of tenofovir dizoproxil fumarate at a dose of 300 mg once a day led to a decrease in AUC and Cmax saquinavir (preparation Invirase® in combination with ritonavir 1000/100 mg twice daily) by 1% and 7%, respectively. However, these changes are not clinically significant. Correction of the dose in such cases is not required.Zalcitabine and / or zidovudine

Monotherapy with saquinavir: simultaneous reception of zalcitabine and / or zidovudine with sac-vinavir does not affect the pharmacokinetic parameters of these drugs. Correction of the dose in such cases is not required.

Saquinavir / ritonavir: Currently, there are no completed studies that study changes in pharmacokinetic parameters with simultaneous prescribing of these drugs.

Non-nucleoside reverse transcriptase inhibitors

Delavirdine

Monotherapy with saquinavir: simultaneous 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. At present, information on the safety of the use of such a combination of drugs is limited, and there is no evidence of efficacy. When combined therapy with delavirdine is recommended control of liver function.

Saquinavir / ritonavir: The interaction between the drug Invirase ® in combination with ritonavir and delavirdine has not been studied.

Efavirenz

Monotherapy with saquinavir: simultaneous administration of efavirenz (600 mg) and saquinavir (1200 mg 3 times a day) reduced the saquinavir AUC by 62%, and the Sa max of saquinavir by 50%.The concentrations of efavirenz also decreased by 10%, however this decrease is not clinically significant. In connection with these results, saquinavir should be used in combination with efavirenz only if the concentration of saquinavir in the blood increases with other antiretroviral drugs, such as ritonavir.

Saquinavir / ritonavir: Clinically significant deviations in concentrations of saquinavir or efavirenz were not observed. Correction of the dose in such cases is not required.

Nevirapine

Monotherapy with saquinavir: simultaneous administration of nevirapine and the drug Invirase ® reduced the aUC of saquinavir by 24%, but did not affect the AUC of nevirapine. These fromThe changes are not clinically significant. Correction of the dose in such cases is not required.

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

HIV protease inhibitors

Atazanavir

Saquinavir / atazanavir: simultaneous administration of atazanavir and Invirase® in combination with ritonavir (1600/100 mg once a day) caused significant changes in the exposure of saquinavir and ritonavir (AUC and _FROM_m_Oh increased by 60% and 42% respectively, AUC and _FROM_m_Oh increased by 41% and 34% respectively). Simultaneous reception of Invirase® in combination with ritonavir and atazanavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

Fosamprenavir

Saquinavir / ritonavir: simultaneous administration of fosamprenavir and Invirase® in combination with ritonavir (1000/100 mg) did not cause clinically significant changes in saquinavir exposure (AUC and C _m_Oh saquinavir decreased by 15% and 9%, respectively, a C_min saquinavir decreased by 24%, but still remained above the threshold of therapeutic effectiveness). Correction of the dose is not required.

Indinavir

Monotherapy with saquiavir: simultaneous use of indinavir (800 mg 3 times a day) and a single dose of the drug Invirase® or saquinavir (600-1200 mg) resulted in an increase AUC_0-24saquinavir in plasma 4.6-7.2 times. The concentration of indinavir in plasma did not change. At present, there is no data on the safety and efficacy of this combination of drugs. Appropriate doses for this combination of drugs have not been established.

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

Lopinavir / ritonavir

Saquinavir / ritonavir: lopinavir 400 mg did not change the pharmacokinetic parameters of saquinavir taken in combination with ritonavir (equilibrium values AUC 0-12 saquinavir - 15130 and 16977 ng * h / ml, C_m_Oh 2410 and 2300 ng / ml and C_m_in 427 and 543 ng / ml, respectively, in combination with and without lopinavir), but significantly reduced the exposure of ritonavir. Nevertheless, the effectiveness of ritonavir remained unchanged in this case. Concentrations of lopinavir in plasma did not change (in comparison with the data of previous studies of the combination of lopinavir / ritonavir).

It is possible to develop an additive effect on the lengthening of intervals QT and / or PR When used with the drug Invirase ® in combination with ritonavir. The simultaneous administration of the drug Invirase ® in combination with ritonavir and lopinavir is contraindicated in connection with the possible development of life-threatening arrhythmias (see section "Special instructions").

Nelfinavir

Unexplained saquinavir: scheme of therapy, including saquinavir (1200 mg 3 times a day) and nelfinavir (750 mg 3 times daily) in addition to 2 nucleoside reverse transcriptase inhibitors, resulted in a longer response (prolongation of the time to virological relapse). There were 392% and 179% increase AUC and C_m_Oh saquinavir, respectively. AUC Nelfinavir increased by 18%, C_m_Oh did not change. With the simultaneous use of nelfinavir and saquinavir, the incidence of diarrhea increased moderately.

Saquinavir / ritonavir: The use of saquinavir in combination with ritonavir and nelfinavir is not recommended.

Ritonavir

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

Ritonavir significantly inhibits the metabolism of saquinavir, which leads to higher concentrations of saquinavir in plasma. The equilibrium values AUC_o_-24 and C_m_Oh saquinavir in patients after taking Invirase® at a dose of 600 mg 3 times a day were 2598 ng * h / ml and 197 ng / ml, respectively.

When taking 1000 mg of Invirase ® in combination with 100 mg of ritonavir twice a day, the equilibrium values AUCo-24, FROM_m_Ohand C_minare 29214 ng * h / ml, 2623 ng / ml and 371 ng / ml, respectively.

