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

Excipients: Copovidone K value 28 - 493.1 mg, sorbitan laurate - 66.7 mg, silicon colloidal dioxide - 13.8 mg, sodium stearyl fumarate - 2.3 mg, calcium hydrophosphate - 89.6 mg;

film sheath: Defect white (Opadry® 16B18449) - 22 mg (hypromellose 2910 (6 mPaxs) - 58.04%, titanium dioxide - 15.43%, macrogol 400 - 9.00%, giprolose - 5.76%, hypromellose 2910 (15 mPa x c) - 5.76%, talc - 4.10%, silicon colloidal dioxide - 0.15%, macrogol 3350 - 1.61%, polysorbate 80 - 0.15%).

Description:

Oval-shaped tablets coated with a film shell, white or almost white with an engraved symbol "ם"and"NK"on one side.

Pharmacotherapeutic group:antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.03 Ritonavir

Pharmacodynamics:

The use of ritonavir as a pharmacokinetic enhancer

The effect of ritonavir as a pharmacokinetic enhancer is based on the activity of ritonavir as a potent inhibitor of cytochrome isoenzyme mediated metabolism CYP3A. Gain levels are associated with the metabolism of the co-administered HIV protease inhibitor and the effect of the HIV protease inhibitor on ritonavir metabolism. The maximum inhibition of metabolism when the HIV protease inhibitor is used together is usually achieved with a dose of ritonavir from 100 mg once a day to 200 mg twice daily and depends on the jointly used HIV protease inhibitor.

The use of ritonavir as an antiretroviral agent

Mechanism of action

Ritonavir is an inhibitor of aspartyl protease HIV-1 and HIV-2 for oral administration, an active peptidomimetic. Inhibition of HIV protease inhibits rupture gag-pol the connection of the polyprotein, which leads to the formation of an immature and infectious virus. Ritonavir has a selective affinity for the HIV protease and shows little activity with respect to aspartyl protease of a human.

Antiviral activity in vitro

Data in vitro evidence that ritonavir is active against all types of HIV tested on various primary and transformed human cell lines. The concentration of the drug, which inhibits 50% and 90% of viral replication in vitro respectively, is about 0.02 μM and 0.11 μM. Similar activity was demonstrated with the use of azidothymidine-sensitive (AZT-sensitive) and AZT-resistant strains of HIV. In studies that evaluated the direct cellular toxicity of ritonavir on certain cell lines, no direct toxicity was detected with the drug at concentrations up to 35 μM; the therapeutic index in vitro amounted to a minimum of 1000.

Resistance

HIV-1 isolates resistant to ritonavir were isolated in vitro. Genotypic analysis of isolates showed the presence of mutations in the HIV protease gene, which led to specific amino acid substitutions in codons 84 (Isoleucine on Valine), 82 (Valine on Phenylalanine), 71 (Alanin on Valin) and 46 (Methionine on Isoleucin). Genotypic and phenotypic analysis of isolates obtained in clinical trials (I/II phase), showed that mutations in the HIV protease gene appeared gradually and in a certain order. Initial mutations originating in positions 82 (Valine to Alanine / Phenylalanine), 54 (Isoleucine to Valine), 71 (Alanine to Valine / Threonine), and 36 (Isoleucine to Leucine) were subsequently followed by combinations of additional mutations at five amino acid positions. It was found that the presence of mutation 82 is necessary, but not enough to form phenotypic resistance. Phenotypic resistance was defined as a decrease in the sensitivity of the virus by 5 or more times compared to the baseline in vitro.

Clinical significance of phenotypic and genotypic changes associated with ritonavir treatment. is currently not installed.

Cross-resistance to other antiretroviral drugs

The possibility of cross-resistance between HIV protease inhibitors has not been fully explored. Therefore, it is not known how treatment with ritonavir will affect the activity of simultaneously or subsequently prescribed HIV protease inhibitors. Serial HIV isolates from six patients treated with ritonavir in vitro a decrease in sensitivity to ritonavir in the absence of a simultaneous decrease in sensitivity to saquinavir in comparison with the corresponding initial isolates. However, isolates from two of these patients showed an 8-fold decrease in sensitivity to indinavir in vitro. Isolates from two of the five patients examined for cross-resistance to amprenavir and nelfinavir showed a decrease in sensitivity to nelfinavir (12-14 fold), and none showed a decrease in susceptibility to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely, since the targets are different enzymes. In vitro one isolate resistant to zidovudine, remained completely sensitive to ritonavir.

Pharmacokinetics:

With a single administration of ritonavir on an empty stomach at a dose of 100, 200, 400, 600, 800 and 1000 mg, the area under the concentration-time curve (AUC) was 3.92 to 123 μg x h / ml, respectively, the maximum concentration (C_mOh) was in the range of 0.416 to 12.7 μg / ml.

The pharmacokinetics of ritonavir depends on the dose - with increasing dose, a proportional increase in the values AUC and C_mOh. The time to reach the maximum concentration (T_mOh) with increasing doses remained constant at a level approximately equal to 3 hours. Kidney clearance is less than 0.1 l / h and relatively constant with different dosages. Absolute bioavailability of ritonavir is not established, since there is no dosage form for parenteral administration. Plasma concentrations of ritonavir after a single dose of 100 mg in tablets are approximately 121.7 ± 53.8 μg h / ml.

With the appointment of the drug during meals, there is a slight decrease in the bioavailability of ritonavir tablets. When administering a single dose of 100 mg of ritonavir tablets simultaneously with the intake of moderately fatty foods (857 kcal, 31% of calories in fat) or foods high in fat (907 kcal, 52% of calories in fat) AUC and C_mOhritonavir on average by 20-23%.

With repeated administration, the accumulation of ritonavir is slightly less than that calculated on the basis of a single dose, and depends on the time of treatment and the dose-related increase in apparent clearanceCl/F). Was found,that the residual concentrations of ritonavir decreased slightly over time, possibly due to induction of enzymes, however, stabilized by the end of two weeks. The equilibrium concentration in plasma of blood at reception of a preparation in a dose of 600 mg 2 times a day is reached by the end of 2 weeks, thus the maximum concentration (С_mOh) and residual concentration in plasma (C_trough) are 11.2 μg / ml and 3.7 μg / ml, respectively. In an equilibrium state, the apparent clearance in patients taking 600 mg twice a day is on average 8.8 ± 3.2 l / h. The half-life of ritonavir is 3-5 hours.

Clinically significant difference AUC and C_mOh men and women were not noted. There was no statistically significant relationship between the parameters of the pharmacokinetics of ritonavir and body weight.

The apparent volume of distribution of ritonavir is about 0.41 ± 0.25 l / kg after a single dose of 600 mg. The binding of ritonavir to plasma proteins in humans is about 98-99%. Ritonavir binds both to alpha₁human acid glycoprotein (AAG), and with human serum albumin (HSA) with a relatively equal affinity. Binding to plasma proteins is constant in the concentration range of 1-100 μg / ml.

Ritonavir is extensively metabolized with the participation of liver cytochrome P450, mainly involving the cytochrome isoenzyme CYP3A and to a lesser extent CYP2D6. In humans, there are 5 metabolites of ritonavir. The main is the oxidative metabolite isopropylthiazole (M-2), whose antiviral activity is the same as ritonavir. but AUC metabolite M-2 is only 3% of AUC the drug itself.

Excretion of ritonavir occurs mainly through the intestine (about 86%).

Special patient groups

Children

In children under the age of 14 years, the equilibrium clearance of ritonavir when taken inwards at a dose of 250 mg / m² up to 400 mg / m² twice a day was approximately 1.5-1.7 times higher than in adults. The concentration of ritonavir in the blood after taking doses from 350 mg / m² up to 400 mg / m² twice a day in children is comparable to the concentration of ritonavir in adults taking 600 mg (about 330 mg / m²) twice a day.

Elderly patients

The pharmacokinetics of ritonavir in patients 50-70 years when administered at a dose of 100 mg in combination with lopinavir or at higher doses but without HIV protease inhibitors does not differ from that of younger patients.

Patients with impaired renal function

Currently, there are no special data regarding this group of patients. However, since ritonavir actively binds to the protein, it is unlikely that it will be largely excreted in hemodialysis or peritoneal dialysis.

Patients with impaired hepatic function

In patients with mild hepatic insufficiency, the effect of ritonavir at a dose of 400 mg on admission twice a day was consistent with that in patients of the control group at a dose of 500 mg twice a day. Thus, in patients with mild hepatic insufficiency, dose adjustment is not required. Sufficient data on the use of ritonavir in patients with impaired liver function of moderate severity no. Liver failure is mild or medium degree gravity has no effect on the binding of ritonavir to plasma proteins.

Indications:

Treatment of HIV-1 infection (in adults and children older than 3 years) as part of combination therapy.

