Inviraza

General characteristics. Structure:

Active agent: саквинавир 500 mg (in the form of a sakvinavir of a mezilat of 571.5 mg);

Excipients: K30 40 povidone of mg, lactose monohydrate of 38.5 mg, croscarmellose sodium of 45 mg, microcrystallic cellulose of 95 mg, magnesium stearate of 10 mg;

Cover substances: gipromelloza of 7.929 mg, titanium dioxide of 4.887 mg, talc of 4.61 mg, dye ferrous oxide of yellow 0.645 mg, dye ferrous oxide of red 0.369 mg, triacetin of 1.559 mg.

Pharmacological properties:

Pharmacodynamics. Action mechanism.
Anti-retrovirus drug, HIV protease inhibitor.
HIV protease is the major virus enzyme necessary for process of specific splitting of virus structural Gag and Gag-Pol polypeptides. These virus polypeptides contain the site of splitting which is distinguished only by HIV protease and closely related virus proteases.
Sakvinavir - a peptidopodobny structural analog of these sites of splitting - is the selection and reversible inhibitor of HIV protease, prevents formation of full-fledged infectious virus particles.
Antiviral activity of in vitro
Sakvinavir shows antiviral activity as concerning laboratory strains, and clinical VICh-1 isolates with typical EC50 And values of the EU 90 (the concentration suppressing 50% and 90% of activity of HIV protease), varying from 1 to 10 nmols/ml and from 5 to 50 nmol/ml, respectively. Anti-virus activity of a sakvinavir of in vitro was estimated on the infected line of T-cells and primary human cultures of lymphocytes and monocytes. Anti-virus activity of in vitro was observed in relation to a set of VICh-1 isolates of group M, except kled In (And, AE, C, D, G, N) and VICh-2 with EC50 0.3-2.5 values nmol/ml. In the presence of 50% of human blood serum or an alfa1-acid glycoprotein (1 mg/ml) antiviral activity of a sakvinavir decreases on average in 25 and 14 times, respectively.
Resistance to a sakvinavir
Antiviral activity of rather initial genotype and phenotype
The genotypic and phenotypical clinical criteria predicting clinical performance of the sakvinavir strengthened ritonaviry were received after carrying out retrospective analyses of clinical trials, and also the analysis of big group of the hospitalized patients.
It was shown that an initial phenotype concerning a sakvinavir (change of sensitivity concerning a standard; the PhenoSense test) is a predictive factor of the virologic answer. The first reduction of the virologic answer was observed at sensitivity reduction more than by 2.3 times. The affirmative virologic answer was not observed at decrease in sensitivity more than by 12 times.
9 codons of protease (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) connected with reduction of the virologic response to therapy sakvinaviry in a combination with ritonaviry (1000/100 mg 2 times a day), at the patients who were earlier not accepting саквинавир are revealed. Existence of 3 and more mutations caused the reduced response to therapy sakvinavirom/ritonaviry.
The interrelation between quantity of these mutations causing resistance to a sakvinavir, and the virologic answer was confirmed during the independent clinical trial including population of patients who received more intensive care earlier including 54% of patients earlier received саквинавир (р =0.0133, see Table 1). The mutation of G48V which was defined in vitro as a mutation characteristic of a sakvinavir earlier was present initially at 3 patients. At all these patients of the response to therapy it was not received.

Table 1. The virologic answer on sakvinavir/ritonavir, stratified by quantity of the initial mutations causing resistance to a sakvinavir

Quantity of the initial mutations causing resistance to a sakvinavir *	The hospitalized patients Number of the patients who were not receiving earlier treatment sakvinaviry		Retrospective analysis of KI Number of the patients who were not receiving/receiving earlier treatment sakvinaviry
	N=138	Change of concentration of VICh-1 of RNA in a blood plasma on 12-20 weeks in comparison with initial	N=114	Change of concentration of VICh-1 of RNA in a blood plasma on the 4th week in comparison with initial
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

* A scale of the mutations associated with sakvinaviry: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M

Efficiency
Comparison of efficiency and safety of therapy sakvinaviry in soft gelatin capsules was carried out to combinations with ritonaviry (1000 mg / 100 mg 2 times a day) and two nukleozidny (NIOT) or nenukleozidny inhibitors of the return transcriptase (NNIOT) and therapy indinaviry to combinations with ritonaviry (800 mg / 100 mg 2 times a day) and two NIOT/NNIOT at more than 300 patients (receiving receiving treatment by HIV protease inhibitor earlier). The combination of a sakvinavir with ritonaviry was characterized by bigger virologic activity in comparison with a combination of an indinavir and a ritonavir, at the same time change of the appointed treatment was considered as virologic failure (research 1).
Comparison of efficiency and safety of therapy sakvinaviry in soft gelatin capsules was carried out to combinations with ritonaviry (1000 mg / 100 mg 2 times a day) and two NIOT/NNIOT and therapy lopinaviry to combinations with ritonaviry (400 mg / 100 mg 2 times a day) and two NIOT/NNIOT at 324 patients (receiving receiving treatment by HIV protease inhibitor earlier). Any patient from group of therapy lopinavirom/ritonaviry did not accept лопинавир before randomization while 16 patients from group of reception of a sakvinavira/ritonavir accepted саквинавир (research 2) earlier.

Table 2. Demographic characteristics of patients from the conducted researches *

	Sakvinavir/ritonavir	Indinavir/ritonavir	Sakvinavir/ritonavir	Lopinavir/ritonavir
	N=148	N=158	N=161	N=163
Floor (men's)	82%	74%	81%	76%
Race (Caucasian / negroid / Mongoloid) (%)	86/9/1	82/12/4	75/19/1	74/19/2
Age, median, years	39	40	40	40
Stage With (classification of CDC) (%)	32%	28%	32%	31%
The patients who were not accepting earlier anti-retrovirus drugs (%)	28%	22%	31%	34%
The patients who were not accepting earlier inhibitors of HIV protease (%)	41%	38%	48%	48%
Median of a reference value of VICh-1 of RNA, log10 of copies/ml (dispersion)	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 of initial number of cells of CD4†, cells/mm3 (dispersion)	272 (135-420)	280 (139-453)	241 (86-400)	239 (95-20)

† Data are obtained from the report of clinical trials

Table 3. Results of therapy in the conducted researches † (in 48 weeks).

Results	Sakvinavir/ritonavir	Indinavir/ritonavir	Sakvinavir/ritonavir	Lopinavir/ritonavir
The appointed treatment, n (%) is begun	148 (94%)	158 (99%)	161 (94%)	163 (98%)
The appointed treatment, n (%) is cancelled	40 (27%)	64 (41%)	48 (30%)	23 (14%)
	É =		É =
Virologic failure at patients ITT/е*#	36/148 (24%)	41/158 (26%)	53/161 (33%)	29/163 (18%)
	É =		É =
Indicator of patients with virus loading <50 copies/ml in 48 weeks, IТТ/е#	97/144 (67%)	106/154 (69%)	90/158 (57%)	106/162 (65%)
	P> 0.05 ‡		É =
Indicator of patients with virus loading <50 copies/ml in 48 weeks, the patients who are on treatment	82/104 (79%)	73/93 (78%)	84/113 (74%)	97/138 (70%)
	P> 0.05 ‡		É =
Median of increase in number CD4 of cells in 48 weeks (cells/mm3)	85	73	110	106

* For both researches: for the patients included in a research with virus loading <200 copies/ml, virologic failure was defined as ≥200 copies/ml. Research 1: for the patients included in a research with virus loading of ≥200 copies/ml, virologic failure was defined as any increase in ≥0.5 log and/or virus loading of ≥50000 copies/ml in 4 weeks, ≥5000 copies/ml in 12 weeks, or virus loading of ≥200 copies/ml in 24 weeks, etc. Research 2: any increase in ≥0.5 log on a separate visit; ≤0.5 log decrease, if virus loading of ≥200 copies/ml in 4 weeks;
≤1.0 log decrease from initial value, if virus loading of ≥200 copies/ml in 12 weeks; and virus loading of ≥200 copies/ml in 24 weeks.
#ITT/е = all patients included in a research / subjected to treatment.
† Data are obtained from the report of clinical trials.
‡ These publications of a research 1.

Influence on ECG indicators

Influence of the drug Inviraza® in a combination with ritonaviry in doses of 1000/100 mg 2 times a day (therapeutic doses) and 1500/100 mg 2 times a day (the dose exceeding therapeutic) on QT interval in 20 h for the 3rd day of administration of drug was studied in a double blind research with 4-component cross design, placebo and active control (moxifloxacin of 400 mg daily) with the assistance of healthy volunteers (men's and female) aged from 18 up to 55 years (N=59).
Considering data of the previous 14-day pharmacokinetic research using repeated doses in which the maximum pharmacokinetic exposure was reached for the 3rd day of administration of drug, as a point for evaluating the 3rd day was chosen. At administration of drug of Inviraza® in a combination with ritonaviry in doses of 1000/100 mg 2 times a day and 1500/100 mg 2 times a day for the 3rd day of a research healthy volunteers had average Cmax values approximately in 3 and 4 times average Cmax values in an equilibrium state at administration of drug of Inviraza® in a combination are higher, respectively, than with ritonaviry in a dose of 1000/100 mg 2 times a day at HIV-positive patients.
In the conducted research for adequate assessment of changes of an interval of QT in various groups QTcS indicator, specific to this research (QT interval corrected rather reference values received prior to administration of drug (dense predose-baseline correction) and depending on ChSS was used (like the amendment of Fridericia)).
For the 3rd day the upper bound of unilateral 95% of a confidence interval for the maximum value of an average difference of indicators of QTcS between both groups of reception of active agent (Inviraza® in a combination with ritonaviry in the therapeutic doses and doses exceeding therapeutic) and group of placebo made> 10 milliseconds (ms) (see Table 4). It was revealed that Inviraza® in a combination with ritonaviry in the doses exceeding therapeutic makes more significant impact on QT interval in comparison with therapeutic doses. Most of participants of a research (89% of patients at reception of therapeutic doses and 80% of the patients receiving drugs in the doses exceeding therapeutic) had QTcS <450 ms, and one participant had no interval of QTc> 500 ms (see also section "Precautionary measures").

