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

Active substanceSaquinavirSaquinavir

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Invirase®

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Hoffmann-La Roche Ltd. Switzerland

Interfast®

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FARMASINTEZ, JSC (Irkutsk) Russia

Dosage form: & nbspfilm-coated tablets

Composition:

Active substance: Saquinavir 500 mg

(In the form of saquinavir mesylate 571.5 mg)

Excipients

Core: Hypromellose 4.0 mg, sodium carboxymethyl starch (primogel) 45.0 mg, copovidone 38.0 mg, silicon colloidal dioxide 10.0 mg, croscarmellose sodium 38.0 mg, magnesium stearate 8.0 mg , polysorbate 80 (twin 80) 3.5 mg, microcrystalline cellulose 92.0 mg.

Finished water-soluble film shell- 6.0 mg / 15.0 mg

(Composition of the coating: hydroxypropylmethylcellulose (hypromellose) 11.13 mg, polyethylene glycol 6000 (Macrogol 6000) 2.145 mg, titanium dioxide 0.525 mg, talc 0.345 mg, iron dye red oxide 0.21 mg, iron oxide yellow oxide - 0.645 mg).

Description:

Tablets covered with a film shell, spherical oval, from light brown to brown. On a cross-section a tablet of white or white with a yellowish shade of color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.01 Saquinavir

Pharmacodynamics:

Mechanism of action

An antiretroviral drug, an HIV protease inhibitor.

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

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

Antiviral activity in vitro

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

Resistance to saquinavir

Antiviral activity relative to the initial genotype and phenotype

Genotypic and phenotypic clinical criteria predicting the clinical efficacy of saquinavir 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-fold. A positive virologic response was not observed with a decrease in sensitivity of more than 12 times.

9 protease codons have been identified (L10F / I / M / R / V, I15A / V, K20I / M / R / T, L24I, I62V, G73S / T, V82A / F / S / T, I84V, L90M) associated with a decrease in the virologic response to saquinavir in combination with ritonavir (1000/100 mg twice daily), in patients who had not previously taken saquinavir. The presence of 3 or more mutations caused a reduced response to saquinavir / ritonavir therapy.

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

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

amount	Hospitalized patients		Retrospective analysis of CI
initial mutations,	The number of patients not		The number of patients not
conditional	previously treated		received / received earlier
resistance to	saquinavir		treatment with saquinavir
saquinavir		Change		Change
	N = 138	concentration of HIV-1 RNA in blood plasma at 12-20 weeks compared with the original	N = 1 14	concentration of HIV-1 RNA in blood plasma at 4 weeks compared with the original
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

Carcinogenicity

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

Mutagenicity

In in vitro studies on mutagenicity and genotoxicity (if necessary with metabolic activation), it was shown that saquinavir does not have mutagenic activity on both bacterial cells (Ames test) and mammalian cells (lung cells of Chinese hamsters V79 / HPRT-test with hypoxanthine guanine phosphoribosyltransferase). Saquinavir does not cause 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 drug exposure values (AUC),of approximately 33% of the exposure in humans when taking saquinavir in combination with ritonavir at the recommended doses of 1000/100 mg 2 times a day.

Teratogenicity

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

Pharmacokinetics:

Suction

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

When taking multiple doses after meals (25-600 mg 3 times a day), there was a greater increase in saquinavir exposure (50 times) than with a proportional increase in the dose (24 times). After repeated administration of saquinavir (600 mg 3twice 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, 1.6-3.8) than after a single dose.

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

Food intake increases the maximum concentration of saquinavir from 3.0 ng / ml to 35.5 ng / ml and the time it reaches from 2.4 to 3.8 hours. This effect of food continues for 2 hours after eating. Therefore, taking saquinavir should be done no later than 2 hours after eating.

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

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

Distribution

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

Exposed to significant hepatic metabolism. Rapid metabolism to mono- and di-hydroxylated inactive derivatives is mediated through the cytochrome P450 system and is performed by the CYP3A4 isoenzyme, which accounts for more than 90% of hepatic metabolism (in vitro studies). After iv introduction, 66% of circulating saquinavir is found unchanged, the rest is metabolites, which corresponds to the extensive metabolism of the "first passage" in the liver.

Systemic clearance after IV infusion of 6, 36 and 72 mg saquinavir is high and is 1.14 l / h / kg (coefficient of variation of 12%), which slightly exceeds the hepatic blood flow. The half-life of the drug from the body is 7 hours.

Excretion

4 days after admission ¹⁴C-saquinavir orally (600 mg) of 88% and 1% of radioactivity are found in faeces and urine, respectively.

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

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

Pharmacokinetics in special clinical groups

Renal insufficiency

The pharmacokinetics of saquinavir in patients with renal insufficiency has not been studied.

Liver failure

The effect of liver dysfunction on the equilibrium pharmacokinetics of saquinavir in combination with ritonavir was studied with the participation of HIV-infected patients (N = 7) with a moderate liver function disorder (grade B (7-9 points) on the Child-Pugh scale). This study included a control group of HIV-infected patients (N = 7) with normal liver function, corresponding to the patients studied by age, sex, body weight and tobacco consumption. In HIV-infected patients with moderate impairment of liver function, the mean (% coefficient of variation) of the AUC_0-12and C_maxsaquinavir were 24.3 (102%) mg * h / mL and 3.6 (83%) mg / mL, respectively. The corresponding values in the control group were 28.5 (71%) mg * h / ml and 4.3 (68%) mg / ml. Regarding AUC_0-12and C_max the geometric mean of pharmacokinetic parameters in patients with impaired hepatic function to the pharmacokinetic parameters of patients with normal liver function (90% confidence interval) was 0.7 (0.3-1.6),suggesting an approximately 30% decrease in pharmacokinetic exposure with impaired hepatic function. In HIV-infected patients with impairedm liver function of the average degree of dose adjustment of saquinavir is not required (see section "Special instructions").

Floor

Not identifiedbut the effect of sex on the pharmacokinetics of saquinavir with a single oral intake of 600 mg in healthy volunteers. In a study of the bioequivalence of saquinavir in 200 mg capsules and coated tablets, 500 mg in combination with ritonavir, a higher exposure of saquinavir in women (AUC at 56%, C_max by 26%), regardless of body weight and age. Clinically significant differences in the efficacy and safety of the registered dosage regimen of saquinavir in men and women have not been identified. Therapy with saquinavir in combination with ritonavir in doses of 1000/100 mg was found to be safe and effective in both sexes.