Contraindications:

- An established hypersensitivity to ritonavir or any other component of the drug;

- dCompensated liver disease (when ritonavir is used as an antiretroviral agent or pharmacokinetic enhancer);

- Pankreatitis;

- dUp to 3 years of age;

- aboutsimultaneous use with the following drugs: alfuzosin, amiodarone, dronedaron, astemizole, bepridil, cisapride, dihydroergotamine, ergometrine, methylergomethrin, ergotamine, enkinide, flecainide, pimozide, propafenone, quinidine, terfenadine, midazolam (for oral administration), triazolam, voriconazole, simvastatin, lovastatin, preparations of St. John's wort perfumed, sildenafil (in cases where it is used to treat pulmonary arterial hypertension), avanafil, fusidic acid, quetiapine, pethidine, piroxicam, propoxyphene, clozapine, vardenafil, diazepam, estazolam, flurazepam, clorazepate, colchicine;

- aboutsimultaneous use with rifabutin when used as an antiretroviral agent in a dose of 600 mg 2 times a day (see section "Interaction with other drugs";

- aboutsimultaneous application of ritonavir / saquinavir and rifampicin;

- eIf you ritonavir is used as a pharmacokinetic enhancer of other HIV protease inhibitors, the information contained in the instructions for the use of appropriate HIV protease inhibitors should be considered.

Carefully:

- Hepatitis;

- other concomitant liver diseases;

- increased activity of "hepatic" enzymes;

- hepatic impairment of moderate severity;

- severe degree of hepatic insufficiency (class C on the Child-Pugh scale) without signs of decompensation (when ritonavir is used as a pharmacokinetic enhancer);

- patients with organic heart diseases, and existing disorders of the conduction system of the heart or patients taking drugs, extending the interval PR (such as verapamil or atazanavir).

- simultaneous use with drugs for the treatment of erectile dysfunction, namely with sildenafil (see "Contraindications"), tadalafil;

- simultaneous use with atorvastatin, trazodone, digoxin, ketoconazole, inhaled or injected through the nose with glucocorticosteroids (for example, fluticasone, budesonide; see "Interaction with Other Drugs"), midazolam (for parenteral use);

- doses of ritonavir higher than 100 mg twice daily with fosamprenavir have not been studied, so joint use is not recommended;

- joint application with Bedakwin;

- joint use of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily).

Pregnancy and lactation:

Since there is currently insufficient data on the experience with ritonavir in pregnant women, it is only possible to prescribe it in this category of patients if the expected benefit to the mother exceeds the potential risk to the fetus.

Data on the excretion of this drug with breast milk in women are absent. HIV-infected women should not breast-feed their children to avoid the transmission of HIV.

Dosing and Administration:

Inside with food.

Norvir® tablets must be swallowed whole, they can not be chewed, broken or crushed.

The use of ritonavir as a pharmacokinetic enhancer

When prescribing reduced doses of ritonavir in combination with other HIV protease inhibitors (for example, in cases where ritonavir is used as a pharmacokinetic enhancer of other HIV protease inhibitors) should also be guided by the information contained in the instructions for use and clinical trial data of the relevant HIV protease inhibitors. The following HIV-1 protease inhibitors are permitted for use in combination with ritonavi as a pharmacokinetic enhancer.

Adults

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.

Atazanavir 300 mg once a day with ritonavir 100 mg once a day.

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Lopinavir / ritonavir (combined form) 400 mg / 100 mg or 800 mg / 200 mg.

Saquinavir (in patients who previously received antiretroviral therapy): 1000 mg twice daily with ritonavir 100 mg twice daily.

Saquinavir (in patients who have not previously received antiretroviral therapy): saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily (tipranavir in combination with ritonavir should not be used in patients who have not previously received antiretroviral therapy).

Darunavir (in patients who previously received antiretroviral therapy): 600 mg twice daily with ritonavir 100 mg twice daily.

It is also possible to prescribe darunavir 800 mg once daily with ritonavir 100 mg once daily.

For more information, including the use of the drug once a day in patients who have previously used antiretroviral therapy, you should carefully study the instructions for the use of darunavir.

Darunavir (in patients who had not previously received antiretroviral therapy): 800 mg once daily with ritonavir 100 mg once daily.

Children

The use of the drug in children younger than 3 years is contraindicated. It is necessary to follow instructions for the use of HIV-1 protease inhibitors, which are approved for use in combination with ritonavir.

Renal insufficiency

Ritonavir is mainly metabolized in the liver. It is possible to use (with caution) ritonavir as a pharmacokinetic enhancer in patients with renal insufficiency, depending on specific HIV protease inhibitors with which it is applied ritonavir. However, since renal clearance of ritonavir is negligible, a decrease in overall clearance is not expected in patients with renal insufficiency. For detailed information on the dosing schedulepatients with renal insufficiency should refer to the instructions for the use of a jointly used HIV protease inhibitor.

Liver failure

Ritonavir is contraindicated as a pharmacokinetic enhancer in patients with decompensated liver disease.

There is no data on the use of ritonavir in patients with a stably severe degree of hepatic insufficiency (class C on the Child-Pugh scale) without signs of decompensation, therefore caution should be exercised when using ritonavir as a pharmacokinetic enhancer in this group of patients due to the risk of increasing the concentration of the co-applied inhibitor HIV proteases. For detailed information on the dosing regimen in patients with hepatic impairment, refer to the instructions for the use of a jointly used HIV protease inhibitor.

The use of ritonavir as an antiretroviral agent

Adults

For 600 mg (6 tablets) twice a day. The daily dose is 1200 mg.

A gradual increase in the dose of Norvir® during the initial period of treatment can improve the tolerability of the drug.The initial dose should be at least 300 mg twice a day for the first 3 days, then the dose is increased (each dose increase by 100 mg twice a day) to 600 mg twice a day for a period not exceeding 2 weeks. Do not continue treatment with Norvir® at a dose of 300 mg twice a day for more than 3 days.

Combined treatment regimens with two HIV protease inhibitors (PIs)

The clinical experience of combination therapy involving the use of therapeutic doses of ritonavir in combination with another HIV protease inhibitor is limited. Ritonavir significantly reduces the metabolism of most other inhibitors of viral proteases. Therefore, when prescribing combination therapy with ritonavir, pharmacokinetic interaction and safety data of the medications used should be taken into account. This class of drugs is characterized by pronounced cross-resistance. Preferably, a combination of two PIs with the lowest cross-resistance should be used. When using ritonavir in these regimens, all of the above factors should be considered.

Children (3 years and older)

Should be appointed ritonavir in combination with other antiviral drugs.

The recommended dose of Norvir® for children is 350-400 mg / m² body surface 2 times a day, and it should not exceed 600 mg 2 times a day.

The initial dose is 250 mg / m² surface of the body, it should be increased at intervals of 2-3 days by 50 mg / m² body surface 2 times a day. If patients do not tolerate the maximum daily dose due to adverse events, the maximum tolerated dose of Norvir® in combination with other antiretroviral drugs is prescribed.

The surface area of the body (PPT) can be calculated by the following formula:

PPT (m²) = √ ([Height (cm) x Body weight (kg)] / 3600).

Elderly patients

Correction of the dose is not required.

Patients with renal insufficiency

Data on the use of ritonavir in patients with renal insufficiency are absent. Bearing in mind that the renal clearance of ritonavir is negligible, it is therefore unlikely that the overall clearance in patients with renal insufficiency will be reduced. Ritonavir is highly associated with plasma proteins, it is unlikely to significantly reduce its concentration as a result of hemodialysis or peritoneal dialysis.

Patients with hepatic insufficiency

Ritonavir is mainly metabolized in the liver. Pharmacokinetic data indicate that dose adjustment in patients with mild and moderate hepatic impairment is not required. Ritonavir contraindicated in patients with decompensated liver disease.

Children

The use of Norvir® in children under 3 years is contraindicated.

Side effects:

The use of ritonavir as a pharmacokinetic enhancer

Undesirable reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the co-administered specific HIV protease inhibitor. For information on adverse reactions, see the instructions for the use of a specific co-administered HIV protease inhibitor.

The use of ritonavir as an antiretroviral agent

Undesirable reactions, obtained in clinical trials and post-marketing period in adult patients

The most frequent reported adverse reactions among patients receiving monotherapy with ritonavir or ritonavir in combination with other antiretroviral drugs, there were disorders of the digestive system (including diarrhea, nausea, vomiting, abdominal pain (in the upper and lower sections)), disorders of the nervous system (including paresthesia and paresthesia of the oral mucosa), and fatigue / asthenic syndrome.

The development of the following adverse reactions from moderate to severe severity, possibly or probably associated with ritonavir, has been reported. Within each group of frequency distribution, the undesirable effects are arranged in decreasing order of importance: very often (> 1/10); often (from> 1/100 up to < 1/10); infrequently (from> 1/1000 up to < 1/100); rarely (> 1/10000 up to < 1/1000); frequency is unknown (it is not possible to set the frequency according to the available data).