Table 4. An indicator of the maximum average ddQTcS value † (ms) for the 3rd day for therapy by the drug Inviraza® in a combination with ritonaviry in therapeutic doses, in the doses exceeding therapeutic and for active control (moxifloxacin) at healthy volunteers.

Treatment	Temporary point of assessment after administration of drug	Indicator of the maximum average ddQTcS value	Standard error	The upper bound of 95% of DI for ddQTcS
Ê¡ó¿Óáºá®/ритонавир 1000/100 mg 2 times a day	12 h	18.86	1.91	22:01
Ê¡ó¿Óáºá®/ритонавир 1500/100 mg 2 times a day	20 h	30.22	1.91	33.36
Моксифлоксацин^	4 h	12:18	1.93	15:36

† The removed difference between QTcS indicators (QT interval corrected rather reference values received prior to administration of drug, specific to this research) in group receiving active treatment and in group of placebo.
^Прием 400 mg only for the 3rd day. Note: in a research QTcS indicator for men was calculated by a formula QT/RR0.319, and for women - QT/RR0.337 that corresponds to the amendment of Fridericia (QTcF=QT/RR0.333).

In this research for the 3rd day lengthening of an interval of PR> 200 ms were observed at 40% of the patients receiving the drug Inviraza®/ritonavir in a dose of 1000/100 mg 2 times a day and at 47% of the patients receiving the drug Inviraza®/ritonavir in a dose of 1500/100 mg 2 times a day. At 3% of the patients receiving moxifloxacin as active control and at 5% of patients from group of placebo PR lengthening> 200 ms was observed. The maximum value of average change of an interval PR in comparison with an indicator prior to administration of drugs made 25 ms in group receiving the drug Inviraza®/ritonavir in a dose of 1000/100 mg 2 times a day, and 34 ms in group receiving the drug Inviraza®/ritonavir in a dose of 1500/100 mg 2 times a day (see also section "Precautionary measures").
Cases of "piruetny" tachycardia (torsade des pointes) and lengthening of an interval of QT> 500 ms in a research were not observed. At some patients the syncope cannot exclude communication between development or a presinkopalny state and lengthening of an interval of PR. Clinical value of these changes observed at healthy volunteers is not known for the HIV-positive patients receiving the drug Inviraza®/ritonavir, however it is necessary to avoid increase in a dose of the drug Inviraza®/ritonavir more than 1000/100 mg 2 times a day.
Preclinical data on safety
Carcinogenicity
No cancerogenic activity of a sakvinavir at administration of drug was revealed to rats and mice for 2 years. Exposure of a sakvinavir in plasma (AUC) at these individuals equaled about 37% and 85% of exposure of a sakvinavir at people at administration of drug of Inviraza® and ritonavir in doses of 1000/100 mg 2 times a day.
Mutagenicity
In the researches in vitro on a mutagenicity and genotoxicity (if necessary - with metabolic activation) it was shown what саквинавир does not render mutagen activity as on bacterial cells (Ames's test), and on cells of mammals (cells of easy Chinese hamsters of V79/HPRT-test with гипоксантингуанинфосфорибозилтрансферазой). Sakvinavir does not cause chromosome mutations of in vivo (micronuclear test on mice) or in vitro in human lymphocytes, and also does not cause primary damage of in vitro DNA (reparative synthesis of DNA).
Influence on fertility
In researches on rats negative influence on reproductive function and fertility at the values of exposure of drug (AUC) making about 33% of exposure at people at administration of drug of Inviraza® in a combination with ritonaviry in the recommended doses of 1000/100 mg 2 times a day was not revealed.
Teratogenecity
In researches on rats and rabbits embriotoksichesky or teratogenic influence of a sakvinavir at the values of exposure of drug (AUC) making about 32% of exposure at people at administration of drug of Inviraza® in a combination with ritonaviry in the recommended doses of 1000/100 mg 2 times a day was not observed.

Pharmacokinetics. Absorption. At reception of a single dose of drug of 600 mg after reception of high-calorific food absolute bioavailability of a sakvinavir makes 4%, varying from 1% to 9%. Most likely bioavailability is limited by a combination of effect of incomplete absorption and the expressed metabolism of "the first passing" through a liver. It was shown that PH value does not play a large role in the significant increase in bioavailability which is observed after meal.
At reception of repeated doses after food (25-600 mg 3 times a day) bigger increase in exposure of a sakvinavir (by 50 times) was noted, than at proportional increase in a dose (by 24 times). After multiple dose of a sakvinavir (600 mg 3 times a day) at HIV - the infected patients the area under a curve "concentration time" in an equilibrium state (AUC) is 2.5 times higher (95% the confidence interval (CI), 1.6-3.8), than after a single dose.
At healthy volunteers of AUC after reception of 600 mg of a sakvinavir on an empty stomach made 24 нг * h/ml (coefficient of variation of 33%), after meal (48 g of protein, 60 g of carbohydrates, 57 g of fats, 1006 kcal) - 161 нг * h/ml (coefficient of variation of 35%).
Meal increases the maximum concentration of a sakvinavir from 3.0 ng/ml to 35.5 ng/ml and time of its achievement from 2.4 to 3.8 h. Similar influence of food continues during 2 h after food. Therefore administration of drug of Inviraza® needs to be carried out no later than 2 h after food.
In a cross research at the HIV-positive patients receiving the drug Inviraza® in a combination from ritonaviry 1000/100 mg 2 times a day at first on an empty stomach (three consecutive receptions), and then after reception of high-calorific food (46 g of fats, 1091 kcal) (three consecutive receptions), AUC0-12 of a sakvinavir equaled 10320 нг * h/ml and 34926 нг * h/ml, respectively. At all patients (except one) achievement of values of the minimum equilibrium concentration of drug (Cssmin) above the lower values of therapeutic range at reception was noted on an empty stomach. Nevertheless, the drug Inviraza® in a combination with ritonaviry should be accepted during 2 h after food.
At the HIV-positive patients receiving саквинавир 600 mg 3 times a day after food, AUC and the maximum concentration in plasma (Cmax) surpassed those at healthy volunteers at the similar mode of dosing approximately twice.
Sakvinavir in soft gelatin capsules of 200 mg or саквинавир in tablets, coated, 500 mg in a combination with ritonaviry in doses of 400/400 mg or 1000/100 mg twice a day provide similar or big system exposure of a sakvinavir for 24 h, than at increase in a dose of a sakvinavir in soft gelatin capsules of 200 mg to 1200 mg / three times in days.
Diarrhea does not influence absorption of a sakvinavir, as well as administration of drug does not exert impact on parameters of gastrointestinal absorption.
Sakvinavir is substrate for protein of multiple medicinal resistance of MDR1 (R-glycoprotein).
Distribution
It is well distributed in fabrics. The average volume of distribution in an equilibrium state later in/in introductions of 12 mg - 700 l (coefficient of variation of 39%). Communication with proteins of plasma - 98%, does not depend on concentration of drug (15-700 ng/ml). Sakvinavir (at reception of 600 mg 3 times a day) is not defined in cerebrospinal fluid.
Metabolism
Is exposed to considerable hepatic metabolism. Bystry metabolism to mono - and di - hydroxylated inactive derivatives is mediated through system of P450 cytochrome and carried out by an isoenzyme of CYP3A4 which is responsible for more than 90% of hepatic metabolism (research in vitro). Later in/in introductions of 66% of the circulating sakvinavir other part - in the form of metabolites is found in not changed look, that corresponds to extensive metabolism of "the first passing" in a liver.
The system clearance in/in infusion of 6, 36 and 72 mg of a sakvinavir high also makes later 1.14 l/h/kg (coefficient of variation of 12%) that slightly exceeds a hepatic blood stream.
The drug elimination half-life makes 7 h of an organism.
Removal
In 4 days after reception of a |4C-sakvinavir in (600 mg) 88% and 1% of radioactivity are found in Calais and urine, respectively.
In 4 days after intravenous administration of a 14C-sakvinavir (10.5 mg) of 81% and 3% of radioactivity are found in Calais and urine, respectively.
After intake of 13% of the sakvinavir circulating in plasma it was presented in not changed look, other part - in the form of metabolites.