When taking saquinavir or Invirase⁸ in combination with ritonavir at a dose of 1000 mg / 100 mg 2 times daily systemic exposure of saquinavir over a 24 hour period was similar or higher than the exposure when taking saquinavir 1200 mg 3 times per day. Correction of the dose is not required.

Tipranavir

Saquinavir / ritonavir: Combination therapy is not recommended, since tipranavir, reinforced with small doses of ritonavir, reduces FROM_min saquinavir on 78% (the clinical significance of this reduction is not established). If, however, a decision is made on the need to prescribe this combination of drugs, it is strongly recommended that saquinavir concentrations in the plasma are monitored.

Inhibitors of fusion

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. Correction of the dose is not required.

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

Chemokine receptor antagonists CCR5

Maraviroc

Saquinavir / ritonavir: with the simultaneous administration of saquinavir, ritonavir (1000 mg / 100 mg twice daily) and maraviroc (100 mg twice daily), the exposure of maraviroc was slightly changed (AUC12 and C_m_Oh increase by 9.77% and 4.78%, respectively). The effect on the concentration of saquinavir and ritonavir was not measured and is not expected. Correction of the dose of Invirase® and ritonavir is not required.The dose of maraviroc should be 150 mg twice a day, monitoring of the patient is necessary.

Other medications Alpha 1-adrenoblockers

Alfuzosin

Saquinavir / ritonavir: it is possible to increase the concentration of alfuzosin in the blood plasma. The combined use of alfuzosin and saquinavir in combination with ritonavir is contraindicated in connection with the possible development of arterial hypotension. Antiarrhythmics

Bepridil, lidocaine, quinidine, amiodarone, flecainide, propafenone

Saquinavir / ritonavir: concentration of bepridil, lidocaine (for systemic use), quinidine, amiodarone, flecainide, propafenone may increase. These antiarrhythmic drugs are contraindicated for joint use with the preparation Invirase ® in combination with ritonavir in connection with the possible development of life-threatening arrhythmias (see the sections "Contraindications" and "Special instructions") /

Ibutilide, sotalol

Saquinavir / ritonavir: joint application with Invirase® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias. Anti-gouty agents

Colchicine

Saquinavir / ritonavir: joint application of colchicine and Invirase® in combination with ritonavir can cause an increase in the concentration of colchicine in plasma blood and is not recommended in connection with a possible increase in the toxicity of colchicine (neuromuscular disorders, in particular rhabdomyolysis), especially in patients with impaired liver and kidney function.

Anticoagulants

Warfarin

Saquinavir / ritonavir: concentrations of warfarin may vary, it is necessary to monitor the international normalized ratio (MHO).

Antiepileptic agents

Karbamasegin, phenobarbital, phenytoin

Monotherapy with saquinavir: carbamazepine, phenobarbital, phenytoin - inducers of microsomal enzymes of the liver (isoenzyme CYP3A4) can reduce the concentration of saquinavir in plasma.

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

Antidepressants

Tricyclic antidepressants (amitriptyline, imipramine)

Saquinavir / ritonavir: ritonavir can increase the concentration of tricyclic antidepressants. Joint use with the drug Invirase® and ritonavir is contraindicated in connection with the possibledevelopment of life-threatening arrhythmias.

Nefazodone

Saquinavir / ritonavir: Nefazodone, as an inhibitor of the isoenzyme CYP3A4, may increase the concentration of saquinavir. The use of this combination is not recommended.

Trazodone

Saquinavir / ritonavir: simultaneous administration of trazodone and the drug Invirase in combination with ritonavir can lead to an increase in trazodone concentrations in the plasma. With the simultaneous use of trazodone and ritonavir, adverse reactions such as nausea, dizziness, lowering blood pressure, and fainting have been observed. Trazodone contraindicated for use with Invirase® in combination with ritonavir in connection with the possible development of life-threatening arrhythmias (see the sections "Contraindications" and "Special instructions").

Antihistamines

Terfenadine, astemisole

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

Because of the high likelihood of a similar interaction, saquinavir in combination with ritonavir should also not be administered together with astemizole.

Antimicrobial medications

Clarithromycin

Saquinavir monotherapy: with the simultaneous use of clarithromycin (500 mg twice a day) and saquinavir (1200 mg 3 times a day) there was an increase AUC and C_max saquinavir by 177% and 187%, respectively. Values AUC and C_max clarithromycin increased by about 40% compared with monotherapy with clarithromycin. Joint use with the drug Invirase® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

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

Erythromycin

Monotherapy with saquiovir: while simultaneous application of erythromycin (250 mg 4 times a day) and saquinavir (1200 mg 3 times a day) there was an increase AUC and C_max saquinavir by 99% and 106%. With the simultaneous use of these drugs, dose adjustments are not required.

Saquinavir / ritonavir: the interaction between saquinavir in combination with ritonavir and erythromycin has not been studied. It is possible to develop an additive effect with respect to lengthening the intervals QT and / or PR When used with the drug Invirase ® in combination with ritonavir (see.sections "Contraindications" and "Special instructions"). Simultaneous use with the drug Invirase ® in combination with ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

Streptogramins (quinupristin / delfopristin)

Saquinavir / ritonavir: inhibit isoenzyme CYP3A4, may increase the concentration of saquinavir. With the simultaneous use of these drugs, it is recommended to monitor the patient's condition in order to detect the toxicity of saquinavir.