Undesirable reactions in clinical trials and post-marketing period in adult patients

Class of organ systems	Frequency	Unwanted reaction
Violations of the blood and lymphatic system	Often	Decrease in the number of leukocytes, a decrease in the concentration of hemoglobin, a decrease in the number of neutrophils, an increase in the number of eosinophils, thrombocytopenia
Violations of the blood and lymphatic system	Infrequently	Increase in the number of neutrophils
Immune system disorders	Often	Hypersensitivity reactions, including hives and swelling of the face
Immune system disorders	Rarely	Anaphylactic reactions
Disorders of nutrition and metabolism	Often	Hypercholesterolemia, hypertriglyceridemia, gout, edema, including peripheral, dehydration (usually associated with symptoms on the part of the digestive system)
	Infrequently	Diabetes
	Rarely	Hyperglycaemia
Disturbances from the nervous system	Highly often	Dysgeusia. paresthesia of the oral mucosa and peripheral paresthesia, headache, dizziness, peripheral neuropathy
Disturbances from the nervous system	Often	Insomnia, agitation, confusion, attention impairment, syncopal conditions, epileptic seizures
Disturbances on the part of the organ of sight	Often	Blurred vision
Cardiological disorders	Infrequently	Myocardial infarction
Disorders from the vascular system	Often	Arterial hypertension, arterial hypotension, including orthostatic arterial hypotension, peripheral hypothermia
Respiratory, thoracic and mediastinal disorders	Highly often	Pharyngitis, pain in the oropharynx, cough
Disorders from the digestive system	Highly often	Abdominal pain (upper and lower divisions), nausea, diarrhea (including severe form with electrolyte disorders), vomiting, digestive disorders
Disorders from the digestive system	Often	Anorexia, flatulence, oral ulcers, bleeding from the organs of the gastrointestinal tract, gastroesophageal reflux disease, pancreatitis
Disorders from the hepatobiliary system	Often	Hepatitis (including increased activity ACT, ALT, GGT), an increase in the concentration of bilirubin in the blood (including jaundice)
Disturbances from the skin and subcutaneous fat	Highly often	Itching, rash (including erythematous and maculopapular rash)
	Often	Acne
	Rarely	Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Disturbances from the musculoskeletal system and connective tissue	Highly often	Arthralgia and back pain
	Often	Myositis, rhabdomyolysis, myalgia, myopathy / elevated CK content
Disorders from the urinary system	Often	Increased urination, impaired renal function (eg, oliguria, increased creatinine concentration)
Disorders from the urinary system	Infrequently	Acute kidney failure
Disorders from the reproductive system and mammary glands	Often	Menorrhagia
Systemic disorders and complications at the site of administration	Highly often	Weakness, including asthenic syndrome, hot flushes, a feeling of heat
	Often	Fever, weight loss
Deviations from the norm, revealed in laboratory and instrumental studies	Often	Increase in the activity of amylase, a decrease in the concentration of free and total thyroxin
	Infrequently	Increase in glucose concentration, increase in magnesium concentration, increase in activity of alkaline phosphatase

The reactions marked as having an unknown frequency of occurrence were noted during the post-registration period.

Individual undesirable reactions

An increase in the activity of hepatic transaminases, five times or more exceeding the upper limit of normal values, the clinical picture of hepatitis and jaundice developed in patients receiving ritonavir as a monotherapy or ritonavir in combination with other antiretroviral drugs.

Metabolic indicators

An increase in body weight, as well as an increase in the concentration of lipids and glucose in the blood can be observed during antiretroviral therapy.In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections may develop. There have also been reports of cases of autoimmune disorders (such as Graves' disease); nevertheless, the time of their development varies greatly, and they can develop many months after the initiation of therapy.

Patients treated with ritonavir, including those with hypertriglyceridemia, experienced cases of pancreatitis (in some cases, fatal). Patients with HIV infection at a late stage may be at a higher risk of developing high blood triglycerides and developing pancreatitis.

There have also been cases of osteonecrosis, in particular in patients with well-known risk factors, with HIV infection at a late stage or who are receiving long-term combined antiretroviral therapy. Their frequency is unknown.

Children

The safety profile of Norvir® in children aged 3 years and older is similar to that of adults.

Overdose:

Data on acute overdose with ritonavir in humans are limited. One patient who participated in the clinical study took a dose of ritonavir 1500 mg / day for 2 days, after which manifestations of paresthesia, which disappeared after lowering the dose, were observed. In the post-marketing period, a report was received on renal failure and eosinophilia in ritonavir overdose.

Ritonavir is characterized by a low acute toxicity potential for oral administration.

Treatment

There is no specific antidote for ritonavir. Treatment of an overdose of ritonavir should include general symptomatic measures, including monitoring of vital signs and the clinical state of the patient. It is also proposed to include in the scheme of treatment of an overdose gastric lavage and the appointment of activated charcoal. As ritonavir is intensively metabolized in the liver and binds highly to plasma proteins, dialysis probably will not allow the removal of the drug from the body at a sufficient level.

Interaction:

The use of ritonavir as a pharmacokinetic enhancer or as an antiretroviral agent

Ritonavir has a high affinity for several isoenzymes of the cytochrome P450 system (CYP) and can inhibit oxidation in terms of the degree of decrease in the series CYP3A4 > CYP2D6. The simultaneous use of ritonavir and drugs, which are mainly metabolized by the cytochrome isoenzyme CYP3A, can lead to an increase in the concentration of another drug in the blood plasma, which can increase or prolong its therapeutic and undesirable effects. For some drugs (eg, alprazolam), the inhibitory effect of ritonavir on the cytochrome isoenzyme CYP3A4 may decrease over time. Ritonavir also has a high affinity for the P-glycoprotein and can inhibit this carrier. The inhibitory effect of ritonavir (with simultaneous use with other HIV protease inhibitors or without other HIV protease inhibitors) against P-glycoprotein activity may decrease over time (eg, for digoxin and fexofenadine - see table "Influence of ritonavir on concomitantly used non-antiretroviral drugs" below). Ritonavir can induce glucuronidation and oxidation under the action of cytochrome isoenzymes CYP1A2, CYP2C8, CYP2C9 and CYP2C19, thereby increasing the biotransformation of some drugs metabolized by these routes and may lead to a decrease in the systemic exposure of such drugs that can eliminate or shorten their therapeutic effect.

Important information on drug interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the instructions for the use of a jointly used HIV protease inhibitor.

Drugs that affect the concentration of ritonavir

The concentration of ritonavir in the blood serum may decrease with the simultaneous use of herbal preparations containing St. John's Wort (Hypericum perforatum). This is due to the induction of St. John's wort by enzymes metabolizing ritonavir. Herbal preparations containing St. John's wort are not to be used in combination with ritonavir. If the patient is already taking St John's wort, then stop taking it and, if possible, check the level of the viral load. The concentration of ritonavir may increase after stopping the intake of St. John's wort.Ritonavir dose adjustment may be required. The inducing effect can persist for at least two weeks after stopping the intake of St. John's wort.

The concentration of ritonavir in the blood serum may change under the action of concomitant medications (for example, delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the drug interaction tables below.

Drugs, the concentrations of which change under the action of ritonavir

The interaction between ritonavir and HIV protease inhibitors, other antiretroviral drugs other than HIV protease inhibitors, and other non-antiretroviral drugs are listed in the tables below.

Interactions medicinal means - Petosnavir with protease inhibitors HIV
Simultaneously used medicinal product	Dose simultaneously applied drug (mg)	The dose of Norvir® (mg)	Estimated medicament	AUC	FROM_min
Amprenavir	600 every 12 hours	100 every 12 hours	Amprenavir²	↑ 64%	↑ 5 times
Amprenavir	Ritonavir increases serum amprenavir concentration as a result of inhibition of cytochrome CYP3A4 isoenzyme. Clinical studies have confirmed the safety and efficacy of prescribing 600 mg of amprenavir twice daily with ritonavir at a dose of 100 mg twice daily. Norvir®, oral solution, should not be used concurrently with amprenavir, oral solution, in children due to the risk of toxicity of the excipients contained in both preparations. For more information, see the amprenavir.
Atazanavir	300 every 24 hours	100 every 24 hours	Atazanavir	↑ 86%	↑ 11 times
			Atazanavir¹	↑ 2 times	↑ 3-7 times
	Ritonavir increases the concentration of atazanavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Clinical studies have confirmed the safety and effectiveness of administration of 300 mg of atazanavir once daily with ritonavir at a dose of 100 mg once a day in previously treated patients. The simultaneous administration of atazanavir with ritonavir in doses exceeding 100 mg once a day was not clinically evaluated. The use of higher doses of ritonavir may affect the safety profile of atazanavir (cardiac effects,hyperbilirubinemia) and therefore simultaneous use is not recommended. Only in the case of combined use of atazanavir, ritonavir and efavirenz should the need to increase the dose of ritonavir to 200 mg once a day should be considered. In this case, it is necessary to carry out a thorough clinical monitoring. For more information, see the atazanavir.
Darunavir	600, one time	100 every 12 hours	Darunavir	↑ 14 times
Darunavir	Ritonavir increases the concentration of darunavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Darunavir should be administered together with ritonavir to ensure its therapeutic effect. Ritonavir in doses higher than 100 mg twice daily, has not been studied with simultaneous use with darunavir. For more information, see the darunavir.
Fosamprenavir	700 every 12 hours	100 every 12 hours	Amprenavir	↑ 2.4 times	↑ 11 times
Fosamprenavir	Ritonavir increases the concentration of amprenavir (formed from fosamprenavir) in serum due to inhibition of the cytochrome isoenzyme CYP3A4. Fosamprenavir should be given together with ritonavir to ensure its therapeutic effect. Clinical studies have confirmed the safety and efficacy of administering fosamprenavir at a dose of 700 mg twice daily with ritonavir at a dose of 100 mg twice daily. Ritonavir in doses higher than 100 mg twice daily, has not been studied with simultaneous use with fosamprenavir. For more information, see the fosamprenavir.
Indinavir	800 every 12 hours	100 every 12 hours	Indinavir³	↑ 178%	BUT
			Ritonavir	↑ 72%	BUT
	400 every 12 hours	400 every 12 hours	Indinavir³	↔	↑ 4 times
			Ritonavir	↔	↔
	Ritonavir increases the concentration of indinavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Appropriate doses for this combination in terms of efficacy and safety have not been established. The minimum benefit of ritonavir mediated pharmacokinetic enhancement is achieved at doses above 100 mg twice a day. In cases of simultaneous application of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily), caution should be used, since the risk of nephrolithiasis may increase.
Nelfinavir	1250 every 12h	100 every 12 hours	Nelfinavir	↑ from 20 to 39%	BUT
	750, one time	500 every 12 hours	Nelfinavir	↑ 152%	BUT
			Ritonavir	↔	↔
	Ritonavir increases the concentration of nelfinavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Appropriate doses for this combination in terms of efficacy and safety have not been established. The minimum benefit of ritonavir mediated pharmacokinetic enhancement is achieved at doses above 100 mg twice a day.
Saquinavir	1000 every 12 hours	100 every 12 hours	Saquinavir⁴	↑ 15 times	↑ 5 times
			Ritonavir	↔	↔
	400 every 12 hours	400 every 12 hours	Saquinavir⁴	↑ 17 times	BUT
			Ritonavir	↔	↔
	Ritonavir increases the concentration of saquinavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Saquinavir should be given only in combination with ritonavir. When ritonavir is given at a dose of 100 mg twice a day in combination with saquinavir at a dose of 1000 mg twice a day, the systemic exposure of saquinavir for 24 hours is similar to or exceeds the system exposure of saquinavir when administered at a dose of 1200 mg three times daily without ritonavir. In a clinical study that examined the interaction of rifampicin at a dose of 600 mg once daily and saquinavir 1000 mg with ritonavir 100 mg twice daily for healthy volunteers,severe hepatic cell toxicity was noted with an increase in transaminase activity to> 20 times the upper limit of the norm after 1-5 days of simultaneous use of these drugs. Because of the risk of severe hepatotoxicity, saquinavir / ritonavir should not be taken with rifampicin. For more information, see the saquinavir.
Tipranavir	500 every 12 hours	200 every 12 hours	Tipranavir	↑ 11 times	↑ 29 times
			Ritonavir	↓ 40%	BUT
	Ritonavir increases the concentration of tipranavir in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Tipranavir should be given along with low doses of ritonavir to ensure its therapeutic effect. Doses of ritonavir less than 200 mg twice daily should not be used with tipranavir, as this may impair the effectiveness of the combination. For more information, see the tipranavir.
	N / A: Not determined. 1. Based on a cross-comparison with 400 mg atazanavir once a day in the form of monotherapy. 2. Based on a cross-comparison with 1200 mg amprenavir twice a day in the form of monotherapy. 3. Based on a cross-comparison with 800 mg of indinavir three times a day in the form of monotherapy. 4. Based on a cross-comparison with 600 mg saquinavir three times a day in the form of monotherapy.