Pharmacokinetics in special clinical groups.
The drug Inviraza® pharmacokinetics at patients with a renal failure was not studied.
Liver failure
Influence of an abnormal liver function on equilibrium pharmacokinetics of a sakvinavir in a combination with ritonaviry was studied with the assistance of HIV-positive patients (N=7) with a moderate abnormal liver function (a class B (7-9 points) on a scale of Chayld-Pyyu). This research included control group of the HIV-positive patients (N=7) with normal function of a liver corresponding to the studied patients on age, sex, body weight and consumption of tobacco. At HIV-positive patients with a moderate abnormal liver function averages (% coefficient of variation) AUC0-12 and Cmax values of a sakvinavir made 24.3 (102%) mg * h/ml and 3.6 (83%) mg/ml, respectively. The corresponding values in control group made 28.5 (71%) mg * h/ml and 4.3 (68%) mg/ml. Concerning AUC0-12 and Cmax the average geometrical pharmacokinetic parameters at patients with an abnormal liver function to pharmacokinetic parameters of patients with normal function of a liver (90% of DI) made 0.7 (0.3-1.6) that allows to assume about 30% reduction of pharmacokinetic exposure at patients with a moderate abnormal liver function. With a moderate abnormal liver function of dose adjustment of a sakvinavir it is not required from HIV-positive patients (see the section "Features of Use by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases" and the section "Precautionary measures"). Influence of a floor on drug Inviraza® pharmacokinetics at single oral administration of 600 mg at healthy volunteers is not revealed. At a research of bioequivalence of a sakvinavir in capsules of 200 mg and tablets, coated, 500 mg in a combination with ritonaviry higher exposure of a sakvinavir is found in women (AUC for 56%, Cmax for 26%), irrespective of the body weight and age. Clinically significant distinctions of efficiency and safety of the registered mode of dosing of a sakvinavir at men and women are not revealed. Therapy sakvinaviry in a combination with ritonaviry in doses of 1000/100 mg was recognized safe and effective at both floors.
Influence of race on pharmacokinetics of a sakvinavir was not studied.
Studying of pharmacokinetic parameters at children up to 16 years and adults is more senior than 65 years was not carried out.

Indications to use:

As a part of a combination therapy with ritonaviry and other anti-retrovirus means for treatment of the adult patients infected with VICh-1.

Route of administration and doses:

Инвираза® it is appointed only in a combination with ritonaviry!
It is recommended to observe strictly ordered mode of administration of drugs.
Inside, in time or no later than 2 hours after meal.
The standard mode of dosing Adults and teenagers is more senior than 16 years:
- in a combination with ritonaviry (the strengthened mode): Ê¡ó¿Óáºá® 1000 mg 2 times a day and ритонавир 100 mg 2 times a day in a combination with other anti-retrovirus drugs; the drug Inviraza® and ритонавир is accepted inside at the same time and no later than 2 hours after meal;
- in a combination with other inhibitors of HIV protease: for acquaintance with the recommended doses and possible side effects of other anti-retrovirus drugs it is necessary to study instructions for their use.
Dosing in special cases
At emergence of the heavy phenomena of toxicity treatment sakvinaviry should be interrupted. Owing to possible increase in plasma concentration at a combination therapy with other anti-retrovirus drugs (for example, with ritonaviry) change of doses of inhibitors of HIV protease can be required.
Recommendations about dosing at special groups of patients are specified in the section "Features of Use by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases".

Precautionary measures
Before therapy
Инвираза® it is appointed only in a combination with ritonaviry.
Patients need to be informed that саквинавир does not cure HIV infection and that at them the diseases associated with it, including opportunistic infections can develop. It is also necessary to report about a possibility of development of the undesirable phenomena at the combined use of several drugs.
Disturbances of conductivity of heart and repolarization
Dozozavisimy lengthening of intervals of QT and PR at the healthy volunteers receiving the drug Inviraza® in a combination with ritonaviry was observed.
Инвираза® in a combination with ritonaviry it is contraindicated to patients with the inborn or documentary confirmed acquired lengthening of an interval of QT, electrolytic disturbances, especially with not corrected hypopotassemia. Existence in the family anamnesis of the patient of cases of sudden death in young age allows to assume existence of inborn lengthening of an interval of QT.
The drug Inviraza® in a combination with ritonaviry is contraindicated at use with some drugs which possess at the same time pharmacokinetic interaction and ability to extend intervals of QT and/or PR (see the section "Contraindications" and "Interaction with Other Medicines and Foodstuff").
Use of the drug Inviraza® in a combination with ritonaviry the patients who are at the same time receiving other medicines, having ability to lengthening of an interval of QT is not recommended. In case of need sharing it is necessary to be careful and conduct an electrocardiographic research at emergence of symptoms of arrhythmia. It is necessary to be careful at use of the drug Inviraza® in a combination with ritonaviry at patients with the accompanying structural heart diseases, disturbances of conductivity of heart, coronary heart disease or a cardiomyopathy as such patients have the increased risk of development of disturbances of cordial conductivity.
It is necessary to stop therapy by the drug Inviraza® in a combination with ritonaviry in case of developing of significant arrhythmias, lengthening of an interval of QT or PR. Most often the changes of an interval of QT connected with drug are possible at women and elderly people.
It is not necessary to exceed the recommended drug Inviraza® doses in a combination with ritonaviry as extent of lengthening of intervals of QT and PR can increase with increase in concentration of drug.
Use of the drug Inviraza® in a combination with ritonaviry in a dose of 2000 mg of 1 times a day / 100 is not recommended to mg of 1 times a day as influence of a similar combination on risk of lengthening of an interval of QT it was not studied.
The patients beginning therapy with the drug Inviraza® in a combination with ritonaviry: prior to therapy it is necessary to conduct an electrocardiographic research. It is not necessary to appoint the drug Inviraza® in a combination with ritonaviry if QT interval> 450 ms. Patients with QT interval <450 ms in 3-4 days after the beginning of therapy should conduct a repeated electrocardiographic research. Therapy by the drug Inviraza® in a combination with ritonaviry should be stopped if QT interval> 480 ms or if the interval of QT increased by more than 20 ms in comparison with a reference value.
The patients continuing therapy by the drug Inviraza® in a combination with ritonaviry in need of purpose of the accompanying therapy by the drugs capable to extend QT interval; or the patients receiving therapy by the drugs capable to extend QT interval, in need of purpose of therapy with the drug Inviraza® in a combination with ritonaviry and if alternative therapy is absent, and the advantage exceeds risk: prior to the accompanying therapy it is necessary to conduct an electrocardiographic research. It is not necessary to appoint the accompanying therapy if QT interval> 450 ms (see the section "Interaction with Other Medicines and (or) Foodstuff"). It is necessary to conduct a repeated electrocardiographic research if initially QT interval <450 ms. If QT interval> 480 ms or an interval of QT increased by more than 20 ms after accession of the accompanying therapy, the attending physician, depending on a clinical situation, has to make the decision on drug withdrawal of Inviraza® in a combination with ritonaviry or/and the accompanying therapy.
With an easy and moderate abnormal liver function of dose adjustment it is not required from HIV-positive patients (data are limited). After the beginning of therapy sakvinaviry at patients with hepatitis B or C, cirrhosis, an alcoholism and/or other diseases of a liver cases of deterioration in a disease of a liver or development of the portal hypertensia which was followed by jaundice, ascites, hypostases and a varicosity of a gullet were observed (at several patients with a lethal outcome). Relationship of cause and effect between development of portal hypertensia and therapy sakvinaviry is not established. It is necessary to monitorirovat symptoms and signs of a gepatoksichnost carefully.
Through kidneys an insignificant part of drug therefore originally it is not necessary to adjust a drug dose at patients with a renal failure is removed. However researches at patients with a heavy renal failure were not conducted in this connection it is necessary to be careful at use of a sakvinavir by such patients.
Children's and advanced age
Efficiency and safety of a sakvinavir at HIV-positive children (16 years are younger) are not established. Information on use of the drug Inviraza® without ritonavir (not strengthened mode) at children is absent, there is only limited information on use of a sakvinavir in soft gelatin capsules (not strengthened mode) for children. Considering considerably smaller concentration of a sakvinavir in blood serum in comparison with adults, children should not use the drug Inviraza® without ritonavir. At use of a sakvinavir in soft gelatin capsules (50 mg/kg 2 times a day) together with nelfinaviry or ritonaviry at children exposure of a sakvinavir increased considerably. At simultaneous use with ritonaviry, the adults accepting саквинавир in soft gelatin capsules 1200 mg 3 times a day can have an exposure of a sakvinavir up to 2 times more, than exposure.
Experience of use for patients is more senior than 60 years is limited.
At the patients receiving HIV protease inhibitors cases for the first time of the revealed diabetes mellitus, a hyperglycemia or a decompensation of the accompanying diabetes mellitus are described.
In certain cases the hyperglycemia was sharply expressed, sometimes was followed by ketoacidosis. At the same time at many patients the associated diseases sometimes demanding purpose of the drugs having ability to increase concentration of glucose in blood took place and to cause development of a diabetes mellitus or hyperglycemia. Relationship of cause and effect between therapy by inhibitors of HIV protease and development of a hyperglycemia and diabetes mellitus is not established.
At treatment inhibitors of HIV protease described cases of strengthening of bleedings, including spontaneous formation of hypodermic hematomas and a hemarthrosis at patients with hemophilia of type A and B. Some patients had to increase a dose of blood-coagulation factors of VIII. More than in half of cases treatment by inhibitor of HIV protease was continued or resumed. It is possible to assume relationship of cause and effect of these undesirable phenomena using HIV protease inhibitors though the mechanism of similar effect is not studied. Patients with hemophilia need to be warned about possible strengthening of bleedings.
Fat redistribution
When performing the combined anti-retrovirus therapy redistribution or an adiposity, including obesity on the central type, an adiposity on the dorzalny surface of a neck and back ("bull hump"), reduction of a hypodermic fatty tissue on extremities, increase in mammary glands due to fatty deposits, and also "cushingoid" was noted (a roundish, crescent-shaped face, a hyperemia of the person, truncal type of obesity, adjournment of fatty tissue in supraclavicular poles). Redistribution of fatty tissue is associated with such metabolic disturbances as a gipertriglitseridemiya, a hypercholesterolemia, insulin resistance and a hyperglycemia. Weight of these disturbances varies both in a class, and between classes of anti-retrovirus drugs (HIV protease inhibitors, nenukleozidny inhibitors of the return transcriptase, nukleozidny inhibitors of the return transcriptase). Treat the factors increasing risk of development of a lipodystrophy: advanced age, therapy duration, use of a stavudin, gipertriglitseridemiya, giperlaktatemiya. Diagnosis includes assessment of physical signs of redistribution of fatty tissue, a research of a glycemia and lipids of blood. In case of detection of these changes it is necessary to consider a question of change of anti-retrovirus therapy and/or to take the measures directed to correction of similar deviations (for example, purpose of hypolipidemic means). Now the mechanism of development of metabolic disturbances and the remote effects, such as increase in risk of cardiovascular diseases, are not known.
Use of the drug Inviraza® in a combination with ritonaviry in doses more than 1000/100 mg 2 times a day usually is followed by increase in frequency of the undesirable phenomena as concentration of a sakvinavir in plasma in the presence of a ritonavir increase. In certain cases combined use of a sakvinavir and ritonavir led to the heavy undesirable phenomena, generally to development of diabetic ketoacidosis and disturbance of functions of a liver, especially at the patients who earlier had liver diseases.
Interaction with other medicines and (or) foodstuff
Simultaneous use of the drug Inviraza® (not strengthened mode) accepted in a combination with other anti-retrovirus drugs with rifabutiny, rifampicin or efavirenzy leads to considerable reduction of concentration of a sakvinavir in plasma therefore combined use of these drugs is not recommended. The recommended dose of the rifabutin accepted in a combination with the drug Inviraza® and ritonaviry makes 150 mg once in 4 days. Information on combined use of a sakvinavir, ritonavir and efavirenz is limited. It is not necessary to appoint rifampicin to the patients accepting the drug Inviraza® with ritonaviry in a combination with other anti-retrovirus drugs because of risk of development of heavy hepatocellular toxicity.
It is not necessary to apply the phytodrugs containing a St. John's Wort made a hole (Hypericum perforatum) and extract of garlic in a combination with the drug Inviraza® (not strengthened mode), owing to possible reduction of concentration of the drug Inviraza® in plasma and its clinical performance.
At simultaneous use of the drug Inviraza® in a combination with ritonaviry with GMG-KOA-reduktazy inhibitors, generally with drugs, metaboliziruyemy with the participation of P450 ZA4 cytochrome (for example, симвастатин and ловастатин), increase in concentration of inhibitors of GMG-KOA-reduktazy in plasma is possible. In rare instances increase in concentration of a simvastatin and lovastatin can become the reason of development of the heavy undesirable phenomena, such as a mialgiya and рабдомиолиз. It is necessary to avoid combined use of these drugs. With care it is recommended to use the drug Inviraza® in a combination with ritonaviry along with atorvastatiny and tserivastatiny (are to a lesser extent metabolized by means of P450 ZA4 cytochrome). In this case it is necessary to reduce a dose of an atorvastatin and a tserivastatin. In need of purpose of GMG-KOA-inhibitors of reductase it is recommended to apply флувастатин or правастатин.
Use of the drug Inviraza® in a combination with ritonaviry reduces concentration of ethinylestradiol. Therefore it is necessary to use other or additional methods of contraception at combined use of the drug Inviraza® in a combination with ritonaviry and estrogensoderzhashchy oral contraceptives.
Simultaneous use of a sakvinavir in a combination with ritonaviry and tipranaviry (the double strengthened mode) leads to considerable decrease in concentration of a sakvinavir in plasma. Therefore joint therapy by these drugs is not recommended. The concomitant use of digoxin and a sakvinavir in a combination with ritonaviry leads to significant increase in concentration of digoxin in plasma. These drugs are recommended to be used with care. It is necessary to reduce a dose of digoxin and to carry out monitoring of its concentration in plasma.
Osteonecrosis. In spite of the fact that the etiology of an osteonecrosis is considered multifactorial (including use of glucocorticosteroids, alcohol consumption, heavy immunosuppression, a high index of body weight), osteonecrosis cases in particular at patients with widespread HIV infection are registered and/or at the long combined anti-retrovirus therapy. It is necessary to recommend to patients to see a doctor at emergence of a joint pain, constraint in joints or difficulty of the movement.
Syndrome of immune reactivation
At the HIV-positive patients having a heavy immunodeficiency at the time of initiation of the combined anti-retrovirus therapy the inflammatory answer to an asimptomny or residual opportunistic infection, or strengthening of symptomatology can develop. As a rule, these reactions were observed within the first several weeks or months after the beginning of the combined anti-retrovirus therapy. Characteristic examples are the Cytomegaloviral retinitis, the generalized and/or focal mikobakterialny infection and pneumonia caused by Pneumocystis carinii. At emergence of any symptom of an inflammation it is necessary to carry out diagnosis and to appoint treatment.
Chronic diarrhea or malabsorption
Information on use of a sakvinavir in the strengthened mode at the patients having chronic diarrhea or malabsorption no.
Data on efficiency and safety of use of a sakvinavir in not strengthened mode at such patients are limited and do not allow to judge a possibility of obtaining subterapevticheky levels of a sakvinavir by them.