Pentamidine, sparfloxacin

Saquinavir / ritonavir: simultaneous application with Invirase® in combination with ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

Fusidic acid

Interaction between Invirase® in combination with ritonavir and fusidic acid has not been studied. The simultaneous use of these drugs can cause an increase in plasma concentrations of fusidic acid and saquinavir / ritonavir. One temporary use of fusidic acid and saquinavir / ritonavir is not recommended because of the possible increase in toxicity of both drugs.

Antifungal means

Ketoconazole

Saquinavir monotherapy: with the simultaneous use of ketoconazole (200 mg per day) and the drug Invirase®, an increase in the concentration of saquinavir in plasma is 1.5 times. An increase in the half-life or a change in the rate of absorption was not noted. The administration of saquinavir in a dose of 600 mg three times a day does not affect the pharmacokinetics of ketoconazole. Dose adjustments with simultaneous use of these two drugs in the doses studied are not required.

Saquinavir / ritonavir: simultaneous application of ketoconazole (200 mg per day) and the preparation Invirase ® in combination with ritonavir (1000 mg / 100 mg twice a day) did not lead to a change in the equilibrium values AUC0-12 and C_m_Oh saquinavir and ritonavir. With the simultaneous use of these drugs with ketoconazole at a dose less than or equal to 200 mg, dose adjustment is not required. However, such an application (ketoconazole 200 mg / day and the preparation Invirase ® in combination with ritonavir 1000 mg / 100 mg twice a day) led to an increase in the equilibrium values of C_m_Oh and AUC0-24 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 combination of drugs. It is not recommended to administer ketoconazole at doses greater than 200 mg per day.

Itraconazole

Monotherapy with saquinavir: itraconazole, like ketoconazole, is a relatively potent inhibitor of the isoenzyme CYP3A4, in connection with which similar interaction can be observed. When concomitantly taking itraconazole and saquinavir, it is recommended that the patient be monitored to determine the toxicity of saquinavir. Saquinavir / ritonavir: The interaction between the drug Invirase®, reinforced with ritonavir, and itraconazole has not been studied.

Fluconazole, miconazole

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

Antimycobacterial drugs

Rifabutin

Saquinavir monotherapy: rifabutin reduces the concentration of saquinavir in plasma by 40%. Monotherapy with saquinavir should not be used concurrently with rifabutin (see section "Special instructions").

Saquinavir / ritonavir: with multiple dosing regimens rifabutin (150 mg once every 3 days) in combination with the preparation Invirase® and ritonavir (1000/100 mg twice daily) somewhat reduced the values AUC_0-12 and C_max saquinavir by 13% (90% CI: -31% -9%) and by 15% (90% CI: -32% -7%), respectively, in healthy volunteers. However, rifabutin had no effect on AUC_0-12 (90% CI: -10% -9%) and C_max(90% CI: -8% -7%) of ritonavir. Correction of the dose is not required.

An evaluation of the effect of multiple dose regimens of Invirase ® in combination with ritonavir (1000/100 mg twice daily) on the pharmacokinetics of rifabutin when administered at a dose of 150 mg once every 3 days or at a dose of 150 mg once every 4 days compared to with monotherapy rifabutinom 150 mg in healthy volunteers daily.

When using rifabutin in a dose of 150 mg once every 3 days in combination with the drug Invirase® and ritonavir values AUC_0-12 and C_maxactive substance (rifabutin + 25-O-deacetyl-rifabutin) increased by 134% (90% CI: 109% -162%) and 130% (90% CI: 98% -167%), respectively. The exposure of rifabutin increased by 53% (90% CI: 36% - 73%) for AUC_0-72and by 86% (90% CI: 57% -119%) for C_max. When rifabutin is used at a dose of 150 mg once every 4 days in combination with the drug Invirase® and ritonavir, the values AUC_0-96 and FROM_maxactive substance (rifabutin + 25-O-deacetyl-rifabutin) increased by 60% (90% CI: 43% -79%) and 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.

In assessing the safety and efficacy of concomitant administration of rifabutin with Invirase® and ritonavir for the treatment / prevention of tuberculosis or infection caused by Mycobacterium avium complex, it is necessary to take into account literature data indicating that the frequency of dosing of rifabutin (once every 4 days) in HIV-infected patients (in contrast to healthy volunteers) may be insufficient to prevent the development of rifabutin resistance. To calculate the concentration of rifabutin in the blood, when used at a dose of 150 mg every other day, the values of rifabutin concentration obtained when applied at a dose of 150 mg once every 3 days or 4 days in combination with the preparation Invirase® and ritonavir in a dose of 1000/100 mg 2 times a day. It turned out that the concentration of rifabutin when used in combination with Invirase® and ritonavir did not differ from that when used in the same dose with other protease inhibitors, ritonavir-boosted (darunavir, lopinavir, fosamprenavir).

Thus, the recommended dose of rifabutin when administered in combination with Invirase ® and ritonavir (1000/100 mg twice daily) is 150 mg every other day.With this dosage regimen of these drugs, it is recommended to monitor the activity of "hepatic" enzymes, as well as the number of neutrophils (to detect neutropenia) in the blood.