Drug interactions - ritonavir with other antiretroviral agents, in addition to HIV protease inhibitors
Simultaneously used medicinal product	Dose simultaneously applied drug (mg)	The dose of Norvir® (mg)	Estimated medicament	AUC	FROM_min
Didanosine	200 every 12 hours	600 every 12 hours 2 hours after taking didanosine	Didanosine	↓ 13%	↔
Didanosine	Due to ritonavir it is recommended to take with food, and didanosine should be taken on an empty stomach, taking these drugs should be divided into 2.5 hours. No dose changes are required.
Delavirdine	400 every 8 hours	600 every 12 hours	Delavirdine¹	↔	↔
			Ritonavir	↑ 50%	↑ 75%
	Based on a comparison with the retrospective data, it can be said that the pharmacokinetics of delavirdine, apparently, will not change under the influence of ritonavir. It may be necessary to reduce the dose of ritonavir when used in combination with delavirdine.
Efavirenz	600 every 24 hours	500 every 12 hours	Efavirenz	↑ 21%
			Ritonavir	↑ 17%
	There was a higher incidence of adverse reactions (eg, dizziness, nausea,paresthesia) and deviations from the norm of the results of laboratory studies (increase in the activity of liver enzymes), when efavirenz were used concomitantly with ritonavir as an antiretroviral agent.
Maraviroc	100 every 12 hours	100 every 12 hours	Maraviroc	↑ 161%	↑ 28%
Maraviroc	Ritonavir increases the concentration of maraviroc in serum as a result of inhibition of the cytochrome isoenzyme CYP3A4. Maraviroc can be prescribed together with ritonavir in order to increase the exposure of maraviroc. For more information, read the instructions for use on the maraviroc.
Nevirapine	200 every 12 hours	600 every 12 hours	Nevirapine	↔	↔
			Ritonavir	↔	↔
	Simultaneous use of ritonavir with nevirapine does not lead to clinically significant changes in the pharmacokinetics of nevirapine or ritonavir.
Raltegravir	400 one time	100 every 12 hours	Raltegravir	↓ 16%	↓ 1%
Raltegravir	The simultaneous use of ritonavir and raltegravir leads to a slight decrease in the concentration of raltegravir.
Zidovudine	200 every 8 hours	300 every 6 hours	Zidovudine	↓ 25%	BUT
Zidovudine	Ritonavir can induce glucuronidation of zidovudine, which leads to a slight decrease in zidovudine concentrations.Dose changes are not required.
	N / A: Not determined 1. Based on a comparison of parallel groups.