Race

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

Age

The study of ophaspharmacokinetic parameters in children under 16 years old and adults over 65 years old was not conducted.

Indications:As part of a combination therapy with ritonavir and other antiretroviral drugs for the treatment of adult patients infected with HIV-1.

Contraindications:

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

Simultaneous reception of terfenadine, astemizole, cisapride, pimozide, amiodarone, flecainide, propafenone, clarithromycin (life-threatening arrhythmias); rifampicin (severe hepatocellular toxicity); alfuzosin (arterial hypotension); Quetiapine (risk of coma development); dihydroergotamine, ergometrine, ergotamine, methylergometrine (acute toxicity); simvastatin, lovastatin (rhabdomyolysis); triazolama, midazolam for oral administration (prolonged / excessive sedation).

Severe hepatic insufficiency.

Children under 16 years.

Saquinavir in combination with ritonavir is contraindicated in patients with:

- congenital or documented by the purchased QT interval elongation;

- electrolyte disorders, especially with uncorrected hypokalemia;

- with simultaneous use with nelfinavir, lopinavir, tricyclic antidepressants, erythromycin, sildenafil, tadalafil, vardenafil;

- when used with some other drugs that have both a pharmacokinetic interaction and the ability to extend QT and / or PR intervals (see "Interactions with Other Drugs");

- with clinically significant bradycardia, cardiac insufficiency with a decrease in the left ventricular ejection fraction, symptomatic arrhythmia in the anamnesis.

Carefully:

Elderly age (over 60 years).

Severe kidney failure.

Disorders of liver function of light and medium degree.

Saquinavir in combination with ritonavir should be used with caution in patients with concomitant structural heart disease, impaired conduction of the heart, coronary heart disease, or cardiomyopathy. Saquinavir in combination with ritonavir with other drugs with known prolonging action for QT and PR intervals, should be used only with extreme caution if absolutely necessary.

Pregnancy and lactation:

Pregnancy

Experiments on animals do not indicate a direct or indirect damaging effect of saquinavir on the development of an embryo or fetus,pregnancy, peri- and postnatal development. The experience of clinical use of the drug in pregnant women is limited. When saquinavir was used in combination with other antiretroviral drugs in pregnant women, seldom reported congenital malformations, congenital anomalies, and other disorders not accompanied by congenital anomalies.

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

Breastfeeding period

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

Dosing and Administration:

Saquinavir is given only in combination with ritonavir! It is recommended to strictly follow the prescribed regimen of taking medications. Inside, during or no later than 2 hours after eating.

Standard dosing regimen

Adults and teenagers over 16 years of age:

- in combination with ritonavir (enhanced regimen): saquinavir 1000 mg twice a day and ritonavir 100 mg twice a day in combination with other antiretroviral drugs; saquinavir and ritonavir take inside at the same time and no later than 2 hours after eating;

- in combination with other HIV protease inhibitors: To familiarize yourself with recommended doses and possible side effects of other antiretroviral drugs, instructions for their use should be studied.

Dosing in special cases

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

Dosing in special patient groups

Pregnancy and the period of breastfeeding

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

Breastfeeding should be discontinued before treatment with saquinavir (see "Pregnancy and Breastfeeding" section).

Patients with hepatic insufficiency

In HIV-infected patients with a disability of the average degree of the liver, dose adjustment of saquinavir is not required. Severe liver failure is a contraindication to the appointment of saquinavir.

Patients with renal insufficiency

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

Childhood

The effectiveness and safety of saquinavir in children under 16 years of age have not been established. The experience of using saquinavir in childhood is limited. Data for the recommended dosage regimen are not available.

Elderly age

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

Side effects:

To describe the frequency of adverse reactions that occur with saquinavir supplemented with ritonavir, the following categories are used: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1 / 100), rarely (> 1/10000, <1/1000), very rarely (<1/10000).

On the part of the blood system and hemopoiesis: very often thrombocytopenia; often - anemia, lymphocytopenia, leukocytopenia; infrequently - neutropenia.

From the sense organs: infrequently - impaired vision.

From the immune system: often - hypersensitivity reactions.

Disorders of nutrition and metabolism: often - diabetes, anorexia, increased appetite; infrequent - a decrease in appetite.

From the psychic sphere: often - decreased libido, sleep disturbance.

From the nervous system: often - headache, peripheral neuropathy, paresthesia, dizziness, changes in taste, infrequent - drowsiness, convulsions.

From the respiratory system: often - shortness of breath.

On the part of the organs of the gastrointestinal tract: very often - diarrhea, nausea; often - bloating, vomiting, flatulence, abdominal pain, pain in the upper abdomen, constipation, dry mouth, indigestion, belching, dry lips, unformed stool; infrequently, pancreatitis.

On the part of the organs of the hepatobiliary system: infrequently - jaundice, hepatitis.

From the laboratory indicators: very often - increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), hypercholesterolemia, hypertriglyceridemia, increase in low-density lipoproteins; often - increased activity of amylase, bilirubin concentration, creatinine.

From the side of the kidneys and urinary tract: infrequently - a violation of kidney function.

From the skin and subcutaneous fat: often - acquired lipodystrophy, alopecia, dry skin, eczema, lipoatrophy, rash, itching; infrequently - Stevens-Johnson syndrome, bullous dermatitis.

From the musculoskeletal system: often - muscle spasm.

Other: often - general weakness (asthenia), fatigue, malaise, an increase in fat tissue, ulceration of the mucosa.

Cases of diabetes mellitus or hyperglycemia, sometimes accompanied by ketoacidosis, have been reported in patients receiving HIV protease inhibitors. In HIV-infected patients, combined antiretroviral therapy is associated with the redistribution of adipose tissue - lipodystrophy, including atrophy of subcutaneous fat on the face and extremities,increased visceral and intra-abdominal fat, increased mammary glands and fat deposition on the dorsal surface of the neck and back ("bull hump").

