Реатаз®

General characteristics. Structure:

Active ingredient: 150 mg or 200 mg of an atanazanavir in the form of an atanazanavir of sulfate of 170,8 mg or 227,8 mg.

Excipients: lactoses monohydrate, кросповидон, magnesium stearate, a solid gelatin capsule *, blackened ** for texts on a cover of capsules.

* Structure of a cover of capsules 150, 200 of mg: titanium dioxide, gelatin, water, a varnish aluminum on the basis of indigo carmine (FD&C No. 2).

** Composition of white ink for texts on a cover of capsules - shellac, titanium dioxide, isopropanol, ammonium hydroxide, propylene glycol, N butanol, симетикон. Composition of blue ink for texts on a cover of capsules - shellac, ethanol anhydrous, isopropanol, butanol, propylene glycol, ammonia, a varnish aluminum on the basis of indigo carmine (FD&C No. 2).

Pharmacological properties:

Pharmacodynamics. Atazanavir is azapeptide inhibitor of VICh-1 protease. This substance selectively inhibits virus-specific processing of virus Gag-Pol of proteins in HIV - the infected cells, preventing formation of mature virions and infection of other cells. In the course of treatment at some patients resistance (resistance) to effect of drug (specific resistance) or to action of both an atazanavir, and other inhibitors of HIV protease (cross resistance) can develop.

Resistance and cross resistance. Resistance and cross resistance to inhibitors of HIV protease was observed in various extent of its manifestation. Resistance to an atazanavir is not always an obstacle for consecutive use of other inhibitors of HIV protease.

Resistance of in vitro (in culture of cells). Sensitivity to an atazanavir was studied on culture of the cells allocated at the patients who before were not receiving Reataz®.

The accurate tendency to decrease in sensitivity to an atazanavir of the strains which found the high level of multiple resistance to other inhibitors of HIV protease is revealed. On the contrary, sensitivity to an atazanavir remained at strains, resistant only to 1 - 2 inhibitors of HIV protease.

Resistance of in vivo. Researches showed accurate dependence of development of resistance on whether the patient received earlier anti-retrovirus therapy, whether and if yes, it was applied атазанавир as the only inhibitor of HIV protease or in a combination with ritonaviry.

The patients who were earlier not receiving anti-retrovirus therapy:

Реатаз® 400 mg (without ritonavir). Cross resistance between atazanaviry and amprenaviry is not revealed. The phenotypical analysis of the isolated strains showed development of the stability specific only to an atazanavir and the sensitivity combined with increase to other inhibitors of HIV proteases.

Реатаз® 300 mg / ритонавир 100 mg. The research of efficiency of a combination atazanavir/ritonavir (in comparison with a combination atazanavir/lopinavir/ritonavir) at the patients who were earlier not receiving anti-retrovirus therapy showed that in 96 weeks after the beginning of therapy only in one case of failure of therapy phenotypical resistance to an atazanavir developed.

The patients who were earlier receiving anti-retrovirus therapy:

Реатаз® or Reataz®/ritonavir. In most cases failures of therapy on the 48th week at patients multiple resistance to various inhibitors of HIV protease, but not specific resistance to an atazanavir developed.

Pharmacokinetics. Pharmacokinetic properties of an atazanavir were estimated on healthy volunteers and HIV - the infected patients.

Absorption: at long administration of drug of Reataz® in a dose of 400 mg once a day along with reception of easy food the maximum equilibrium concentration of an atazanavir in plasma is established approximately in 2,7 hours after reception. Steady equilibrium concentration of an atazanavir is reached between the 4th and 8th days of reception.

Influence of food: use of the drug Reataz® together with food improves its bioavailability and reduces pharmacokinetic variability. Use of a combination of Reataz®/ritonavir with food improves bioavailability of an atazanavir.

Distribution: атазанавир for 86% contacts serum proteins, at the same time extent of linkng with proteins does not depend on concentration. In similar degree атазанавир communicates with alfa-1 an acid glycoprotein and albumine. Atazanavir is defined in spinal and seed liquids.

Metabolism: атазанавир it is metabolized generally by means of CYP3A4 isoenzyme with formation of the oxidized metabolites. Metabolites are allocated in bile in a free look or in the form of conjugates with glucuronic acid. An insignificant part of an atazanavir is metabolized by N-dealkylation and hydrolysis.

Removal: After single introduction of a 14C-atazanavir (400 mg), in Calais and urine 79% and 13% of the general radioactivity were defined, respectively. The share of not changed atazanavir in Calais and urine made, respectively, about 20% and 7% of the entered dose. The average elimination half-life of an atazanavir at healthy volunteers and HIV - the infected adults made about 7 hours at reception in a dose of 400 mg a day with easy food.

Patients with a liver failure. Atazanavir is metabolized and brought preferential by a liver. Influence of abnormal liver functions on pharmacokinetic parameters after administration of drug Reataz" in a dose of 300 mg was not studied. Concentration of an atazanavir at joint reception and without ritonavir can increase at patients with a liver failure of average and heavy degree.

Patients with a renal failure. At healthy volunteers removed with urine not changed атазанавир made about 7% of the accepted dose. There are no pharmacokinetic data for the patients with a renal failure accepting the drug Reataz® with ritonaviry.

Use of the drug Reataz® without ritonavir was studied at the patients with a heavy renal failure including who are on a hemodialysis, accepting drug in a dose of 400 mg once a day Results showed decrease in pharmacokinetic parameters by 30-50% at the patients who are on a hemodialysis in comparison with patients with normal function of kidneys. The mechanism of this decrease is unknown.

