NORVIR
Active material: Ritonavir
When ATH: J05AE03
CCF: Viricide, active against HIV
ICD-10 codes (testimony): B24
When CSF: 09.01.04.02
Manufacturer: ABBOTT LABORATORIES Ltd. (Great Britain)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Soft Capsules gelatin, white, with printed black ink trademark firm Abbott, “100” and “DS”; contents of capsules – transparent liquid.
| 1 caps. | |
| ritonavir | 100 mg |
Excipients: ethanol, butylhydroksytoluol, oleic acid, polioksil 35 Castor oil, water.
The composition of the shell capsules: gelatin, sorbitol (contains anhydrous sorbitol and mannitol), glycerol, Purified water, Titanium dioxide, triglycerides srednecepochnye, lecithin, ink black.
84 PC. – plastic bottles (1) – packs cardboard.
84 PC. – plastic bottles (4) – packs cardboard.
Pharmacological action
Antiviral drug for HIV infection.
Ritonavir – aspartil-HIV protease inhibitor-1 and HIV-2 for admission into, Active peptidomimetik. HIV protease inhibition prevents the tearing of the gag-pol connection poliproteina, that leads to the formation of immature and incapable to virus infection. Ritonavir has selective affinity to proteaze HIV and shows little activity against human protease aspartil.
Antiviral activity of ritonavir was assessed in vitro on lymphoid cell lines and lymphocytes to suppress virus replication at 50% (EU50) ranged from 0.0038 to 0.153 micromole depending on isolates of HIV-1. The average value of the EU50 It was 0.022 mmol. In MT4 cells shown additivoe effect of ritonavir in combination with zidovudine (ZDV) or DDI (DDI) in the case of HIV-1.
Study of cytotoxicity of ritonavir in several cell lines showed, that concentration of more 20 micromole ritonavir inhibits the growth of normal cells in the 50%, point O. therapeutic index in vitro for ritonavir is not less than 1000.
Isolates of HIV-1, resistant to ritonavir, in vitro were identified. Genotipicheskij analysis of isolates showed the presence of mutations in the protease gene of HIV, that led to the spceificheskim replacements of amino acids in kodonah 84 (isoleucine to valine), 82 (valine to phenylalanine), 71 (alanine to valine) and 46 (methionine to isoleucine). Genotipicheskij and phenotypic analysis of isolates, obtained in clinical research (Phase I/II), showed, that mutations in the protease of HIV occurred gradually and in a specific order. Initial mutations, arising out of the provisions of the 82 (valine in alanine/phenylalanine), 54 (isoleucine to valine), 71 (alanine to valine/threonine) and 36 (isoleucine to Leucine), Subsequently, accompanied by combinations of mutations in 5 amino acid positions. It has been found, that the presence of mutations 82 necessary, but not enough to form a phenotypic resistance. Is phenotypic resistance was defined as a decrease in the sensitivity of virus in ≥ 5 times compared to baseline levels in vitro. The clinical significance of phenotypic and genotypic changes, treatment ritonavir is not installed.
Possibility of cross-resistance among protease inhibitors has not fully investigated. Unknown, ritonavir treatment will affect the activity simultaneously or subsequently appointed by protease inhibitors. Serial isolates of HIV, received from 6 patients during treatment with ritonavir, in vitro showed reduced sensitivity to ritonavir in the absence of a simultaneous reduction of sensitivity to sakvinaviru compared with the corresponding source isolates. However, isolates from 2 from these 6 patients 8 x showed reduced sensitivity to indinaviru in vitro. Isolates from 2 from 5 patients, studied on the existence of cross-resistance to amprenaviru and nelfinaviru, demonstrated reduced susceptibility to nelfinaviru (12-14-45-fold), and none was found reducing sensitivity to amprenaviru. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely, because the targets are different enzymes. In vitro one isolate, resistant to zidovudine, remained fully sensitive to ritonavir.
Pharmacokinetics
Pharmacokinetics of ritonavir dozozavisima: When increasing doses of ritonavir increased the value of the AUC and Cmax plasma.
