Composition, form of production and packaging
The tablets covered with a cover from light orange to grayish or brownish-orange color, oval, cylindrical, biconcave; on one side the engraving "SQV 500", on the other - "ROCHE".
saquinavir mesylate 571.5 mg,
which corresponds to the content of saquinavir 500 mg
Excipients: povidone K30 - 40 mg, lactose monohydrate - 38.5 mg, croscarmellose sodium - 45 mg, microcrystalline cellulose - 95 mg, magnesium stearate - 10 mg.
The composition of the membrane: hypromellose - 7.929 mg, titanium dioxide - 4.887 mg, talc - 4.61 mg, iron oxide oxide yellow - 0.645 mg, iron oxide oxide red 0.369 mg, triacetin 1.559 mg.
120 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
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 analog 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 EC 50 and EC 90 values вЂ‹вЂ‹(concentrations that inhibit 50% and 90% of HIV protease activity) ranging from 1 to 10 nmol / ml and from 5 up to 50 nmol / ml, respectively. The antiviral activity of saquinavir was invitro evaluated on the infected T cell line and in the primary human cultures of lymphocytes and monocytes. Antiviral activity in vitro was observed for a set of isolates of HIV-1 group M, except clades B (A, AE, C, D, G, H) and HIV-2 with EC 50 values вЂ‹вЂ‹of 0.3-2.5 nmol / ml. In the presence of 50% human blood serum or alpha1-acid glycoprotein (1 mg / ml), the antiviral activity of saquinavir decreases by an average of 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 supplemented with ritonavir were obtained after retrospective analyzes of clinical trials and the 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 virological 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 amount 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 who received saquinavir earlier ( p = 0.0133, see Table 1 ). G48V, 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
Number of initial mutations causing resistance to saquinavir * Hospitalized patients Retrospective analysis of CI
Number of patients not previously treated with saquinavir Number of patients not receiving / previously treated with saquinavir
N = 138 Change in HIV-1 RNA concentration in blood plasma at 12-20 weeks compared to baseline N = 114 Change in HIV-1 RNA concentration in blood plasma at week 4 compared with 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, L24I, I62V, G73S / T, V82A / F / S / T, I84V, L90M
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) and two NRTIs / NNRTIs for 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 in the saquinavir / ritonavir group took saquinavir earlier (study 2).
Table 2. Demographic characteristics of patients from the studies conducted вЂ
Saquinavir / ritonavir Indinavir / ritonavir Saquinavir / ritonavir Lopinavir / ritonavir
N = 148 N = 158 N = 161 N = 163
Gender (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 (CDC classification) (%) 32% 28% 32% 31%
Patients who did not previously take antiretroviral drugs (%) 28% 22% 31% 34%
Patients who had not previously taken HIV protease inhibitors (%) 41% 38% 48% 48%
Median of the initial value of HIV-1 RNA, log 10 copies / ml (range) 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 the initial number of CD4 + cells, cells / mm 3 (spread) 272 (135-420) 280 (139-453) 241 (86-400) 239 (95-420)
вЂ Data from the clinical trial report
Table 3. Results of therapy in the conducted studies вЂ (after 48 weeks).
Results of saquinavir / ritonavir Indinavir / ritonavir saquinavir / ritonavir Lopinavir / ritonavir
Initiated treatment, n (%) 148 (94%) 158 (99%) 161 (94%) 163 (98%)
The 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 вЂЎ P = 0.12
Patients with viral load <50 copies / ml at 48 weeks, patients treated 82/104 (79%) 73/93 (78%) 84/113 (74%) 97/138 (70%)
P> 0.05 вЂЎ P = 0.48
Median increase in the number of 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.
вЂ Data are from a clinical trial report.
вЂЎ Study publication data 1.