The effect of ritonavir on concomitantly used drugs that are not antiretroviral agents
Simultaneously used medicines	Dose simultaneously applied medicines (mg)	The dose of Norvir® (mg)	Influence at AUC of concomitantly used drugs	Influence on C_m_Ohsimultaneously used medicinal means
Antagonist alpha₁-adernoreceptors
Alfuzosin	The simultaneous use of ritonavir can lead to an increase in the concentration of alfuzosin in the blood plasma and therefore it is contraindicated.
Derivatives of amphetamines
Amphetamine	When used as an antiretroviral agent ritonavir, probably inhibits the cytochrome isoenzyme CYP2D6, and as a result, an increase in the concentration of amphetamine and its derivatives is expected. It is recommended that the therapeutic and undesirable effects be closely monitored when these drugs are prescribed concomitantly with antiretroviral doses of ritonavir.
Analgesics
Buprenorphine	16 every 24 hours	100 every 12 hours	↑ 57%	↑ 77%
Norbuprenorphine			↑ 33%	↑ 108%
Glucuronide metabolites			↔	↔
	An increase in the concentration of buprenorphine and its active metabolite in blood plasma did not lead to clinically significant pharmacodynamic changes in the population of patients with tolerance to opioids. Therefore, adjusting the dose of buprenorphine or ritonavir with the simultaneous administration of these drugs may not be required. If ritonavir is used in combination with another HIV protease inhibitor and buprenorphine, please read the instructions for using the drug for the concomitantly used HIV protease inhibitor to obtain dosage information.
Pethidine, piroxicam, propoxyphene	The simultaneous use of ritonavir can lead to an increase in the concentration of pethidine, piroxicam and propoxyphene in the blood plasma and therefore it is contraindicated.
Fentanyl	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A4 and as a result, an increase in fentanyl concentration in the blood plasma is expected. When ritonavir and fentanyl are used concomitantly, therapeutic and side effects (including respiratory depression) should be closely monitored.
Methadone¹	5, one time	500 every 12 hours	↓ 36%	↓ 38%
	An increase in the dose of methadone may be required when concomitant with ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer due to the induction of glucuronation. The issue of dose adjustment should be considered based on the patient's clinical response to methadone therapy.
Morphine	The concentration of morphine may decrease due to the induction of glucuronation by the simultaneous administration of ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer.
Antiarrhythmics
Amiodarone, beprideil, dronedaron, enkinide, flecainide, propafenone, quinidine	The simultaneous use of ritonavir can lead to an increase in the concentration of amiodarone, beprinid, dronedarone, enkinin, flecainide, propafenone and quinidine in blood plasma and is therefore contraindicated
Digoxin	0.5 once intravenously	300 every 12 hours, 3 days	↑ 86%	BUT
	0,4 one time in	200 every 12 hours, 13 days	↑ 22%	↔
	This interaction may be due to the modification of the P-glycoprotein-mediated efflux transport of digoxinthe effect of ritonavir when the latter is used as an antiretroviral agent or as a pharmacokinetic enhancer. The increase in digoxin concentration observed in patients receiving ritonavir, can decrease with the passage of time as the induction develops.
Anti-asthmatic agents
Theophylline¹	3 mg / kg every 8 hours	500 every 12 hours	↓ 43%	↓ 32%
	An increase in the dose of theophylline may be required with simultaneous administration with ritonavir due to the induction of cytochrome CYP1A2 isoenzyme.
Antineoplastic agents
Afatinib	20 mg, once	200 every 12 hours (1 hour before the administration of apathinib)	↑ 48%	↑ 39%
	40 mg, once	200 every 12 hours (concomitantly with the administration of apathinib)	↑ 19%	↑ 4%
	40 mg, once	200 every 12 hours (6 hours after taking apatinib)	↑ 11 %	↑ 5%
	Serum concentrations may increase due to inhibition of the protein resistance of breast cancer (BCRP) and P-glycoprotein by ritonavir. Increase AUC and C_max depends on the time of taking ritonavir. Caution should be exercised when using apathinib with ritonavir (see the instructions for use of apathinib). It is necessary to monitor adverse reactions associated with apathinib.
Seritinib	Serum concentration may increase due to inhibition of cytochrome isoenzyme CYP3A and P-glycoprotein by ritonavir. Caution should be exercised in the joint use of seritinib and ritonavir. It is necessary to monitor adverse reactions associated with seritinib.
Dasatinib, nilotinib, vincristine, vinblastine	Concentration in the serum can increase with simultaneous administration with ritonavir, which leads to a possible increase in the frequency of undesired reactions.
Anticoagulants
Rivaroxaban	10, one time	600 every 12 hours	↑ 153%	↑ 55%
	Inhibition of the cytochrome isoenzyme CYP3A and P-glycoprotein leads to an increase in plasma concentration of rivaroxaban and its pharmacodynamic effects, which can lead to an increased risk of bleeding. Thus, the use of ritonavir in patients receiving rivaroxaban, Not recommended.
Vorapaksar	Serum concentration may increase due to inhibition of cytochrome isoenzyme CYP3A and P-glycoprotein by ritonavir. The combined use of vorapaxar and ritonavir is not recommended (see the instructions for using vorapaksar).
Warfarin S-Warfarin R-Warfarin	5, one time	400 every 12 hours	↑ 9% ↓33%	↓ 9% ↔
	Induction of cytochrome isoenzymes CYP1A2 and CYP2C9 leads to an increase in the concentration R-warfarin, while the effects on the pharmacokinetics S- Warfarin with concomitant administration with ritonavir is practically not noted. Reduction in concentration R- warfarin can lead to a decrease in the degree of anticoagulation, therefore it is recommended to monitor anticoagulant parameters if warfarin is administered concomitantly with ritonavir when the latter is used as an antiretroviral agent or as a pharmacokinetic enhancer.
Anticonvulsants
Carbamazepine	Ritonavir inhibits the cytochrome CYP3A4 isoenzyme when used as a pharmacokinetic enhancer or as an antiretroviral agent, and as a result, an increase in carbamazepine plasma concentration is expected. When ritonavir and carbamazepine are used concomitantly, therapeutic and undesirable effects must be closely monitored.
Divalproex, lamotrigine, phenytoin	Ritonavir induces oxidation by cytochrome isoenzymeCYP2C9 and glucuronation when used as a pharmacokinetic enhancer or as an antiretroviral agent, and as a result, the concentration of anticonvulsants in the blood plasma is expected to decrease. When ritonavir is used together with these drugs, it is recommended to carefully monitor their serum concentration or therapeutic effects. Phenytoin can reduce the concentration of ritonavir in the blood serum.
Antidepressants
Amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline	Ritonavir can inhibit the cytochrome isoenzyme CYP2D6 when used as an antiretroviral agent, and as a result is expected to increase the concentration of desipramine, imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. With the simultaneous use of antiretroviral doses of ritonavir with these drugs, it is recommended to carefully monitor their therapeutic and undesirable effects.
Desipramine	100, single oral intake	500 every 12 hours	↑145%	↑ 22%
	AUC and C_m_Oh 2-hydroxymetabolite decreased by 15 and 67%, respectively.It is recommended to reduce the dose of desipramine while concomitantly with ritonavir when the latter is used as an antiretroviral agent.
Trazodone	50, one time	200 every 12 hours	↑ 2.4 times	↑ 34%
	There was an increase in the frequency of unwanted reactions associated with trazodone when it was concomitantly administered with ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer. If trazodone is prescribed concomitantly with ritonavir, this combination should be used with caution, first assigning the lowest effective dose of trazodone and controlling the therapeutic efficacy and tolerability.
Remedies for treating gout
Colchicine	An increase in the concentration of colchicine when it is concomitantly prescribed with ritonavir is expected. Life-threatening and fatal cases with simultaneous application of colchicine and ritonavir (cytochrome isoenzyme inhibitor CYP3A4 and P-glycoprotein) in patients with renal and / or hepatic insufficiency. The combined use of colchicine and ritonavir is contraindicated. For more information,instruction on the use of colchicine.
Antihistamines
Astemizole, terfenadine	Simultaneous application of ritonavir can lead to an increase in the concentration of astemizole and terfenadine in the blood plasma and therefore it is contraindicated.
Fexofenadine	Ritonavir can alter the P-glycoprotein mediated effexive transport of fexofenadine when used as an antiretroviral agent or as a pharmacokinetic enhancer, which increases the concentration of fexofenadine. An increase in the concentration of fexofenadine may decrease with time as induction develops.
Loratadin	Ritonavir inhibits cytochrome isoenzyme CYP3A when used as a pharmacokinetic enhancer or as an antiretroviral agent, and as a result, an increase in the concentration of loratadine in the blood plasma is expected. When ritonavir and loratadine are used concomitantly, therapeutic and undesirable effects must be closely monitored.
Antimicrobial agents
Fusidic acid	The simultaneous use of ritonavir can lead to an increase in the concentration of fusidic acid and ritonavir in the blood plasma andso it is contraindicated.
Rifabutin¹ Metabolite 25-ABOUT-deacetyl rifabutin	150 per day	500 every 12 hours	↑ 4 times ↑ 38 times	↑ 2.5 times ↑ 16 times
	Due to the pronounced increase AUC rifabutin, simultaneous use of rifabutin with ritonavir as an antiretroviral agent it is contraindicated. A reduction in the dose of rifabutin to 150 mg 3 times a week for certain HIV protease inhibitors may be indicated, while concomitant administration with ritonavir as a pharmacokinetic enhancer. You should read the appropriate instructions for use for a concomitantly used HIV protease inhibitor. Please read the official guidelines for the treatment of tuberculosis in HIV-infected patients.
Rifampicin	Although rifampicin can induce ritonavir metabolism. limited data indicate that, with the simultaneous use of high doses of ritonavir (600 mg twice daily) with rifampicin, the additional inducing effect of rifampicin (in addition to its own ritonavir effect) is small and may not have a clinically significant effect on the concentration of ritonavir in high-dose ritonavir therapy. Influence of ritonavir on rifampicin is unknown.
Voriconazole	200 every 12 hours	400 every 12 hours	↓ 82%	↓ 66%
	200 every 12 hours	100 every 12 hours	↓ 39%	↓ 24%
	The simultaneous use of ritonavir as an antiretroviral agent and voriconazole contraindicated because of a decrease in the concentration of voriconazole. The simultaneous use of voriconazole and ritonavir as a pharmacokinetic enhancer should be avoided unless the benefit / risk assessment for the patient justifies the use of voriconazole.
Atovahon	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, induces glucuronidation, and as a result, a decrease in the concentration of atovahona in the blood plasma is expected. It is recommended to closely monitor the concentration of atovahona in the serum or its therapeutic effects with concomitant administration with ritonavir.
Bedakvilin	Studies of interaction with ritonavir alone have not been conducted. In the study of the interaction of a single dose of Bedakville and lopinavir / ritonavir in multiple applications AUC Bedakvilina increased by 22%. This increase is probably due to the action of ritonavir, and a more pronounced effect can be observed with their long-term simultaneous application.Due to the risk of adverse events associated with Bedakville, simultaneous use should be avoided. If the benefit outweighs the risk, simultaneously prescribe Bedakvilin with ritonavir is necessary with caution. It is recommended to monitor the electrocardiogram more frequently and to monitor the activity of transaminases (see the instructions for the use of Bedakville).
Clarithromycin 14-OH-metabolite of clarithromycin	500 every 12 hours	200 every 8 hours	↑ 77% ↓ 100%	↑ 31% ↓ 99%
	Due to the large therapeutic range of clarithromycin, there is no need to reduce its dose in patients with normal renal function. Clarithromycin at doses greater than 1 g per day should not be concomitantly administered with ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer. For patients with renal insufficiency, a decrease in the dose of clarithromycin should be considered: with a clearance of creatinine from 30 to 60 ml / min, the dose of clarithromycin should be reduced by 50%, with a clearance of creatinine <30 ml / min, the dose of clarithromycin should be reduced by 75%.
Delamanid	Studies of interaction with ritonavir alone have not been conducted.In a study of interaction in healthy volunteers, in which dobamanide was administered at a dose of 100 mg twice daily and lopinavir / ritonavir in a dose of 400/100 mg twice a day for 14 days, there was an increase in exposure of the metabolite Delamanide DM-6705 by 30%. Due to the risk of lengthening the interval QTc, associated with a metabolite DM-6705, if the simultaneous application of delananide and ritonavir is deemed necessary, it is recommended that ECG monitoring be carried out very often throughout the treatment period with delamanide (see instructions for the application of Delamanide).
