Crixivan® (Crixivan®)

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  • Crixivan®
    capsules inwards 
    Merck Sharp and Doum B.V.     Netherlands
    • Dosage form: & nbspcapsules
    Composition:

    1 capsule contains:

    Capsules 200 mg

    active substance: indinavir sulfate 250 mg (equivalent to 200 mg indinavir);

    Excipients: lactose 74.8 mg, magnesium stearate 3.26 mg;

    capsule shell: gelatin, titanium dioxide, inks for capsules 200 mg: TekPrint™ SB- 6018, ink blue; for capsules 400 mg: TekPrint™ SB-4020, the ink is green.

    Capsules 400 mg

    active substance: indinavir sulfate 500 mg (equivalent to 400 mg indinavir;

    atExcipients: lactose 149.6 mg, magnesium stearate 6.52 mg;

    capsule shell: gelatin, titanium dioxide, inks for capsules 200 mg: TekPrint™ SB- 6018, ink blue; for capsules 400 mg: TekPrint™ SB-4020, the ink is green.

    Description:

    Capsules 200 mg: Hard gelatinous translucent capsules of white color (size 1) with an inscription "CRIXIVAN ™ 200 mg & quot ;, printed in blue ink.

    Capsules 400 mg: Hard gelatinous translucent capsules of white color (size 00) with an inscription "CRIXIVAN ™ 400 mg & quot ;, printed in green ink.

    Contents of capsules: granular powder of white or almost white color.
    Pharmacotherapeutic group:Antiviral [HIV] agent
    ATX: & nbsp

    J.05.A.E.02   Indinavir

    Pharmacodynamics:

    Indinavir is a specific HIV protease inhibitor that has activity against the human immunodeficiency virus (HIV). Indinavir has an inhibitory effect on the recombinant HIV-1 and HIV-2 protease, with about 10-fold greater selectivity for HIV-1 than HIV-2. Indinavir reversibly binds to the active site of the HIV protease, completely inhibiting the enzyme, and thus prevents the cleavage of the protein precursors of the virus that occurs when finalized new virus particles are formed. The resulting particles lose the ability to be included in the cycle of virus multiplication.

    Indinavir has no significant effect on other proteases, including renin, cathepsin D, elastase and coagulation factor Ha.

    Microbiology

    The use of indinavir in a concentration of 50 to 100 nmol / l was accompanied by inhibition of viral replication by 95% (IC95) (compared to the control infected with the virus, without treatment) in human T-lymphocyte cultures infected with several types of HIV-1, adapted to the cell line (LAI, MN and RF). A similar suppression of HIV-1 infection was observed in the primary culture of human monocytes / macrophages infected with a macrophage-tropic type of virus (SF 162).

    Besides, indinavir in a concentration of 25 to 100 nmol / L, 95% inhibits viral replication in cultures activated by mitogen of human peripheral blood mononuclear cells infected with various primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors, including zidovudine and non-nucleoside reverse transcriptase inhibitors. In the incubation of human T-lymphocytes infected with a type LAI HIV-1, with indinavir and zidovudine, didanosine or a non-nucleoside reverse transcriptase inhibitor, synergistic antiretroviral activity was observed.

    Resistance to medicines

    In some patients, the ability to suppress viral RNA is observed, but the amount of CD4 + cells often remains above the value observed before treatment. The termination of suppression of viral RNA was associated with the substitution of a sensitive virus by resistant types.Resistance correlates with the accumulation of mutations in the viral genome, which lead to an increase in amino acid substitutions in the HIV protease.

    At least 11 amino acid residues in the HIV-1 protease have been identified, the substitution of which leads to resistance. No single replacement can cause significant resistance to indinavir; resistance is mediated by the co-expression of multiple and diverse substitutions. In general, a higher level of resistance is the result of an increase in the number of replacements in the 11 identified positions. Replacement in these positions consistently accumulate, apparently, as a result of the constant replication of the virus.

    It should be noted that a decrease in suppression of viral RNA is more often observed when treatment with indinavir begins with lower doses than the dose 2,4 g / day, recommended for oral use.

    Treatment with indinavir should be started at the recommended doses in order to strengthen the suppression of viral replication, and, thus, to stop the emergence of resistant viruses.

    Cross-resistance

    Isolates from HIV-1 infected patients with decreased susceptibility to indinavir show a crossdifferent types and severity of resistance to a number of HIV protease inhibitors, including ritonavir and saquinavir. There was complete cross-resistance between indinavir and ritonavir, but the cross-resistance to saquinavir among the isolates varied. Many of the amino acid substitutions in the HIV protease, which were defined as associated with resistance to ritonavir and saquinavir, were also associated with resistance to indinavir. The simultaneous use of indinavir with a nucleoside analogue (which was not previously used in this patient) can reduce the likelihood of development of resistance to both indinavir and this nucleoside analogue.

    Pharmacokinetics:

    Absorption

    When administered on an empty stomach indinavir quickly absorbed, time to reach the maximum concentration in the blood plasma (TmOh) is about 0.8 hours. A more pronounced dose-proportional increase in the concentration of indinavir in blood plasma in the dose range from 200 mg to 800 mg has been noted. In the dose range of 800-1000 mg, this increase in indinavir concentration was less pronounced. Due to the short half-life, which is about 1,8 h, with repeated use of indinavir, its concentration in the blood plasma increased slightly. The bioavailability of a single dose of indinavir 800 mg was approximately 65%. In studies involving healthy volunteers, it has been shown that there are diurnal fluctuations in indinavir pharmacokinetics. When taking 800 mg of indinavir every 8 h, the maximum concentration (CmOh) in the blood plasma after taking the drug morning, afternoon and evening was 15550 nmol / l, 8720 nmol / l and 8880 nmol / l, respectively. Concentration in the blood plasma through 8 h after taking the drug was 220 nmol / l, 210 nmol / l and 370 nmol / l, respectively. In adult patients infected with HIV-1, the following geometric mean values ​​were obtained: area under the concentration-time curve AUC0-8h - 27813 nM * h, Cmax - 11144 nM, concentration of indinavir in blood plasma after 8 hours after administration - 211 nM.

    Effect of food intake on absorption

    Taking indinavir with a high-calorie, high in fat and protein, food led to a slowdown and a decrease in absorption, while AUC decreased by approximately 80%, and CmOh - on 86%. When taking the drug with low-calorie food (for example, dried toast with jelly,apple juice and coffee with skim milk and sugar or corn flakes with skim milk and sugar) AUC and CmOh were comparable with the corresponding indices when taking indinavir on an empty stomach.

    Distribution

    Indinavir has an average ability to bind to blood plasma proteins (39% of the active substance remains in an unbound state). Data on the penetration of indinavir into the tissues of the central nervous system have not been obtained.