Influence on ECG parameters
The effect of the drug 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 therapeutic) per QT interval through 20 hours on the 3rd day of drug administration was studied in double-blind study with 4-component cross-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. Mean values вЂ‹вЂ‹of C max when taking the drug Invirase in combination with ritonavir in 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 average C max values вЂ‹вЂ‹in the equilibrium state when taking the drug Invirase in combination with ritonavir at a dose of 1000/100 mg twice a day in 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 and therapeutic doses) and the placebo group was> 10 milliseconds (msec) see Table 4). It was found that Invirase in combination with ritonavir at doses exceeding the therapeutic renders a more significant effect on the QT interval compared with the therapeutic doses. In the majority of study participants (89% of patients receiving therapeutic doses and 80% of patients receiving drugs at doses exceeding therapeutic ones), QTcS was <450 msec, and no participant had a QTc interval> 500 msec (see also "Measures precautions ").
Table 4. Mean maximum ddQTcS вЂ (ms) at day 3 for therapy with Invirase in combination with ritonavir in therapeutic doses, at dosages higher than therapeutic doses and for active control (moxifloxacin) in healthy volunteers.
Treatment Time point of evaluation after drug administration Mean maximum value of ddQTcS Standard error Upper 95% CI limit for ddQTcS
Invirase / ritonavir 1000/100 mg twice daily 12 hours 18.86 1.91 22.01
Invirase / ritonavir 1500/100 mg twice daily 20 hours 30.22 1.91 33.36
Moxifloxacin ^ 4 h 12.18 1.93 15.36
вЂ Derived difference between QTcS values вЂ‹вЂ‹(QT interval adjusted for baseline pre-treatment values вЂ‹вЂ‹specific for this study) in the active treatment group and in the placebo group.
Admission 400 mg only on the third day.
Note: in the study, the QTcS value for men was calculated using the formula QT / RR 0.319 , and for women QT / RR 0.337 , which corresponds to the Fridericia correction (QTcF = QT / RR 0.333 ).
In this study, on day 3, an extension of the PR interval> 200 msec was observed in 40% of patients receiving Invimerazine / ritonavir at a dose of 1000/100 mg twice daily, and 47% of patients receiving the drug Invirase / ritonavir at a dose of 1500 / 100 mg twice a day. In 3% of patients receiving moxifloxacin as active control, and 5% of patients in the placebo group, PR> 200 msec was elongated. The maximum value of the average change in the PR interval compared to the pre-treatment intake was 25 msec in the group receiving Invirase / ritonavir at a dose of 1000/100 mg twice a day and 34 msec in the group receiving Invirase / ritonavir 1,500 / 100 mg twice a day (see also the section "Precautions").
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 lengthening 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 over 1000/100 mg twice daily should be avoided.
Preclinical safety data
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.
In studies of invitro mutagenicity and genotoxicity (if necessary with metabolic activation), saquinavir was shown to have no 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 (micronucleus test in mice) or in vitro in human lymphocytes, nor does it cause primary DNA damage in vitro (reparative DNA synthesis).
Impact on fertility
In studies on rats there was no adverse effect on reproductive function and fertility at exposure values вЂ‹вЂ‹(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.
In studies on rats and rabbits, there was no embryotoxic or teratogenic effect of saquinavir at exposure values вЂ‹вЂ‹(AUC) of approximately 32% of exposure in humans when taking Invirase in combination with ritonavir at recommended doses of 1000/100 mg twice daily.
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 was shown that the pH value 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). After repeated administration of saquinavir (600 mg 3 times a day) in HIV-infected patients, the area under the concentration-time curve in the equilibrium state (AUC) is 2.5 times 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 x 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 cross-sectional study, in HIV-infected patients who received Invirase in combination with ritonavir 1000/100 mg twice daily at first on an empty stomach (three consecutive doses) and then after intake of high-calorie food (46 g fat, 1091 kcal) (three consecutive doses ), AUC 0-12 saquinavir was 10320 ng x h / ml and 34,926 ng x h / ml, respectively. All patients (except one) had the achievement of the minimum equilibrium concentration of the drug (Cssmin) above the lower values вЂ‹вЂ‹of the therapeutic range for fasting. Nevertheless, the drug Invirase in combination with ritonavir should be taken within 2 hours after eating.