Features of use:

Features of use of drug by pregnant women, women during breastfeeding, the children and adults having chronic diseases
Pregnancy and period of breastfeeding
Experiments on animals do not demonstrate the direct or indirect damaging effect of a sakvinavir on development of an embryo or fruit, the course of pregnancy, peri-and post-natal development. Experience of a clinical use of drug at pregnant women is limited. At use of a sakvinavir in a combination with other anti-retrovirus drugs at pregnant women, it was seldom reported about inborn malformations, congenital anomalies, and also other disturbances which were not followed by congenital anomalies.
During pregnancy саквинавир it is necessary to apply only if the possible advantage for mother justifies potential risk for a fruit.
The data obtained on animals and at the person of rather possible penetration of a sakvinavir into breast milk no. It is not possible to estimate possible side effects of a sakvinavir at babies, therefore, feeding by a breast should be stopped prior to treatment sakvinaviry. HIV-positive women are not recommended to nurse in order to avoid transfer of the HIV virus to the child.
Patients with a liver failure
With a moderate abnormal liver function of dose adjustment of a sakvinavir it is not required from HIV-positive patients. The heavy liver failure is a contraindication to purpose of the drug Inviraza®.
Patients with a renal failure
With easy and moderate degree of a renal failure of dose adjustment of a sakvinavir it is not required from patients. At use of the drug Inviraza® for patients with a heavy renal failure it is necessary to show care.
Children's age
Efficiency and safety of a sakvinavir at children up to 16 years are not established. There is limited information on use of a sakvinavir in soft gelatin capsules (not strengthened mode) at children. Information on use of the drug Inviraza® without ritonavir (not strengthened mode) at children is absent. Considering considerably smaller concentration of a sakvinavir in blood serum in comparison with adults, children should not appoint the drug Inviraza® without ritonavir. Preliminary data at children demonstrate that at use of a sakvinavir in soft gelatin capsules in a combination with ritonaviry concentration of a sakvinavir in plasma exceeds that at use of a sakvinavir in soft gelatin capsules without ritonavir.
Advanced age
Experience of use for patients is more senior than 60 years is limited. The dosing given for the recommendation of the mode is absent.

Influence of drug on ability to manage vehicles and mechanisms
Special researches were not conducted. Data on a possibility of the drug Inviraza® Exert Impact on Ability to manage vehicles, mechanisms are absent. However during the work with cars and mechanisms it is necessary to consider a profile of safety of drug.

Side effects:

Data of clinical trials
Diarrhea, nausea, fatigue, vomiting, meteorism and abdominal pains were the most frequent undesirable phenomena with at least possible communication with the mode strengthened ritonaviry.
For the description of frequency of the side reactions arising at use of the sakvinavir strengthened ritonaviry the following categories are used: very often (≥10%) and it is frequent (≥1%, <10%).

System of an organism		Undesirable reactions
		Severity 3-4	All severity
From skin and a hypodermic fatty tissue	Often	The acquired lipodystrophy.	The acquired lipodystrophy, alopecia, xeroderma, eczema, lipoatrophia, rash, itch.
From a nervous system	Often		Headache, peripheral neuropathy, paresthesia, dizziness, change of flavoring feelings.
From the mental sphere	Often		Decrease in a libido, sleep disorder.
From bodies of digestive tract	Very often		Diarrhea, nausea.
	Often	Diarrhea, nausea, vomiting.	Abdominal distention, vomiting, meteorism, abdominal pains, pain in upper parts of a stomach, lock, dryness in a mouth, dyspepsia, an eructation, dryness of lips, not properly executed chair.
From kostnomyshechny system	Often		Muscular spasm.
From immune system	Often		Hypersensitivity reactions.
Disturbances of food and metabolism	Often	Diabetes mellitus.	Diabetes mellitus, anorexia, increase in appetite.
From respiratory system	Often		Asthma.
From system of blood and bodies of a hemopoiesis	Often	Anemia.	Anemia.
From laboratory indicators	Very often		Increase in activity of ALT and ACT; increase in concentration of cholesterol; lipoproteids of low density and triglycerides; thrombocytopenia.
	Often		Increase in activity of amylase, concentration of bilirubin, creatinine; decrease in hemoglobin; lymphocytopenia; leykotsitopeniya.
Other	Often	Fatigue.	General weakness (adynamy), fatigue, indisposition, increase in fatty tissue.