    Metabolism

    Metabolism of indinavir was studied in healthy volunteers taking the drug orally in a dose of 400 mg and 1000 mg. When taking indinavir in a dose of 400 mg, labeled with a radioactive isotope 14C, approximately 83% of the active substance was found in the feces and 19% in the urine. Seven major metabolites and the following metabolic pathways were determined: glucidine nitropyridine, pyridine N-oxidation with hydroxylation of the indane ring in the third position and without hydroxylation, 3'-hydroxylation of indane, p-hydroxylation of the phenylmethyl group, N-depyridomethylation with 3'-hydroxylation or without.

    Research in vitro on microsomes of the human liver showed that the only isoenzyme of cytochrome P450, which plays a major role in the oxidative metabolism of indinavir, is isoenzyme CYP3A4.Analysis of urine and plasma samples of volunteers who received indinavir, showed that indinavir metabolites contribute insignificantly to the inhibition of HIV protease activity in vivo.

    Excretion

    In the dose range of 200-1000 mg, taken by healthy volunteers and HIV-1-infected patients, there was slightly more than a dose-proportional increase in excretion of indinavir with urine. The renal clearance (116 ml / min) of indinavir within the clinical dose range is independent of concentration. Less than 20% of indinavir is excreted by the kidneys unchanged. The average index of renal excretion of unchanged indinavir after a single fasting at a dose of 700 mg is 10.4%, and after taking a dose of 1000 mg - 12.0%. Indinavir quickly excreted from the body with a half-life of 1.8 hours.

    Individual patient groups

    Liver failure due to cirrhosis

    In patients with mild and moderate hepatic insufficiency and clinically established cirrhosis, data were obtained on a decrease in the metabolic rate of indinavir, which resulted in an increase in the mean AIS0-8h after a single dose of 400 mg approximately 60%.The average half-life of indinavir increased to about 2.8 hours. Pharmacokinetics in patients with severe hepatic insufficiency was not studied.

    Renal insufficiency

    In patients with renal insufficiency, the pharmacokinetics of indinavir has not been studied. With urine unchanged, less than 20% of the dose of indinavir taken.

    Floor

    The pharmacokinetics of indinavir in men and women is comparable. These data were obtained from the study of pharmacokinetics in 10 HIV-seropositive women who received CRYCIVAN® at a dose of 800 mg every 8 h with zidovudine in a dose 200 mg every 8 h and lamivudine in a dose of 150 mg twice a day for one week. Clinically significant differences between pharmacokinetic parameters of indinavir in these women and in HIV-seropositive men (summary control retrospective data) were not revealed.

    Race

    On the pharmacokinetics of indinavir, race does not seem to affect.

    Elderly patients

    The safety and efficacy of indinavir in elderly patients has not been established.

    Indications:

    Treatment of HIV-1 infection in combination with other antiretroviral drugs (analogues of nucleosides) in adults.

    Contraindications:

    Hypersensitivity to the active substance and excipients.

    In monotherapy or in combination with ritonavir, simultaneous administration with the following drugs: amiodarone, terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam, pimozide, ergot alkaloids, simvastatin or lovastatin.

    Simultaneous use with drugs with a narrow therapeutic effect, which are substrates of isoenzyme CYP3A4. Inhibition of CRYXIVAN® and ritonavir by isoenzyme CYP3A4 can cause an increase in the concentration of these drugs in the blood plasma, which can potentially lead to serious or life-threatening reactions.

    In combination with low doses of ritonavir and without it, simultaneous application of rifampicin.

    Simultaneous application with St. John's wort perfumed (Hypericum perforatum) or with preparations containing St. John's Wort.

    Therapy with ritonavir and indinavir in patients with liver disease in the stage of decompensation (ritonavir is metabolized primarily in the liver and is excreted through the liver).

    Combination therapy with CRYCIVAN® and ritonavir with alfuzosin, pethidine,piroxicam, propoxyphene, bepridilum, encinamide, flecainide, propafenone, quinidine, fusidic acid, clozapine, dical clorazepate, diazepam, estazolam, flurazepam, rosuvastatin and other HIV protease inhibitors.

    In patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption, since the preparation contains lactose.

    Carefully:

    In patients with urolithiasis, tubulointerstitial nephritis, renal insufficiency, hemophilia A and B, hyperglycemia, diabetes mellitus, lipodystrophy, osteonecrosis, musculoskeletal disorders, simultaneous administration with isoenzyme inducers CYP3A4 (possible decrease in the concentration of indinavir, increased risk of developing tolerance), with inhibitors of HMG-CoA reductase (atorvastatin, interaction with pravastatin and fluvastatin has not been studied), sildenafil, tadalafil and vardenafil.

    The use of the drug CRYXIVAN® and atazanavir may be accompanied by hyperbilirubinemia (with an increase in the fraction of unconjugated bilirubin).Since combined treatment with these drugs has not been studied in clinical trials, their simultaneous administration to patients is not recommended.

    Pregnancy and lactation:

    Adequate strictly controlled studies in pregnant women were not conducted. CRYCXIVAN® should be used during pregnancy only if the intended benefit to the mother is significantly greater than the potential risk to the fetus.

    Non-teratogenic effects

    In rhesus monkeys, the administration of indinavir to newborns caused a slight increase in transient physiological hyperbilirubinemia, which is observed in this species after birth. The introduction of indinavir to pregnant rhesus monkeys in the third trimester of pregnancy did not cause this phenomenon in newborns; However, there was only limited penetration of indinavir through the placenta. Hyperbilirubinemia was detected in healthy volunteers as well as in patients infected with HIV-1, taking different doses of CRYCIVAN®. Occasionally, this was accompanied by an increase in the activity of serum transaminases. However, due to the fact that this compound can potentially enhance the physiological bilirubinemia observed in newborn infants,the use of CRYCIVAN® in pregnant women until the moment of delivery should be carefully weighed.

    HIV-infected women are not recommended breastfeeding because of the risk of infection of the newborn. It is not established whether CRYCIVAN® is excreted in human milk. However, since many medications can penetrate into breast milk, and because of the potential for unwanted effects of CRYCXIVAN®, the mother should be advised to stop breastfeeding if she takes CRYXIVAN®.

    Dosing and Administration:

    Adults

    The recommended dose of CRYCIVAN® is 800 mg (usually in the form of two capsules of 400 mg) orally every 8 h. The maximum daily dose of CRYCIVAN® is 2.4 g.

    Alternatively, a combined treatment with CRYCIVAN® at a dose of 400 mg and ritonavir 100 mg is possible. Both drugs are taken orally twice a day, regardless of food intake.