Age/floor. Clinically significant differences of pharmacokinetic parameters depending on age or a sex of patients are noted.

Pregnant women. Values of the most equilibrium concentration (Cmax) and the area under curve (AUCs) for an atazanavir were 26-40% higher at women in a puerperal period (4-12 weeks), than at HIV-positive not pregnant patients. The minimum concentration of an atazanavir in a puerperal period was approximately twice higher than that which was observed at HIV-positive not pregnant women before.

Children. The size of absorption of an atazanavir at children is higher, than at adult patients. Small children have an insignificant tendency to higher clearance of drug when rationing on body weight. Variability of pharmacokinetic parameters at children is also higher, than at adults.

Race. Researches did not show any influence of race of patients on pharmacokinetic parameters of an atazanavir.

Indications to use:

VICh-1 an infection, in a combination with other anti-retrovirus drugs, at the patients who were earlier receiving or not receiving anti-retrovirus therapy.

Route of administration and doses:

Drug is accepted inside as a part of a combination therapy. The decision on the beginning of therapy is made by the doctor having experience of treatment of HIV infection. Efficiency and safety of use of the drug Reataz® in a combination with ritonaviry in a daily dose more than 100 mg is not studied; use of the doses of a ritonavir exceeding 100 mg a day can change a profile of safety of the drug Reataz® therefore it is not recommended.

Adults. The dosing mode for the patients who were earlier not receiving anti-retrovirus therapy:
- Реатаз® 400 mg once a day during food;

- Реатаз® 300 mg and ритонавир 100 mg once a day during food.

The dosing mode for the patients who were earlier receiving anti-retrovirus therapy:
- Реатаз® 300 mg and ритонавир 100 mg once a day during food.

Use of the drug Reataz® without ritonavir is not recommended for patients with the adverse virologic result of earlier carried out anti-retrovirus therapy.

Children. Drug Reataz® doses for children of 6 years are also more senior are calculated on body weight (see the table below); doses for children should not exceed the doses applied to treatment of adult patients. The Reataz® capsules are appointed to children in a combination with ritonaviry (in the form of capsules or tablets). Both drugs should be accepted at the same time, once a day during food.

Calculation of doses of the drug Reataz® for children on body weight.

Body weight (kg)	Dose of the drug Reataz® (mg)	Dose of a ritonavir (mg)
> 15 <20	150	100
> 20 <40	200	100
> 40	300	100

To children at the age of 13 years with body weight not less than 40 kg, earlier not receiving anti-retrovirus therapy and not transferring ритонавир are also more senior, appoint the drug Reataz® (without ritonavir) in a dose of 400 mg a day during food.

To children at the age of 13 years with body weight not less than 40 kg receiving jointly тенофовир are also more senior, antagonists of H2 receptors or inhibitors of a proton pomp, it is impossible to apply Reataz® without ritonavir.

Patients with a renal failure. Dose adjustment is not required for the patients who are not on a hemodialysis. For the patients on a hemodialysis who were earlier not receiving anti-retrovirus therapy, the drug Реатаз® 300 of mg is appointed only in a combination from ritonaviry 100 mg.

To the patients with a heavy renal failure who are on a hemodialysis and earlier receiving anti-retrovirus therapy, it is not necessary to use the drug Reataz®.

Patients with a liver failure. It is necessary to be careful at purpose of the drug Reataz® without ritonavir to patients with a liver failure of easy or average degree. At a liver failure of average degree (7-8 points / a class B on classification of Chayld-Pyyu), it is recommended to lower a dose to 300 mg once a day.

Реатаз® at any modes of dosing it is not necessary to apply at a liver failure of heavy degree. Use of the drug Reataz® in a combination with ritonaviry at patients with a liver failure was not studied therefore this combination should not be applied at these patients.

Elderly patients. Clinical trials of drug did not include enough patients at the age of 65 years and are more senior. Based on pharmacokinetic data, dose adjustment depending on age is not required.

Combination therapy. Didanozin: диданозин it is necessary to accept on an empty stomach, and Reataz® during meal therefore at a combination therapy it is recommended to accept диданозин in 2 hours after administration of drug of Reataz® with food.

Tenofovir: use of a combination of Реатаз® 300 mg and ритонавир 100 mg together with tenofoviry 300 mg is recommended (all drugs should be accepted during meal once a day). Drug Reataz® use (without ritonavir) together with tenofoviry is not recommended.

Features of use:

Pregnancy and lactation. Реатаз® it has to be applied at pregnancy, only if the potential advantage of use for mother exceeds potential risk for a fruit. During pregnancy it is necessary to apply a drug Reataz® combination in a dose of 300 mg together with 100 mg of a ritonavir of 1 times a day. Dose adjustment usually is not required, however, for the women who were earlier receiving anti-retrovirus therapy in the II and III trimesters of pregnancy if the drug Reataz® is appointed together with tenofoviry or antagonists of H2-histamine receptors, the recommended dose of the drug Reataz® makes 400 mg jointly from 100 mg of a ritonavir once a day. The pregnant women who were earlier receiving anti-retrovirus therapy have not enough data on simultaneous use of the drug Reataz®, tenofovir and antagonists of H2-histamine receptors.

In a puerperal period dose adjustment is not required, however it is necessary to provide careful medical observation of the patient regarding identification of side reactions as increase in concentration of drug within the first two months after the delivery is possible.