The undesirable reactions observed at administration of drug of Inviraza® in not strengthened mode are included below.
From a nervous system: hypesthesia, incoordination, intracraneal hemorrhage.
From the mental sphere: confusion of consciousness, depression, alarm, suicide attempt, sleeplessness, disturbance of a libido.
From skin and a hypodermic fatty tissue: Stephens-Johnson's syndrome, violent dermatitis, medicinal rash, heavy skin reactions connected with an abnormal liver function.
From bodies of gepatobiliarny system: jaundice, portal hypertensia, an exacerbation of chronic diseases of a liver (with an abnormal liver function 4 degrees).
From an organism in general: fever, ulcerations of a mucous membrane, thorax pain.
From a musculoskeletal system: muscular weakness and polyarthritis.
From system of blood and bodies of a hemopoiesis: hemolitic anemia and neutropenia.
From bodies of digestive tract: ascites, pancreatitis and intestinal impassability.
Disturbances of food and metabolism: reduced appetite.
High-quality and malignant new growths (including cysts and polyps): skin papillomas, acute myeloid leukemia.
From an urinary system: nephrolithiasis.
From cardiovascular system: spasm of peripheral vessels.
From laboratory indicators: increase in activity of a kreatininfosfokinaza (KFK), hyperglycemia, hypoglycemia.

Post-marketing observation
From immune system: hypersensitivity reactions.
Disturbances of food and metabolism:

diabetes mellitus or the hyperglycemia which sometimes is followed by ketoacidosis;
lipodystrophy: at HIV-positive patients the combined anti-retrovirus therapy is associated with redistribution of fatty tissue - the lipodystrophy including an atrophy of subcutaneous fat on a face and extremities, increase in visceral and intrabdominalny fat, increase in mammary glands and an adiposity on the dorzalny surface of a neck and back ("bull hump");
gipertriglitseridemiya, hypercholesterolemia, insulin resistance, hyperglycemia and giperlaktatemiya.
From a nervous system: drowsiness, spasms.
From system of blood and bodies of a hemopoiesis: strengthening of bleedings, including spontaneous formation of hypodermic hematomas and a hemarthrosis at the patients with hemophilia of type A and B receiving treatment by HIV protease inhibitors.
From bodies of gepatobiliarny system: hepatitis.
From musculoskeletal and connecting fabric: at use of inhibitors of HIV protease, especially in a combination with nukleozidny analogs, it was reported about increase in activity of KFK, mialgiya, a miositis and seldom a rabdomioliza. Osteonecrosis cases, especially at patients with the standard risk factors, extended by HIV - an infection are registered or at the long combined anti-retrovirus therapy. Frequency is unknown.
From kidneys and urinary tract: renal failure.
At HIV-positive patients with a heavy immunodeficiency at the time of initiation of the combined anti-retrovirus therapy the inflammatory answer to asimptomny or residual opportunistic infections (a syndrome of immune reactivation) can develop.

Interaction with other medicines:

In the majority of the conducted researches on medicinal interaction use of the drug Inviraza® in not strengthened mode was studied. Information on use of the drug Inviraza® in a combination with ritonaviry (the strengthened mode) is limited. The results received during the researches on use of the drug Inviraza® in not strengthened mode can not reflect completely effects of use of the drug Inviraza® in a combination with ritonaviry. The complete information about interaction of medicines, including data of the researches conducted using the sakvinavir in soft gelatin capsules which is earlier presented at the market is provided in this section.
Sakvinavir is metabolized by an isoenzyme of CYP3A4 of system of P450 cytochrome and is substrate for the R-glycoprotein (P-gp).
Drugs which are metabolized by an isoenzyme of CYP3A4 or influence activity of an isoenzyme of CYP3A4 and/or R-glycoprotein, can change pharmacokinetics of a sakvinavir. Similarly саквинавир can change pharmacokinetics of other drugs which are substrate of an isoenzyme CYP3A4 or R-glycoprotein.
Ritonavir as powerful inhibitor of an isoenzyme CYP3A4 and R-glycoprotein, can exert impact on pharmacokinetics of other drugs. At purpose of a combination therapy it is necessary to consider possible interactions with ritonaviry.
Considering the results received at use of the drug Inviraza® in a combination with ritonaviry healthy volunteers concerning dozozavisimy lengthening of intervals of QT and PR (see sections of "Contraindication", "Precautionary measure", "Pharmakoterapevtichesky Group"), the additive effects concerning lengthening of intervals of QT and PR can arise at use of drugs of the following classes: antiarrhytmic means of LA or the III class, neuroleptics, tricyclic antidepressants, inhibitors of phosphodiesterase of the 5th type (IFDE-5), separate antibacterial and antihistaminic drugs, and also other medicines (see below). These additive effects can lead to increase in risk of developing of ventricular arrhythmias, especially "piruetny" tachycardia (torsade des pointes). Thus, it is necessary to avoid joint administration of drug of Inviraza® in a combination with ritonaviry and the listed medicines, in the presence of other alternative therapeutic opportunities. The medicines which are at the same time possessing pharmacokinetic interaction with the drug Inviraza® in a combination with ritonaviry and ability to extend intervals of QT and PR are strictly contraindicated. It is not recommended to combine the drug Inviraza® and ритонавир with other medicines possessing the known prolonging action concerning intervals of QT and PR. Therefore, in urgent cases the similar combination has to be used with care.

Nukleozidny inhibitors of the return transcriptase
Didanozin
Sakvinavir/ritonavir (the strengthened mode): the single dose of a didanozin in a dose of 400 mg led to reduction of AUC and Cmax of the sakvinavir accepted in a combination with ritonaviry (1600 mg / 100 mg 4 times a day for 2 weeks) healthy volunteers, approximately, respectively, however did not exert impact on the minimum concentration (Cmin) of a sakvinavir on 30% and 25%. These changes have probably no certain clinical importance.
Monotherapy sakvinaviry (not strengthened mode): interaction between sakvinaviry and didanoziny was not studied.

Tenofovir
Sakvinavir/ritonavir: the concomitant use of a tenofovir was dizoproksit by a fumarata with the drug Inviraza® in a combination with ritonaviry did not exert clinically significant impact on exposure of a sakvinavir. Reception of a tenofovir of a dizoproksil of a fumarat in a dose of 300 mg led once a day to reduction of AUC and Cmax of a sakvinavir (Inviraza® in a combination from ritonaviry 1000/100 mg twice a day) for 1% and 7%, respectively. However, these changes are not clinically significant. Dose adjustment in such cases is not required. Zaltsitabin and / silt and zidovudine
Monotherapy sakvinaviry: the concomitant use of a zaltsitabin and/or a zidovudine with sakvinaviry does not exert impact on pharmacokinetic parameters of these drugs. Sakvinavir/ritonavir: there are no complete researches studying changes of pharmacokinetic parameters at co-administration of these medicines now.

Nenukleozidny inhibitors of the return transcriptase
Delavirdin
Monotherapy sakvinaviry: the concomitant use leads to increase in AUC of a sakvinavir for 348% that in certain cases can be followed by increase in "hepatic" transaminases. Now information on safety of use of such combination of medicines is limited, and data on efficiency are absent. At a combination therapy with delavirdiny control of function of a liver is recommended. Sakvinavir/ritonavir: interaction between the drug Inviraza® in a combination with ritonaviry and delavirdiny was not studied.

Efavirenz
Monotherapy sakvinaviry: the concomitant use of an efavirenz (600 mg) and a sakvinavira (1200 mg 3 times a day) reduced AUC of a sakvinavir by 62%, and Cmax of a sakvinavir for 50%. Concentration of an efavirenz also decreased by 10%, however this decrease is not clinically significant. Due to these results, саквинавир it is necessary to apply in a combination with efavirenzy, only if concentration of a sakvinavir in blood increases at reception of other anti-retrovirus drugs, for example, of a ritonavir.
Sakvinavir/ritonavir: clinically significant deviations in concentration of a sakvinavir or efavirenz are noted.

Not Virapinum
Monotherapy sakvinaviry: the concomitant use of not Virapinum and the drug Inviraza® reduced AUC of a sakvinavir by 24%, but did not exert impact on AUC of not Virapinum. These changes are not clinically significant. Dose adjustment in such cases is not required. Sakvinavir/ritonavir: interaction between the drug Inviraza® in a combination with ritonaviry and not Virapinum was not studied.

HIV protease inhibitors
Fosamprenavir
Sakvinavir/ritonavir: the concomitant use of a fosamprenavir and the drug Inviraza® in a combination with ritonaviry (1000/100 mg) did not cause clinically significant changes of exposure of a sakvinavir (AUC and Cmax of a sakvinavir decreased respectively by 15% and 9%, and Cmin of a sakvinavir decreased by 24%, but nevertheless remained above a threshold of a therapeutic effectiveness). Dose adjustment is not required.

Indinavir
Monotherapy sakvinaviry: simultaneous use of an indinavir (800 mg 3 times a day) and a single dose of the drug Inviraza® or a sakvinavir (600-1200 mg) gave to uvelicheniyuauc0-24 a sakvinavir in plasma at 4.6-7.2 time. Concentration of an indinavir in plasma did not change. Now data on safety and efficiency of such combination of drugs are absent. The corresponding doses for this combination of medicines are not established.
Sakvinavir/ritonavir: reception of low doses of a ritonavir leads to increase in concentration of an indinavir that can lead to development of a nephrolithiasis.