In patients receiving combined antiretroviral therapy, there were metabolic disorders: hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In patients with hemophilia type A and B receiving treatment with HIV protease inhibitors, increased bleeding was noted, including spontaneous subcutaneous hematoma formation and hemarthrosis.

When using HIV protease inhibitors, especially in combination with nucleoside analogues, increased activity of CK, myalgia, myositis and rarely rhabdomyolysis was reported. Osteonecrosis cases have been reported, especially in patients with common risk factors, advanced HIV infection, or long-term combined antiretroviral therapy. The frequency is unknown.

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

Overdose:

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

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

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

Interaction:

In most of the studies on drug interaction, the use of saquinavir in an unresponsive regimen has been studied. Information on the use of saquinavir in combination with ritonavir (enhanced regimen) is limited. The results obtained in the studies on the use of saquinavir in the unresponsive regimen,may not completely reflect the effects of saquinavir in combination with ritonavir.

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

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

Nucleoside reverse transcriptase inhibitors

Didanosine

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

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

Tenofovir

Saquinavir / ritonavir: simultaneous administration of tenofovir with saquinavir in combination with ritonavir did not have a clinically significant effect on saquinavir exposure. Taking tenofovir 300 mg once a day resulted in a decrease in AUC and C_max saquinavir (saquinavir in combination with ritonavir 1000/100 mg twice daily) by 1% and 7%, respectively. However, these changes are not clinically significant. Correction of the dose in such cases is not required.

Zalcitabine and / or zidovudine

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

Saquinavir / ritonavir: Currently, there are no completed studies that study changes in pharmacokinetic parameters with simultaneous prescribing of these drugs. Correction of the dose is not required.

Non-nucleoside reverse transcriptase inhibitors

Delavirdine

Monotherapy with saquinavir: simultaneous administration leads to an increase in the AUC of saquinavir by 348%, which in some cases may be accompanied by an increase in "hepatic" transaminases. At present, information on the safety of the use of such a combination of drugs is limited, and there is no evidence of efficacy. When combined therapy with delavirdine is recommended control of liver function.

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

Efavirenz

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

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

Nevirapine

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

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

HIV protease inhibitors

Atazanavir

With simultaneous application, an increase in plasma concentration and AUC of saquinavir is noted; the concentration of atazanavir does not change. It is possible to increase the PR interval. The simultaneous use of atazanavir and the combination of saquinavir / ritonavir is contraindicated in connection with the possible development of life-threatening arimia.

Fosamprenavir

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

Indinavir

Monotherapy with saquinavir: simultaneous use of indinavir (800 mg 3 times a day) and a single dose of saquinavir (600-1200 mg) led to an increase in AUC_0-24 saquinavir in plasma in 4.6-7.7 times. The concentration of indinavir in plasma did not change. At present, there is no data on the safety and efficacy of this combination of drugs. Appropriate doses for this combination of drugs have not been established.

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

Lopinavir / ritonavir

Saquinavir / ritonavir: taking lopinavir at a dose of 400 mg did not lead to a change in the pharmacokinetic parameters of saquinavir taken in combination with ritonavir (equilibrium values of AUC_0-12 saquinavir - 15130 and 16977 ng * h / ml, C_max 2410 and 2300 ng / ml and C_m_in 427 and 543 ng / ml, respectively, in combination with and without lopinavir), but significantly reduced the exposure of ritonavir. Nevertheless, the effectiveness of ritonavir remained unchanged in this case.Concentrations of lopinavir in plasma did not change (in comparison with the data of previous studies of the combination of lopinavir / ritonavir).

The simultaneous use of saquinavir with ritonavir and lopinavir is contraindicated in connection with the possible development of life-threatening arimies (see the sections "Contraindications" and "Special instructions").

Nelfinavir

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

Saquinavir / ritonavir: The average geometric ratio of AUC0-12 and Cmaxnefinavir (1250 mg twice daily) in the presence or absence of saquinavir in combination with ritonavir (1000 mg / 100 mg twice daily) was 0.94 (90% confidence interval: 0.72- 1.22) and 0.95 (90% confidence interval: 0.77-1.16), respectively. In the presence of saquinavir in combination with ritonavir, AUC_0-12 and C_max metabolite of nelfinavir M8 decreased by 2.25 times (90% confidence interval: 1.47-3.44) and 1.74 times (90% confidence interval: 1.25-2.4), respectively. However, the safety profile of nelfinavir did not change.

The average geometric ratio of AUC_0-12 and C_max saquinavir in combination with ritonavir (1000 mg / 100 mg twice daily) in the presence or absence of nelfinavir (1250 mg twice daily) was 1.13 (90% confidence interval: 0.73-1.74) and 1, 09 (90% confidence interval: 0.73-1.61), respectively.

The simultaneous use of saquinavir in combination with ritonavir and nelfinavir is contraindicated.

Ritonavir

Saquinavir does not affect the pharmacokinetics of ritonavir after a single or multiple intake in healthy volunteers. Ritonavir significantly inhibits the metabolism of saquinavir, which leads to higher concentrations of saquinavir in plasma. The equilibrium values of AUC_0-12 and C_max saquinavir in patients after taking the drug at a dose of 600 mg 3 times a day were 2598 ng * h / ml and 197 ng / ml, respectively.

When 1000 mg of saquinavir is taken in combination with 100 mg of ritonavir, the equilibrium values of AUC0-12, C_max and C_m_inare 29214 ng * h / ml, 2623 ng / ml and 371 ng / ml, respectively.

When saquinavir was taken in combination with ritonavir at a dose of 1000 mg / 100 mg twice daily, the systemic exposure of saquinavir over the 24-hour period was similar or exceeded its exposure with saquinavir 1200 mg 3 times a day.

Tipranavir

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

CCR5 receptor antagonists

Maraviroc

Saquinavir / ritonavir increases the concentration of maraviroc in the blood plasma. When used concomitantly with a combination of saquinavir / ritonavir maraviroc should be prescribed in a dose of 150 mg 2 times a day. Clinical monitoring of patients is recommended.

Inhibitors of fusion

Enfuvirtide

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

Monotherapy with saquinavir: the interaction between saquinavir and enfuvirtide has not been studied.