Because of risk of development of a heavy hyperbilirubinemia and potential risk of development of jaundice in newborns observation of them during the first days of life is necessary; in the prenatal period it is necessary to provide additional monitoring of a fruit.

Also there are no data on whether gets атазанавир into breast milk. Due to a possibility of transfer of HIV from mother the child with milk, and also in view of risk of development of serious side effects in the child, should not nurse at drug use.

Patients need to be warned that anti-retrovirus therapy does not prevent risk of transfer of HIV through blood or during sexual contacts in this connection it is necessary to observe precautionary measures.

Sugar diabetes / hyperglycemia. Against the background of treatment HIV protease inhibitors at some HIV-positive patients noted a hyperglycemia, emergence of a diabetes mellitus or an aggravation of already available diabetes mellitus. Diabetic ketoacidosis was in certain cases noted. Relationship of cause and effect between therapy by inhibitors of HIV protease and these cases is not established.

Hemophilia. At patients with hemophilia of type A and B against the background of treatment inhibitors of HIV protease noted bleedings, including spontaneous skin hemorrhages and a hemarthrosis. Some of these patients needed introduction of blood-coagulation factors of VIII. In most cases treatment by inhibitors of HIV protease was continued or resumed after a break.

Relationship of cause and effect between therapy by inhibitors of HIV protease and these cases is not established.

Redistribution of a fatty tissue (lipodystrophy). Isolated cases of redistribution of a fatty tissue were celebrated that was shown by obesity on the central type, increase in a fatty tissue in a dorsotservikalny zone ("a buffalo hump"), weight loss of extremities and the person, increase in a breast, "a cushingoid face". Relationship of cause and effect between therapy by inhibitors of HIV protease and these cases is not established.

Immunity recovery syndrome. HIV-positive patients at the beginning of the combined anti-retrovirus therapy can have signs of inflammatory reaction in response to the proceeding asymptomatically or residual opportunistic infections (caused by Mycobacterium avium, a cytomegalovirus, Pneumocystis jiroveci or tuberculosis). Inspection and the corresponding treatment can be required.

The cases of autoimmune diseases (for example, Greyvs's disease) arising at immunity recovery were noted, however time of the beginning of development of such diseases varied at different patients and could come in many months after the beginning of therapy atazanaviry.

Liver failure. Atazanavir is metabolized, mainly, in a liver therefore at patients with a liver failure drug should be used with care because of possible increase in its concentration.

Patients with a viral hepatitis In or With or the superactivity of transaminases noted prior to treatment have a risk of further increase in activity of transaminases.

Hyperbilirubinemia. At the patients receiving Reataz® cases of reversible increase in the indirect (free) bilirubin connected with UDF-glyukuronoziltransferaza's (UGT) inhibition were noted. It is necessary to consider that the increase in activity of transaminases which is noted at the raised bilirubin at the patients receiving Reataz® can be caused by other diseases which are also followed by a hyperbilirubinemia.

There are no long-term data on safety of use for the patients having more than by 5 times the exceeding norm is long the remaining concentration of bilirubin. If jaundice or yellowing of scleras represent a cosmetic problem for the patient, it is possible to consider the possibility of purpose of anti-retrovirus therapy alternative to the drug Reataz®. The dose decline of the drug Reataz® is not recommended in view of lack of data on efficiency of reduced doses.

Lengthening of P-Q and P-R of an interval. Atazanavir can extend P-Q and P-R an interval at some patients. It is necessary to be careful at use of drug for patients with disturbances of cordial conductivity. It is necessary to be careful at combined use of the drug Reataz® with the drugs extending P-Q and P-R an interval (for example, атенолол, diltiazem, verapamil).

Lengthening of Q-T of an interval. Cases of lengthening of Q-T of an interval at some patients were noted. It is necessary to be careful at use of drug for patients with disturbances of cordial conductivity. It is necessary to be careful at combined use of the drug Reataz® with the drugs extending Q-T an interval (for example, кларитромицин, салметерол).

Rash. Makulopapulezny rash, usually from easy to average degree, can be observed within the first 3 weeks from the beginning of therapy by the drug Reataz®. At most of patients rash disappears within 2 weeks at therapy continuation. Use of drug has to be stopped at development of heavy degree of rash. Also Stephens-Johnson's syndrome, a multiformny erythema and toxic skin reaction (DRESS) can be noted., including medicinal rash, an eosinophilia and system symptoms.

Nephrolithiasis and cholelithiasis. During the post-market researches on safety of use of the drug Reataz® for HIV-positive patients cases of a nephrolithiasis and/or a cholelithiasis were noted. Some patients needed hospitalization for performing necessary therapy, at some patients complications were observed. In the presence of symptoms of a nephrolithiasis and/or a cholelithiasis it is necessary to interrupt temporarily therapy or to completely stop administration of drug.

Concomitant use of glucocorticosteroids. In need of reception of glucocorticosteroids administration of drugs, CYP3A4 (beclomethasone) which are not substrates of an isoenzyme is recommended.

Concomitant use of not Virapinum, efavirenz, vorikonazol. Not Virapinum, being CYP3A4 isoenzyme inductor, reduces action of an atazanavir. Besides, because of increase in concentration of not Virapinum its toxicity therefore this combination is not recommended increases.