Lopinavir/ritonavir
Sakvinavir/ritonavir: reception of a lopinavir in a dose of 400 mg did not lead to change of pharmacokinetic parameters of the sakvinavir accepted in a combination with ritonaviry (equilibrium AUC0-12 values of a sakvinavir - 15130 and 16977 нг * h/ml, Cmax 2410 and 2300 of ng/ml and Cmin 427 and 543 of ng/ml respectively in a combination with lopinaviry and without it), but considerably reduced exposure of a ritonavir. Nevertheless, efficiency of a ritonavir in this case remained former. Concentration of a lopinavir in plasma did not change (in comparison with data of the previous researches of a combination lopinavir/ritonavir). Dose adjustment is not required.
Lopinavir/ritonavir it is necessary to use with care because of possible additive effect on lengthening of intervals of QT and/or PR at use with the drug Inviraza® in a combination with ritonaviry (see sections of "Contraindication" and "Precautionary measure").

Nelfinavir
Not strengthened саквинавир: the scheme of therapy including саквинавир (1200 mg 3 times a day) and нелфинавир (750 mg 3 times a day) in addition to 2 nukleozidny inhibitors of the return transcriptase, led to longer answer (prolongation of time prior to a virologic recurrence). 392% and 179% increase in AUC and Cmax of a sakvinavir, respectively were observed. AUC of a nelfinavir increased by 18%, Cmax did not change. At simultaneous use of a nelfinavir and sakvinavir the frequency of developing of diarrhea moderately increased.

Sakvinavir/ritonavir: the average geometrical relation of AUC0-12 and Cmax of a nelfinavir (1250 mg) at presence or lack of a sakvinavir at a combination with ritonaviry (1000 mg / 100 mg 2 times a day) made 2 times a day 0.94 (90% of DI: 0.72-1.22) and 0.95 (90% of DI: 0.77-1.16), respectively. In the presence of a sakvinavir in a combination with ritonaviry, AUC0-12 and Cmax of a metabolite of a nelfinavir M8 decreased at 2:25 time (90% of DI: 1.47-3.44) and at 1.74 time (90% of DI: 1.25-2.4), respectively. However, the profile of safety of a nelfinavir did not change.
The average geometrical relation of AUC0-12 and Cmax of a sakvinavir in a combination with ritonaviry (1000 mg / 100 mg) at presence or lack of a nelfinavir (1250 mg 2 times a day) made 2 times a day 1.13 (90% of DI: 0.73-1.74) and 1.09 (90% of DI: 0.73-1.61), respectively. At patients good tolerance of this combination of drugs was noted.

Ritonavir
Sakvinavir does not exert impact on pharmacokinetics of a ritonavir after single or multiple dose at healthy volunteers.
Ritonavir considerably inhibits metabolism of a sakvinavir that results in higher concentration of a sakvinavir in plasma. Equilibrium znacheniyaauc0-24 and Cmax of a sakvinavir at patients after administration of drug of Inviraza® in a dose of 600 mg 3 times a day made 2598 нг * h/ml and 197 ng/ml, respectively.
At reception of 1000 mg of the drug Inviraza® in a combination from 100 mg of a ritonavir two once a day equilibrium znacheniyaauc0-24, Cmax and Cmin are equal 29214 нг * h/ml, 2623 ng/ml and 371 ng/ml, respectively.
At reception of a sakvinavir or the drug Inviraza® in a combination with ritonaviry in a dose of 1000 mg / 100 mg 2 times a day system exposure of a sakvinavir throughout the 24-hour period was similar or exceeded its exposure at reception of a sakvinavir in a dose of 1200 mg 3 times a day.

Tipranavir
Sakvinavir/ritonavir: the combination therapy as типранавир, strengthened by small doses of a ritonavir, lowers Cmin of a sakvinavir by 78% (the clinical importance of this decrease not drugs is not recommended

Lntiaritmichesky means (bepridit, lidocaine, quinidine)
Sakvinavir/ritonavir: bepridit concentration, lidocaine, quinidine can increase. These antiarrhytmic means are contraindicated for combined use with the drug Inviraza® in a combination with ritonaviry in connection with possible development of zhizneugrozhayushchy cardiac arrhythmias (see sections of "Contraindication" and "Precautionary measure").

Anticoagulant (warfarin)
Sakvinavir/ritonavir: concentration of warfarin can change, it is necessary to control the international normalized relation (INR).

Antiepileptic means (carbamazepine, phenobarbital, Phenytoinum)
Monotherapy sakvinaviry: carbamazepine, phenobarbital, Phenytoinum - inductors of microsomal enzymes of a liver (CYP3A4 isoenzyme) can reduce concentration of a sakvinavir in plasma.
Sakvinavir/ritonavir: interaction with the drug Inviraza® in a combination with ritonaviry and these drugs was not studied.

Antidepressants
Tricyclic antidepressants (amitriptyline, Imipraminum)
Sakvinavir/ritonavir: ритонавир can increase concentration of tricyclic antidepressants, control of concentration of tricyclic antidepressants in blood at combined use is recommended.

Nefazodon
Nefazodon as CYP3A4 isoenzyme inhibitor, can increase concentration of a sakvinavir. At simultaneous use of Nefazodon and the drug Inviraza® it is recommended to control a condition of the patient for the purpose of detection of toxicity of a sakvinavir.

Trazodonum
Sakvinavir/ritonavir: the concomitant use of Trazodonum and the drug Inviraza® in a combination with ritonaviry can lead to increase in concentration of Trazodonum in plasma. At Simultaneous use of Trazodonum and ritonavir such undesirable reactions as nausea, dizziness, a lowering of arterial pressure and a faint were observed. Trazodonum is contraindicated for use with the drug Inviraza® in a combination with ritonaviry in connection with possible development of the zhizne-menacing arrhythmias (see sections of "Contraindication" and "Precautionary measure").

Antihistamines (терфенадин, астемизол)
The concomitant use of a terfenadin and sakvinavir leads to increase in AUC of a terfenadin in plasma that is associated with lengthening of an interval of QTc. Terfenadin is contraindicated to the patients accepting саквинавир in a combination with ritonaviry.
Because of high probability of similar interaction, саквинавир in a combination with ritonaviry it is also not necessary to appoint together with astemizoly.

Drugs for prevention and treatment of infections
Klaritromitsin
Monotherapy sakvinaviry: at simultaneous use of a klaritromitsin (on 500 mg 2 times a day) and a sakvinavira (on 1200 mg 3 times a day) increase in AUC and Cmax of a sakvinavir by 177% and 187%, respectively was noted. AUC and Cmax values of a klaritromitsin increased approximately by 40% in comparison with monotherapy klaritromitsiny. At simultaneous use of these drugs in the studied doses throughout limited time of correction of doses it is not required.
Sakvinavir/ritonavir: interaction between sakvinaviry in a combination with ritonaviry and klaritromitsiny was not studied.

Erythromycin
Monotherapy sakvinaviry: at simultaneous use of erythromycin (250 mg 4 times a day) and a sakvinavira (1200 mg 3 times a day) increase in AUC and Cmax of a sakvinavir by 99% and 106% was noted. At simultaneous use of these drugs of correction of doses it is not required.
Sakvinavir/ritonavir: interaction between sakvinaviry in a combination with ritonaviry and erythromycin was not studied. It is necessary to apply with care erythromycin because of possible additive effect to lengthening of intervals of QT and/or PR at use with the drug Inviraza® in a combination with ritonaviry (see sections of "Contraindication" and "Precautionary measure").
Streptogramina (hinupristin/dalfopristin)
Sakvinavir/ritonavir: inhibit CYP3A4 isoenzyme, can increase concentration of a sakvinavir. At simultaneous use of these drugs it is recommended to control a condition of the patient for the purpose of detection of toxicity of a sakvinavir.

Antifungal means
Ketokonazol
Monotherapy sakvinaviry: at simultaneous use of a ketokonazol (200 mg a day) and the drug Inviraza® increase in concentration of a sakvinavir in plasma by 1.5 times is noted. Increase in an elimination half-life or change of speed of absorption was not noted. Reception of a sakvinavir in a dose of 600 mg three times a day does not influence pharmacokinetics of a ketokonazol. Dose adjustment at simultaneous use of these two drugs in the studied doses is not required.
Sakvinavir/ritonavir: simultaneous use of a ketokonazol () and the drug Inviraza® in a combination with ritonaviry (1000 mg / 100 mg 2 times a day) did not lead 200 mg a day to change of equilibrium AUC0-12 and Cmax values of a sakvinavir and ritonavir. At simultaneous use of these drugs with ketokonazoly in a dose of smaller or equal 200 mg of correction of doses it is not required. However similar use (кетоконазол 200 mg a day and Inviraza® in a combination from ritonaviry 1000 mg / 100 mg 2 times a day) led to increase in equilibrium Cmax and AUC0-24 values of a ketokonazol by 45% (90% of DI: 32-59%) and 168% (90% of DI: 146-193%), respectively. These data need to be considered at making decision on a dose of a ketokonazol in this combination of drugs. Purpose of a ketokonazol in doses more than 200 mg a day is not recommended.