Absorption
Absorption of the drug to prandial increases by 12%. The one-time prandial capsules of ritonavir dose 100, 200, 400, 600, 800 and 1000 mg, AUC ranged from 3.92 to 123 mcg × h/ml, respectively, Cmax was within the range of 0.416 to 12.7 ug / ml. Tmax approximately 2 h when taking the drug on an empty stomach and 4 hours after meals and with increasing doses of the drug remains constant. Renal clearance is <0.1 l/h and relatively constant when applying different doses. Absolute bioavailability of ritonavir is not installed, because there is no dosage form for injecting. The one-time admission after eating capsules of ritonavir dose 600 mg AUC was 121.7 ± 33.4 µg × h/ml.
After repeated admission prandial cumulation of ritonavir is somewhat less, than calculated on the basis of a single dose, and depends on the time of treatment and dose-depending increase ground clearance (C1/F). It has been found, that concentration of ritonavir was decreased slightly over time, perhaps, due to the induction of enzymes, However, stabilized towards the end of the two weeks.
Css in the blood plasma in the employment drug dose 600 mg 2 times/day is reached by the end of 2 of the week, wherein Cmax and residual concentration in the plasma (Ctrough) are respectively 11.2 ug / ml 3.7 ug / ml. In equilibrium this patients, taking 600 mg 2 times / day, average, is 8.8 ± 3.2 l /.
Clinically significant difference the AUC and Cmax men and women have not been. Statistically reliable relationship between the pharmacokinetics parameters of ritonavir and weighing not detected.
Distribution
In Кажущийсяd ritonavir is about 0.41 ± 0.25 l/kg after a single dose 600 mg. Ritonavir binding to plasma proteins in humans is about 98-99%. Ritonavir is associated both with alpha1-sour glikoproteidom man, and human serum albumin with relatively the same affinity. Linking plasma protein is continuously in the range of concentrations 1-100 ug / ml.
Metabolism
Ritonavir intensive metabolised involving liver cytochrome P450 system Isoenzymes, Basically, with the participation of izofermenta CYP3A to a lesser extent CYP2D6. A person found 5 metabolites of ritonavir. The principal is oxidative metabolite of izopropiltiazola (M-2), antiviral activity of which is the same with ritonavir. But AUC metabolite m-2 is only 3% from the AUC drug.
Deduction
Excretion of ritonavir comes, primarily, with feces – about 86%. T1/2 Ritonavir 3-5 no.
Pharmacokinetics in special clinical situations
In children aged 14 years equilibrium klirens ritonavir ingestion dose from 250 mg / m2 to 400 mg / m2 2 times per day was approximately 1.5-1.7 times higher, than in adults. Concentration of ritonavir in the blood after administration of doses from 350 mg / m2 to 400 mg / m2 2 times/day in children compared with the concentration of ritonavir in adults, taking 600 mg (about 330 mg / m2) 2 times / day.
In elderly patients ritonavir pharmacokinetics in the application of the dose of 100 mg in combination with lopinavir or in higher doses, but without protease inhibitors did not differ in patients aged 50-70 years old and younger patients.
Currently, there are no data on ritonavir pharmacokinetics in the application in patients with renal insufficiency. But, because ritonavir actively binds to the protein, unlikely, He will be greatly raised when hemodialysis or peritoneal dialysis.
In patients with mild hepatic insufficiency correction dose is not required, because ritonavir dose 400 upon receipt mg 2 times/day corresponded to such activity in patients of the control group in a dose 500 mg 2 times / day. Sufficient data on the use of ritonavir in patients with moderate hepatic insufficiency no. Liver failure mild or moderate does not affect the binding of ritonavir with blood plasma proteins.
Testimony
-in a combination therapy for HIV infection in adults and children older than 3 years.
Dosage regimen
The drug is taken orally during meals.
In Adult The recommended dose is 600 mg (6 caps.) 2 times / day. A gradual increase in dose of Norvir in an initial period of treatment can improve the acceptability of the drug.