In HIV-infected patients who received saquinavir 600 mg 3 times a day after meals, the AUC and maximum plasma concentration (C max ) were approximately twice that of healthy volunteers in 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 doses of saquinavir in soft gelatin capsules 200 mg to 1200 mg / three times a day.
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 the multidrug resistance protein MDR1 (P-glycoprotein).
Well distributed in the tissues. Middle V d at steady state after i / v injection of 12 mg - 700 l (coefficient of variation 39%). Communication with plasma proteins - 98%, independent of the drug concentration (15-700 ng / ml) .Sakvinavir (while taking 600 mg three times a day) is not detected in the cerebrospinal fluid.
Undergoes significant hepatic metabolism. Rapid metabolism to inactive mono- and dihydroxylated derivatives is mediated by the cytochrome P450 isoenzyme performed and CYP3A4, it is responsible for more than 90% of hepatic metabolism (invitro studies). After the on / in the 66% of circulating saquinavir found in unmodified form, the remaining part - in the form of metabolites that corresponds to extensive metabolism "first pass" hepatic.
Systemic clearance after i / v infusion of 6, 36 and 72 mg saquinavir high and amounts to 1.14 L / h / kg (12% coefficient of variation) that slightly exceeds the hepatic blood flow.
T 1/2 of the drug from the body is 7 hours.
4 days after receiving 14 C-saquinavir inside (600 mg), 88% and 1% of the radioactivity detected in the feces and urine, respectively.
After 4 days on / in the 14 C-saquinavir (10.5 mg) was 81% and 3% of the radioactivity detected in the feces and urine, respectively.
After ingestion of 13% of circulating plasma saquinavir was introduced in unmodified form, the remaining part - in the form of metabolites.
Pharmacokinetics in special clinical groups
Pharmacokinetics Invirase in patients with renal insufficiency has not been studied.
Effect on liver function abnormalities equilibrium pharmacokinetics saquinavir in combination with ritonavir was investigated involving HIV-infected patients (N = 7) with moderate hepatic impairment (class B (7-9 points) in Child-Pugh). The study included a control group of HIV-infected patients (N = 7) with a normal liver function corresponding investigated patients by age, sex, body weight and tobacco consumption. In HIV-infected patients with moderate hepatic impairment average (% coefficient of variation) values of AUC 0-12 and C max of saquinavir were 24.3 (102%) mg x hr / ml, and 3.6 (83%) mg / mL, respectively. The corresponding values in the control group were 28.5 (71%) mg x hr / ml, and 4.3 (68%) mg / mL. Relative to the AUC 0-12and C max geometric mean pharmacokinetic parameters in patients with impaired liver function to the pharmacokinetic parameters in patients with normal liver function (90% CI) was 0.7 (0.3-1.6), suggesting that about 30% reduction in the pharmacokinetic exposure in patients with moderate hepatic impairment . In HIV-infected patients with moderate hepatic impairment dose adjustment of saquinavir is not required (see. Section "Peculiarities of pregnant women, women during the breastfeeding period, children and adults with chronic illness" and "Precautions" section).
Revealed no influence gender on the pharmacokinetics of the drug Invirase at a single oral dose of 600 mg in healthy volunteers. In a bioequivalence study saquinavir 200 mg capsules and tablets, coated tablets, 500 mg in combination with ritonavir was found higher in women saquinavir exposure (AUC by 56%, C max 26%), regardless of body weight and age. No clinically significant differences in the efficacy and safety of the registered saquinavir dosing regimen in both men and women have been identified. Saquinavir therapy in combination with ritonavir 1000/100 mg was recognized safe and effective in both sexes.
The influence of race on the pharmacokinetics of saquinavir has not been studied.
The study of pharmacokinetic parameters in children under 16 and adults over 65 years of age was conducted.
- as part of combination therapy with ritonavir and other antiretroviral agents for the treatment of adult patients with HIV-1.
Invirase is assigned only in combination with ritonavir!
Recommended strictly observe the prescribed drugs receive mode.