Itrakonazol
Monotherapy sakvinaviry: итраконазол, like a ketokonazol, is rather powerful inhibitor of an isoenzyme CYP3A4 in this connection similar interaction can be observed. At a concomitant use of an itrakonazol and a sakvinavir it is recommended to control a condition of the patient for the purpose of detection of toxicity of a sakvinavir. Sakvinavir/ritonavir: interaction between the drug Inviraza®, strengthened ritonaviry, and itrakonazoly was not studied. флуконазол / Miconazolum
Flukonazol and Miconazolum are inhibitors of an isoenzyme CYP3A4 and can increase plasma concentration of a sakvinavir. Special researches of this combination of drugs were not conducted.

Antimikobakterialny drugs it is established). If, nevertheless, the decision on need of purpose of this combination of drugs is made, it is strongly recommended to carry out Monitoring of concentration of a sakvinavir in plasma.

Fusion inhibitors
Enfuvirtid
Sakvinavir/ritonavir: simultaneous use of an enfuvirtid and sakvinavir in a combination with ritonaviry (1000 mg / 100 mg 2 times a day) did not lead to clinically significant changes of pharmacokinetics of these drugs.
Monotherapy sakvinaviry: interaction between sakvinaviry and enfuvirtidy was not studied.

Other medicinal
Rifabutin
Monotherapy sakvinaviry: рифабутин reduces concentration of a sakvinavir in plasma by 40%. Monotherapy sakvinaviry should not be applied along with rifabutiny.
Sakvinavir/ritonavir: at the repeated mode of dosing рифабутин (150 mg once in 3 days) in a combination with the drug Inviraza® and ritonaviry (1000/100 mg 2 times a day) reduced AUC0-12 and Cmax values of a sakvinavir by 13% a little (90% of DI:-31% - 9%) and for 15% (90% of DI:-32% - 7%), respectively, at healthy volunteers. However, рифабутин did not exert impact on AUC0-12 (90% of DI:-10% - 9%) and Cmax (90% of DI:-8% - 7%) a ritonavira. Dose adjustment is not required.
Impact assessment of the repeated mode of a drug dosing of Inviraza® in a combination with ritonaviry (1000/100 mg 2 times a day) on pharmacokinetics of a rifabutin was carried out at its use in a dose of 150 mg once in 3 days or in a dose of 150 mg once in 4 days in comparison with monotherapy of rifabutiny 150 mg daily. At use of a rifabutin in a dose of 150 mg once in 3 days in a combination with the drug Inviraza® and ritonaviry, AUC0-72 and Cmax values of active agent (рифабутин + 25-O-dezatsetil-rifabutin) increased by 134% (90% of DI: 109% - 162%) and for 130% (90% of DI: 98% - 167%), respectively. Exposure of a rifabutin increased by 53% (90% of DI: 36% - 73%) for AUC0-72 and for 86% (90% of DI: 57% - 119%) for Cmakh-At use of a rifabutin in a dose of 150 mg once in 4 days in a combination with the drug Inviraza® and ritonaviry, AUC0-96 and Cmax values of active agent (рифабутин + 25-O-dezatsetil-rifabutin) increased by 60% (90% of DI: 43% - 79%) and for 111% (90% of DI: 75% - 153%), respectively. At this mode of dosing exposure of a rifabutin did not change for AUC0-96 (90% of DI:-10% - 13%) also increased by 68% (90% of DI: 38% - 105%) FOR Cmax.
The recommended dose of a rifabutin at use in a combination with the drug Inviraza® and ritonaviry (1000/100 mg 2 times a day) makes 150 mg once in 4 days. At this mode of dosing of these drugs monitoring of activity of "hepatic" enzymes, and also numbers of neutrophils (for identification of a neutropenia) in blood is recommended.
On the basis of the available data at use of a rifabutin in a combination with the drug Inviraza® and ritonaviry (1000/100 mg 2 times a day) it is not recommended to apply рифабутин 2 times a week. This mode of dosing can lead to increase in exposure of a rifabutin and its metabolites up to the values reached at daily administration of drug in a dose of 300 mg that can lead to increase in frequency and weight of the undesirable phenomena connected with reception of a rifabutin (see the section "Precautionary measures").

Rifampicin
Monotherapy sakvinaviry: the concomitant use of rifampicin (600 mg once a day) reduces concentration of a sakvinavir in plasma by 80%. The concomitant use of rifampicin and a sakvinavir is not recommended as it can give to decrease in concentration of Sakvinavir below of therapeutic.
Sakvinavir/ritonavir: the concomitant use of rifampicin at the patients with tuberculosis accepting саквинавир in a combination with ritonaviry (1600 mg / 200 mg a day), reduced AUC of a sakvinavir by 50%, however concentration of a sakvinavir remained within therapeutic. Also concentration of a sakvinavir remained within therapeutic with the patients with tuberculosis accepting the drug Inviraza® strengthened ritonaviry, 1000/100 mg 2 times a day and 450 mg of rifampicin daily or the drug Inviraza® in a combination from ritonaviry, 400/400 mg twice a day, and rifampicin of 600 mg daily. At reception of a similar combination of drugs there is a possibility of development of acute hepatocellular toxicity, therefore, rifampicin should not be applied at the patients accepting the drug Inviraza® in a combination with ritonaviry within anti-retrovirus therapy.

Benzodiazepines
Midazolam
Monotherapy sakvinaviry: at concomitant oral administration of midazolam (7.5 mg) саквинавир (1200 mg 3 times a day) increased Cmax and AUC midazolam by 235% and 514%, respectively. Sakvinavir increased a midazolam elimination half-life from 4.3 to 10.9 h and absolute bioavailability of midazolam from 41 to 90% that was followed by disturbance of psychomotor activity and strengthening of sedation. At simultaneous use of midazolam and a sakvinavir a dose of midazolam it is necessary to reduce and apply significantly this combination with care. At intravenous administration of midazolam (0.05 mg/kg) and reception of a sakvinavir the clearance of midazolam decreased by 56%, and the elimination half-life increased from 4.1 to 9.5 h, at the same time only the subjective feeling of effect of midazolam amplified.
Sakvinavir/ritonavir: at a concomitant single dose in midazolam (7.5 mg) in 2 weeks of administration of drug of Inviraza®/ritonavira (1000/100 mg twice a day) increase in Cmax of midazolam by 4.3 time and AUC midazolam by 12.4 times was observed. Инвираза®/ритонавир increased a midazolam elimination half-life from 4.7 to 14.9 h. Oral administration of midazolam is contraindicated to the patients accepting саквинавир in a combination with ritonaviry. It is necessary to be careful at parenteral administration of midazolam to the patients accepting the drug Inviraza®. Data on a concomitant use of a sakvinavir in a combination with ritonaviry and to intravenous administration of midazolam are absent. On the basis of these researches on combined use of modulators of an isoenzyme of CYP3A4 and midazolam at an intravenous way of introduction it is possible to assume possible increase in plasma concentration of midazolam by 3-4 times. Simultaneous use of the drug Inviraza® and intravenous administration of midazolam should be carried out in chambers of an intensive care or in departments with a possibility of timely carrying out clinical monitoring and adequate treatment in case of respiratory depression and/or long sedation. Dose adjustment, especially in cases of numerous administration of midazolam is necessary.
Alprazolam, dipotassium clorazepate, diazepam and flurazepam
Sakvinavir/ritonavir: increase in concentration of benzodiazepines and risk of strengthening of their sedation is possible. These drugs are recommended to be used with care, if necessary it is necessary to reduce a dose of benzodiazepines.
Blockers of slow calcium channels
Felodipin, nifedipine, никардипин, diltiazem, нимодипин, verapamil, амлодипин, низолдипин, исрадипин
Sakvinavir/ritonavir: increase in concentration of these drugs is possible. These drugs in a combination with the drug Inviraza® and ritonaviry should be applied with care, clinical monitoring of a condition of patients is recommended.

Glucocorticosteroids
Dexamethasone
Is the inductor of an isoenzyme CYP3A4 and can reduce concentration of a sakvinavir. At a concomitant use efficiency of a sakvinavir can decrease. These drugs are recommended to be used with care.
Interaction between the drug Inviraza® in a combination with ritonaviry and dexamethasone was not studied.

Flutikazon, будесонид
Several cases of an Icenco-Cushing syndrome at simultaneous use of These glucocorticosteroids (an inhalation or intranasal way of introduction) are described and a small dose of a ritonavir. In need of a combination therapy it is necessary to consider the possibility of transfer of patients into beclomethasone inhalations.

Cardiac glycosides
Digoxin
The concomitant use of a single dose of digoxin (0.5 mg) after two weeks of administration of drug of Inviraza® in a combination with ritonaviry (1000/100 mg 2 times a day) led to increase in Cmax and AUC0-12 of digoxin by 27% and 49%, respectively. These drugs are recommended to be used with care. It is necessary to reduce a dose of digoxin and to carry out monitoring of its concentration in plasma.

Alkaloids of an ergot and their derivatives
Digidroergotamin, ergometrine, ergotamine, methylergometrine
Simultaneous use of these drugs with the drug Inviraza® in a combination with ritonaviry is contraindicated, owing to a possibility of development of acute toxicity.