    The preparation CRYCXIVAN® should be applied:

    - in combination with approved antiretroviral drugs (eg, with nucleoside or non-nucleoside reverse transcriptase inhibitors) for the treatment of adult patients with HIV-1 infection.

    Because CRYCXAN® should be taken at intervals 8 h, the scheme of reception of a preparation convenient for the patient is selected. For optimal absorption, CRYCXIVAN® should be taken with water, after 1 h before or after 2 h after a meal. Crikvisan® can be taken with other liquids, such as skimmed milk, juice, coffee or tea. It is possible to take light food with a low fat content. To ensure a sufficient supply of fluids, adults are advised to drink at least 1.5 liters of fluid per day.

    Patients with renal colic need a short break in taking CRIXIVAN® (for example, for 1-3 days), copious drinking, in some cases, cancellation of therapy may be required.

    Concomitant treatment

    Rifabutin

    When Rifabutin and CRYCIVAN® are taken concomitantly, it is recommended that the dose of rifabutin be reduced to half the standard dose (refer to the medical instructions for rifabutin) and increase the dose of CRYCXIVAN to 1000 mg every 8 h.

    Ketoconazole

    When taking concomitantly with ketoconazole, you should consider reducing the dose of CRYCIVAN® to 600 mg every 8 h.

    Itraconazole

    When taking concomitantly with itraconazole at a dose of 200 mg twice a day, the dose of CRYCIVAN® should be reduced to 600 mg every 8 h.

    Delavirdine

    When taking 400 mg doses of Delavirdine concomitantly three times a day, the possibility of reducing the dose of CRYCIVAN® to 600 mg every 8 h.

    Efavirenz

    At simultaneous admission with efavirenz in a dose of 600 mg, it is recommended that the dose of CRYCIVAN® be increased to 1000 mg every 8 h.

    Patients with concomitant diseases

    Liver failure due to liver cirrhosis: in patients with mild or moderate hepatic insufficiency caused by cirrhosis, the dose of CRYCIVAN® should be reduced to 600 mg every 8 h.

    Side effects:

    Very often (≥10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (< 1/10000), the frequency is unknown (according to available data, the frequency is not set).

    The most common side effects, probably probably and definitely associated with taking CRYXIVAN®, were weakness / fatigue, abdominal pain, diarrhea, nausea, vomiting, dizziness, headache, dry skin, skin rash and taste distortion. In 9.8% of patients, urolithiasis was noted, manifested by pain in the back, hematuria (including microhematuria). As a rule, these phenomena were not accompanied byimpaired renal function and were reversible in the case of a short interruption in treatment (for 1-3 days) and sufficient intake of fluid.

    Post-market observations

    In the post-marketing period and clinical studies of drug use, the following adverse events were additionally reported:

    From the digestive system: Often - nausea, vomiting, diarrhea, indigestion; often - flatulence, dryness of the oral mucosa, reflux esophagitis; the frequency is unknown - liver function abnormalities, hepatitis, hepatic insufficiency, pancreatitis.

    From the hematopoiesis: frequency unknown - increased frequency of spontaneous bleeding in patients with hemophilia, thrombocytopenia, anemia, including acute hemolytic anemia.

    From the endocrine system: the frequency is unknown - the newly diagnosed diabetes mellitus or hyperglycemia, or exacerbation of diabetes mellitus.

    Allergic reactions: frequency unknown - anaphylactoid reactions.

    From the central nervous system and sense organs: Often - headache, dizziness; often - insomnia, hypoesthesia, paresthesia; frequency unknown - impaired sensitivity of the oral mucosa, impaired vision.

    From the skin and subcutaneous fat: Often - a rash, dry skin; often - skin itching; frequency unknown - rash, including erythema multiforme and Stevens-Johnson syndrome, vasculitis, alopecia, hyperpigmentation, urticaria, cases of ingrown toenail finger and / or paronychia.

    From the musculoskeletal system: often - myalgia; the frequency is unknown - myositis, rhabdomyolysis, osteonecrosis (in patients receiving long-term combined treatment with antiviral drugs).

    From the genitourinary system: often - urolithiasis in adults, dysuria; frequency unknown - pyelonephritis, renal insufficiency, interstitial nephritis (sometimes with the deposition of indinavir crystals), in some patients the phenomena of interstitial nephritis persist after discontinuation of CRIXIVAN® preparation.

    Other: very often, weakness / fatigue, perversion of taste, abdominal pain; frequency is unknown - with combined antiviral therapy - redistribution of adipose tissue (lipodystrophy) with predominant localization in the face,the posterior surface of the neck, the chest, the anterior abdominal wall and the retroperitoneum, metabolic disturbances, increased insulin resistance, and characteristic changes in laboratory parameters (hypertriglyceridemia, hypercholesterolemia, hyperlactatemia).

    From the laboratory indicators: very often an increase in the average volume of erythrocytes, neutropenia, an increase in the activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), asymptomatic hyperbilirubinemia (predominantly with an increase in indirect bilirubin), in some cases in combination with increased activity of ALT, ACT or alkaline phosphatase, proteinuria, hematuria, asymptomatic pyuria, in some cases in combination with an increase in the concentration of creatinine, crystalluria.

    Post-registration experience:

    frequency unknown - hypertriglyceridemia, hypercholesterolemia, increased activity of creatine kinase.

    Overdose:

    There were reports of an overdose of CRYCIVAN®. The most frequent symptoms were: from the gastrointestinal tract - nausea, vomiting, diarrhea and from the urinary system - urolithiasis, pain in the lumbar region, hematuria.

    If these symptoms are identified, a short-term break or withdrawal of CRYCXIVAN® therapy, abundant drinking, symptomatic therapy is recommended.

    It is not established whether CRYCIVAN® is excreted in peritoneal dialysis or hemodialysis.

    Interaction:

    In the metabolism of indinavir isoenzyme participates CYP3A4 cytochrome P450.

    Therefore, other drugs, biotransformation of which occurs with the participation of this isoenzyme, or capable of altering its activity, may influence the pharmacokinetics of indinavir. In its turn, indinavir is able to influence the pharmacokinetic parameters of other drugs.

    Combined treatment with indinavir and ritonavir may have an additional effect on the pharmacokinetics of drugs with the same biotransformation mechanism.

    CRYCXYAN® with or without ritonavir should not be combined with the following drugs: amiodarone, terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam, pimozide, ergot alkaloids, simvastatin or lovastatin.

    Simultaneous use with drugs with a narrow therapeutic effect, which are substrates of the isoenzyme CYP3A4

    Inhibition of CRYXIVAN® and ritonavir by isoenzyme CYP3A4 can cause an increase in the concentration of these drugs in the blood plasma, causing severe or life-threatening reactions.

    Information on the characteristics of drug interaction CRYCXIVAN is presented in the tables.