Initial dose is at least 300 mg 2 times per day during the first 3 days, next dose 100 mg 2 times / day to 600 mg 2 times per day over a period of time, not exceeding 2 weeks. You should not continue treatment ritonavir dose 300 mg 2 times/day more 3 days.
The patient should be informed about the most frequent adverse reactions (gastrointestinal disorders moderate and severe, paresthesia), that may decrease during treatment.
Combined regimens with two protease inhibitors HIV
Clinical experience of dual therapy, providing for the use of therapeutic doses of ritonavir in combination with another protease inhibitor, limited. When planning a dual therapy with use of ritonavir should take into account pharmacokinetic interaction and safety data used medicines. Should include a combination of two protease inhibitors with the smallest cross-resistant.
Together with the use of ritonavir with sakvinavirom should conduct a careful titration of dose, When the initial dose of ritonavir is 300 mg 2 times / day.
If you are applying with indinavir ritonavir also should conduct careful titration of dose, starting treatment with doses of ritonavir 200 mg 2 times / day, gradually increasing it for 2 weeks on 100 mg 2 times / day to 400 mg 2 times / day.
In older children 3 years ritonavir should be used in combination with other antiviral drugs.
The recommended dose is 350-400 mg / m2 2 times/day and should not exceed 600 mg / m2 2 times / day. The initial dose is 250 mg / m2, next dose 50 mg / m2 2 times / day at intervals 2-3 day.
If patients do not tolerate maximum daily dose due to side effects, appoint maximum dose portable ritonavir in combination with other antiviral drugs.
Body surface area (BSA) is calculated by the formula: BSA (m2)= the square root of (height in cm × body weight (kg))/3600.
The safety and efficacy of ritonavir at children under 3 years not installed.
In elderly patients correction dose is not required.
Side effect
The most often Adult patients experienced fatigue, gastrointestinal (nausea, diarrhea, vomiting, anorexia, abdominal pain, taste disturbance) and neurological disorders, including okolorotovye and peripheral paresthesias.
Side effects, observed more, than 2% patients in clinical studies phase II, whose relationship with the acquisition of ritonavir is possible or not installed:
From the central and peripheral nervous system: anxiety, insomnia, dizziness, headache, hyperesthesia, paresthesia, drowsiness.
The respiratory system: increased cough, pharyngitis.
From the digestive system: dry mouth, dyspepsia, belching, flatulence, ulceration of the oral cavity.
On the part of the musculoskeletal system: myalgia.
Metabolism: hyperlipidemia, weight loss.
Dermatological reactions: maculo-papular rash, itch, skin rash, Sweating.
Other: fever, pain, asthenia.
Side effects, observed less, than 2% patients in clinical studies phase II, whose relationship with the acquisition of ritonavir is possible or not installed:
From the central and peripheral nervous system: sleep disturbance, amnesia, afazija, ataxia, convulsions, dystaxia, neuralgia, peripheral and sensory neuropathy, paralysis, ageusia, tremor, violation of the visual fields, violation of smell, anxiety, confusion, depression, emotional instability, euphoria, hallucinations, nervousness, personality disorder, thinking abnormality.
Cardio-vascular system: palpitations, collapse, gemorragii, hypotension, migraine, peripheral vascular disorders, orthostatic hypotension, tachycardia, myocardial infarction, chest pain.
The respiratory system: bronchospasm, dyspnoea, nosebleeds, Ikotech, gipoventilyatsiya, interstitial pneumonia, lesions of the lung, rhinitis.
From the digestive system: violations of the Chair, diarrhea with blood, cheilitis, colitis, constipation, dysphagia, esophagitis, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal bleeding, gingivitis, ileitis, candidiasis of the oral mucosa, pancreatitis, Periodontal abscess, tenesmus, thirst, kholangit, hepatitis, gepatomegaliya, liver, hepatic failure.
From the urinary system: dizurija, hematuria, stones in the kidneys, pain in the kidneys, nocturia, polyuria, pyelonephritis, uretrit, increased urination, urinary retention, renal failure.