Rifampicin

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

Saquinavir / ritonavir: simultaneous reception of rifampicin in patients with tuberculosis, taking saquinavir in combination with ritonavir (1600 mg / 200 mg per day), reduced AUC 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®, reinforced with ritonavir, 1000/100 mg twice daily and 450 mg of rifampicin daily, or Invirase® in combination with ritonavir 400/400 mg twice daily and rifampicin 600 mg daily. When taking such a combination of drugs, it becomes possible to develop acute hepatocellular toxicity, therefore, rifampicin It should not be used in patients taking Invirase ® in combination with ritonavir in antiretroviral therapy.

Benzodiazepines

Midazolam

Saquinavir monotherapy: with simultaneous oral administration of midazolam (7.5 mg) saquinavir (1200 mg 3 times a day) increased C_m_Oh and AUC 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 a violation of psychomotor activity and increased sedation. With the simultaneous use of midazolam and saquinavir, 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 administration of saquinavir, midazolam clearance decreased by 56%, and the elimination half-life increased from 4.1 to 9.5 hours, while only the subjective feeling of midazolam increased.

saquinavir / ritonavir: while simultaneous single-dose administration of midazolam (7.5 mg) after 2 weeks of taking the drug Invirase® / ritonavir (1000/100 mg twice daily) there was an increase from_maxmidazolam in 4.3 times and auc midazolam in 12.4 times. the drug Invirase® / ritonavir increased the half-life of midazolam from 4.7 to 14.9 hours, oral administration of midazolam is contraindicated in patients taking saquinavir in combination with ritonavir. caution should be exercised when parenterally administering midazolam to patients taking the drug Invirase®. data on the simultaneous administration of saquinavir in combination with ritonavir and intravenous administration of midazolam are not available. based on data from studies on the joint use of isoenzyme modulators cyp3a4 and midazolam with the intravenous route of administration, it is possible to assume a possible increase in plasma concentrations of midazolam by 3-4 times. simultaneous use of the drug Invirase® and intravenous administration of midazolam should be carried out in intensive care units or in offices with the possibility of timely clinical monitoring and adequate treatment in the event of respiratory depression and / or prolonged sedation. a dose adjustment is necessary, especially in cases of repeated administration of midazolam. alprazolam, dical clorazepate, diazepam and flurazepam

saquinavir / ritonavir: it is possible to increase the concentration of benzodiazepines and the risk of increasing their sedative effect. these drugs should be used with caution, if necessary, reduce the dose of benzodiazepines.

triazolam

saquinavir / ritonavir: it is possible to increase the concentration of triazolam in plasma. simultaneous use with the drug Invirase ® in combination with ritonavir is contraindicated due to the risk of developing longer / excessive sedation and respiratory depression.

blockers of "slow" calcium channels

felodipine, nifedipine, nicardipine, diltiazem, nimodipine, verapamil, amlodipine, nizoldshhn, isradipine

saquinavir / ritonavir: it is possible to increase the concentration of these drugs. These drugs in combination with the drug Invirase® and ritonavir should be used with caution, clinical monitoring of patients is recommended.

glucocorticosteroids

dexamethasone

is an isoenzyme inducer cyp3a4 and can reduce the concentrations of saquinavir. while concomitant administration of saquinavir may decrease. these drugs are recommended with caution.

The interaction between the drug Invirase® in combination with ritonavir and dexamethasone has not been studied.

fluticasone, budesonide

several cases of iscenko-cushing syndrome are described with simultaneous application of these glucocorticosteroids (inhalation or intranasal route of administration) and a small dose of ritonavir. If combined therapy is necessary, the possibility of transferring patients to inhaled biclamethasone should be considered.

nonselective antagonists of endothelin receptors

bosentan

the interaction between the drug Invirase® and bosentan has not been studied. while simultaneous use of the drug Invirase ® in combination with ritonavir and bosentan, an increase in the concentration of bosentan and a decrease in the concentration of saquinavir / ritonavir in plasma are possible. in some cases, a dosage adjustment of bosentan may be required. In the case of simultaneous administration of saquinavir / ritonavir and bosentan, the patient's tolerability of bosentan and antiviral therapy should be monitored.

cardiac glycosides

digoxin

simultaneous administration of a single dose of digoxin (0.5 mg) after two weeks of taking the drug Invirase® in combination with ritonavir (1000/100 mg twice daily) resulted in an increase in c_max and auc0-12 digoxin by 27% and 49%, respectively.these drugs should be used with caution. It is necessary to reduce the dose of digoxin and monitor its concentrations in the plasma.

ergot alkaloids and their derivatives

dihydroergotamine, ergometrine, ergotamine, methylergometrine

simultaneous use of these drugs with the drug Invirase ® in combination with ritonavir is contraindicated, due to the possibility of developing acute toxicity. blockers of n2-histamine receptors ranitidine

monotherapy with saquinavir: with concurrent administration of the drug Invirase®, ranitidine and food, saquinavir exposure was increased (auc on 67%) in comparison with reception only a preparation инвираза® and food. these changes are not clinically significant. correction of the dose is not required.

saquinavir / ritonavir: interaction between the drug Invirase ® in combination with

ritonavir and ranitidine was not studied.

immunosuppressants

cyclosporine, tacrolimus, sirolimus

saquinavir / ritonavir: may increase the concentration of immunosuppressants. it is recommended to monitor the therapeutic concentrations of cyclosporine, tacrolimus, sirolimus with simultaneous admission.