Erythromycin, itraconazole	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A4, and as a result, an increase in the concentration of erythromycin and itraconazole in the blood plasma is expected. It is recommended to closely monitor the therapeutic and undesirable effects of erythromycin and itraconazole when administered concomitantly with ritonavir.
Ketoconazole	200 per day	500 every 12 hours	↑ 3,4 times	↑ 55%
	Ritonavir inhibits the isoenzyme of cytochrome CUR3A-mediated ketoconazole metabolism.Owing to the increased incidence of gastrointestinal or hepatic adverse reactions, the need to reduce the dose of ketoconazole when it is administered concomitantly with ritonavir should be considered when using the latter as an antiretroviral agent or as a pharmacokinetic enhancer.
Sulfamethoxazole / trimethoprim²	800/160, once Correction of simultaneous doses of those	500 every 12 hours	↓ 20% / ↑ 20%	↔
	Correction of the dose of sulfamethoxazole / trimethoprim during simultaneous therapy with ritonavir is usually not required.
Antipsychotics / Neuroleptics
Clozapine, pimozide	The simultaneous use of ritonavir can lead to an increase in the concentration of clozapine or pimozide in the blood plasma and therefore it is contraindicated.
Haloperidol, risperidone, thioridazine	Ritonavir can inhibit the cytochrome isoenzyme CYP2D6 when used as an antiretroviral agent, and as a result, an increase in the concentrations of haloperidol, risperidone and thioridazine is expected. It is recommended that the therapeutic and undesirable effects be closely monitored when these drugs are administered simultaneously with antiretroviral doses of ritonavir.
Quetiapine	It is expected that due to inhibition of the cytochrome isoenzyme CYP3A ritonavir will increase the concentration of quetiapine. The simultaneous administration of the drug Norvir® and quetiapine is contraindicated, as this may lead to an increase in toxicity associated with the use of quetiapine.
β₂-adrenomimetic (long-acting)
Salmeterol	Ritonavir inhibits cytochrome isoenzyme CYP3A4, and as a result, a marked increase in the concentration of salmeterol in the blood plasma is expected. Simultaneous use of ritonavir and salmeterol is not recommended.
Blocks of "slow" calcium channels
Amlodipine, diltiazem. nifedipine	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A4, and as a result, the concentration of calcium channel blockers in the blood plasma is expected to increase. It is recommended that the therapeutic and undesirable effects be carefully monitored when these medications are prescribed concomitantly with ritonavir.
Endothelin antagonists
Boszentan	The simultaneous use of bosentan and ritonavir can increase the maximum concentration (C_m_Oh) in the equilibrium state and bosentan AUC.
Riotsiguat	Serum concentration may increase due to inhibition of cytochrome isoenzyme CYP3A and P-glycoprotein by ritonavir. Joint use of riotsiguata and ritonavir is not recommended (see instructions for the use of riotsiguata).
Derivatives of ergot alkaloids
Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Simultaneous application of ritonavir can lead to an increase in the concentration of ergot alkaloids in the blood plasma and therefore it is contraindicated.
Drugs affecting mothe GI tract
Cisapride	The simultaneous use of ritonavir can lead to an increase in the concentration of cisapride in the blood plasma and is therefore contraindicated.
HCV protease inhibitor
Symeprevir	200 once a day	100 every 12 hours	↑ 7.2 times	↑ 4.7 times
	Ritonavir increases the concentration of simeprevir in the blood plasma by inhibiting the cytochrome isoenzyme CYP3A4. It is not recommended simultaneous application of ritonavir with simeprevir.
Inhibitors of HMG-CoA reductase
Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin	It is expected that the concentration in the blood plasma of those inhibitors of HMG-CoA reductase, which are largely metabolized by the cytochrome isoenzyme CYP3A4, such as lovastatin and simvastatin, while concomitant administration with ritonavir as an antiretroviral agent or as a pharmacokinetic enhancer will be markedly increased. Due to the fact that increased concentrations of HMG-CoA reductase inhibitors may increase the risk of myopathy, including rhabdomyolysis, a combination of these drugs with ritonavir is contraindicated. Atorvastatin is less metabolized by the cytochrome isoenzyme CYP3A. Despite the fact that the elimination of rosuvastatin does not depend on cytochrome isoenzyme CYP3A, An increase in the exposure of rosuvastatin with simultaneous application with ritonavir is described. The mechanism of this interaction is unclear, but may be the result of inhibition of the vector. In concurrent administration with ritonavir as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest effective doses of atorvastatin or rosuvastatin should be used.The metabolism of pravastatin and fluvastatin does not depend on cytochrome isoenzyme CYP3A4. and their interaction with ritonavir is not expected. If treatment with a HMG-CoA reductase inhibitor is indicated, it is recommended that pravastatin or fluvastatin.
Hormonal contraceptives
Ethinylestradiol	50 mcg, once	500 every 12 hours	↓ 40%	↓ 32%
	Due to a decrease in the concentration of ethinylestradiol, barrier or other contraceptives other than hormonal drugs should be used, while using estrogen-containing contraceptives and ritonavir as an antiretroviral agent or as a pharmacokinetic enhancer. Ritonavir can change the profile of uterine bleeding and reduce the effectiveness of estradiol-containing contraceptives.
Immunosuppressive drugs
Cyclosporine, tacrolimus, everolimus	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A4, and as a result, an increase in the concentration of cyclosporine, tacrolimus or everolimus in the blood plasma is expected. It is recommended that the therapeutic and undesirable effects be closely monitored when these drugs are administered simultaneously with ritonavir.
Inhibitors of phosphodiesterase (PDE-5)
Avanafil	50, one time	600 every 12 hours	↑ 13 times	↑ 2.4 times
	Simultaneous use of avanafil with ritonavir it is contraindicated.
Sildenafil	100, one time	500 every 12 hours	↑ 11 times	↑ 4 times
	Simultaneous use of sildenafil for the treatment of erectile dysfunction with ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer should be used with caution; The dose of sildenafil should not exceed 25 mg every 48 hours. Simultaneous use of sildenafil for the treatment of pulmonary arterial hypertension with ritonavir it is contraindicated.
Tadalafil	20, once	200 every 12 hours	↑124%	↔
	Simultaneously appoint tadalafil for the treatment of erectile dysfunction with ritonavir as an antiretroviral agent or as a pharmacokinetic enhancer should be cautiously and in reduced doses (no more than 10 mg of tadalafil every 72 hours) and more often to monitor unwanted reactions. If tadalafil It is used for the treatment of pulmonary arterial hypertension simultaneously with ritonavir, it is necessary to familiarize with the instruction on the use of tadalafil.
Vardenafil	5, one time	600 every 12 hours	↑ 49 times	↑ 13 times
	The simultaneous use of vardenafil with ritonavir it is contraindicated.
Sedative / hypnotics
Clorazepate, diazepam, estazolam, flurazepam, midazolam for oral administration and for parenteral administration	The simultaneous use of ritonavir can lead to an increase in the concentration of clozra- enate, diazepam, estazolam and flurazepam in the blood plasma, and therefore it is contraindicated. Midazolam is largely metabolized by the cytochrome isoenzyme CYP3A4. Simultaneous use with Norvir® can cause a significant increase in the concentration of this benzodiazepine. Studies of drug interaction with the simultaneous use of the drug Norvir® with benzodiazepines have not been conducted. Based on data for other inhibitors of the cytochrome isoenzyme CYP3A4, the concentration of midazolam in the blood plasma is expected to be significantly higher when midazolam appointed in the form for oral administration. Therefore, the simultaneous use of the drug Norvir^® with midazolam for oral administration is contraindicated, and caution should be exercised while using Norvir® and midazolam for parenteral administration.The data for the simultaneous use of midazolam for parenteral administration with other HIV protease inhibitors indicate a possibility of an increase in the concentration of midazolam in blood plasma by 3-4 times. If Norvir® is used concomitantly with midazolam for parenteral administration, this should be done at the intensive care unit (ICU) or under similar conditions that provide clinical control and appropriate medical care in the event of respiratory depression and / or prolonged sedation. Consider the possibility of correcting the dose of midazolam. especially if midazolam is appointed repeatedly.
Triazolam	0,125, once	200, 4 doses	↑> 20 times	↑ 87%
	The simultaneous use of ritonavir can lead to an increase in the concentration of triazolam in the blood plasma and is therefore contraindicated.
Pethidine Metabolite norethypeidine	50, inside once	500 every 12 hours	↓ 62% ↑ 47%	↓ 59% ↑ 87%
	Use of pethidine and ritonavir contraindicated as a result of an increase in the concentration of the metabolite, norethidine, which exerts an anesthetic and stimulating activity of the central nervous system.Increased concentrations of neterpetidine may increase the risk of CNS effects (eg, seizures).
Alprazolam	1, one time	200 every 12 hours, 2 days	↑ 2.5 times	↔
		500 every 12 hours, 10 days	↓ 12%	↓ 16%
	Ritonavir after the initiation of its administration inhibits the metabolism of alprazolam. After using ritonavir for 10 days, no inhibitory effect of ritonavir was observed. Care must be taken during the first few days when alprazolam is concomitantly administered with ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer, before the development of alprazolam metabolism induction.
Buspirone	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A, and as a result, an increase in the concentration of buspirone in the blood plasma is expected. It is recommended to closely monitor therapeutic and undesirable effects when buspirone is given concomitantly with ritonavir.
Sleeping Pills
Zolpidem	5	200, 4 doses	↑ 28%	↑ 22%
	Zolpidem and ritonavir can be used simultaneously with careful monitoring of possible excessive sedation.
Means for the treatment of nicotine addiction
Bupropion	150	100 every 12 hours	↓ 22%	↓ 21%
	150	600 every 12 hours	↓ 66%	↓ 62%
	Bupropion is mainly metabolized by cytochrome isoenzyme CYP2B6. With the simultaneous use of bupropion with repeated doses of ritonavir, the concentration of bupropion is expected to decrease. These effects are believed to reflect the induction of bupropion metabolism. Nevertheless, since it was also shown that ritonavir inhibits cytochrome isoenzyme CYP2B6 in vitro, do not exceed the recommended dose of bupropion. In contrast to the long-term use of ritonavir, there was no significant interaction with bupropion after short-term administration of low doses of ritonavir (200 mg twice daily for 2 days), indicating a possible onset of a decrease in bupropion concentrations several days after initiation of simultaneous therapy with ritonavir.
Glucocorticosteroids
Fluticasone propionate, aqueous nasal spray	200 mcg once daily	100 every 12 hours	↑ ~ 350 times	↑ ~ 25 times
	Cases of systemic effects of corticosteroids, including Cushing's syndrome and suppression of adrenal function, were described (in the above study, the concentration of cortisol in the blood plasma decreased by 86%), in patients who received ritonavir and an inhalation or intranasal form of fluticasone propionate; Similar effects may also be noted when ritonavir is administered with other glucocorticosteroids that are metabolized by the cytochrome isoenzyme CYP3A, for example, budesonide. Consequently, simultaneous administration of ritonavir when used as an antiretroviral agent or as a pharmacokinetic enhancer and these glucocorticosteroids is not recommended unless the potential benefit of the treatment exceeds the risk of systemic effects of glucocorticosteroids. Consider the possibility of reducing the dose of glucocorticosteroids with careful monitoring of local and systemic effects or transferring the patient to a glucocorticosteroid that is not a substrate of the cytochrome isoenzyme CYP3A4 (eg, beclomethasone). Moreover, in the case of glucocorticosteroid cancellation, a gradual dose reduction over a longer period may be required.
Dexamethasone	Ritonavir, when used as a pharmacokinetic enhancer or as an antiretroviral agent, inhibits the cytochrome isoenzyme CYP3A, and as a result, an increase in the concentration of dexamethasone in the blood plasma is expected. It is recommended to closely monitor therapeutic and undesirable effects when dexamethasone is given concomitantly with ritonavir.
Prednisolone	20	200 every 12 hours	↑ 28%	↑ 9%
	It is recommended to closely monitor therapeutic and undesirable effects when prednisolone is given concomitantly with ritonavir. AUC metabolite prednisolone increased by 37 and 28% after 4 and 14 days of ritonavir therapy, respectively.
	N / A: Not determined. Based on comparison of parallel groups. Sulfamethoxazole was used concomitantly with trimethoprim.