From the senses: visual impairment, amblyopia/unclear vision, .Aloe, diplopia, sore eyes, iritis, photophobia, uveitis, pathological changes in jelektrookulogramme, jelektroretinogramme; earache, hearing disorder, increased formation of earwax, noise in ears, dizziness.
On the part of the musculoskeletal system: arthralgia, arthrosis, backache, Joint infringement, muscle spasms (convulsions), muscular weakness, myositis, pain in the neck, stiff neck, apnoea apnoea (teak), gait disturbance.
On the part of the endocrine system: diabetes.
Reproductive system: impotence, decreased libido.
From the hematopoietic system: anemia, ecchymosis, leukopenia, lymphadenopathy, Lymphocytosis, thrombocytopenia.
Metabolism: beri, kaxeksija, degidratatsiya, swelling, glycosuria, gout, hypercholesterolemia, peripheral edema, redistribution/accumulation of fat in tissues.
Dermatological reactions: acne, contact dermatitis, xerosis, eczema, swelling of the face, folliculitis, Molluscum Contagiosum, photosensitivity, psoriasis, seborrhea, hives, vesiculobullous rash.
Other: allergic reactions, chest pain, chills, flu-like symptoms, malaise, gipotermiя.
Side effects, registered with the marketing experience of ritonavir:
From the central and peripheral nervous system: convulsions, whose relationship with the acquisition of ritonavir is not installed.
Cardio-vascular system: myocardial infarction.
Reproductive system: menorragija.
Metabolism: degidratatsiya, usually associated with gastrointestinal disorders (sometimes accompanied by arterial gipotenziei, fainting or renal failure).
From the laboratory parameters: increase/decrease of glucose (<1%), sodium, Potassium, xloridov, total calcium, Magnesium; creatinine increase (<1%), inorganic phosphorus (<1%), Uric acid (2%), total bilirubin (1%), Alkaline phosphatase (1%), ACT (4%), GOLD (6%), LDH (<1%), triglycerides (7%), GGT (12%), amilazы (2%), CPK (8%); the number of leukocytes (1-16%), the number of neutrophils (1-3%), the number of eosinophils (2%), prothrombin time (1%), APTT (<1%), decrease in hemoglobin (3%), gematokrita (8%), Albumin (<1%), platelet count (<1%).
The nature of the observed side effects from children was similar to those of adult patients. Vomiting, diarrhea and skin rashes/allergies were the only ones associated with the admission of the drug side effects of moderate to severe, observed more, than 2% children, taking ritonavir.
The following changes in laboratory parameters 3-4 the degree of observed more, than 3% children, received treatment ritonavir as monotherapy or in combination with reverse transcriptase inhibitors: neutropenia (9%), increase in amylase (7%), thrombocytopenia (5%), anemia (4%) and improving ACT(3%).
Contraindications
- Severe degree of renal insufficiency;
-simultaneous application al'fuzozina, amiodarona, astemizola, bepridil, cisapride, digidroэrgotamina, Ergometrine, metilargometrina, ergotamine, jenkainida, flekainida, clozapine, pimozida, propafenone, xinidina, Terfenadine, midazolama, triazolama, vorikonazola, simvastatin, Lovastatin, rifaʙutina, pethidine, piroxicam, dekstropropoksifena, fuzidovoj acid, DIPOTASSIUM klorazepata, estazolama, diazepama, flurazepama, bupropion, preparations of Hypericum perforatum;
- Children up to age 3 years;
-hypersensitivity to ritonavir and/or preparation components.
FROM caution the drug should be used in patients with moderate hepatic insufficiency, hepatitis, other related liver diseases, When you raise liver enzymes.
The simultaneous use of ritonavir with certain antihistamines, sedatives, hypnotics, antiarrhythmic drugs can lead to potentially severe and/or life-threatening side effects due to the possible impact of ritonavir on the metabolism of drugs in the liver.
Pregnancy and lactation
Currently, there are no adequate data on the use of ritonavir in pregnant women.
Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.
HIV-infected women should not breastfeed their children, to avoid transmitting HIV infection.