inhibitors of GMG-co-reductase

saquinavir / ritonavir: there is a significant increase in concentration simvastatin and lovastatin, which leads to rhabdomyolysis. simvastatin and lovastatin Do not use in combination with saquinavir / ritonavir.

metabolism atorvastatin and cerivastatin to a lesser extent depends on the activity of the isoenzyme cyp3a4, in combination, they should be used in smaller doses, patients are carefully observed for the development of myopathy (muscle weakness, muscle pain, increased activity of kfc).

pravastatin and fluvastatin not metabolized by isoenzyme cyp3a4. if the use of inhibitors of GMH-co-reductase is indicated, it is recommended to use pravastatin or fluvastatin.

selective beta2-adrenomimetics of long-term action

salmeterol

saquinavir / ritonavir: it is possible to increase the concentration of salmeterol in plasma. the simultaneous use of salmeterol and the drug Invirase® in combination with ritonavir is not recommended because of an increased risk of developing cardiovascular complications, in particular, lengthening the interval qt, heartbeat, sinus tachycardia.

narcotic analgesics

methadone

saquinavir / ritonavir: It is possible to develop an additive effect on the lengthening of intervals qt and / or pr when used with the drug Invirase ® in combination with ritonavir. simultaneous use with the drug Invirase ® in combination with ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias (see the sections "contraindications" and "special instructions").

oral contraceptives

ethinyl estradiol

saquinavir / ritonavir: reduces the concentration of ethinyl estradiol. should use other or additional methods of contraception.

inhibitors of phosphodiesterase type 5 (Iphde-5) sildenafil

simultaneous administration of saquinavir (1200 mg 3 times a day) and sildenafil (a single dose of 100 mg), which is the substrate of the isoenzyme cyp3a4, led to an increase in_m_Oh and auc sildenafil by 140% and 210%, respectively. sildenafil had no effect on the pharmacokinetic parameters of saquinavir. joint use with the drug Invirase® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

tadalafil

saquinavir / ritonavir: with simultaneous admission, an increase in the concentrations of tadalafil is possible.joint use with the drug Invirase® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

vardenafil

saquinavir / ritonavir: with simultaneous admission, an increase in the concentrations of vardenafil is possible. joint use with the drug Invirase® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

drugs that increase the motility of the gastrointestinal tract

metoclopramide

There is no evidence of a decrease in plasma concentrations of saquinavir with simultaneous use of drugs that stimulate the passage of food through the digestive tract.

cisapride

saquinavir / ritonavir: Exposure of cisapride is expected to increase (auc) and lengthening the interval qtc, since cisapride is metabolized by part cyp3a4. cisapride is contraindicated in patients taking saquinavir in combination with ritonavir, because of the possible occurrence of life-threatening arrhythmias (see the sections "contraindications" and "special instructions").

difemanyl

saquinavir / ritonavir: joint use with the drug Invirase ® and ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias (see.section "contraindications" and "special instructions")

antipsychotic drugs (antipsychotics)

pimozide

saquinavir / ritonavir: increased exposure of pimozide (auc), Associated with the additive effect on the lengthening of the interval qt and / or pr (see sections "contraindicationand "special instructions.") Pimozide is contraindicated in patients taking saquinavir in combination with ritonavir (see the "contraindications" section).

quetiapine

The interaction of quetiapine with the drug Invirase® in combination with ritonavir has not been studied. simultaneous use with the drug Invirase® is contraindicated due to the risk of increasing the toxicity of quetiapine and the severity of unwanted reactions (see the "Contraindications" section).

clozapine, haloperidol, mesoridazine, phenothiazine, sertindole, sultopride, thioridazine

saquinavir / ritonavir: simultaneous use with the drug Invirase ® in combination with ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

proton pump inhibitors

omeprazole

saquinavir / ritonavir: simultaneous use of omeprazole (40 mg daily) and the drug Invirase ® in combination with ritonavir (1000/100 mg 2 times a day) led to an increase in equilibrium values auc and with_m_Oh saquinavir by 82% (90% confidence interval (di): 44% -131%) and 75% (90% di: 38% -123%), respectively. plasma concentrations of ritonavir did not change significantly. the simultaneous use of the drug Invirase® in combination with ritonavir and other proton pump inhibitors is not available. the use of the drug Invirase ® in combination with ritonavir simultaneously with omeprazole or other inhibitors of the proton pump is not recommended.

vasodilators

vincamine (for intravenous administration)

saquinavir / ritonavir: simultaneous use with the drug Invirase ® in combination with ritonavir is contraindicated in connection with the possible development of life-threatening arrhythmias.

grapefruit juice

monotherapy with saquiovir: increase the exposure of saquinavir in healthy volunteers with a single intake of grapefruit juice by 50% and 100% when using double-concentration juice, which has no clinical significance and does not require correction of the dose of saquinavir.

saquinavir / ritonavir: the interaction was not studied.