    Table 1. Interaction of indinavir with other medications and recommendations for dosing

    Medical products in accordance with the field of application

    Interaction

    Recommendations for simultaneous application

    Treatment of HIV infection

    Antiretroviral drugs

    Didanosine (buffered dosage form)

    There were no studies on the interaction. For the absorption of indinavir, the normal pH of the stomach is necessary, the acid promotes the rapid decay of didanosine, which contains buffering substances to increase the pH. When ddI was administered 3 hours after indinavir, there was no change in antiretroviral activity.

    Indinavir and didanosine, containing buffer substances, are appointed on an empty stomach with a break of at least 1 hour.

    Didanosine (enteric coated tablets) 400 mg once (indinavir 800 mg once)

    Indinavir: the dose does not change (monotherapy indinavir in a dose of 800 mg once).

    Didanosine: the dose does not change.

    It is used without changing the dose of drugs, regardless of the time of ingestion.

    Stavudine 40 mg twice daily

    (indinavir 800 mg 3 times / day)

    Indinavir AUC: without changes.

    Indinavir Cmin: without changes (indinavir 800 mg 3 times / day). Stavudine AUC: increases by 21% Cmin: not studied.

    Indinavir and listed medications can be administered without changing the dose.

    Zidovudine 200 mg 3 times / day (indinavir 1000 mg 3 times / day)

    Indinavir AUC: without changes.

    Indinavir Cmin: without changes (indinavir 1000 mg 3 times / day).

    Zidovudine AUC: without changes.

    Zidovudine Cmin: an increase of 51%.

    Zidovudine / Lamivudine 200/150 mg 3 times / day (indinavir 800 mg 3 times / day)

    Indinavir AUC: without changes.

    Indinavir Cmin: without changes (indinavir 800 mg 3 times / day). Zidovudine AUC: an increase of 39%. Zidovudine Cmin: without changes.

    Lamivudine AUC: without changes.

    Lamivudine Cmin: without changes.

    Delavirdine 400 mg 3 times / day (indinavir 600 mg 3 times / day)

    Indinavir AUC: an increase of 53%. Indinavir Cmin: an increase of 298%

    (indinavir 800 mg 3 times / day).

    It is recommended to reduce the dose of CRIXIVAN® to 400-600 mg once (taking 3 times / day with an interval of 8 hours).

    Delavirdine 400 mg 3 times / day (indinavir 400 mg 3 times / day)

    Indinavir AUC: without changes.

    Indinavir Cmin: an increase of 118%

    (indinavir 800 mg 3 times / day).

    Delavirdine: unchanged.


    Efavirenz 600 mg 1 time / day (indinavir 1000 mg 3 times / day)

    Indinavir: decrease AUC on 33-46%, Cmin by 39-57%, Cmax by 5-29% (in comparison with the regime indinavir 800 mg 3 times / day).

    There are no special recommendations.

    Efavirenz 200 mg once (indinavir 800 mg 3 times / day)

    An increase in the dose of indinavir to 1000 mg does not compensate for the effect of efavirenz. Indinavir AUC: a decrease of 31%.


    Indinavir Cmin: decrease by 40%.

    Efavirenz AUC: without changes.

    Nevirapine 200 mg 2 times / day (indinavir 800 mg 3 times / day)

    Indinavir AUC: a decrease of 28%.

    Nevirapine: No change (inducer CYP3A).

    Increase in the dose of indinavir to 1000 mg 3 times / day with combined treatment with nevirapine.

    Amprenavir 1200 mg 2 times / day (indinavir 1200 mg 2 times / day)

    Amprenavir AUC: an increase of 90%.

    Indinavir: unchanged.

    Doses for combined treatment with these drugs have not been established.

    Ritonavir 100 mg 2 times / day. (indinavir 800 mg 2 times / day)

    Indinavir AUC24h: an increase of 178%.

    Indinavir Cmin: increase 11 times (monotherapy with indinavir 800 mg 3 times / day).

    Ritonavir AUC: an increase of 72%.

    Ritonavir Cmin: an increase of 62%.

    The most convenient doses for this combination treatment, taking into account efficacy and safety, are not established. Preliminary data from clinical trials suggest an alternative dosing regimen using CRYCIVAN® at a dose of 400 mg, and ritonavir 100 mg, both applied 2 times / day. The combined use of 800 mg of indinavir and 100 mg of ritonavir 2 times / day is accompanied by an increased risk of side effects.

    Indinavir 800 mg 2 times / day with ritonavir increases the risk of nephrolithiasis and requires compliance with precautionary measures (ensuring adequate hydration).

    Ritonavir 200 mg 2 times / day (indinavir 800 mg 2 times / day)

    Indinavir AUC24h: an increase of 266%.

    Indinavir Cmin: increase by 24 times (monotherapy with indinavir 800 mg 3 times / day).


    Ritonavir AUC: an increase of 96%.


    Ritonavir Cmin: an increase of 371%.

    Ritonavir 400 mg 2 times / day (indinavir 800 mg 2 times / day)

    Indinavir AUC24h: an increase of 220%.


    Indinavir Cmin: increase by 24 times (monotherapy with indinavir 800 mg 3 times / day).

    Ritonavir AUC24h: without changes.

    Ritonavir 400 mg 2 times / day (indinavir 400 mg 2 times / day)

    Indinavir AUC24h: an increase of 68%.


    Indinavir Cmin: increase 10 times (monotherapy with indinavir 800 mg 3 times / day).

    Ritonavir 100 mg 2 times / day (indinavir 400 mg 2 times / day)

    Ritonavir AUC24h: without changes.

    Indinavir AUC and Cmin: without changes (monotherapy with indinavir 800 mg 3 times / day).

    Saquinavir 600 mg once (indinavir 800 mg 3 times / day)

    Saquinavir AUC: increase by 500%.

    Saquinavir Cmin: an increase of 190% (relative to saquinavir 600 mg once).

    Acceptable doses for combined treatment with these drugs are not established.

    Saquinavir 800 mg once (indinavir 800 mg 3 times / day)

    Saquinavir AUC: an increase of 620%.

    Saquinavir Cmin: increase by 450% (relative to saquinavir 800 mg once).

    Saquinavir 1200 mg once (indinavir 800 mg 3 times / day)

    Saquinavir AUC: an increase of 360%.

    Saquinavir Cmin: an increase of 450% (relative to saquinavir 1200 mg once).

    The design of this study did not allow us to determine the extent of saquinavir influence on indinavir, but an almost twofold increase is assumed AUC24h: indinavir with


    joint appointment with saquinavir.

    Atazanavir

    (indinavir)

    Each of the drugs is capable of inducing hyperbilirubinemia with an increase in the fraction of the indirect (unconjugated) bilirubin.