Cautions
Reception of ritonavir is accompanied by a change in triglycerides, cholesterol, GOLD, ACT, GGT, CKF and uric acid. Appropriate laboratory tests should be conducted prior to the therapy of ritonavir and repeat with the periodic intervals during it or if clinical signs or symptoms, arising during treatment.
Ritonavir treatment as monotherapy or in combination with sakvinavirom leads to a significant increase in the concentration of triglycerides and total cholesterol. Triglycerides and cholesterol should be carried out before starting treatment with ritonavir and at periodic intervals during it, must be assigned appropriate therapy in case of violation of these indicators.
In patients with hemophilia a or b type, receiving treatment for protease inhibitors, incidents strengthen bleeding, including spontaneous skin hematomas and education gemartroza. Some patients was appointed as an additional factor VIII. More, than half of the cases described treatment of protease inhibitors was continued or resumed. Although a causal link is established, mechanism of interaction is unknown.
Patients, receiving ARVS, There is redistribution/accumulation of body fat from his deposition in the back and neck (“buffalo hump”), a decrease in body fat in the face and extremities, an increase in mammary gland and “kushingoidnoj” appearance.
Immune system recovery Syndrome was described in HIV-infected patients, receiving combination ANTIRETROVIRAL THERAPY, including ritonavir. During the initial phase of ART patients may worsen previously asymptomatic or residual opportunistic infections (incl. caused by Micobacterium Avium, Cytomegalovirus, pneumonia, caused by Pneumocystis carinii, tuberculosis), that may require further observation and treatment.
Allergic reactions have been described, include hives, weak skin rashes, bronchospasm and angioedema. There are also reports of rare cases of anaphylaxis, and Stevens-Johnson Syndrome.
Patients, taking ritonavir as monotherapy or in combination with other antiretroviral drugs, found 5 x increase in liver transaminaz, clinical manifestations of hepatitis and jaundice. Risk raising transaminaz in patients, with hepatitis b or c. Therefore, in patients with liver diseases, change in liver enzymes or hepatitis, ritonavir should be appointed with caution.
There have been reports of violation of the liver, and in several cases with fatal outcome. Latest, usually, observed in patients, receiving a large number of related drugs and/or having a late-stage AIDS. Of a causal relationship with taking ritonavir was not installed.
Some patients, receiving therapy of ritonavir, experienced pancreatitis with hypertriglyceridemia. Cases of fatal. In patients with advanced AIDS risk increasing triglycerides and pancreatitis rises. Pancreatitis should be suspected if there are typical clinical symptoms (nausea, vomiting, abdominal pain) or changes in laboratory parameters (incl. elevated levels of serum amylase or lipase). Patients, where have these signs or symptoms, should be examined, and, If the diagnosis of pancreatitis, ritonavir therapy should be discontinued.
Reported for the first time caused diabetes, weighting of existing diabetes mellitus and hyperglycemia in HIV-infected patients, receiving therapy in protease inhibitors. Some patients for the treatment of these conditions required the appointment or correction of the dose of insulin or oral hypoglycemic drugs. In some cases, developing diabetic ketoacidosis. Sometimes hyperglycemia continued after the lifting of the other protease inhibitors. The causal relationship between these phenomena and therapy, protease inhibitors has not been installed.
Systemic corticosteroid effects, including syndrome kushinga and oppression napochechnikov functions, have been described together with the appointment of ritonavir with inhalation or intranazal'nym flutikazonom propionate. The development of similar symptoms when used with ritonavir with other inhaled CORTICOSTEROIDS, which are metabolized similar to flutikazonom (ʙudezonid) cannot be deleted. Caution in case of simultaneous use of ritonavir and any of the aforementioned inhaled or intranazalnah GKS.
Metabolism inhibitors of HMG-CoA reductase inhibitors (simvastatin, Lovastatin) much depends on the metabolism of izofermenta CYP3A, Thus the simultaneous use of ritonavir with lovastatinom or simvastatinom is not recommended because of the increased risk of myopathy, including rhabdomyolysis. There is also a need to proceed with caution and reduce dosages while appointing atorvastatin, that is metabolized by CYP3A4, to a lesser extent, izofermentom. When, If the patient shows treatment of inhibitor of HMG-CoA reductase inhibitors, It is recommended that you use the Pravastatin or fluvastatin.