Received reports on the development of adverse reactions from the cardiovascular and nervous system, while concomitant administration of ritonavir with disopyramide, mexiletine or nefazadone. It is impossible to exclude the possibility of drug interaction.

In addition to the above interactions, one should consider the possibility of increasing the therapeutic and toxic effects due to the displacement of the concomitantly used drugs with proteins, since ritonavir largely binds to proteins.

The use of ritonavir as a pharmacokinetic enhancer

Important information on drug interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the instructions for use for the concomitantly used HIV protease inhibitor.

Proton pump inhibitors and H antagonists_2-receptors

Proton pump inhibitors and antagonists H₂receptors (e.g., omeprazole or ranitidine) can reduce concentrations of concomitantly used HIV protease inhibitors. For more information on the effect of simultaneous use of drugs that reduce the acidity of gastric juice, you should read the instructions for use for a concurrently used HIV protease inhibitor.

Based on studies of interaction with ritonavir-enhanced HIV protease inhibitors (lopinavir / ritonavir, atazanavir), it can be said that simultaneous administration of omeprazole or ranitidine does not significantly affect the effectiveness of ritonavir when it is used as a pharmacokinetic enhancer, despite a slight change in exposure (about 6-18%).

Special instructions:

Ritonavir does not cure HIV-1 infection and AIDS. In patients receiving ritonavir or any other antiretroviral therapy, opportunistic infections and other complications of HIV-1 infection can continue to develop.

With the use of ritonavir in combination antiretroviral therapy, effective suppression of the virus has been proven, which significantly reduces the risk of sexual transmission of HIV, however, the risk of HIV transmission can not be completely excluded.

Patients should comply with appropriate safety measures to prevent the transmission of HIV.

When ritonavir is administered in combination with other HIV protease inhibitors (for example, in cases where ritonavir is used as a pharmacokinetic enhancer other protease inhibitors HIV) the information contained in the instructions for the use of appropriate HIV protease inhibitors should be considered.

Patients should be informed of the most common adverse events, such as moderate to severe gastrointestinal disorders, paresthesia, which may decrease during treatment.

When ritonavir is used as an antiretroviral agent or a pharmacokinetic enhancer

Patients with chronic diarrhea or malabsorption

Additional monitoring is recommended if diarrhea occurs. The relatively high incidence of diarrhea during ritonavir treatment can lead to impaired absorption and reduced effectiveness (due to decreased compliance) of ritonavir or other concomitant medications. Serious persistent vomiting and / or diarrhea associated with the use of ritonavir can also lead to impaired renal function. It is recommended to monitor kidney function in patients with a history of renal dysfunction.

Hemophilia

In patients with hemophilia type A or B receiving treatment with HIV protease inhibitors, there have been cases of increased bleeding, including spontaneous formation of cutaneous hematomas and hemarthrosis. Some patients were additionally assigned factor VIII. In more than half of the cases described, treatment with HIV viral protease inhibitors has been continued or resumed. There are allegations of a causal relationship,although the mechanism of action was not established. Patients with hemophilia should be informed of the possibility of increased bleeding.

Body weight and metabolic parameters

During antiretroviral therapy, weight gain, increased levels of lipids and glucose in the blood can occur. Such changes may be partly related to disease control and lifestyle. To increase the concentration of lipids in some cases, there are evidence of the impact of therapy, while evidence of a relationship of weight gain with any specific treatment is not there. When tracking the level of lipids and glucose in the blood should be guided by developed guidelines for the treatment of HIV infection. Disorders of lipid metabolism should be adjusted in accordance with clinical need.

Redistribution of fat

Against the backdrop of antiretroviral therapy, there is a redistribution / accumulation of fat with deposition in the central parts of the body, in the back, neck, the appearance of a "buffalo hump", a reduction in fat deposits on the face and limbs, enlargement of the mammary glands and Cushingoid.The mechanism and the long-term consequences of these side effects are unknown. Their connection with therapy is not established.

Disorders of lipid metabolism

The use of ritonavir in the form of monotherapy or in combination with saquinavir is accompanied by a significant increase in the concentrations of triglycerides and cholesterol. Determination of the concentration of triglycerides and cholesterol must be carried out before the start of therapy and periodically during the treatment with ritonavir.

Disorders of lipid metabolism should be adjusted in accordance with clinical recommendations.

Pancreatitis

Patients receiving ritonavir therapy experienced cases of pancreatitis, including two cases of hypertriglyceridemia. Several cases have been reported with a fatal outcome. Patients in the late stage of AIDS may be at increased risk for developing hypertriglyceridemia and pancreatitis.

Pancreatitis should be suspected when characteristic clinical symptoms appear (nausea, vomiting, abdominal pain) or changes in laboratory tests (increased serum lipase or amylase activity). Patients who have had similar symptoms and signs need a checkup,and when confirming the diagnosis of pancreatitis - the abolition of ritonavir.

Immunodeficiency Syndrome

The development of the immune reconstitution syndrome has been reported in HIV-infected patients who received combined antiretroviral therapy, including those who received Norvir®. During the initial phase of combined antiretroviral therapy, when the immune response occurs, the patient may develop an inflammatory response to asymptomatic or residual opportunistic infections (such as infections caused by Mycobacterium avium, cytomegalovirus infection, pneumonia caused by Pneumocystis jiroveci pneumonia, or tuberculosis), which may require further examination and treatment.

Against the backdrop of the development of immune reconstitution syndrome, autoimmune diseases such as Graves' disease, polymyositis and Guillain-Barre syndrome have been observed, but the timing of these events may vary significantly and be several months from the start of therapy.

It is necessary to carry out symptomatic treatment of any inflammatory reactions.

Diseases of the liver

Ritonavir should not be given to patients with decompensated liver disease. When prescribing combined antiretroviral therapy in patients with chronic hepatitis B or C, there is an increased risk of developing severe and potentially life-threatening adverse reactions from the liver. In the case of concomitant antiviral therapy for hepatitis B or C, it is necessary to read the instructions for the use of appropriate drugs.

Patients with a history of impaired liver function, including chronic active hepatitis, with combined antiretroviral therapy, there may be an increased incidence of liver function abnormalities; these patients should be carefully monitored in accordance with standard treatment protocols. If these patients develop symptoms of worsening liver disease, consideration should be given to discontinuing or discontinuing treatment.

Kidney Diseases

Due to the fact that renal clearance of ritonavir is negligible, general clearance is not expected to decrease in patients with renal insufficiency. There have been reported cases of kidney failure, impaired renal function,increase in creatinine concentration, hypophosphatemia and proximal tubulopathy (including Fanconi syndrome) with concomitant use with tenofovir disoproxil fumarate in clinical practice.

Osteonecrosis

Osteonecrosis has been reported, especially in patients with progressive HIV and / or long-term use of combined antiretroviral therapy, although the etiology of this complication is considered multifactorial (risk factors including glucocorticosteroids, alcohol use, severe immunosuppression, high body mass index). If the patient feels pain in the joints, their stiffness, difficulty in moving, he should consult a doctor.

Interval lengthening PR

Against the background of taking ritonavir in some patients there was a moderate asymptomatic lengthening of the interval PR. When ritonavir was taken, rare cases of atrioventricular blockade of degree II and III were reported in patients with organic heart disease and with existing disorders of the conduction system of the heart or in patients taking drugs that extend the interval PR (such as verapamil or atazanavir).In such patients ritonavir should be used with caution.