    Combined treatment with atazanavir and indinavir in clinical trials has not been studied, it is not recommended to prescribe both drugs simultaneously.

    Antibiotics

    Sulfamethoxazole / trimethoprim 800 mg / 160 mg 2 times / day (indinavir 400 mg 3 times / day)

    Indinavir AUC and Cmin: without changes (with respect to indinavir 400 mg 4 times / day).

    Sulfamethoxazole AUC and Cmin: without changes.

    Indinavir and sulfamethoxazole / trimethoprim may be used without dose adjustment.

    Antifungal means

    Fluconazole 400 mg once (indinavir 1000 mg 3 times / day)

    Indinavir AUC: decrease by 24%.

    Indinavir Cmin: without changes (relative to indinavir 1000 mg 3 times / day).

    Indinavir and fluconazole can be used without dose adjustment.

    Itraconazole 200 mg 2 times / day (indinavir 600 mg 3 times / day)

    Indinavir AUC: without changes.

    Indinavir Cmin: an increase of 49% (relative to indinavir 800 mg 3 times / day).

    The dose of CRYCIVAN® is reduced to 600 mg 3 times / day.

    Ketoconazole 400 mg once (indinavir 600 mg 3 times / day)

    Indinavir AUC: decrease by 20%.

    Indinavir Cmin: an increase of 29% (relative to indinavir 800 mg 3 times / day).

    It is necessary to reduce the dose of CRYCXIVAN® to 600 mg 3 times / day.

    Ketoconazole 400 mg once (indinavir 400 mg 3 times / day)

    Indinavir AUC: a decrease of 56%.

    Indinavir Cmin: decline


    by 27% (relative to indinavir 800 mg 3 times / day).


    Drugs active against mycobacteria

    Isoniazid 300 mg once (indinavir 800 mg 3 times / day)

    Indinavir AUC and Cmin: without changes (with respect to indinavir 800 mg 3 times / day).

    Isoniazid AUC and Cmin: without changes.

    Indinavir and isoniazid apply simultaneously without dose adjustment.

    Rifabutin 300 mg once (indinavir 800 mg 3 times / day)

    Indinavir AUC: a decrease of 34%.

    Indinavir Cmin: decrease of 39% (relative to indinavir 800 mg 3 times / day).

    Adequate doses with simultaneous application are not established, therefore the combined treatment is not recommended.


    Rifabutin AUC: increase by 173% Rifabutin Cmin: an increase of 244% (relative to rifabutin 300 mg 1 time / day).


    Rifabutin 150 mg once (indinavir 800 mg 3 times / day)

    Indinavir AUC: a decrease of 32%.



    Indinavir Cmin: decrease by 40% (relative to indinavir 800 mg 3 times / day).



    Rifabutin AUC: an increase of 54%.



    Rifabutin Cmin: increase by 99% (relative to rifabutin 300 mg 1 time / day).



    Comparative data on the use of rifabutin 150 mg once in combination with indinavir



    800 mg 3 times / day and only rifabutin in a dose of 150 mg are absent.


    Rifampicin 600 mg once (indinavir 800 mg 3 times / day)

    Indinavir AUC: a decrease of 92% (relative to indinavir 800 mg 3 times / day).

    This effect is due to induction of the isoenzyme CYP3A4 rifampicin.

    The combined use of rifampicin with indinavir is contraindicated.

    Narcotic analgesics

    Methadone 20-60 mg once (indinavir 800 mg 3 times / day)

    Indinavir AUC: without changes (relative to indinavir 800 mg 3 times / day).

    Methadone AUC and Cmin: without changes.

    Methadone and indinavir can be applied simultaneously, dose adjustment is not carried out.

    Antiarrhythmic drugs

    Quinidine 200 mg once (indinavir 400 mg once)

    Indinavir AUC and Cmin: unchanged (relative to indinavir 400 mg, once). An increase in the concentration of quinidine (indinavir inhibition of isoenzyme CYP3A4).

    Simultaneous use of quinidine and CRYCXIVAN® preparation - with caution, control of the therapeutic concentration of quinidine.

    The combined treatment with indinavir and ritonavir with quinidine is contraindicated.

    Drugs for the treatment of bronchial asthma

    Theophylline 250 mg once (indinavir 800 mg 3 times / day)

    Theophylline AUC and Cmin: without changes.

    Indinavir and theophylline can be used without dose adjustment.

    Anticoagulants

    Warfarin

    Not studied, combined use can lead to an increase in the concentration of warfarin in the blood plasma.

    It may be necessary to adjust the dose of warfarin.

    Antiepileptic drugs

    Carbamazepine, phenobarbital, phenytoin

    Indinavir exerts an inhibitory effect on the isoenzyme CYP3A4 and is supposed to increase the concentration of antiepileptic drugs in blood plasma, and the latter can reduce the concentration of indinavir.

    It is necessary to carefully monitor the therapeutic efficacy and side effects when combined with indinavir.

    Antidepressants

    Venlafaxine 50 mg 3 times / day (indinavir 800 mg once)

    Indinavir AUC: decrease of 28% (relative to indinavir 800 mg once).

    Venlafaxine and active metabolite O-desmethyl-venlafaxine: unchanged.

    The clinical significance of the results is unknown.

    Blocks of "slow" calcium channels

    Dihydropyridine derivatives, for example, felodipine, nifedipine, nicardipine

    Increase in plasma concentration of blockers of "slow" calcium channels dihydropyridine series. Metabolism of blockers of "slow" calcium channels is carried out by means of the CYP3A4 isoenzyme, and indinavir is its inhibitor.

    Use with caution, monitoring of the condition of patients is recommended.

    Herbal remedies

    St. John's wort perforated (Hypericum perforatum) 300 mg 3 times / day

    (indinavir 800 mg 3 times / day)

    Indinavir AUC: a decrease of 54%.

    Indinavir Cmin: decline by 81% (relative to indinavir 800 mg 3 times / day). Decrease in the concentration of indinavir due to the induction of metabolism of the drug and / or transport proteins by St. John's wort penetrated.

    Preparations of plant origin, containing St. John's Wort, contraindicated in the therapy with CRYCIVAN®. If the patient receives a drug containing St. John's Wort, the disinfection should be stopped, the concentration of the virus and, if possible, indinavir should be determined. The concentration of indinavir in plasma with the withdrawal of St. John's wort can increase, which will require a reduction in the dose of CRYCIVAN®. The induction effect can persist for 2 weeks after the withdrawal of St. John's wort treatment.

    Blockers H2-gistaminovyh receptors

    Cimetidine 600 mg 2 times / day (indinavir 400 mg once)

    Indinavir AUC and Cmin: without changes (relative to indinavir 400 mg once).