Inside, during or no later than 2 hours after a meal.
Standard dosing regimen
Adults and adolescents over 16 years: in combination with ritonavir (enhanced mode) Invirase 1000 mg two times / day, and ritonavir 100 mg of 2 times / day in combination with other antiretroviral drugs; Invirase ritonavir and the drug is taken orally and simultaneously within 2 hours after ingestion; in combination with other HIV protease inhibitors to familiarize with the recommended dose and the possible side effects of other antiretroviral drugs should examine instructions for use.
If there severe toxicity phenomena saquinavir treatment should be interrupted. Because of the possible increase in plasma concentrations in combination therapy with other antiretroviral drugs (e.g., RTV) may require a change doses of HIV protease inhibitors.
In HIV-infected patients with moderate hepatic impairment dose adjustment of saquinavir is not required. Severe hepatic failure is a contraindication to the destination Invirase drug.
Patients with mild to moderate renal insufficiency correction dose is not required saquinavir. In applying the drug Invirase in patients with severe renal insufficiencycaution should be exercised.
The efficacy and safety of saquinavir in children under 16 years of age have not been established. There is limited information on the use of saquinavir soft gelatin capsules (unboosted mode) in children. Information about the use of the drug Invirase without ritonavir (unboosted mode) have no children. Given the much lower concentration of saquinavir in the blood serum as compared to adults, children should not be given the drug Invirase without ritonavir. Preliminary data in children suggest that the application of saquinavir soft gelatin capsules in combination with ritonavir, saquinavir plasma concentrations greater than that in the application of saquinavir soft gelatin capsules without ritonavir.
Experience with patients older than 60 years is limited. These recommendations for dosing regimen are not available.
Data from clinical studies
the most common adverse events ckak least possible connection with the regime of ritonavir were diarrhea, nausea, fatigue, vomiting, flatulence, and abdominal pain.
Very often (10%?) And often (1%, <10%?): The following categories are used to describe the frequency of adverse reactions arising from the application of saquinavir, ritonavir,.
Adverse reactions of the organism System
Severity 3-4 all degrees of severity
of the skin and subcutaneous fat is often Acquired lipodystrophy. Acquired lipodystrophy, alopecia, dry skin, eczema, lipoatrophy, rash, itching.
From the nervous systemOften headache, peripheral neuropathy, paresthesia, dizziness, change in taste.
On the part of the psychic sphere often Decreased libido, sleep disorder.
On the part of the gastrointestinal tract is often diarrhea, nausea.
Diarrhea often, nausea, vomiting. Bloating, vomiting, flatulence, abdominal pain, pain in the upper abdomen, constipation, dry mouth, dyspepsia, eructation, dry mouth, shapeless stool.
On the part of the musculoskeletal system are often muscular spasm.
Immune system Frequently Hypersensitivity reactions.
Eating disorders and metabolic Often diabetes. Diabetes, anorexia, appetite increase.
The respiratory system is often short of breath.
From the blood system and organs of blood is often anemia. Anemia.
From the laboratory parameters is often increased activity of ALT and AST; increased cholesterol concentrations; low density lipoproteins and triglycerides;thrombocytopenia.
Often Increased amylase, bilirubin, creatinine; reduction of hemoglobin; lymphocytopenia; leykotsitopeniya.
Other Fatigue often. General weakness (asthenia), fatigue, malaise, increased adipose tissue.
The following are unwanted reactions observed when receiving Invirase drug in unamplified mode.
From the nervous system: hypoesthesia, impaired coordination, intracranial hemorrhage.
On the part of the psychic sphere : confusion, depression, anxiety, suicide attempt, insomnia, impaired libido.
Skin and subcutaneous tissue:Stevens-Johnson syndrome, bullous dermatitis, drug rashes, severe skin reactions associated with impaired liver function.
From the side of the hepatobiliary system: jaundice, portal hypertension, exacerbation of chronic liver disease (with impaired liver function Grade 4).
On the part of the body as a whole: fever, ulceration of the mucous membranes, chest pain.