Phytopreparations containing St. John's wort (hypericum perforatum)

monotherapy with saquinavir: some phytopreparations may contain components that are inhibitors or inducers of isoenzyme cyp3a4 or p-glycoprotein, and lead to a change in the pharmacokinetics of saquinavir. It is possible to reduce the concentration of saquinavir in the plasma, the loss of the virologic response and the emergence of resistance to one of the components of antiretroviral therapy. Phytopreparations containing St. John's wort (hypericum perforatum), Do not use in patients taking the drug Invirase®. the inducing effect of St. John's wort preparations can persist for at least 2 weeks after their cancellation.

saquinavir / ritonavir: the interaction was not studied.

medicinal preparations and biologically active additives (bad), containing the extract of garlic

monotherapy with saquinavir: It is possible to reduce the concentration of saquinavir in the plasma, the loss of the virologic response and the emergence of resistance to one of the components of antiretroviral therapy. while taking medications or bad drinks containing a garlic extract (a dose approximately equal to two 4 grams of garlic cloves) and saquinavir (1200 mg three times a day), a healthy decrease was observed in healthy volunteers auc saquinavir by 51%, a decrease in the mean minimum saquinavir concentration (8 hours after dosing) by 49% and a decrease with_m_Oh on 54%. medicines and bad products containing garlic extract should not be used in patients taking saquinavir.

saquinavir / ritonavir: the interaction was not studied. other possible interactions

although no special studies have been conducted, simultaneous administration of saquinavir / ritonavir and other drugs that are substrates of isoenzyme cyp3a4 (dapsone, disopyramide, quinine, fentanyl, alfentanil), can increase the plasma concentrations of these drugs, so the use of such combinations is contraindicated in connection with the possible development of life-threatening arrhythmias (see the sections "contraindications" and "special instructions").

simultaneous administration of the drug Invirase® in combination with ritonavir with drugs that are Substrates of p-glycoprotein (eg, azithromycin), can lead to an increase in the concentrations of these drugs in the plasma, so when using such combinations, you should monitor the patient's condition for the appearance of symptoms of toxicity.

an increase in the concentrations of saquinavir in plasma also results in the appointment of combinations with inhibitors of the isoenzyme cyp3a4. in this case, it is recommended to monitor the patient's condition for signs of toxicity. simultaneous administration with drugs that are inducers of the isoenzyme of cyp3a4 or p-glycoprotein, in contrast, can reduce saquinavir concentrations in plasma. information on a decrease in saquinavir concentrations in plasma when taken together with drugs that reduce the passage of food through the gastrointestinal tract (for example, metoclopramide), absent.

Special instructions:

Before starting therapy

The drug Invirase ® is used 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 report the possibility of developing adverse events in the combined use of several drugs.

Disturbances in cardiac conduction and repolarization

There was a dose-dependent lengthening of the QT and PR intervals in healthy volunteers who received Invirase ® in combination with ritonavir.

The drug Invirase ® in combination with ritonavir is contraindicated in patients with congenital or documented acquired acquired lengthening of the QT interval, electrolyte disorders, especially with uncorrected hypokalemia. The presence of sudden death in a young age in the family history of the patient suggests the presence of an innate lengthening of the QT interval.

The drug Invirase ® in combination with ritonavir is contraindicated when used with certain drugs that have both a pharmacokinetic interaction and the ability to lengthen the intervals of QT and / or PR (see the section "Contraindications" and "Interaction with other medicinal products").

It is not recommended to use Invirase ® in combination with ritonavir in patients who simultaneously receive other drugs that have the ability to extend the QT interval. If necessary, use caution and conduct an electrocardiographic examination if arrhythmia occurs. Caution should be exercised when using Invirase ® in combination with ritonavir in patientswith concomitant structural heart diseases, impaired conduction of the heart, ischemic heart disease or cardiomyopathy, since such patients have an increased risk of developing cardiac conduction disorders.

It is necessary to stop therapy with Invirase ® in combination with ritonavir in case of significant arrhythmias, lengthening of the interval QT or PR. Most often, interval changes QT, associated with the drug, are possible in women and the elderly.

Do not exceed the recommended dose of the drug Invirase ® in combination with ritonavir, since the degree of lengthening intervals QT and PR may increase with increasing drug concentration.

The use of Invirase ® in combination with ritonavir at a dose of 2000 mg once a day / 100 mg once a day is not recommended, since the effect of such a combination on the risk of lengthening the interval QT not studied.

Patients starting therapy with Invirase® in combination with ritonavir

Before the start of therapy, an electrocardiographic study should be performed. Do not start therapy with Invirase ® in combination with ritonavir, if the interval QT>450 ms. Patients with an interval QT<450 ms before the start of treatment is recommended during the therapy to conduct an electrocardiographic study. Patients who have not previously

who received saquinavir therapy and begin therapy with Invirase® / ritonavir 500/100 mg twice a day for the first 7 days followed by a dose change of up to 1000/100 mg twice a day for which the initial value is the interval QT<450 msec, it is recommended to conduct a repeat electrocardiographic study 10 days after the start of therapy.

Therapy with Invirase ® in combination with ritonavir should be discontinued if the interval QT increased> 480 msec or if the interval QT increased by more than 20 msec compared with the initial value (see the section "Pharmacodynamics", subsection "Influence on ECG parameters").

Patients who continue treatment with Invirase® in combination with ritonavir, if it is necessary to prescribe concomitant therapy with drugs capable of lengthen the interval QT; or patients receiving therapy with drugs capable of lengthen the interval QT, if it is necessary to administer therapy with Invirase® in combination with ritonavir, and if alternative therapy is not available, and the benefit exceeds the risk

Before the start of concomitant therapy, an electrocardiographic study is necessary. Do not administer concomitant therapy if the interval QT>450 msec (see section "Interaction with other drugs"). Required conduct a repeat electrocardiographic study, if the initial interval QT<450 ms. If the interval QT>480 ms or interval QT increased by more than 20 ms after the addition of concomitant therapy, the attending physician, depending on the clinical situation, must decide to discontinue Invirase ® in combination with ritonavir and / or concomitant therapy.