Other medications

Antiarrhythmic drugs (beprideal, lidocaine (with systemic application), quinidine)

With simultaneous use, it is possible to increase the concentrations of antiarrhythmic drugs in the blood plasma. These antiarrhythmic drugs are contraindicated for joint use with saquinavir in combination with ritonavir in connection with the possible development of life-threatening cardiac arrhythmias (see the sections "Contraindications" and "Special instructions").

Other antiarrhythmics (amiodarone, flecainide, propafenone, sotalol, ibutilide)

With simultaneous application with saquinavir / ritonavir, their concentrations may increase. The simultaneous use of these drugs with a combination of saquinavir / ritonavir is contraindicated in connection with the risk of developing life-threatening arrhythmias.

Anticoagulants (warfarin)

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

Antiepileptic agents (carbamazepine, phenobarbital, phenytoin)

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

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

Antidepressants

Tricyclic antidepressants (amitriptyline, imipramine)

Saquinavir / ritonavir: ritonavir may increase the concentration of tricyclic antidepressants. The simultaneous use of saquinavir and ritonavir with tricyclic antidepressants is contraindicated in connection with the possible risk of developing life-threatening arrhythmias

Nefazodone

Monotherapy with saquinavir: Nefazodone, as an inhibitor of the isoenzyme CYP3A4, can increase the concentration of saquinavir and its toxicity. The simultaneous use of saquinavir and nefazodone is not recommended.

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

Trazodone

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

Antihistamines (terfenadine, astemizole)

Simultaneous reception of terfenadine and saquinavir leads to an increase in the AUC of terfenadine in the plasma, which is associated with the prolongation of the QTc interval. Terfenadine is contraindicated in patients taking saquinavir in combination with ritonavir. Because of the high likelihood of a similar interaction, saquinavir in combination with ritonavir should also not be administered together with astemizole.

Antimicrobial medications

Clarithromycin

Monotherapy with saquinavir: with the simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (1200 mg 3 times a day) there was an increase in AUC and C_maxsaquinavir by 177% and 187%, respectively. The values of AUC and C_max clarithromycin increased by about 40% compared with monotherapy with clarithromycin.With the simultaneous use of these drugs in the doses studied for a limited time, dose adjustment is not required. The use of this combination is contraindicated in connection with the possible risk of life-threatening arrhythmias.

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

Erythromycin

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

Saquinavir / ritonavir: the interaction between saquinavir in combination with ritonavir and erythromycin has not been studied. The use of this combination is contraindicated in connection with the possible risk of life-threatening arrhythmias.

Streptogramins (quinupristin / delfopristin)

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

Pentamidine, sparfloxacin, halofaintrin

With simultaneous use with saquinavir in combination with ritonavir, the risk of ventricular arrhythmias increases, in particular arrhythmias of the ventricular tachysystolic type "pirouette" (torsade des pointes). The simultaneous use of saquinavir and ritonavir with these drugs is contraindicated.

Fusidic acid

Although interaction with fusidic acid has not been studied, concomitant use can lead to an increase in the concentrations of both fusidic acid and saquinavir / ritonavir.

Antifungal means

Ketoconazole

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

Saquinavir / ritonavir: simultaneous use of ketoconazole (200 mg / day) and saquinavir in combination with ritonavir (1000 mg / 100 mg twice daily) did not change the equilibrium values of AUC_0-12 and C_max saquinavir and ritonavir.With the simultaneous use of these drugs with ketoconazole at a dose less than or equal to 200 mg, dose adjustment is not required. However, such an application (ketoconazole 200 mg per day and saquinavir in combination with ritonavir 1000 mg / 100 mg twice a day) led to an increase in the equilibrium values of C_max and AUC_0-24ketoconazole by 45% (90% confidence interval: 32-59%) and 168% (90% confidence interval: 146-193%), respectively. These data should be taken into account when deciding on the dose of ketoconazole in this combination of drugs. It is not recommended to administer ketoconazole at doses greater than 200 mg per day.

Itraconazole

Monotherapy with saquinavir: Itraconazole, like ketoconazole, is a relatively potent inhibitor of the CYP3A4 isoenzyme, and this can lead to a similar interaction. When concomitantly taking itraconazole and saquinavir, it is recommended that the patient be monitored to determine the toxicity of saquinavir.

Saquinavir / ritonavir: the interaction between saquinavir, ritonavir-enhanced, and itraconazole has not been studied.

Fluconazole / miconazole

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

Antimycobacterial drugs

Rifabutin

Monotherapy with saquinavir: rifabutin reduces the concentration of saquinavir in plasma by 40%. Monotherapy with saquinavir should not be used concomitantly with rifabutin. Saquinavir / ritonavir: with multiple dosing regimens rifabutin (150 mg once every 3 days) in combination with saquinavir and ritonavir (1000/100 mg twice daily) somewhat reduced the AUC_0-12 and C_max saquinavir by 13% (90% confidence interval: -31% -9%) and by 15% (90% confidence interval: -32% -7%), respectively, in healthy volunteers. But, rifabutin did not influence the AUC_0-12 (90% confidence interval: -10% -9%) and C_max (90% confidence interval: -8% - 7%) of ritonavir. Correction of the dose is not required.

The effect of a multiple dosage regimen of saquinavir in combination with ritonavir (1000/100 mg 2 times a day) on the pharmacokinetics of rifabutin when administered at a dose of 150 mg once every 3 days or at a dose of 150 mg once every 4 days compared with monotherapy rifabutin 150 mg daily. When rifabutin is used in a dose of 150 mg once every 3 days in combination with saquinavir and ritonavir, the values of AUC_0-72 and Cmax of the active substance (rifabutin + 25-O-deacetyl-rifabutin) increased by 134% (90% confidence interval: 109% - 162%) and 130% (90% confidence interval: 98% - 167%), respectively.The exposure of rifabutin increased by 53% (90% confidence interval: 36% - 73%) for AUC_0-72 and by 86% (90% confidence interval: 57% - 119%) for Cmax. When rifabutin is used in a dose of 150 mg once every 4 days in combination with saquinavir and ritonavir, the values of AUC_0-96 and Cmax of the active substance (rifabutin + 25-O-deacetyl-rifabutin) increased by 60% (90% confidence interval: 43% - 79%) and 111% (90% confidence interval: 75% -153%), respectively. In this dosage regimen, the exposure of rifabutin did not change for AUC_0-96 (90% confidence interval: -10% -13%) and increased by 68% (90% confidence interval: 38% -105%) for C_max.