Based on the results of the study drug interaction with ketoconazole, other potent CYP3A4 inhibitor, and al'fuzozinom, in the presence of ritonavir (600 mg 2 times / day), You should expect a significant increase in impact al'fuzozina. Therefore, al'fuzozin should not be administered together with ritonavir.
Reported, that the use of tipranavir when combined with ritonavir dose 200 mg has been accompanied by the development of hepatitis c 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, Since the risk of hepatotoxic action of these drugs they have upgraded.
Together with the use of ritonavir increases plasma concentration DIPOTASSIUM klorazepata, diazepama, estazolama, flurazepama, midazolam and triazolam, Therefore, the risk of excessive sedative and respiratory depression.
Use in Pediatrics
In older children 3 years ritonavir should be used in combination with other antiviral drugs.
Effects on ability to drive vehicles and management mechanisms
Ritonavir is not specifically tested with regard to its possible impact on the ability to control the car and work with mechanisms. Since drowsiness and dizziness are the known adverse effects of ritonavir, This should be taken into consideration when driving and working with the mechanisms.
Overdose
Observation of acute overdose in humans are limited.
Symptoms: the patient, host 1500 mg/day ritonavir in two days, experienced paresthesia, prekrativshiesja with a decrease in dosage. In another case, reported on the development of renal failure, accompanied by Eosinophilia.
Treatment: is to undertake support activities, including monitoring vital performance and condition of the patient. It is recommended that washed through the stomach probe and the introduction of activated carbon. There is no specific antidote. Because ritonavir intensive metabolised by the liver and is largely associated with blood plasma proteins, to remove large quantities of the drug will not be effective dialysis.
Drug Interactions
Preparations, are inducers of CYP3A: phenobarbital, Carbamazepine, Dexamethasone, phenytoin, rifampin and rifabutin, lead to increased clearance of ritonavir, as a result of which decreases its concentration in the blood plasma.
Rifampicin causes a decrease in AUC and Cmax Ritonavir, While clarithromycin and fluconazole increase the values for the above parameters, and DDI and AZT does not affect them. Fluoxetine increases the AUC ritonavir, but it Cmax has no effect.
When smoking tobacco AUC ritonavir is reduced by 18%.
Ritonavir has high affinity to multiple izofermentam zitohroma r450, You can sort by degree of shrinkage in a row: CYP3A4>SYP2D6>SYP2C9>SYP2C19>>SYP2A6, SYP1A2, SYP2E1.
Proved, that ritonavir may increase the activity of gljukuronoziltransferazy, that may require increased dosages, biotransformirujushhihsja under the action of this enzyme, due to their effectiveness while applying.
There have been reports about the development of adverse reactions on the part of the cardiovascular and nervous system while appointing ritonavir with dizopiramidom, mexiletine, nefazodone, fluoxetine.
Statistically significant decreases (C)max alprazolam (16%) and its sedative effect together with the use of ritonavir. You may experience slight psychomotor violations.
Together with the use of ritonavir amprenavir concentrations.
Buspirone is metabolized primarily by CYP3A4, Therefore, its concentration may significantly increase, Consequently recommended lower doses buspirona together with ritonavir.
Metabolism significantly inhibited, as a result of which Cmax == increases by 31%, Cmin – on 182% and AUC of 77%. Almost completely suppressed the formation of 14-gidroksiklaritromicina (the major metabolite of clarithromycin). Due to the wide therapeutic range == no need to reduce the dose in patients with normal renal function. For patients with renal insufficiency dose should be adjusted: at CC 30-60 mL/min dose clarithromycin should be reduced by 50%, at CC<30 mL/min dose clarithromycin should be reduced by 75%. Dose == >1 g/d should not be appointed in combination with ritonavir.