Patients with mild to moderate dysfunction

Therapy with Invirase ® in combination with ritonavir is contraindicated in patients with decompensated liver disease (see section "Contraindications"). In patients with chronic hepatitis B or C who are receiving combined antiretroviral therapy, the risk of developing adverse events (including fatal) from the liver is increased. In case of simultaneous use of antiretroviral therapy for hepatitis B or C in a patient, it is necessary to carefully read the medical information on the drugs used.

With simultaneous use of combined antiretroviral therapy in patients with a history of liver failure (including chronic active hepatitis), the incidence of hepatic impairment increases. It is necessary to carefully monitor the symptoms and signs of impaired liver function. If signs of impaired liver function appear, interrupt or cancel therapy. In HIV-infected patients with a mild and moderate impairment of liver function, dose adjustment is not required (data are limited). Nevertheless, due to the different exposure of the drug in this population, careful monitoring of the safety profile (including signs of arrhythmia) and a virologic response is recommended (see the sections "Dosage and Administration" and "Pharmacological properties"). After initiation of saquinavir therapy, patients with hepatitis B or C, cirrhosis, chronic alcoholism, and / or other liver diseases experienced impairment of liver disease or portal hypertension, accompanied by jaundice, ascites, edema and varicose veins of the esophagus (in several fatal patients ).The causal relationship between the development of portal hypertension and saquinavir therapy has not been established. It is necessary to carefully monitor the symptoms and signs of hepatotoxicity.

Patients with impaired renal function

A small part of the drug is excreted through the kidneys, therefore, it is not necessary to initially adjust the dose of the drug in patients with impaired renal function. However, studies in patients with severe renal failure have not been conducted, and therefore caution should be exercised when using saquinavir in such patients.

Children and the elderly

The effectiveness and safety of saquinavir in HIV-infected children (under 16 years of age) have not been established. Information on the use of the drug Invirase® without ritonavir (unresponsive regimen) in children is absent, there is only limited information on the use of saquinavir in soft gelatin capsules (unresponsive regimen) in children. Given the significantly lower concentration of saquinavir in serum compared to adults, children should not use Invirase® without ritonavir. When using saquinavir in soft gelatin capsules (50 mg / kg 2 times a day) together with nelfinavir or ritonavir in children, saquinavir exposure increased significantly.When used simultaneously with ritonavir, exposure of saquinavir may be up to 2 times greater than exposure in adults receiving saquinavir in soft gelatin capsules 1200 mg 3 times a day.

Experience in patients over 60 years of age is limited. Patients of elderly and senile age may be more susceptible to the effect of the drug on QT and / or PR interval.

Lactose intolerance

The preparation Invirase® contains lactose. Patients with hereditary intolerance to galactose, lactase deficiency or glucose-galactose malabsorption should not take the drug.

Diabetes

In patients receiving HIV protease inhibitors, cases of newly diagnosed diabetes mellitus, hyperglycemia, or decompensation of concomitant diabetes mellitus are described. In some cases, hyperglycemia was severe, sometimes accompanied by ketoacidosis. At the same time, many patients had concomitant diseases, sometimes requiring the appointment of drugs that have the ability to increase the concentration of glucose in the blood and cause the development of diabetes mellitus or hyperglycemia.The causal relationship between the therapy of HIV protease inhibitors and the development of hyperglycemia and diabetes mellitus is not established.

Hemophilia

In the treatment of HIV protease inhibitors, cases of increased bleeding are described, including spontaneous subcutaneous hematoma formation and hemarthrosis in patients with hemophilia type A and B. Some patients had to increase the dose of coagulation factor VIII. In more than half the cases, treatment with the HIV protease inhibitor has been continued or resumed. One can assume a causal relationship of these undesirable phenomena with the use of HIV protease inhibitors, although a mechanism likeeffect has not been studied. Patients with hemophilia should be warned about the possible increase in bleeding.

Redistribution of fat

When combined antiretroviral therapy was used, fat redistribution or deposition was noted, including obesity by the central type, fat deposition on the dorsal surface of the neck and back ("bovine hump"), reduction of subcutaneous fat on the limbs, enlargement of the mammary glands due to fat deposits, as well as "cushingoid" (rounded, moonlike face, facial hyperemia, trunk type of obesity, adipose tissue deposition in supraclavicular fossa).Redistribution of adipose tissue is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance and hyperglycemia. The severity of these disorders varies both within the class and between classes of antiretroviral drugs (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors). Factors that increase the risk of lipodystrophy include: elderly age, duration of therapy, stavudine, hypertriglyceridemia, hyperlactatemia. Diagnosis includes assessment of physical signs of fat tissue redistribution, blood glucose and blood lipids. If these changes are detected, consideration should be given to changing the antiretroviral therapy and / or taking measures to correct such abnormalities (eg, prescribing hypolipidemic drugs). Currently, the mechanism of development of metabolic disorders and long-term effects, such as an increased risk of cardiovascular disease, are not known.The use of Invirase ® in combination with ritonavir in doses greater than 1000/100 mg twice a day is usually accompanied by an increase in the incidence of adverse events, as saquinavir concentrations in plasma in the presence of ritonavir increase. In some cases, the combined use of saquinavir and ritonavir has led to severe adverse events, mainly to the development of diabetic ketoacidosis and impaired liver function, especially in patients who previously had liver disease.