The recommended dose of rifabutin when administered in combination with saquinavir and ritonavir (1000/100 mg twice daily) is 150 mg once every 4 days. With this dosage regimen of these drugs, it is recommended to monitor the activity of "hepatic" enzymes, as well as the number of neutrophils (to detect neutropenia) in the blood.

When rifabutin is used in combination with saquinavir and ritonavir (1000/100 mg twice daily), it is not recommended rifabutin 2 times per week. This dosing regimen can lead to an increase in the exposure of rifabutin and its metabolites to values,achieved with daily intake of the drug at a dose of 300 mg, which can lead to an increase in the incidence and severity of adverse events associated with taking rifabutin (see section "Special instructions").

Rifampicin

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

Saquinavir / ritonavir: simultaneous reception of rifampicin in patients with tuberculosis taking saquinavir in combination with ritonavir (1600 mg / 200 mg per day), reduced the saquinavir AUC by 50%, but the concentration of saquinavir remained within the therapeutic range. Also, the concentration of saquinavir remained within the therapeutic range in patients with tuberculosis, taking saquinavir, ritonavir-boosted, 1000/100 mg twice daily, and 450 mg rifampicin daily, or saquinavir in combination with ritonavir, 400/400 mg twice daily, and rifampicin 600 mg daily. When taking such a combination of drugs, it becomes possible to develop acute hepatocellular toxicity, therefore, rifampicin Do not use in patients who take saquinavir in combination with ritonavir in antiretroviral therapy.

Preparations for the treatment of gout

Colchicine

With the simultaneous use of colchicine with a combination of saquinavir / ritonavir, colchicine concentration in the blood plasma can increase. In connection with the possible increased toxic effects of colchicine (myopathy, rhabdomyolysis) is not recommended colchicine simultaneously with a combination of saquinavir / ritonavir, especially in patients with impaired renal or hepatic function.

Neuroleptics

Quetiapine

When used simultaneously with saquinavir / ritonavir, quetiapine concentration in the plasma may be increased (by inhibition of CYP3A with saquinavir / ritonavir). In connection with the possible increase in the toxic effects of quetiapine and the risk of coma development, simultaneous use of drugs is contraindicated.

Benzodiazepines

Midazolam

Monotherapy with saquinavir: with simultaneous oral administration of midazolam (7.5 mg) saquinavir (1200 mg 3 times daily) increased C_max and AUC of midazolam by 235% and 514%, respectively. Saquinavir increased the half-life of midazolam from 4.3 to 10.9 h and the absolute bioavailability of midazolam from 41 to 90%, which was accompanied by a violation of psychomotor activity and increased sedation.With the simultaneous use of midazolam and saquinavir, the dose of midazolam should be significantly reduced and this combination should be used with caution. With intravenous administration of midazolam (0.05 mg / kg) and administration of saquinavir, midazolam clearance decreased by 56%, and the half-life increased from 4.1 to 9.5 hours, while only the subjective feeling of midazolam increased. Saquinavir / ritonavir: with simultaneous single-dose administration of midazolam (7.5 mg) after 2 weeks of taking saquinavir / ritonavir (1000/100 mg twice daily), there was an increase in C_max midazolam in 4.3 times and AUC of midazolam in 12.4 times.

Saquinavir / ritonavir increased the half-life of midazolam from 4.7 to 14.9 hours. Oral administration of midazolam is contraindicated in patients taking saquinavir in combination with ritonavir. Caution should be exercised when parenterally administering midazolam to patients taking saquinavir. Data on the simultaneous administration of saquinavir in combination with ritonavir and intravenous administration of midazolam are not available. Based on the data of studies on the joint use of modulators of the isoenzyme CYP3A4 and midazolam in the intravenous route of administration, a possible increase in plasma concentrations of midazolam by 3-4 times can be assumed.The simultaneous use of saquinavir and intravenous midazolam should be in intensive care units or departments with the possibility of timely clinical monitoring and adequate treatment in the case of respiratory depression and / or prolonged sedation. A dose adjustment is necessary, especially in cases of repeated administration of midazolam.

Triazolam

Saquinavir / ritonavir: may increase plasma concentrations of triazolam, which increases the risk of developing life-threatening side effects (including respiratory depression). The use of triazolam is contraindicated in patients receiving saquinavir in combination with ritonavir.

Alprazolam, dikalia clorazepate, diazepam and flurazepam

Saquinavir / ritonavir: Possible increase in the concentration of benzodiazepines and the risk of increased sedation. These drugs should be used with caution, if necessary, reduce the dose of benzodiazepines. Blocks of "slow" calcium channels

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

Saquinavir / ritonavir: Possible increase in the concentration of these drugs.These drugs in combination with saquinavir / ritonavir should be used with caution, clinical monitoring of patients' condition is recommended.

Alpha-blockers

Alfuzosin

With simultaneous use with saquinavir / ritonavir, an increase in the concentration of alfuzosin is possible, which can lead to hypotension. The use of this combination is contraindicated.

Beta-adrenomimetics

Salmeterol

With the joint application of saquinavir and salmeterol, an increase in salmeterol in the blood plasma is noted, which increases the risk of side effects from the cardiovascular system inherent in salmeterol, incl. prolongation of QT interval, palpitation, sinus tachycardia. Simultaneous use of salmeterol and saquinavir is not recommended.

Antagonists of endothelin receptors

Boszentan

With the simultaneous use of bosentan and the combination of saquinavir / ritonavir, an increase in bosentan concentrations and a decrease in saquinavir / ritonavir concentrations in the blood plasma is possible. With simultaneous application, it is necessary to monitor the effectiveness of HIV therapy,and patients should be closely monitored for toxicity associated with bosentan. It may be necessary to adjust the dosage of bosentan.

Glucocorticosteroids

Dexamethasone

It is an inducer of the isoenzyme CYP3A4 and can reduce the concentrations of saquinavir. With simultaneous administration, the effectiveness of saquinavir may decrease. Dexamethasone in combination with saquinavir is recommended with caution.