Blockers of H2-histamine receptors
Ranitidine
Monotherapy sakvinaviry: at a concomitant use of the drug Inviraza®, ranitidine and food exposure of a sakvinavir (AUC by 67%) in comparison with reception only of the drug Inviraza® and food increased. These changes are not clinically significant. Dose adjustment is not required.
Sakvinavir/ritonavir: interaction between the drug Inviraza® in a combination with ritonaviry and ranitidine was not studied.
Immunodepressants Cyclosporine, такролимус, сиролимус
Sakvinavir/ritonavir: concentration of immunodepressants can increase. Monitoring of therapeutic concentration of cyclosporine, a takrolimus, sirolimus at a concomitant use is recommended.
GMG-KOA-reduktazy inhibitors Sakvinavir/ritonavir: significant increase in concentration of a simvastatin and lovastatin is observed that leads to a rabdomioliz. Simvastatin and ловастатин it is not necessary to apply in a combination with sakvinavirom/ritonaviry.
Metabolism of an atorvastatin and tserivastatin to a lesser extent depends on activity of an isoenzyme of CYP3A4, in a combination they should be used in smaller doses, patients are carefully observed regarding development of a myopathy (muscular weakness, muscle pain, increase in activity of KFK).
Pravastatin and флувастатин are not metabolized by CYP3A4 isoenzyme. If use of inhibitors of GMG-KOA-reduktazy is shown, it is recommended to use правастатин or флувастатин.

Narcotic analgetics
Methadone
Sakvinavir/ritonavir: the concomitant use of a sakvinavir in a combination with ritonaviry (2 times a day) and methadone (60-120 mg once a day) led 1000/100 mg to reduction of AUC methadone by 19%. Dose adjustment is not required. However it is necessary to apply with care because of possible additive effect on lengthening of intervals of QT and/or PR at use with the drug Inviraza® in a combination with ritonaviry (see sections of "Contraindication" and "Precautionary measure").

Oral contraceptives (ethinylestradiol)
Sakvinavir/ritonavir: reduces concentration of ethinylestradiol. It is necessary to use other or additional methods of contraception.
Inhibitors of phosphodiesterase of the 5th type (IFDE-5)

Sildenafil
Also sildenafit simultaneous use of a sakvinavir (1200 mg 3 times a day) (a single dose of 100 mg), CYP3A4 isoenzyme which is substrate, led to increase in Cmax and AUC of a sildenafil by 140% and 210%, respectively. Sildenafil did not exert impact on pharmacokinetic parameters of a sakvinavir. These drugs are recommended to be used with care. It is necessary to reduce a dose of a sildenafil (no more than 25 mg each 48 h). At a concomitant use with the drug Inviraza® in a combination with ritonaviry, it is necessary to recommend to the patient to watch carefully the state regarding development of the undesirable phenomena.

Tadalafil
Sakvinavir/ritonavir: at a concomitant use increase in concentration of a tadalafil is possible. These drugs are recommended to be used with care. It is necessary to reduce a dose of a tadalafil (no more than 10 mg each 72 h). At a concomitant use with the drug Inviraza® in a combination with ritonaviry, it is necessary to recommend to the patient to Watch carefully the state regarding development of the undesirable phenomena.

Vardenafil
Sakvinavir/ritonavir: at a concomitant use increase in concentration of a vardenafil is possible. These drugs are recommended to be used with care. It is necessary to reduce a dose of a vardenafil (no more than 2.5 mg each 72 h). At a concomitant use with the drug Inviraza® in a combination with ritonaviry, it is necessary to recommend to the patient to watch carefully the state regarding development of the undesirable phenomena. The drugs increasing motility of digestive tract Shchizaprid
Sakvinavir/ritonavir: increase in exposure of a tsizaprid (AUC) and lengthening of an interval of QTc. Tsizaprid is contraindicated at the patients accepting саквинавир in a combination with ritanaviry, because of possible developing of the zhizne-menacing arrhythmias (see sections of "Contraindication" and "Precautionary measure").

Antipsychotic means (neuroleptics)
Pimozidum
Sakvinavir/ritonavir: the increase in exposure of Pimozidum (AUC) which is associated with the additive effect on lengthening of an interval of QT and/or PR (see sections of "Contraindication" and "Precautionary measure"). Pimozidum is contraindicated at the patients accepting саквинавир in a combination with ritonaviry (see the section "Contraindications").
Inhibitors of the proton pump (омепразол) Sakvinavir/ritonavir: simultaneous use of an omeprazol (daily) and the drug Inviraza® in a combination with ritonaviry (1000/100 mg 2 times a day) led 40 mg to increase in equilibrium AUC and Cmax values of a sakvinavir by 82% (90% of DI: 44% - 131%) and 75% (90% of DI: 38% - 123%), respectively. Concentration of a ritonavir in plasma considerably did not change. Data on simultaneous use of the drug Inviraza® in a combination with ritonaviry and other inhibitors of the proton pump are absent. In a combination with omeprazoly or other inhibitors of the proton pump it is recommended to apply with care, controlling a condition of the patient regarding a possibility of development of toxicity of a sakvinavir.

Grapefruit juice
Monotherapy sakvinaviry: increase in exposure of a sakvinavir at healthy volunteers at a single dose of grapefruit juice for 50% and for 100% at the use of juice of double concentration that has no clinical value and does not demand dose adjustment of a sakvinavir.
Sakvinavir/ritonavir: interaction was not studied.
The phytodrugs containing a St. John's Wort made a hole (Hypericum perforatum)
Monotherapy sakvinaviry: some phytodrugs may contain the components which are inhibitors or inductors of an isoenzyme CYP3A4 or R-glycoprotein and to lead to change of pharmacokinetics of a sakvinavir. Reduction of concentration of a sakvinavir in plasma, loss of the virologic answer and emergence of resistance to one of components of anti-retrovirus therapy is possible. The phytodrugs containing a St. John's Wort made a hole (Hypericum perforatum) should not be applied at the patients accepting the drug Inviraza®.
Sakvinavir/ritonavir: interaction was not studied.
The medicines and the dietary supplements (DS) containing garlic extract
Monotherapy sakvinaviry: reduction of concentration of a sakvinavir in plasma, loss of the virologic answer and emergence of resistance to one of components of anti-retrovirus therapy is possible. At a concomitant use of the medicines or dietary supplement containing garlic extract (the dose approximately equal to two 4-gram garlic gloves) and a sakvinavir (1200 mg three times a day), at healthy volunteers reduction of AUC of a sakvinavir by 51%, reduction of average minimum concentration of a sakvinavir (8 h after acceptance of a dose) for 49% and reduction of Cmax by 54% was observed. The medicines and dietary supplement containing garlic extract should not be applied at the patients accepting саквинавир. Sakvinavir/ritonavir: interaction was not studied.
Other possible interactions
Though special researches were not conducted, the concomitant use of a sakvinavira/ritonavir and other drugs which are CYP3A4 isoenzyme substrates (dapsone, Disopyramidum, quinine, fentanyl, apfentanit) can increase concentration in plasma of these drugs therefore such combinations should be used with care (see sections of "Contraindication" and "Precautionary measure").
The concomitant use of the drug Inviraza® in a combination with ritonaviry with the drugs which are R-glycoprotein substrates (for example, azithromycin) can lead to increase in concentration of these drugs in plasma therefore at use of such combinations it is necessary to watch a condition of the patient regarding emergence of symptoms of toxicity.
In plasma leads to increase in concentration of a sakvinavir also purpose of combinations with CYP3A4 isoenzyme inhibitors. In that case, it is recommended to watch a condition of the patient regarding emergence of symptoms of toxicity.
The concomitant use with the drugs which are inductors of an isoenzyme CYP3A4 or the R-glycoprotein, on the contrary, can reduce concentration of a sakvinavir in plasma.
Information on reduction of concentration of a sakvinavir in plasma at joint reception with the drugs reducing time of passing of food on digestive tract (for example, Metoclopramidum), no.

Contraindications:

Hypersensitivity to a sakvinavir or any other component of drug, a ritonavir.
The concomitant use of a terfenadin, astemizol, tsizaprid, Pimozidum, Amiodaronum, flekainid, propafenon (zhizne-menacing to arrhythmia); rifampicin (heavy hepatocellular toxicity); dihydroergotamine, ergometrine, ergotamine, methylergometrine (acute toxicity); simvastatina, lovastatina (рабдомиолиз); triazolama, midazolam of oral administration (long/excessive sedation).
Heavy liver failure.
Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.
The drug Inviraza® in a combination with ritonaviry is contraindicated to patients with:

the inborn or documentary confirmed acquired lengthening of an interval of QT;
electrolytic disturbances, especially with not corrected hypopotassemia;
when using with some drugs which possess at the same time pharmacokinetic interaction and ability to extend intervals of QT and/or PR (see the section "Interaction with Other Medicines and Foodstuff").

Overdose:

Now clinical experience of overdose of a sakvinavir at people is limited.
The acute or chronic overdose at monotherapy sakvinaviry does not lead to serious complications.
In a combination with other inhibitors of HIV protease the following symptoms are possible: the general weakness, fatigue, diarrhea, nausea, vomiting, a hair loss, dryness in a mouth, a hyponatremia, weight reduction, orthostatic hypotension.
Treatment: there is no specific antidote. The actions directed to maintenance of the vital functions including control of the main vital signs, ECG, observation of a clinical condition of the patient. It is necessary to prevent the subsequent absorption of drug. As саквинавир highly contacts proteins of a blood plasma, use of dialysis is inexpedient.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated. 500 mg
On 120 tablets in a bottle from polyethylene of the high density (HDPE) with the screwing-up cover opening when pressing. The cover has control of the first opening. The way of opening of a bottle is given in a cover in the form of the scheme. Each bottle together with the application instruction is placed in a cardboard pack.