The combination therapy the drugs Reataz® and эфавиренз leads to reduction of effect of the drug Reataz® therefore it should be avoided. If use of this combination is absolutely necessary, it is allowed to apply it only at the patients who were earlier not receiving anti-retrovirus therapy. At the same time Реатаз® 400 mg and ритонавир appoint 100 mg in the form of a single dose during food, and эфавиренз - on an empty stomach, before going to bed. Combined use of a vorikonazol (200 mg 2 times a day) with a combination of Reataz®/ritonavir at patients with at least one functional allele of an isoenzyme of CYP2C19 led to decrease in concentration of a vorikonazol and atazanavir in a blood plasma. Combined use of a vorikonazol (200 mg 2 times a day) with a combination of Reataz®/ritonavir at patients without functional allele of an isoenzyme of CYP2C19 led to increase in concentration of a vorikonazol and decrease in concentration of an atazanavir in a blood plasma. Combined use of a vorikonazol and combination of Reataz®/ritonavir is recommended only when the potential advantage of use of a vorikonazol exceeds risk. At use of such combination therapy it is necessary to carry out careful monitoring of side effects of a vorikonazol, and also efficiency of a vorikonazol and an atazanavir who can decrease.

The lowered acidity of a gastric juice (increase in PH value of a gastric juice). Concentration of an atazanavir can decrease at increase in PH value of a gastric juice, irrespective of the reasons which caused this increase.

Osteonecrosis. In rare instances at use of the combined anti-retrovirus therapy during a long span osteonecrosis cases, especially at patients with risk factors (high body weight, alcohol intake, the accompanying use of corticosteroids) were noted, At emergence in the patient of morbidity in joints or difficulties at the movement it is necessary to consider a possibility of development of an osteonecrosis.

Children. There are no recommendations about the drug dosing mode Reataz at children 6 years are younger. The drug Reataz® also children should not appoint younger than 3 months. The profile of safety of the drug Reataz® at children of 6 years is also more senior is comparable to that at adult patients.

Influence on ability to manage vehicles and mechanisms. Special researches on studying of influence of the drug Reataz® on ability to manage vehicles and to work with mechanisms were not conducted. Cases of dizziness were noted during treatment by the drug Reataz®.

Side effects:

Adults. The most frequent side reactions of any severity noted at use of the drug Reataz® and one or several nukleozidny, nucleotide and nenukleozidny inhibitors of the return transcriptase (more than 10%, are "very frequent") were: nausea (20%), jaundice (13%) and diarrhea (10%).

Jaundice was noted several days later or months after an initiation of treatment and at less, than led 1% of patients to drug withdrawal. The lipodystrophy of average or heavy degree noted at administration of drug of Reataz® and one or more nukleozidny, nucleotide and nenukleozidny inhibitors of the return transcriptase, and, perhaps, connected with treatment was noted at 5% of patients.

Side reactions of the moderated or expressed degree according to the standard classification are included below: "very often" (> 1/10), is "frequent" (> 1/100, <1/10), "infrequently" (> 1/1000, <1/100), is "rare" (> 1/10000, <1/1000) and is "very rare" (<1/10000).

From an immune sistemy:nechasto - allergic reactions.

From the central nervous system: often - a headache, infrequently - peripheral neuropathy, dizziness, memory loss, drowsiness, concern, a depression, sleep disorders, change of character of dreams, sleeplessness, orientation disturbance.

From digestive tract: often - an abdominal pain, diarrhea, dyspepsia, nausea, vomiting; infrequently - dryness in a mouth, a food faddism, a meteorism, gastritis, pancreatitis, aphthous stomatitis, abdominal distention.

From skin and hypodermic cellulose: often - rash; infrequently - baldness, an itch, urticaria; seldom - a vazodilatation, vezikulobullezny rash, eczema, post-marketing data (frequency is not established) - a Quincke's disease, Stephens-Johnson's syndrome, a multiformny erythema, toxic skin reaction (DRESS) including medicinal rash, an eosinophilia and system symptoms.

From a musculoskeletal system and connecting fabrics: infrequently - an arthralgia, a muscular atrophy, a mialgiya; seldom - a myopathy.

From an urinary system: infrequently - a hamaturia, the speeded-up urination, a proteinuria, a nephrolithiasis; seldom - pains in kidneys, post-marketing data (frequency is not established) - intersticial nephrite.

From sense bodys: often - yellowness of scleras.

From a metabolism: infrequently - anorexia, the increased appetite, decrease in body weight, increase in body weight, post-marketing data (frequency is not established) - a hyperglycemia, a diabetes mellitus.

From reproductive system: infrequently - a gynecomastia.

From cardiovascular system: infrequently - increase in arterial pressure, a syncope, is rare - hypostases, tachycardia.

Post-marketing data (frequency is not established) - atrioventricular (AY) blockade of the second and third degree, lengthening of an interval of QTc, cardiac arrhythmias like "torsades des pointes".

From respiratory system: infrequently - an asthma.

From a liver and biliary tract: often - jaundice; infrequently - hepatitis; seldom - a gepatosplenomegaliya, post-marketing data (frequency is not established) - a cholelithiasis, cholecystitis, a cholestasia.

Disorders of the general character: often - the general weakness, fatigue; infrequently - stethalgias, fever, an indisposition, gait disturbance.

Patients have separate cases of bleedings, spontaneous skin reactions and a hemarthrosis with hemophilia of type A and B at use of inhibitors of protease, redistribution of a fatty tissue (lipodystrophy).