The interaction between saquinavir in combination with ritonavir and dexamethasone has not been studied.

Fluticasone, budesonide

Several cases of Itenko-Cushing syndrome are described with simultaneous application of these glucocorticosteroids (inhalation or intranasal route of administration) and a small dose of ritonavir. If combination therapy is necessary, the possibility of transferring patients to inhaled bi-lactamazone should be considered.

Cardiac glycosides

Digoxin

Simultaneous administration of a single dose of digoxin (0.5 mg) after two weeks of taking saquinavir in combination with ritonavir (1000/100 mg2 times a day) resulted in an increase in C_max and AUC_0-12 digoxin by 27% and 49%, respectively. Digoxin in combination with saquinavir is recommended with caution. It is necessary to reduce the dose of digoxin and monitor its concentrations in the plasma.

Ergot alkaloids and their derivatives

Dihydroergotamine, ergometrine, ergotamine, methylergometrine

The simultaneous use of these drugs with saquinavir in combination with ritonavir is contraindicated, due to the possibility of developing acute toxicity.

Blockers H₂-gistaminovyh receptors

Ranitidine

Saquinavir monotherapy: with simultaneous administration of saquinavir, ranitidine and food, the exposure of saquinavir (AUC by 67%) was increased compared with only saquinavir and food intake. These changes are not clinically significant. Correction of the dose is not required.

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

Immunosuppressive drugs

Cyclosporine, tacrolimus, sirolimus

Saquinavir / ritonavir: The concentration of immunosuppressants may increase. It is recommended to monitor the therapeutic concentrations of cyclosporine, tacrolimus, sirolimus when taken concomitantly with saquinavir in combination with ritonavir.

Inhibitors of HMG-CoA reductase

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

The metabolism of atorvastatin and cerivastatin is less dependent on the activity of the isoenzyme CYP3A4. In combination, they should be used in smaller doses. Patients are carefully observed for the development of myopathy (muscle weakness, muscle pain, increased activity of CK).

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

Narcotic analgesics

Methadone

Saquinavir / ritonavir: simultaneous administration of saquinavir in combination with ritonavir (1000/100 mg twice daily) and methadone (60-120 mg once daily) resulted in a 19% reduction in methadone AUC. The use of methadone concomitantly with the combination of saquinavir / ritonavir is contraindicated because of the possible additive effect on the prolongation of the QT and / or PR intervals (see the sections "Contraindications" and "Special instructions").

Oral contraceptives (ethinyl estradiol)

Saquinavir / ritonavir: reduces the concentration of ethinylestradiol.should use other or additional methods of contraception.

Correctors of cerebral circulation disorders

wincamine

simultaneous application of saquinavir and ritonavir with vincamine (for intravenous administration) is contraindicated in connection with the possible risk of life-threatening arrhythmias.

inhibitors of phosphodiesterase type 5 (Iphde-5)

sildenafil

simultaneous application of saquinavir (1200 mg 3 times a day) and sildenafil (a single dose of 100 mg), which is the substrate of the isoenzyme cyp3a4, led to an increase in c_maxand auc sildenafil by 140% and 210%, respectively. simultaneous use of sildenafil and combination of saquinavir / ritonavir is contraindicated in connection with the possible risk of life-threatening arrhythmias.

tadalafil

saquinavir / ritonavir: with simultaneous admission, it is possible to increase the concentrations of tadalafil. the use of this combination is contraindicated in connection with the possible risk of developing life-threatening arrhythmias.

vardenafil

saquinavir / ritonavir: concomitant administration may increase vardenafil concentrations. the use of this combination is contraindicated in connection with the possible risk of developing life-threatening arrhythmias.

drugs that increase the motility of the gastrointestinal tract

cisapride

saquinavir / ritonavir: may increase the exposure of cisapride (auc) and prolong the interval of qtc. cisapride is contraindicated in patients taking saquinavir in combination with ritanavir, because of the possible occurrence of life-threatening arrhythmias (see the sections "contraindications" and "special instructions").

drugs that slow down the passage of food through the gastrointestinal tract information on reducing the concentration of saquinavir in plasma when taken together with drugs that slow down the passage of food through the gastrointestinal tract (for example, metoclopramide) is absent.

antipsychotic drugs (antipsychotics)

pimozide

saquinavir / ritonavir: may cause an increase in exposure to pimozide (auc) associated with an additive effect on the elongation of the qt and / or pr interval (see the "contraindications" and "special instructions" sections), pimozide is contraindicated in patients taking saquinavir in combination with ritonavir, in connection with the possible risk of developing life-threatening arrhythmias.

sulphopride, sertindole ,clozapine, thioridazine, mvzoridazine, phenothiazine, haloperidol

while simultaneous application of these drugs with saquinavir in combination with ritonavir, an increase in the concentrations of neuroleptics in the plasma and prolongation of the interval qt are possible. simultaneous use of these antipsychotic drugs with a combination of saquinavir / ritonavir contraindicated in connection with the possible risk of life-threatening arrhythmias.

proton pump inhibitors (omeprazole)

saquinavir / ritonavir: simultaneous use of omeprazole (40 mg daily) and saquinavir in combination with ritonavir (1000/100 mg twice daily) resulted in an increase in the equilibrium values of auc and c_maxsaquinavir by 82% (90% confidence interval: 44% - 131%) and 75% (90% confidence interval: 38% - 123%), respectively. plasma concentrations of ritonavir did not change significantly.

simultaneous application of a combination of saquinavir / ritonavir with omeprazole is not recommended.

data on the simultaneous use of saquinavir in combination with ritonavir and other proton pump inhibitors are not available. simultaneous use with a combination of saquinavir / ritonavir is not recommended.

grapefruit juice

monotherapy with saquinavir: increased exposuresaquinavir in healthy volunteers with single dose of grapefruit juice by 50% and 100% at the use of double-strength juice that has no clinical significance and requires no dose adjustment of saquinavir. saquinavir / ritonavir: the interaction was not studied.