Delavirdine – CYP3A4 inhibitor-metaboliziruemah drugs. Increases the equilibrium (C)max and AUC of ritonavir on 50% and 75% respectively, require lower doses of ritonavir. In turn, ritonavir does not affect the farmakokinetiku delavirdine.
Ritonavir increases by 145% AUC dezipramina, Therefore, provision should be made for reducing the dose dezipramina for patients, taking it in combination with ritonavir.
Ritonavir lowers equilibrium (C)max and AUC of didanosine for 16% and 13% respectively. To avoid incompatibility of drugs is recommended at intervals of not less than, than 2.5 no.
The simultaneous use of ritonavir (300 mg every 12 no) and digoxin resulted in a significant increase in the level of Digoxin. Caution must be exercised, exercising adequate monitoring of Digoxin in plasma.
Capsules with ritonavir is contained 12% ethanol, Therefore, you should avoid combination of ritonavir with disulfiram or medications, having such disul'firamu action, eg, metronidazole.
Together with the use of ritonavir increased the jefavirenza AUC equilibrium 21%. In this context, 17% increased AUC of ritonavir.
Simultaneous application flutikazon propionata ritonavir and leads to an increase in the concentration of fluticasone propionate.
Expected, that the use of ritonavir in combination with fuzidovoj acid increases the concentration of as fuzidovoj acid, and ritonavir in plasma.
You should not take the Hypericum perforatum (Hypericum perforatum) in combination with ritonavir, Since the concentration of ritonavir in plasma decreased due to the induction of CYP3A4. Resulting in reduced therapeutic effectiveness and develop resistance to ritonavir.
Ritonavir inhibits the metabolism of indinavir, flowing with the involvement of CYP3A, and leads to an increase in the concentration of indinavir plasma. The risk of nefrolitiaza can be increased when combined with indinavir ritonavir at doses, equal to or exceeding 800 mg 2 times / day. It is necessary to maintaining adequate hydration to patients and carrying out monitoring of their condition.
The simultaneous use of ritonavir with ketoconazole (200 mg / day) resulted in a marked rise in plasma ketoconazole levels: average AUC0-24 increased to 244% and Cmax – on 55%. Average T1/2 ketoconazole increased with 2.7 to 13.2 no. The mean values of AUC0-24 and Cmax ritonavir increased the 18% and 10% respectively. Ritonavir dose not need to be adjusted while admission to ketoconazole, While dose ketoconazole ≥ 200 mg/day should not be used in combination with ritonavir. The lower dose of ketoconazole.
The simultaneous use of ritonavir with methadone caused decreased concentration of methadone. You may need to increase the dose of methadone.
Interaction between ritonavir and nelfinavirom, probably, happens with both inhibition, and the induction of cytochrome P450 system Isoenzymes. At the same time with a significant increase in the concentration of M8 (the main active metabolite of nelfinavir), the concentration of the nelfinavir is increased to a lesser extent.
The simultaneous use of ritonavir with combined forms of ethinyl estradiol (for the reception inside, or in the form of a patch) It was in reducing average AUC of ethinyl estradiol on 32%, a Cmax – on 40%. You should increase the dose contraceptive, containing ethinyl estradiol, or use alternative methods of contraception.
The simultaneous use of rifabutin with ritonavir results in multiple (from 4 to 35 time) increase in AUC of rifabutin and its active metabolite, 25-o-dezacetil rifabutin respectively, What is the clinical significance. It is recommended to reduce the dose of rifabutin, at least, on 3/4 from the usual daily dose. 300 mg (ie. 150 mg a day or 3 times a week). It is recommended that, if necessary, further dose reduction.
Research pharmacokinetics in patients indicate, that the simultaneous use of saquinavir with ritonavir saquinavir concentration potentiate causes in the blood (AUC, 17-45-fold increase). Long combination therapy at doses >400 mg 2 times per day each drug has been accompanied by an increase in the frequency of adverse reactions. Nor should appoint saquinavir and ritonavir together with rifampicin because of the risk of severe hepatotoxic action, manifested increased liver transaminaz.