Most often (more than 10%, are "very frequent") the following deviations of laboratory indicators at the patients receiving treatment which part were Reataz® and one or more nukleozidny, nucleotide and nenukleozidny inhibitors of the return transcriptase were noted: increase in the general bilirubin (87%), especially indirect (untied) bilirubin in blood serum.

Other significant deviations of laboratory parameters were noted at> 2% of patients ("often"): increase in activity of a kreatinfosfokinaza (7%), increase in activity of alaninaminotranspherase (5%), decrease in amount of neutrophilic leukocytes (5%), increase in activity of aspartate aminotransferase (3%), increase in activity of a lipase (3%). Cancellation of treatment in view of development of side effects was required from 5% of the patients who both were receiving, and not receiving anti-retrovirus therapy.

Children. The profile of safety of the drug Reataz® at children of 6 years is also more senior is comparable to that at adult patients. The most frequent side effects are cough, fervescence, jaundice, yellowing of scleras, rash, vomiting, diarrhea, a headache, peripheral hypostases, extremity pains, a nose congestion, morbidity when swallowing, an asthma, liquid allocations from a nose. Symptomless atrioventricular (AV) blockade of the 2nd degree was in rare instances noted.

The most frequent (more than 10%, are "very frequent") deviations of laboratory indicators of the 3rd and 4th degree at children were: increase in the general bilirubin (> 3,2 mg/dl; 58%), neutropenia (9%) and hypoglycemia (4%). Other deviations of laboratory indicators 3-4 degrees were observed with a frequency less than 3%.

Interaction with other medicines:

Atazanavir is metabolized in a liver with participation of system of P450 cytochrome; it is also inhibitor of an isoenzyme CYP3A4 entering this system.

Combined use of the drug Reataz® and other drugs with the same ways of metabolism, (blockers of "slow" calcium channels, some inhibitors 3-гидрокси-3-метилглутарил-коэнзим-А-редуктазы (GMG-KOA-reduktazy), immunodepressants, phosphodiesterase inhibitors) can lead to increase in concentration of one of them in plasma that can lead to strengthening of expressiveness or prolongation of its therapeutic and side effects.

Combined use of the drug Reataz® and the drugs inducing an isoenzyme of CYP3A4 (rifampicin) can lead to considerable falling of concentration of an atazanavir in plasma and to decrease thereof its therapeutic activity. Combined use of the drug Reataz® and the drugs inhibiting CYP3A4 isoenzyme can lead to increase in concentration of an atazanavir in plasma.

Expressiveness CYP3A4 isoenzyme - the mediated interactions of an atazanavir with other drugs (change of effect of an atazanavir or change of effect of other drug) can change at administration of drug of Reataz® with ritonaviry, powerful inhibitor of an isoenzyme CYP3A4.

For completeness of information on interactions of medicines with ritonaviry it is necessary to study the application instruction of a ritonavir.

Drugs which should not be applied together with the drug Reataz®:

Quinidine: use together with a combination of Reataz®/ritonavir is contraindicated in connection with risk of serious and life-threatening arrhythmias.

Rifampicin: at combined use of an atazanavir with rifampicin concentration of an atazanavir in a blood plasma considerably decreases that leads to decrease in a therapeutic effectiveness and development of resistance to the drug Reataz®. Simultaneous use of an atazanavir and rifampicin contraindicated.

Irinotekan: атазанавир inhibits UDF-glyukuronoziltransferaza (UGT) and can exert impact on metabolism of an irinotekan, causing increase in its toxicity therefore combined use of an atazanavir with irinotekany is contraindicated.

Bepridil: in connection with high risk of development of life-threatening side effects combined use with the drug Reataz® is contraindicated.

Ergotamine derivatives (dihydroergotamine, ergotamine, ergometrine, methylergometrine): in connection with high risk of development of life-threatening side effects combined use with the drug Reataz® is contraindicated. Manifestations of acute toxicity of derivatives of ergotamine: peripheral vasospasm, ischemia of extremities and other zones.

Tsizaprid: in connection with high risk of development of life-threatening side effects (arrhythmia) combined use with the drug Reataz® is contraindicated.

Lovastatin, симвастатин: the increased risk of development of a myopathy, including рабдомиолиз.

Inhalation beta2-adrenomimetik (салметерол): the increased risk of development of side effects from cardiovascular system, inherent a salmeterola, including lengthening of an interval of Q-T, a heart consciousness, sinus tachycardia. Combined use of a salmeterol and the drug Reataz® is not recommended.

Pimozidum: in connection with high risk of development of life-threatening side effects (arrhythmia) combined use with the drug Reataz® is contraindicated.

Indinavir: the combined use with the drug Reataz® is not recommended as both drugs can cause a hyperbilirubinemia.

Midazolam, to triazoles: combined use with the drug Reataz® is contraindicated in connection with a possibility of increase in concentration of midazolam / триазолама and high risk of extension of sedation and respiratory depression.

Warfarin: at combined use with the drug Reataz® the risk of development of heavy, life-threatening bleedings therefore this combination is not recommended increases.

Drugs of a St. John's Wort of made a hole (Hypericum perforatum): the combination with the drug Reataz® is contraindicated as concentration of an atazanavir in plasma can decrease, leading to loss of therapeutic action and development of resistance.

Astemizol: at combined use with a combination the drug Reataz®/ritonavir raises risk of development of heavy, life-threatening side effects therefore this combination is not recommended.

Terfenadin: at combined use with a combination the drug Reataz®/ritonavir raises risk of development of heavy, life-threatening side effects therefore this combination is not recommended.