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

monotherapy saquinavir: some may contain herbal components which are inhibitors or inducers isoenzyme cyp3a4 or p-glycoprotein, and lead to a change in the pharmacokinetics of saquinavir. It is possible to reduce the concentration of saquinavir in the plasma, the loss of the virologic response and the emergence of resistance to one of the components of antiretroviral therapy. phytopreparations containing Hypericum perforatum should not be used in patients taking saquinavir. if the patient is already taking phytopreparations containing St. John's Wort, the reception of these drugs must be discontinued. the effect of inducing action on cytochrome p450 may persist for at least 2 weeks after discontinuation of St. John's wort.

saquinavir / ritonavir: the interaction was not studied.

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

monotherapy SQV: saquinavir may decrease plasma concentration, loss of virological response and the emergence of resistance to one of antiretroviral therapy components. while taking medications or dietary supplement containing garlic extract (dose approximately equal to two 4 gram garlic cloves) and saquinavir (1200 mg three times daily), in healthy volunteers observed a decrease auc saquinavir 51% decrease in the average minimum concentration saquinavir (8 hours after taking the dose) by 49% and a decrease in c_maxon 54%. medicines and bad products containing garlic extract should not be used in patients taking saquinavir.

saquinavir / ritonavir: the interaction was not studied.

other possible interactions

Although specific studies have been conducted, concomitant use of saquinavir / ritonavir and other drugs that are substrates of CYP3A4 isoenzyme (dapsone, disopyramide, quinine, fentanyl,alfentanil) may increase the plasma concentrations of these drugs, so the use of such combinations is contraindicated due to an increased risk of life-threatening cardiac arrhythmias (see the "contraindications" section).

simultaneous administration of saquinavir in combination with ritonavir and drugs that are substrates of p-glycoprotein (eg, azithromycin) can lead to an increase in the concentrations of these drugs in plasma, so when using such combinations, one should observe the patient's condition for the appearance of symptoms of toxicity.

an increase in the concentrations of saquinavir in plasma also results in the appointment of combinations with inhibitors of the isoenzyme cyp3a4. in this case, it is recommended to monitor the patient's condition for signs of toxicity. simultaneous administration with drugs that are inducers of the isoenzyme of cyp3a4 or p-glycoprotein, in contrast, can reduce saquinavir concentrations in plasma.

Special instructions:

Before starting therapy

Saquinavir is given only in combination with ritonavir.

Patients should be informed that saquinavir does not cure HIV infection and that they may develop associated diseases, including opportunistic infections. It is also necessary to report the possibility of developing adverse events in the combined use of several drugs.

Disturbances in cardiac conduction and repolarization

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

Saquinavir in combination with ritonavir is contraindicated in patients with congenital or documented acquired length of QT interval, electrolyte disorders, especially with uncorrected hypokalemia. The presence in the family history of the patient of cases of sudden death at a young age suggests the presence of an innate lengthening of the QT interval. Saquinavir in combination with ritonavir is contraindicated when used with certain drugs that have both a pharmacokinetic interaction and the ability to extend the QT and / or PR intervals (see "Contraindications" and "Interactions with Other Drugs").

It is not recommended to use saquinavir in combination with ritonavir in patients who are simultaneously receiving other drugs that are capable of prolonging the QT interval. If necessary, use caution and conduct an electrocardiographic examination if arrhythmia occurs. Caution should be exercised when using saquinavir in combination with ritonavir in patients with concomitant structural heart disease, impaired cardiac conduction, ischemic heart disease, or cardiomyopathy, since such patients have an increased risk of developing cardiac conduction disorders. It is necessary to stop the therapy with saquinavir in combination with ritonavir in case of significant arrhythmias, prolongation of the QT interval or PR. Most often, changes in the QT interval associated with the drug are possible in women and the elderly.

Do not exceed recommended doses of saquinavir in combination with ritonavir, as the extent of QT and PR interval prolongation may increase with increasing drug concentration.

The use of saquinavir in combination with ritonavir at a dose of 2000 mg once daily / 100 mg once a day is not recommended because the effect of such a combination on the risk of prolonging the QT interval has not been studied.

Patients starting saquinavir therapy in combination with ritonavir: Before the start of therapy, an electrocardiographic study should be performed. Do not assign saquinavir in combination with ritonavir, if the interval QT> 450 ms. Patients with an interval of QT <450 msec 3-4 days after the start of therapy should be re-electrocardiographic study. Therapy with saquinavir in combination with ritonavir should be discontinued if the QT interval is> 480 msec, or if the QT interval is increased by more than 20 msec compared to the baseline value.

Patients who continue with saquinavir in combination with ritonavir, if appropriate concomitant therapy with drugs that can prolong the RT interval; or patients receiving therapy with drugs that can extend the QT interval if saquinavir therapy is required in combination with ritonavir, and if alternative therapy is not available and the benefit exceeds risk: Before the onset of concomitant therapy, an electrocardiographic study is necessary.Do not administer concomitant therapy if the QT interval is> 450 msec (see section "Interaction with Other Drugs").

It is necessary to conduct a repeated electrocardiographic study if the initial QT interval is <450 ms. If the interval QT> 480 msec or the QT interval has increased by more than 20 ms after the addition of concomitant therapy, the attending physician, depending on the clinical situation, must decide to abolish saquinavir in combination with ritonavir and / or concomitant therapy.

Information for patients

Patients should be provided with the following information on cardiac conduction and repolarization disorders:

- The patient initiating saquinavir / ritonavir therapy should be alerted to the possibility of arrhythmias associated with prolongation of the QT or PR interval and that if symptoms of arrhythmia (such as a heartbeat, fainting, or a prefumor condition) appear, consult a doctor immediately.

- The physician should be informed of cases of sudden death at a young age in the patient's family, since this may be a sign of an innate lengthening of the QT interval.

- Patients should be cautioned not to exceed the recommended dose.

Renal insufficiency

A small part of the drug is excreted through the kidneys, so it is not necessary to adjust the dose initially in patients with impaired renal function (with mild and moderate renal failure). However, in patients with severe renal insufficiency no studies have been performed, therefore caution should be exercised when using saquinavir with such patients.

Diseases of the liver

Data on the use of saquinavir in patients with liver disease are limited.

Care should be taken when prescribing the drug to patients with impaired liver function of mild or moderate degree. Severe liver failure is a contraindication to the appointment of saquinavir.