Syndrome of immune reactivation (inflammatory immune reconstitution syndrome)

During the initial phase of combined antiretroviral therapy, including Invirase ®, in patients with severe immunodeficiency, a systemic inflammatory response to previously asymptomatic or opportunistic infections and autoantigens or increased symptoms may occur. This reaction can cause serious clinical conditions or exacerbation of symptoms, which in turn may require further evaluation and treatment.

The immune reactivation syndrome may also be manifested by the development of autoimmune disorders (eg, Graves' disease) that develop at different times of therapy.The development of autoimmune disorders is possible many months after the initiation of therapy. Typical examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pneumocystis carinii. If any symptom of inflammation occurs, you should diagnose and prescribe a treatment.

Interaction with other drugs and (or) food products The simultaneous use of the drug Invirase® (unresponsive regimen), taken in combination with other antiretroviral drugs, with rifabutin, rifampicin, or efavirenz leads to a significant decrease in the concentrations of saquinavir in the plasma, so the joint use of these drugs is not recommended. The recommended dose of rifabutin, taken in combination with the drug Invirase® and ritonavir, is 150 mg every other day. Information on the joint use of saquinavir, ritonavir and efavirenz is limited. Do not assign rifampicin patients taking the drug Invirase® with ritonavir, in combination with other antiretroviral drugs because of the risk of developing severe hepatocellular toxicity.

Do not use Phytopreparations containing St. John's wort (Hypericum perforatum) and extract of garlic, in combination with Invirase®(unresponsive regimen), due to a possible decrease in the concentration of the drug Invirase ® in plasma and its clinical efficacy.

Interaction with ritonavir: the recommended dose of the drug Invirase ® in combination with ritonavir 1000 mg / 100 mg 2 times a day. With an increase in the dose of ritonavir, an increase in the incidence of adverse events is possible. Simultaneous use of saquinavir and ritonavir led to the development of serious adverse events (diabetic ketoacidosis, impaired liver function), especially in patients with liver diseases in history.

With the simultaneous use of the drug Invirase ® in combination with ritonavir with inhibitors of HMG-CoA reductase, mainly with drugs metabolized with the participation of cytochrome P450 ZA4 (for example, simvastatin and lovastatin), it is possible to increase concentrations of HMG-CoA reductase inhibitors in plasma. In rare cases, an increase in the concentrations of simvastatin and lovastatin may cause severe undesirable phenomena, such as myalgia and rhabdomyolysis. It is necessary to avoid the joint use of these drugs.

With caution, it is recommended to use Invirase ® in combination with ritonavir simultaneously with atorvastatin and cerivastatin (less metabolized by cytochrome P450 3A4). In this case, the dose of atorvastatin and cerivastatin should be reduced. If it is necessary to prescribe inhibitors of HMG-CoA reductase, it is recommended to apply fluvastatin or pravastatin. The use of Invirase ® in combination with ritonavir reduces concentration ethinylestradiol. Therefore, other or additional methods of contraception should be used when the drug Invirase® is used in combination with ritonavir and estrogen-containing oral contraceptives.

The simultaneous use of saquinavir in combination with ritonavir and fluticasone (or other glucocorticosteroids metabolized by isoenzyme CYP3A4) Not recommended. Simultaneous use of these drugs is possible only if the potential benefit of therapy exceeds the risk of systemic effects of glucocorticosteroids (including Cushing's syndrome and suppression of adrenal function).

The simultaneous use of saquinavir in combination with ritonavir and typrinavir (double enhanced regimen) leads to a significant decrease in saquinavir concentrations in plasma. Therefore, joint therapy with these drugs is not recommended. Simultaneous reception digoxin and saquinavir in combination with ritonavir leads to a significant increase in digoxin concentrations in plasma. These drugs should be used with caution. It is necessary to reduce the dose of digoxin and monitor its concentrations in the plasma.

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 in particular in patients with advanced HIV infection and / or prolonged combined antiretroviral therapy have been reported. Patients should be advised to consult a doctor if joint pain occurs, joint stiffness, or difficulty in moving. Chronic diarrhea or malabsorption

Information on the use of saquinavir in enhanced regimen in patients with chronic diarrhea or malabsorption is absent.

Data on the efficacy and safety of saquinavir in unresponsive regimens in these patients are limited and do not allow judging the possibility of obtaining subtherapeutic concentrations of saquinavir.

Effect on the ability to drive transp. cf. and fur:Special studies were not conducted. Data on the possibility of the drug Invirase® to influence the ability to drive vehicles, mechanisms are absent. However, when working with machines and mechanisms, the drug safety profile should be taken into account (dizziness, fatigue and visual impairment are possible). If these phenomena occur, you should refrain from working with machines and mechanisms.

Form release / dosage:

Tablets coated with a coating, 500 mg

Packaging:

For 120 tablets in a bottle of high density polyethylene (HDPE) with a screw cap that opens when pressed. The lid has control of the first opening. The method of opening the vial is shown on the lid in the form of a scheme. Each vial with the instruction for use is placed in a cardboard box.

Storage conditions:Store at a temperature not higher than 30 ° C. Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001436/07

Date of registration:09.07.2007

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Invirase® (Invirase®)