On the part of the musculoskeletal system: muscle weakness and arthritis.
From the blood system and hematopoiesis: hemolytic anemia and neutropenia.
On the part of the gastrointestinal tract: ascites, pancreatitis and intestinal obstruction.
Eating disorders and metabolic: decreased appetite.
Benign and malignant tumors (including cysts and polyps): skin papilloma, acute myelogenous leukemia.
Urinary system: nephrolithiasis.
Cardio-vascular system: a spasm of peripheral vessels.
From the laboratory parameters: increase in activity (CPK), hyperglycemia, hypoglycemia.
Immune system: Hypersensitivity reactions.
Eating disorders and metabolism:diabetes or hyperglycemia, sometimes accompanied by ketoacidosis; Lipodystrophy: in HIV-infected patients, combination antiretroviral therapy is associated with a redistribution of fat tissue - lipodystrophy, including atrophy of subcutaneous fat in the face and extremities, increased visceral and intrabdominalnogo fat, breast enlargement and fat deposition on the dorsal surface of the neck and back ( "buffalo hump" ); hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.
From the nervous system: drowsiness, seizures.
From the blood system and the blood:increased bleeding, including spontaneous formation of subcutaneous hematoma and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors.
From the side of the hepatobiliary system: hepatitis.
From the musculoskeletal and connective tissue under the application of HIV protease inhibitors, particularly in combination with nucleoside analogues reported opovyshenii CPK, myalgia, myositis and rhabdomyolysis infrequently. Cases of osteonecrosis, especially in patients with generally accepted risk factors for patients with HIV infection or during prolonged combination antiretroviral therapy. The frequency is unknown.
On the part of the kidney and urinary tract: renal dysfunction.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy may develop an inflammatory response to asymptomatic or residual opportunistic infections (immune reactivation syndrome).
- hypersensitivity to saquinavir or any other component of the preparation, ritonavir;
- simultaneous reception of terfenadine, astemizole, cisapride, pimozide, amiodarone, flecainide, propafenone (life-threatening arrhythmias); rifampicin (severe hepatocellular toxicity); dihydroergotamine, ergometrine, ergotamine, metilergometrina (acute toxicity); simvastatin, lovastatin (rhabdomyolysis); triazolam, midazolam oral use (long / excessive sedation);
severe hepatic impairment;
- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
The drug Invirase in combination with ritonavir is contraindicated in patients with:
- congenital or acquired documented lengthening QT interval;
- electrolyte disturbances, particularly in uncorrected hypokalaemia;
- when used with certain drugs that have both pharmacokinetic interaction and the ability to prolong QT intervals and / or PR (see "Interaction with other drugs and food.").
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. Clinical experience with the drug in pregnant women is limited. In the application of saquinavir in combination with other antiretroviral agents in pregnant women rarely reported congenital malformations, congenital anomalies and other irregularities are not accompanied by congenital anomalies.
During pregnancy, saquinavir should be used only if the potential benefit to the mother justifies the potential risk to the fetus.
Data obtained in animals and humans with respect to the possible penetration of saquinavir in breast milk, no. To evaluate the possible side effects of saquinavir in infants is not possible, therefore breast-feeding should be discontinued before treatment with saquinavir. HIV-positive women are advised not to breast-feed in order to avoid transmission of HIV to the child.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with mild to moderate renal insufficiency correction dose is not required saquinavir. In applying the drug Invirase in patients with severe renal impairment caution should be exercised.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In HIV-infected patients with moderate hepatic impairment dose adjustment of saquinavir is not required. Severe hepatic failure is a contraindication to the destination Invirase drug.
APPLICATION FOR CHILDREN
The efficacy and safety of saquinavir in children under 16 years of age have not been established. There is limited information on the use of saquinavir soft gelatin capsules (unboosted mode) in children. Information about the use of the drug Invirase without ritonavir (unboosted mode) have no children. Given the much lower concentration of saquinavir in the blood serum as compared to adults, children should not be given the drug Invirase without rit