    Indinavir and cimetidine can be administered simultaneously without dose adjustment.

    Inhibitors of HMG-CoA reductase

    Lovastatin, simvastatin

    Indinavir is an isoenzyme inhibitor CYP3A4 and promotes a significant increase in the concentration in the blood plasma of HMG-CoA reductase inhibitors, which depend on the isoenzyme metabolism CYP3A4.

    Combination therapy is contraindicated due to the high risk of myopathy, including rhabdomyolysis.

    Rosuvastatin

    The interaction has not been studied. The combination of lopinavir / ritonavir + rosuvastatin was studied:

    Rosuvastatin AUC: an increase of 2.08 times.

    Rosuvastatin CmOh: an increase of 4.66 times (the mechanism is unknown).

    Combination is not recommended

    Atorvastatin

    Increased concentrations of atorvastatin. The severity of the increase in the concentration of atorvastatin in the blood plasma to a lesser extent depends on the isoenzyme CYP3A4 compared with lovastatin and simvastatin.

    The use of minimally possible doses of atorvastatin with caution, with careful observation.

    Pravastatin, fluvastatin

    The interaction was not studied. Metabolism of pravastatin and fluvastatin does not depend on isoenzyme CYP3A4. Interaction with the participation of transport proteins is not excluded.

    Interaction is not established. If there is no alternative choice, the application is possible under condition of clinical observation.

    Immunosuppressive means

    Cyclosporin

    The concentration of cyclosporine is significantly increased in patients receiving HIV protease inhibitor therapy, including indinavir.

    The content of cyclosporine in the blood plasma requires a significant correction of the dose of the drug and clinical observation.

    Hormonal contraceptives (for systemic use)

    Norethisterone / ethinylestradiol 1/35 once (indinavir 800 mg 3 times / day)

    Norethisterone AUC: an increase of 26%.

    Norethisterone Cmin: an increase of 44%.

    The simultaneous use of indinavir and norethisterone / ethinylestradiol 1/35 is possible without dose adjustment.

    Inhibitors of phosphodiesterase 5

    Sildenafil 25 mg once

    (indinavir 800 mg 3 times / day)

    Indinavir AUC: an increase of 11%.

    Sildenafil AUC: an increase of 340%. Simultaneous administration of the drug CRYCXYAN® and sildenafil probably leads to an increase in the concentration of sildenafil due to competitive inhibition of metabolic pathways.

    In patients receiving indinavir, the dose of sildenafil should not exceed 25 mg with an interval between administrations of 48 hours.

    Vardenafil 10 mg once (indinavir 800 mg 3 times / day)

    Vardenafil AUC: 16-fold increase. Simultaneous administration of the drug CRYCXYAN® and vardenafil probably leads to an increase in vardenafil concentration by competitive inhibition of metabolic pathways.

    In patients receiving indinavir, the dose of vardenafil should not exceed 2.5 mg with an interval of 24 hours.

    Tadalafil

    The interaction was not studied.

    Simultaneous use of the drug CRYCXIVAN® and tadalafil is probably accompanied by an increase in the concentration of tadalafil by competitive inhibition of metabolic pathways.

    In patients receiving indinavir, the dose of tadalafil should not exceed 10 mg with an interval of 72 hours.

    Sedatives / hypnotics

    Midazolam (parenteral route of administration)

    It has not been studied, it is assumed that the combined use significantly increases the concentration midazolam, especially when it is ingested. Metabolism of midazolam is carried out with the participation of the isoenzyme CYP3A4.

    Simultaneous administration of CRYCIVAN® and midazolam is not permitted.

    Carefully -simultaneous application of the drug CRYCXIVAN® and parenteral administration of midazolam. The introduction of midazolam is carried out in the intensive care unit, with mandatory clinical observation in connection with possible respiratory depression and increased sedation. It may be necessary to reduce the dose of midazolam, especially if the drug is injected repeatedly.

    Glucocorticosteroids for systemic use

    Dexamethasone

    The interaction has not been studied. An increase in the dose of dexamethasone (oppression of the isoenzyme CYP3A4).

    It is possible to reduce the concentration of indinavir in the blood plasma (induction of isoenzyme CYP3A4).

    Clinical observation is recommended for the detection of side effects with simultaneous use of dexamethasone and indinavir.

    TTable 2. Combined treatment (indinavir and ritonavir). Interaction with other medicinal products and recommendations for dosing.

    Medical products in accordance with the field of application

    Interaction

    Recommendations for simultaneous application

    Treatment of HIV infection

    Antiretroviral drugs

    Amprenavir

    Amprenavir 1200 mg 2 times / day AUC: an increase of 90% with the use of indinavir in a dose of 800 mg 3 times / day.

    Amprenavir 600 mg 2 times / day

    AUC: an increase of 64% with the simultaneous use of ritonavir in a dose of 100 mg 2 times / day (relative to amprenavir 1200 mg 2 times / day).

    Ritonavir increases the concentration of amprenavir in blood plasma due to oppression of the isoenzyme CYP3A4.

    There is insufficient data on the interaction of indinavir / ritonavir and amprenavir.

    Adequate doses for this combination of drugs have not been established. Oral solutions containing ritonavir and

    amprenavir, should not be given to children at the same time because of the danger of toxic effects of excipients.

    Efavirenz 600 mg 1 time / day (indinavir / ritonavir 800/100 mg 2 times / day)

    Indinavir AUC: decrease by 25%.

    Indinavir Cmin: decrease by 50% (relative to indinavir / ritonavir 800/100 mg 2 times / day) Ritonavir AUC: a decrease of 36%.

    Ritonavir Cmin: a decrease of 39%.

    Efavirenz AUC: without changes.

    An increase in the dose of indinavir / ritonavir in combination treatment with efavirenz has not been studied.

    Drugs active against mycobacteria

    Rifabutin

    Interactions with indinavir / ritonavir have not been studied.

    It is proposed to reduce the concentration of indinavir in the blood plasma and increase the concentration of rifabutin.

    Adequate doses in combined treatment with indinavir and ritonavir and simultaneous use of rifabutin are not established, combined treatment is not recommended.

    Rifampicin

    Rifampicin is an isoenzyme inducer CYP3A4.

    It is shown that it reduces AUC indinavir by 92%, which can lead to the development of resistance and virologic decompensation. When trying to compensate for the dose and when using other HIV protease inhibitors with ritonavir, a high incidence of liver damage was observed.

    The use of rifampicin and CRYCIVAN® together with low doses of ritonavir is contraindicated.

    Other antimicrobial agents

    Atovahon

    Interaction with the combined use of indinavir / ritonavir has not been studied. Ritonavir induces glucuronidation and is believed to reduce the concentration in the plasma of atovahona.