Alfuzozin: in view of potentially possible increase in concentration of an alfuzozin which can lead to development of hypotension, combined use with a combination the drug Reataz®/ritonavir is not recommended.

For the drugs given below change of the mode of dosing in connection with the expected interactions can be required.

Anti-retrovirus means for treatment of HIV. Nukleozidny inhibitors of the return transcriptase: Didanozin: use of the capsules of a didanozin covered with a kishechnorastvorimy cover together with the drug Reataz® or with the drugs Reataz® and/or ритонавир and food reduces bioavailability of a didanozin. Didanozin it is necessary to accept in 2 hours after administration of drug of Reataz®.

Nucleotide inhibitors of the return transcriptase: Tenofovir: тенофовир reduces activity of an atazanavir at simultaneous use, атазанавир increases concentration of a tenofovir in a blood plasma. High concentration of a tenofovir can strengthen the side effects connected with reception of a tenofovir including action on function of kidneys therefore it is necessary to carry out monitoring of side effects of a tenofovir at patients.

Nenukleozidny inhibitors of the return transcriptase: Efavirenz: the combination therapy the drugs Reataz® and эфавиренз leads to reduction of effect of the drug Reataz® therefore it should be avoided. If use of this combination is absolutely necessary, it is allowed to apply it only at the patients who were earlier not receiving anti-retrovirus therapy. At the same time Реатаз® 400 mg and ритонавир appoint 100 mg in the form of a single dose during food, and эфавиренз - on an empty stomach, before going to bed.

Not Virapinum: not Virapinum, being CYP3A4 isoenzyme inductor, reduces action of an atazanavir. Besides, because of increase in concentration of not Virapinum its toxicity therefore this combination is not recommended increases.

Protease inhibitors: Botseprevir: at combined use of the drug Реатаз® 300 of mg / ритонавир 100 mg once a day with botsepreviry in a dose of 800 mg three times a day concentration of an atazanavir in blood decreases while concentration of a botseprevir significantly does not change.

Sakvinavir (soft gelatin capsules): the effect of a sakvinavir increases at joint reception with the drug Reataz®. The data allowing to make the corresponding recommendations about dosing of this combination no.

Ritonavir: at combined use with the drug Reataz® concentration of an atazanavir increases.

Other inhibitors of HIV protease: simultaneous use of a combination of Reataz®/ritonavir with other inhibitors of HIV protease is not recommended.

Other drugs. Antacids and buffer drugs: at combined use with antiacid and buffer drugs concentration of an atazanavir in a blood plasma decreases. Реатаз® it is necessary to apply in 2 hours prior to or in 1 hour after reception of such drugs.

Antiarrhytmic drugs: Amiodaronum, lidocaine (at parenteral administration), quinidine: at simultaneous use with the drug Reataz® increase in their concentration is possible. Reception in such combinations demands the increased care, it is recommended to watch concentration of these drugs in plasma. The combination of Reataz®/ritonavir is contraindicated for combined use with quinidine because of possibility of serious or life-threatening reactions (arrhythmia).

Beta adrenoblockers: Atenolol: at simultaneous use of the drug Reataz® with beta adrenoblockers of clinically significant pharmacokinetic interactions it is not expected therefore correction of the mode of dosing is not required.

Blockers of "slow" calcium channels: Diltiazem: combined use with the drug Reataz® leads to strengthening of effect of diltiazem and its metabolite - a dezatsetildiltiazema. The diltiazem dose decline for 50% and control of an ECG is recommended.

Other blockers of "slow" calcium channels, such, as фелодипин, nifedipine, никардипин and verapamil: it is necessary to be careful at combined use, titration of a dose of blockers of "slow" calcium channels, control of an ECG is necessary.

Antagonists of receptors of endothelin (бозентан): бозентан it is metabolized by means of CYP3A4 isoenzyme, being its inductor. Concentration of an atazanavir in plasma can decrease at simultaneous use of the drug Reataz® with bozentany, but without ritonavir. In this regard the combination of Reataz®/bozentan can be applied only with ritonaviry. The dosing modes are included below:
- Purpose of a bozentan to the patients accepting Reataz®/ritonavir within not less than 10 days: бозентан in a dose of 62,5 mg of 1 times a day or every other day (depending on individual portability).

- Purpose of a combination of Reataz®/ritonavir to the patients accepting бозентан: to stop reception of a bozentan not less than in 36 hours prior to reception of a combination of Reataz®/ritonavir. Not earlier than after 10 days after the beginning of reception of a combination of Reataz®/ritonavir to resume reception of a bozentan in a dose of 62,5 mg of 1 times a day or every other day (depending on individual portability).

GMG-KOA-reduktazy inhibitors: Atorvastatin: at combined use with the drug Reataz® action of an atorvastatin can amplify. The risk of a myopathy, including рабдомиолиз, can increase. It is necessary to be careful. It is necessary to apply the smallest effective doses of an atorvastatin in combinations with the drug Reataz® or Реатаз®/ритонавир.

Rozuvastatin: the dose of a rozuvastatin at combined use with atazanaviry should not exceed 10 mg/day. At simultaneous use of a rozuvastatin and atazanavir the risk of development of a myopathy, including рабдомиолиз increases.

Pravastatiya, флувастатин: potential of interactions in combinations with the drug Reataz® or Реатаз®/ритонавир is unknown.

Inhibitors of a proton pomp: during treatment the drug Reataz® inhibitors of a proton pomp are appointed only if their use is extremely shown.