We recommend that you use caution sil'denafil patients, receiving ritonavir. Reception sil'denafila in combination with ritonavir causes significant (11-45-fold) increase in AUC of sil'denafila in plasma, and therefore increases the risk of adverse reactions, associated with sil'denafilom (incl. hypotension, fainting, visual impairment, prolonged erection).
Tadalafil in combination with ritonavir should be used with caution, in small doses – not >10 mg every 72 h with reinforced monitoring of the development of adverse events.
Vardenafil in combination with ritonavir should be used with caution, in small doses – not >2.5 mg every 72 h with reinforced monitoring of the development of adverse events.
The simultaneous use of ritonavir with the combination of sulfamethoxazole/trimethoprim caused 20% decrease in AUC of sulfamethoxazole and 20% increase in AUC of trimethoprim. Dosage adjustment of sulfamethoxazole/trimethoprim during therapy of ritonavir is not usually required.
You may need to increase the dose of theophylline, Since the application in combination with ritonavir caused decrease in AUC of theophylline at 43%.
The simultaneous use of ritonavir and trazodona may increase the concentration of trazodona. Such undesirable phenomena, nausea, dizziness, arterial hypotension and syncope. Caution must be exercised in the appointment by trazodone in combination with ritonavir: You may need to reduce the dose by trazodone.
The simultaneous use of ritonavir on 400 mg every 12 h reduces the AUC vorikonazola in equilibrium on average 82%. Joint appointment of these drugs is not recommended.
Warfarin concentration can vary while applying together with ritonavir. It is recommended that you monitor the indicators of blood coagulation.
When odnovremenom the use of ritonavir reduced Cmax and AUC of zidovudine by approximately 27% and 25% respectively. However, changes in dose of zidovudine in applying with ritonavir is not required.
Ritonavir resulted in a significant increase in AUC (≥3 times) the following drugs: alfetanil, Amiodarone, atorvastatin, bromocriptine, buspirone, verapamil, Dexamethasone, diltiazem, indinavir, izradipin, itraconazole, Carbamazepine, ketoconazole, lidokain, lovastatin, loratadine, mikonazol, nefazodon, nikardipin, nimodipine, nisoldipin, nitrendipine, nifedipine, rifabutin, saquinavir, sertraline, simvastatin, sirolimus, tacrolimus, Tamoxifen, felodipine, Fentanyl, fluticasone propionate, fuzidovaja acid, quinones, cyclosporine, Erythromycin.
Ritonavir results in a moderate increase in AUC (in 1.5-3 times) preparations: Amitriptyline, Bupropion, venlafaxine, vynblastyn, vynkrystyn, haloperidol, hydrocodone, desipramine, deksfenfluramin, diazepam, disopyramide, dronabinol, zolpidem, imipramine, clarithromycin, clomipramine, clonazepam, dikaliя klorazepat, maprotilin, mexiletine, methamphetamine, metoprolol, nortryptylyn, Oxycodone, ondansetron, paclitaxel, paroxetine, penbutolol, perphenazine, pindolol, prednisolone, dextropropoxyphene, risperidone, tioridazin, trazodone, tramadol, trimipramin, fluoxetine, flurazepam, chlorpromazine, эstazolam, etoposide, эtosuksimid.
Ritonavir resulted in moderate increase or decrease AUC drugs: gliʙurid, glimeprid, glipizide, diclofenac, Ibuprofen, Indomethacin, ifosfamide, lansoprazole, lozartan, omeprazole, piroxicam, proguanil, propranolol, tolbutamid, flurbyprofen, cyclophosphamide.
Together with the use of ritonavir may decrease in AUC of drugs: atovahon, hydromorphone, divalpreks, diphenoxylate, Ketoprofen, ketorolac, klozapyn, clofibrate, codeine, lamotrigine, loperamide, Lorazepam, pethidine, methadone, metoclopramide, morphine, naproxen, oxazepam, Propofol, temazepam, theophylline, phenytoin, ethinylestradiol.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at a temperature of 2 ° to 8 ° C; Do not freeze. Shelf life – 2 year.
Open a bottle can be stored without a refrigerator at a temperature of no higher than 25° c 30 days.