Patients with chronic hepatitis B or C who simultaneously take antiretroviral drugs are at increased risk of adverse effects on the liver with possible fatal outcome. These patients should be carefully monitored, both clinically and laboratory.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk for liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If signs of impaired liver function appear, consideration should be given to the possibility of interrupting or canceling therapy.

A careful monitoring of the safety of therapy (including signs of cardiac arrhythmia) and a virologic response in this category of patients is required.

After initiation of therapy saquinavir in patients with hepatitis B or hepatitis C, cirrhosis, alcoholism, and / or other diseases of the liver were observed cases worsening liver disease or development of portal hypertension, accompanied by jaundice, ascites, edema and esophageal varices (in several patients with lethal ). The causal relationship between the development of portal hypertension and saquinavir therapy has not been established.

Hyperglycemia and diabetes mellitus

In patients receiving HIV protease inhibitors, cases of newly diagnosed diabetes mellitus, Hyperglycemia or decompensation of concomitant diabetes mellitus.

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

Patients with hemophilia

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

Redistribution of fat

In carrying out the combination antiretroviral therapy observed redistribution and fat deposition, including obesity of the central type, deposition of fat on the dorsal surface of the neck and back ( "buffalo hump"), a decrease of subcutaneous fat in the limbs, breast enlargement due to fat deposits, and "kushingoid" (round, moon face, flushing of the face, truncal obesity type, deposition of adipose tissue in the supraclavicular fossa).

Redistribution of adipose tissue is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, and hyperglycemia. The severity of these disorders varies within a class, as well as between classes of antiretroviral agents (HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors). Factors that increase the risk of lipodystrophy include: elderly age, duration of therapy, stavudine, hypertriglyceridemia, hyperlactatemia. Diagnosis includes assessment of physical signs of fat tissue redistribution, blood glucose and blood lipids.If these changes are detected, consideration should be given to changing the antiretroviral therapy and / or taking measures to correct such abnormalities (eg, prescribing hypolipidemic drugs). Currently, the mechanism of development of metabolic disorders and long-term effects, such as an increased risk of cardiovascular disease, are not known.

The use of saquinavir in combination with ritonavir in doses greater than 1000/100 mg twice a day is usually accompanied by an increase in the incidence of adverse events, as saquinavir concentrations in plasma in the presence of ritonavir increase. In some cases, the combined use of saquinavir and ritonavir has led to severe adverse events, mainly to the development of diabetic ketoacidosis and impaired liver function, especially in patients who previously had liver disease.

Interaction with other drugs

The simultaneous use of saquinavir (unresponsive regimen), taken in combination with other antiretroviral drugs, with rifabutin, rifampicin or efavirenz leads to a significant decrease in the concentrations of saquinavir in the plasma, so the joint use of these drugs is not recommended. The recommended dose of rifabutin, taken in combination with saquinavir and ritonavir, is 150 mg once every 4 days. Information on the joint use of saquinavir, ritonavir and efavirenz is limited. Do not assign rifampicin patients receiving saquinavir with ritonavir, in combination with other antiretroviral drugs because of the risk of developing severe hepatocellular toxicity.

Do not use phytopreparations, containing St. John's wort (Hypericum perforatum) and garlic extract, in combination with saquinavir (unresponsive regimen), due to a possible decrease in saquinavir concentrations in plasma and its clinical efficacy.

With the simultaneous use of saquinavir in combination with ritonavir with inhibitors of HMG-CoA reductase, mainly with drugs metabolized with the participation of cytochrome P450 ZA4 (for example, simvastatin and lovastatin), it is possible to increase concentrations of HMG-CoA reductase inhibitors in plasma.In rare cases, an increase in the concentrations of simvastatin and lovastatin may cause severe adverse events such as myalgia and rhabdomyolysis. It is necessary to avoid the joint use of these drugs. With caution, it is recommended to apply saquinavir in combination with ritonavir concomitantly with atorvastatin and cerivastatin (less metabolized by cytochrome P450 ZA4).

In this case, the dose of atorvastatin and cerivastatin should be reduced. If it is necessary to prescribe inhibitors of HMG-CoA reductase, it is recommended to apply fluvastatin or pravastatin.

The use of saquinavir in combination with ritonavir reduces concentration ethinylestradiol. Therefore, other or additional methods of contraception should be used when saquinavir is used together with ritonavir and estrogen-containing oral contraceptives.

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

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis in particular in patients with advanced HIV infection and / or prolonged combined antiretroviral therapy have been reported. Patients should be advised to consult a doctor if joint pain occurs, joint stiffness, or difficulty in moving.

Syndrome of immune reactivation

In HIV-infected patients with severe immunodeficiency at the time of initiation of combined antiretroviral therapy, an inflammatory response to an asymptomatic or residual opportunistic infection, or an increase in symptoms, may develop.As a rule, these reactions were observed during the first few weeks or months after the onset of combined antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pneumocystis carinii. If any symptom of inflammation occurs, you should diagnose and prescribe a treatment. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

Chronic diarrhea or malabsorption

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

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

Effect on the ability to drive transp. cf. and fur:

Special studies were not conducted.Data on the possibility of saquinavir to influence the ability to drive vehicles and mechanisms are not available.

However, when working with machines and mechanisms, the safety profile of the preparation should be taken into account. Dizziness, fatigue, and visual impairment have been reported with the administration of saquinavir, and if these undesirable phenomena appear from these activities, abstinence should be avoided.

Form release / dosage:

Tablets, film-coated 500 mg.

Packaging:

Primary packaging of medicinal product.

For 10 tablets in a contour mesh package made of a polyvinyl chloride film and foil of aluminum printed lacquered.

On 60, 120, 240, 360 tablets in a can of polymer with a cover pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing paper, or from polymer materials, self-adhesive.

Secondary packaging of medicinal product.

For 6 or 10 contour squares, together with the instruction for use, they are placed in a pack of cardboard for consumer tare subgroups chrome or chromium-ester or other similar quality.The packets are placed in a group package.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare of subgroups chrome or chrome - ersatz or other similar quality.

The packets are placed in a group package.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002435

Date of registration:18.04.2014 / 17.02.2016

Expiration Date:18.04.2019

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp30.10.2017

Illustrated instructions

Instructions

Interfast® (Interfast®)