    Clinical observation and identification of side effects when combined use of combined treatment with indinavir and ritonavir and atovahona.

    Erythromycin, itraconazole

    Interaction with indinavir and ritonavir has not been studied.Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and it is assumed that they increase the concentration in the blood plasma of erythromycin and itraconazole.

    Clinical observation, the identification of side effects in the joint use of these drugs.

    Ketoconazole

    Interaction with indinavir and ritonavir has not been studied. Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and it is assumed that they increase the concentration in ketoconazole plasma. The combined use of ritonavir and ketoconazole is associated with a higher incidence of side effects from the gastrointestinal tract and liver.

    Clinical observation, the identification of side effects in the joint use of these drugs. It is necessary to reduce the dose of ketoconazole with simultaneous treatment with indinavir and ritonavir.

    Narcotic analgesics

    Fentanyl

    Interaction with indinavir and ritonavir has not been studied. Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and it is suggested that they increase the concentration of fentanyl in blood plasma.

    Clinical observation, the identification of side effects in the joint use of these drugs.

    Methadone

    Interaction with indinavir and ritonavir has not been studied.

    Significant influence of monotherapy of indinavir on AUC methadone was not detected.

    The decrease AUC methadone with other HIV protease inhibitors. Ritonavir can induce glucuronidation of methadone.

    An increase in the dose of methadone in combination with ritonavir / indinavir may be required. Correction of the dose - depending on the effectiveness of the therapy.

    Morphine

    The interaction has not been studied. It is possible to reduce the dose of morphine due to the induction of glucuronation in the joint use of ritonavir.

    Clinical observation, the identification of side effects in the joint use of these drugs.

    Antiarrhythmic drugs

    Digoxin 0.4 mg once Ritonavir 200 mg 2 times / day

    Interactions with indinavir / ritonavir have not been studied.

    Increase AUC digoxin by 22%.

    Ritonavir can increase the concentration of digoxin in the blood plasma due to a change in P-glycoprotein-mediated release of digoxin. It is necessary to control the concentration of digoxin in the blood plasma.

    Anticoagulants

    Warfarin

    Ritonavir 400 mg 2 times / day

    Interactions with indinavir / ritonavir have not been studied.The concentration of the dextrorotatory warfarin isomer may decrease, leading to an increase in blood coagulation, due to the induction of isoenzymes CYP1A2 and CYP2C9 ritonavir.

    Coagulation indicators should be monitored when combined with warfarin with indinavir / ritonavir.

    Antiepileptic drugs

    Carbamazepine

    Interactions with indinavir / ritonavir have not been studied.

    Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and, as expected, contribute to an increase in the concentration of carbamazepine.

    It is necessary to carefully monitor the therapeutic efficacy and side effects when combined with indinavir.

    Valproate Seminars, lamotrigine, phenytoin

    Interactions with indinavir / ritonavir have not been studied. Ritonavir induces glucuronation and oxidation involving isoenzyme CYP2C9 and is supposed to help reduce the concentration of antiepileptic drugs.

    It is recommended to monitor the concentration of drugs of this group in the blood plasma when they are used together, as well as clinical observation. Phenytoin can reduce the concentration of ritonavir in the blood plasma.

    Antidepressants

    Trazodone 50 mg once Ritonavir 200 mg 2 times / day

    The interaction has not been studied. Trazodone AUC: an increase of 2.4 times.

    At appointment with ritonavir the frequency of side effects of trazodone is noted.

    With caution use this combination of drugs, starting with the minimum possible dose of trazodone, a clinical observation for the evaluation of efficacy and tolerability.

    Antihistamines

    Fexofenadine

    Interactions with indinavir / ritonavir have not been studied. Ritonavir can alter the release of fexofenadine mediated by P-glycoprotein when combined, leading to an increased fexofenadine concentration.

    Clinical observation is recommended to assess the efficacy and safety of this combination of drugs.

    Loratadin

    Interactions with indinavir / ritonavir have not been studied.

    Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and is supposed to increase the concentration of loratadine in the blood plasma.

    Clinical surveillance and safety assessment are recommended combined treatment.

    Blocks of "slow" calcium channels

    Diltiazem 120 mg once (indinavir / ritonavir 800/100 mg 2 times / day)

    Diltiazem: increase AUC0-24h on 43%.

    AUC indinavir / ritonavir - without change.

    It is necessary to take into account the decrease in the concentration of preparations of blockers of "slow" calcium channels, since it is possible to increase their effectiveness.

    Amlodipine 5 mg once (indinavir / ritonavir 800/100 mg 2 times / day)

    Amlodipine - increase AUC24h on 80%.

    AUC indinavir / ritonavir - without change.

    Inhibitors of HMG-CoA reductase

    The recommendations are the same as for monotherapy with indinavir.

    Immunosuppressive means

    Cyclosporin

    (indinavir / ritonavir 800/100 2 times / day)

    In one study, prior to initiation of treatment with indinavir / ritonavir 800/100 mg 2 times / day or lopinavir / ritonavir 400/100 mg 2 times / day, it was necessary to reduce the dose of cyclosporin by 5-20% within the therapeutic range of doses. The concentration of cyclosporine is significantly increased in patients receiving HIV protease inhibitor therapy, including indinavir.

    It is necessary to correct the dose of cyclosporine in the blood plasma in accordance with the minimum concentration of cyclosporine in the blood plasma.

    Tacrolimus

    Interactions with indinavir / ritonavir have not been studied. Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and is believed to increase the concentration of tacrolimus in the blood plasma.

    Clinical surveillance and safety assessment are recommended combined treatment.

    Inhibitors of phosphodiesterase 5

    Sildenafil, tadalafil

    The interaction was not studied.

    The recommendations are the same as for monotherapy with indinavir.

    Vardenafil

    The interaction was not studied.

    Do not exceed the maximum dose of vardenafil 2.5 mg with an interval of 72 hours with combined treatment with HIV protease inhibitors.

    Sedatives / hypnotics

    Buspirone

    Interactions with indinavir / ritonavir have not been studied. Indinavir and ritonavir - inhibitors of isoenzyme CYP3A4, and is believed to increase the concentration of buspirone in the blood plasma.

    Clinical observation, safety assessment in combination with buspirone with indinavir / ritonavir.

    Midazolam (parenteral route of administration)

    Interactions with indinavir / ritonavir have not been studied. It is assumed that the combined use significantly increases the concentration of midazolam, especially when it is ingested (oppression of the isoenzyme CYP3A4).

    Simultaneous administration of CRYXIVAN® and midazolam is not recommended.