Allergic reactions

Allergic reactions including urticaria, skin rashes, bronchospasm and angioedema have been described. There are also reports of rare cases of anaphylaxis and Stevens-Johnson syndrome.

When developing allergic reactions, it is necessary to stop using the drug.

Diabetes mellitus / hyperglycemia

Post-registration studies recorded cases of newly developed diabetes mellitus, weighting of existing diabetes mellitus and hyperglycemia in HIV-infected patients receiving HIV protease inhibitor therapy. Some patients needed the appointment or correction of a dose of insulin or hypoglycemic drugs for oral administration to treat these phenomena. In some cases, diabetic ketoacidosis developed. Sometimes hyperglycemia persisted even after the withdrawal of HIV protease inhibitors. The causal relationship between these phenomena and HIV protease inhibitor therapy has not been established. When using lopinavir / ritonavir in patients with diabetes mellitus, it is necessary to monitor the concentration of glucose in the blood.

Laboratory Tests

The intake of ritonavir is accompanied by a change in the concentration of triglycerides, cholesterol, uric acid, ALT activity, ACT, GGT and KFK. Appropriate laboratory tests should be performed prior to the initiation of ritonavir therapy and repeated at a periodic interval during or with clinical signs or symptoms occurring during treatment.

Interaction with other drugs

The use of ritonavir as an antiretroviral agent

The following warnings and precautions should be taken into account when ritonavir is used as an antiretroviral agent. If ritonavir is used as a pharmacokinetic enhancer in a dose of 100 mg and 200 mg, it can not be assumed that the following warnings and precautions will also be applied. When ritonavir is used as a pharmacokinetic enhancer, it is necessary to take full account of the warnings and precautions for the appropriate HIV protease inhibitor. so you should read the instructions for use of the drug.

PDE-5 Inhibitors

Special caution should be exercised when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients using ritonavir. It is expected that the simultaneous use of ritonavir with these drugs will significantly increase their concentration in the blood plasma and can lead to the development of unwanted reactions, such as hypotension and prolonged erection. The simultaneous use of avanafil or vardenafil with ritonavir is contraindicated. Simultaneous use of sildenafil and ritonavir is contraindicated in patients with pulmonary arterial hypertension.

Inhibitors of HMG-CoA reductase

Inhibitors of HMG-CoA reductase simvastatin and lovastatin are largely metabolized by the cytochrome isoenzyme CYP3A4, therefore simultaneous use of ritonavir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. It is also necessary to use caution and reduce doses while simultaneously prescribing ritonavir with atorvastatin, which is less metabolized by the cytochrome isoenzyme CYP3A4. Despite the fact that the elimination of rosuvastatin does not depend on cytochrome isoenzyme CYP3A, An increase in the exposure of rosuvastatin with simultaneous application with ritonavir is described. The mechanism of this interaction is not clear, but can be the result of inhibition of the vector. In concurrent administration with ritonavir as a pharmacokinetic enhancer or as an antiretroviral agent, the smallest possible doses of atorvastatin or rosuvastatin should be used. The metabolism of pravastatin and fluvastatin does not depend on cytochrome isoenzyme CYP3A4, and their interaction with ritonavir is not expected. If treatment with a HMG-CoA reductase inhibitor is indicated, it is recommended that pravastatin or fluvastatin.

Colchicine

Among patients who took colchicine and potent inhibitors of the cytochrome isoenzyme CYP3A, such as ritonavir, cases of life-threatening and lethal interaction of drugs have been identified. The combined use of colchicine and ritonavir is contraindicated.

Digoxin

Caution should be exercised when prescribing ritonavir to patients receiving digoxin, because it is expected that simultaneous application of ritonavir with digoxin will lead to an increase in the concentration of digoxin. The increase in digoxin concentration may decrease with time.

Patients who are already taking digoxin, its dose should be reduced by half when starting ritonavir therapy, and patients should be observed more carefully than usual, within a few weeks after the onset of simultaneous application of ritonavir and digoxin.

Patients who are already taking ritonavir, digoxin should be introduced into the treatment regimen more gradually than under normal conditions. The concentration of digoxin during this period should be controlled more intensively, if necessary, with dose adjustments based on clinical, electrocardiographic data and digoxin concentration in the blood.

Ethinylestradiol

Use barrier or other contraceptives other than hormonal drugs when using ritonavir in therapeutic or low doses, since ritonavir can reduce the effectiveness of hormonal contraceptives and change the profile of uterine bleeding with concomitant administration with estradiol-containing contraceptives.

Glucocorticosteroids

It is not recommended simultaneous application of ritonavir with fluticasone or other glucocorticosteroids, which are metabolized by the cytochrome isoenzyme system CYP3A4, unless the potential benefit of treatment exceeds the risk of systemic effects of corticosteroids, including Cushing's syndrome and suppression of adrenal function.

Trazodone

Caution should be exercised when prescribing ritonavir to patients receiving trazodone. Trazodone is a substrate of cytochrome isoenzyme CYP3A4, and it is expected that simultaneous application of ritonavir will lead to an increase in trazodone concentration. AT interaction studies (with a single application) in healthy volunteers unwanted reactions like nausea, dizziness, arterial hypotension and fainting.

Rivaroxaban

It is not recommended to apply ritonavir in patients receiving rivaroxaban, due to increased risk of bleeding.

Rioctigua

Joint use is not recommended because of the possible increased exposure to riotsiguata.

Vorapaksar

Joint use is not recommended because of the possible increase in the impact of the vorapaksar.

Bedakvilin

Strong inhibitors of the cytochrome isoenzyme CYP3A4, such as HIV protease inhibitors, can increase the exposure of Bedakville, which in turn can increase the risk of adverse events associated with poorakwin. Thus, the administration of Bedakville in combination with ritonavir should be avoided. Nevertheless, if the benefit outweighs the potential risk, simultaneously assign Bedakvilin with ritonavir is necessary with caution. It is recommended that the electrocardiogram is monitored more frequently and that transaminase activity is monitored (see the instructions for use for Bedakville).

Delamanid

Simultaneous application of Delamanide with a strong cytochrome isoenzyme inhibitor CYP3A (ritonavir) may increase the exposure of the metabolite delamanide, which may lead to lengthening of the interval QTc. Thus, if concomitant use of Delamanide and ritonavir is necessary, it is recommended that ECG is very often monitored throughout the treatment period by Delamanide (see instructions for use for Delamanide).

Ritonavir when used as a pharmacokinetic enhancer

The interaction profiles with HIV protease inhibitors used concomitantly with a low dose of ritonavir depend on the specific concurrently used HIV protease inhibitor.

The description of the mechanisms and possible mechanisms that contribute to the profile of interaction with the PI see the section "Interaction with other drugs". Also, you should read the instructions for using the appropriate PI.

Saquinavir

Do not assign ritonavir in doses above 100 mg twice a day. It was shown that higher doses of ritonavir are associated with an increased incidence of unwanted reactions. Simultaneous use of saquinavir and ritonavir led to the development of severe adverse reactions, mainly diabetic ketoacidosis and liver disorders, especially in patients with already existing liver diseases.

Due to the risk of severe hepatotoxicity (manifested as an increase in the activity of transaminases), saquinavir / ritonavir should not be administered together with rifampicin.

Tipranavir

There is evidence that simultaneous use of tipranavir in combination with ritonavir in a dose of 200 mg was accompanied by the development of hepatitis with clinical manifestations and hepatic decompensation with lethal outcomes in several cases.Particular caution should be exercised in patients with concomitant chronic hepatitis B or C, because they are at increased risk of hepatotoxic effects of these drugs.

Doses of ritonavir less than 200 mg twice daily should not be used with tipranavir, as this may impair the combination efficiency profile.

Fosamprenavir

Ritonavir at doses higher than 100 mg twice daily has not been studied with simultaneous use with fosamprenavir in clinical studies. The use of higher doses of ritonavir may worsen the safety profile of the combination, and is therefore not recommended.

Atazanavir

Simultaneous use of atazanavir with ritonavir in doses higher than 100 mg once a day has not been studied in clinical studies. The use of higher doses of ritonavir may worsen the safety profile of atazanavir (cardiac effects, hyperbilirubinemia), and therefore joint use is not recommended. If atazanavir with ritonavir applied simultaneously with efavirenz, a dose of ritonavir can be increased to 200 mg once a day. In this case, careful clinical monitoring is necessary.For more information, see the instructions for use of atazanavir.

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

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, since the drug may cause drowsiness, dizziness and other side effects that may affect these abilities.

Studies of the ability to drive vehicles and control mechanisms have not been carried out.

Form release / dosage:

Tablets, film-coated, 100 mg.

Packaging:

For 30 or 60 tablets in a vial of high-density polyethylene with a polypropylene or polyethylene lid, laminated foil and inner film.

One bottle of 30 or 60 tablets together with instructions for use in a cardboard pack; or 3 bottles of 30 tablets together with 3 instructions for use in a cardboard pack.

Storage conditions:

In a dry place, at a temperature of 15 to 30 ° C. Store in the original vial.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001272

Date of registration:24.11.2011 / 19.02.2014

Expiration Date:24.11.2016

Date of cancellation:2017-05-25

The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia

Manufacturer: & nbsp

AbbVie Deutschland GmbH & Co. KG Germany

Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia

Information update date: & nbsp25.05.2017

Illustrated instructions

Instructions

Norvir® (Norvir®)