At combined use of the drug Реатаз® 400 of mg or a combination of Реатаз® 300 mg / ритонавир 100 mg from omeprazoly 40 mg (all drugs once a day) concentration of an atazanavir in a blood plasma considerably decreased that can lead to decrease in therapeutic activity of drug and to resistance development.

To patients with HIV in the absence of the possible or revealed decrease in sensitivity are recommended to apply a combination of Реатаз® 400 mg to an atazanavir / ритонавир 100 mg with omeprazoly in the maximum dose of 20 mg once a day (or other drug from group of inhibitors of a proton pomp in an equivalent dose).

It is not recommended to apply омепразол in a dose more than 20 mg a day (or other drug from group of inhibitors of a proton pomp in an equivalent dose).

Blockers of H2-histamine receptors: concentration of an atazanavir in a blood plasma considerably decreased at combined use of the drug Реатаз® 400 of mg with famotidine of 40 mg twice a day once a day that can lead to decrease in therapeutic activity of drug or to resistance development.

At treatment of the patients who were earlier not receiving therapy, Реатаз® 400 mg can be applied with food in 2 hours prior to and not less than in 10 hours after use of blockers of H2-histamine receptors once a day. However the single dose of blockers of H2-histamine of receptors should not exceed the dose corresponding to a dose of famotidine of 20 mg, and their general daily dose should not exceed the dose corresponding to 40 mg of famotidine.

Alternatively, Реатаз® 300 mg from ritonaviry 100 mg can be applied during food, in 2 hours prior to and not less than in 10 hours after use of blockers of H2-histamine receptors in a single dose, comparable from 40 mg of famotidine once a day.

At treatment of the patients who were earlier receiving therapy, the daily dose of blockers of H2-histamine of receptors should not exceed the dose corresponding to 40 mg of famotidine. Such patients have Реатаз® 300 mg / ритонавир it is necessary to apply 100 mg with food in 2 hours prior to and not less than in 12 hours after use of blockers of N2-of histamine receptors (once a day) in the dose corresponding to 40 mg of famotidine once a day. Alternatively, Реатаз® 300 mg / ритонавир 100 mg can be applied during food along with blockers of H2-histamine receptors, in 2 hours prior to and not less than in 10 hours after use of blockers of H2-histamine receptors in the dose which is not exceeding a dose which corresponds to 20 mg of famotidine once a day. This dose can be accepted one or twice a day. At appointment such patients of a combination of Reataz®/ritonavir and тенофовир with a blocker of H2-histamine of receptors should apply the following mode of dosing: Реатаз® 400 mg and ритонавир 100 mg once a day.

Immunodepressants (cyclosporine, такролимус, сиролимус): at combined use of cyclosporine, a takrolimus, sirolimus and the drug Reataz® increase in blood of concentration of immunodepressants therefore monitoring of their concentration is recommended is possible.

Antidepressants: Tricyclic antidepressants: at combined use of drug Reataz with tricyclic antidepressants emergence of the serious and/or life-threatening side reactions connected with antidepressants is possible. It is recommended to control concentration of these drugs at combined use with the drug Reataz®.

Trazodonum: at combined use of Trazodonum with the drug Reataz® or with a combination of Reataz®/ritonavir increase in concentration of Trazodonum in a blood plasma is possible. At combined use of Trazodonum and ritonavir it was reported about developing of nausea, dizziness, a lowering of arterial pressure and a short-term loss of consciousness. At combined use of Trazodonum with CYP3A4 isoenzyme inhibitors, such as Reataz®, it is necessary to apply smaller doses of Trazodonum.

Benzodiazepines: Midazolam is metabolized by CYP3A4 isoenzyme. In spite of the fact that researches were not conducted, at combined use of the drug Reataz® and midazolam it is possible to expect significant increase in concentration of the last. At the same time increase in concentration of midazolam at oral administration will be much higher, than at parenteral administration. Use of the drug Reataz® together with midazolam for intake, contraindicated. Data on simultaneous use of the drug Reataz® with midazolam in the form of injections are absent; on the basis of data on simultaneous use of other inhibitors of HIV protease with midazolam it is possible to assume possible increase in concentration of midazolam in plasma by 3-4 times. At combined use of the drug Reataz® with injection midazolam it is necessary to be careful, control respiratory function and duration of sedation. Correction of the mode of dosing is in certain cases necessary.

Antiepileptic drugs: Carbamazepine: at co-administration of carbamazepine and the drug Reataz® without ritonavir concentration of an atazanavir in a blood plasma can decrease. In this regard co-administration of carbamazepine and the drug Reataz® without ritonavir is not recommended. As ритонавир can increase concentration of carbamazepine in a blood plasma, at the patients accepting carbamazepine and beginning treatment with the drug Reataz® and ritonaviry the carbamazepine dose decline can be required.

Phenytoinum, phenobarbital: at co-administration of Phenytoinum or phenobarbital and the drug Reataz® without ritonavir concentration of an atazanavir in a blood plasma can decrease. In this regard co-administration of Phenytoinum or phenobarbital and the drug Reataz® without ritonavir is not recommended. As ритонавир can reduce concentration of Phenytoinum and phenobarbital in a blood plasma, at the patients accepting Phenytoinum or phenobarbital together with the drug Reataz® and ritonaviry dose adjustment of Phenytoinum or phenobarbital can be required.