    With caution - the simultaneous use of the drug CRYCXIVAN® and midazolam with its parenteral administration. The introduction of midazolam is carried out in the intensive care unit with mandatory clinical observation in connection with possible respiratory depression and increased sedation. It may be necessary to reduce the dose of midazolam, especially if the drug is administered repeatedly.

    Glucocorticosteroids for systemic use

    Dexamethasone

    The interaction has not been studied. An increase in the dose of dexamethasone (oppression of the isoenzyme CYP3A4). It is possible to reduce the concentration of indinavir in the blood plasma (induction of isoenzyme CYP3A4).

    Clinical observation is recommended for the detection of side effects with simultaneous use of dexamethasone and a combination of indinavir / ritonavir.
    Special instructions:

    Care should be taken when taking CRIXIVAN® together with other HMG-CoA reductase inhibitors that are metabolized by isoenzyme CYP3A4 (eg, atorvastatin), which may be accompanied by an increased risk of myopathy, including rhabdomyolysis.

    Ritonavir increases the concentration of indinavir in blood plasma, indinavir may affect the concentration of ritonavir. To date, there is insufficient data on the safety and efficacy of this combination in patients.

    Urolithiasis and tubulointerstitial nephritis

    When taking Crikivan®, adults reported urolithiasis. In some cases, urolithiasis was accompanied by symptoms of acute or chronic renal failure, in most cases, these phenomena were reversible. In case of exacerbation of urolithiasis, with pain in the lumbar region, with hematuria (including microhematuria) or without it, one should consider the possibility of a short-term interruption in treatment with the drug (for 1-3 days) or cancellation of treatment. Drinking plenty is recommended for all patients receiving CRYCIVAN® treatment.

    Cases of interstitial nephritis with calcification of the medulla of the kidneys and cortical atrophy in patients with asymptomatic leucocyturia (more than 100 leukocytes in the field of vision) were studied.If a persistently expressed leukocyturia is found, further examination is needed (determination of the concentration of creatinine, bilirubin in the blood plasma, ultrasound of the bladder and kidneys).

    Patients with concomitant diseases

    There are reports of spontaneous bleeding, including spontaneous skin hematomas and hemarthroses, in patients with hemophilia A and B receiving treatment with HIV protease inhibitors. In some patients, there was a need to introduce a coagulation factor VIII. In most cases, treatment with HIV protease inhibitors has been continued or re-initiated. The causal relationship between the treatment of HIV protease inhibitors and these episodes has not been established. Patients with hemophilia should be informed of the possibility of an increased likelihood of bleeding.

    In patients with hepatic insufficiency from mild to moderate severity due to cirrhosis, a reduction in the dose of indinavir is required due to a slowdown in the metabolism of indinavir. Studies of the safety of the drug in patients with severe hepatic insufficiency have not been conducted.Care should be taken in connection with a possible increase in the concentration of indinavir.

    Patients with renal insufficiency

    The dose of CRYXIVAN® should be reduced due to a decrease in the metabolic rate of the drug.

    Acute hemolytic anemia

    It was reported that acute hemolytic anemia, which in some cases was severe and rapidly progressed. Immediately after the diagnosis becomes clear, it is necessary to start measures for the treatment of hemolytic anemia, including the cancellation of the preparation CRYCXIVAN®.

    Diseases of the liver

    It was reported that patients receiving treatment with CRYCIVAN® can develop hepatitis, including, in rare cases, liver failure. Since most of these patients have other diseases and / or they receive both other treatments, the cause-and-effect relationship between CRYCXIVAN® preparation and these phenomena is not established.

    Hyperglycaemia

    There are reports of primary detection of diabetes mellitus or hyperglycemia, as well as exacerbation of existing diabetes mellitus in HIV-infected patients receiving treatment with HIV protease inhibitors.Many of these reports relate to patients with multiple diseases that require treatment with drugs that lead to diabetes or hyperglycaemia. Some patients require the administration or correction of a dose of insulin or oral hypoglycemic agents to treat these disorders. In some cases, diabetic ketoacidosis develops.

    In most cases, treatment with HIV protease inhibitors continued, in some cases treatment was withdrawn or suspended. In some patients, after the withdrawal of the HIV protease inhibitor, hyperglycemia persisted regardless of whether diabetes was initially detected. The causal relationship between HIV protease inhibitor treatment and these phenomena has not been established.

    Lipodystrophy

    Combined antiretroviral therapy is associated with the redistribution of adipose tissue (lipodystrophy). The long-term consequences of these phenomena are unknown. Knowledge of the mechanism of development is incomplete. A link between visceral lipomatosis and HIV protease inhibitors, lipoatrophy and nucleoside inhibitors of reverse transcriptase is suggested.A higher risk of lipodystrophy is associated with individual factors, such as advanced age, and factors associated with therapy, such as the duration of antiretroviral therapy and metabolic disorders. Physical examination should include an assessment of physical signs of lipodystrophy. The need to measure the lipid profile of fasting blood serum and the concentration of blood glucose should be considered. If lipid metabolism is disturbed, appropriate therapy should be provided.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections may occur and cause unwanted clinical manifestations or worsening of current symptoms. Typically, these reactions occur in the first few weeks or months after the onset of combined antiretroviral therapy. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, pneumonia caused by Pneumocystis carinii. Any inflammatory symptoms should be studied and appropriate therapy prescribed.

    It should be protected from moisture. The drug should be dispensed and stored only in the original vials. Silica gel desiccant (desiccant) should remain in the vial.

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

    Studies to study the influence of indinavir on the ability to drive vehicles and work with mechanisms have not been carried out.

    Given the potential for developing dizziness and blurred vision while treating CRYCXIVAN®, care should be taken when driving and working with the machines.

    Form release / dosage:

    Capsules, 200 mg and 400 mg.

    Packaging:

    Capsules 200 mg: Pabout 180, 270 or 360 capsules in an opaque white bottle made of high-density polyethylene (HDPE), with a foil padding on the neck of the bottle, equipped with a silica gel desiccant (desiccant), a plastic lid with a device against opening the bottle by children. One bottle together with the instruction for use is placed in a cardboard box.

    Capsules 400 mg: on 90 or 180 capsules in an opaque bottle of white color from high-density polyethylene (HDPE), with a foil padding on the neck of the bottle, equipped with a silica gel desiccant (desiccant), a plastic lid with a device against opening the bottle by children. One bottle together with the instruction for use is placed in a cardboard box.

    Storage conditions:

    In a tightly closed vial at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:П N011421 / 02
    Date of registration:09.04.2008 / 18.03.2013
    Expiration Date:Unlimited
    Date of cancellation:2016-05-17
    The owner of the registration certificate:Merck Sharp and Doum B.V.Merck Sharp and Doum B.V. Netherlands
    Manufacturer: & nbsp
    Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.
    Information update date: & nbsp22.01.2018
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