Lamotridzhin: at combined use of a lamotridzhin and the drug Reataz® with ritonaviry concentration of a lamotridzhin in a blood plasma can decrease. In this regard dose adjustment of a lamotridzhin can be required. At combined use of a lamotridzhin and the drug Reataz® without ritonavir decrease in concentration of a lamotridzhin in a blood plasma is noted therefore dose adjustment of a lamotridzhin is not required.

Makrolidny antibiotics: Klaritromitsin: at combined use of a klaritromitsin with the drug Reataz® concentration of a klaritromitsin increases that can cause lengthening of a QT interval therefore the dose of an antibiotic has to be lowered by 50%.

Oral contraceptives: Ethinylestradiol and Norethisteronum or норгестимат: at combined use with the drug Reataz® of concentration of ethinylestradiol and Norethisteronum increase. Combined use of a combination of Reataz®/ritonavir with ethinylestradiol and norgestimaty reduces average concentration of ethinylestradiol and increases average concentration of a 17-deatsetilnorgestimat, active metabolite of a norgestimat.

In case of combined use of oral contraceptives and a combination of Reataz®/ritonavir it is recommended to apply contraceptives with the content of ethinylestradiol not less than 30 mkg. If together with contraceptives Reataz® without ritonavir is used, the content of ethinylestradiol in oral contraceptives should not exceed 30 mkg. At combined use of the drug Reataz® and oral contraceptives it is necessary to be careful as the effect of increase in concentration of progestogens is unknown; the risk of development of an acne, a dislipidemiya and resistance to insulin can increase. At increase in concentration of Norethisteronum decrease in concentration of LPVP or increase in resistance to insulin, especially at women with the accompanying diabetes mellitus is possible.

It is recommended to apply the smallest effective doses of each component of an oral contraceptive, it is reasonable to use other reliable methods of contraception also. Combined use of the drug Reataz® or a combination of Reataz®/ritonavir with other forms of hormonal contraceptives (contraceptive plasters, contraceptive vulval rings, injection contraceptives) or with the oral contraceptives containing the progestogens other than Norethisteronum or a norgestimat and also with the drugs containing less than 25 mkg of ethinylestradiol was not studied therefore these methods of contraception should not be applied in combination with the drug Reataz®.

Drugs for treatment of gout (colchicine): colchicine is CYP3A4 isoenzyme substrate, its effect can amplify at its use along with the drug Reataz®.

The recommended colchicine doses at use along with the drug Reataz® are given below. Bad attack of gout: 0,6 mg - the 1st reception, then 0,3 mg in an hour after the first reception. Repeated use of this scheme is possible not earlier than through the 3rd days.

Prevention of bad attacks of gout:
- if the usual mode of dosing made 0,6 mg 2 times a day, it is necessary to lower a dose to 0,3 mg 2 times a day;

- if the usual mode of dosing made 0,6 mg once a day, it is necessary to lower a dose to 0,3 mg every other day.

Family Mediterranean fever: the maximum daily dose of colchicine makes 0,6 mg. It is possible to divide this dose into 2 receptions - on 0,3 mg 2 times a day.

Protivomikobakterialny drugs: Rifabutin: activity of a rifabutin at combined use with the drug Reataz® increases. At a concomitant use of these drugs the dose decline of a rifabutin to 75% of a usual dose is recommended: 150 mg every other day or three times a week. Careful monitoring of side reactions at the patients accepting рифабутин and Reataz® or a combination of Reataz®/ritonavir is necessary; further dose adjustment of a rifabutin can be required.

Inhibitors of phosphodiesterase-5 (FDE-5): Use at erectile dysfunction. Sildenafil, tadalafit, vardenafit: at combined use of inhibitors of HIV protease with phosphodiesterase-5 inhibitors perhaps significant increase in concentration of inhibitors of phosphodiesterase-5 and strengthening of their side effects. Are recommended reduction of doses: sildenafit - 25 mg not more often than each 48 hours at use with ritonaviry or without it; tadalafit - 10 mg not more often than each 72 hours at use with ritonaviry or without it; vardenafit - 2,5 mg not more often than each 72 hours at use from ritonaviry and 2,5 mg not more often than each 24 hours at use without ritonavir; monitoring of side reactions is necessary.

Use at pulmonary hypertensia. Sildenafil: use together with the drug Reataz® at pulmonary hypertensia is contraindicated.

Tadalafil:
- for the patients accepting the drug Reataz® within not less than seven days: tadalafit appoint in a dose 20 mg of 1 times a day. The dose can be raised to 40 mg of 1 times a day (depending on individual portability);

- for the patients accepting tadalafit: to stop reception of a tadalafil not less than in 24 hours prior to administration of drug of Reataz®. Not earlier than in seven days after the beginning of administration of drug of Reataz® to resume reception of a tadalafil in a dose of 20 mg of 1 times a day. The dose can be raised to 40 mg of 1 times a day (depending on individual portability);

Antifungal drugs: Ketokonazol, итраконазол: only combined use of a ketokonazol with the drug Reataz® without ritonavir was studied; concentration of an atazanavir when using this combination slightly increase.

Ketokonazol and итраконазол can increase concentration of an atazanavir and a ritonavir in a blood plasma. It is necessary to be careful at use of a ketokonazol and itrakonazol in daily doses higher than 200 mg together with a combination of Reataz®/ritonavir.

Vorikonazol: combined use of a vorikonazol (200 mg 2 times a day) with a combination of Reataz®/ritonavir at patients with at least one functional allele of an isoenzyme of CYP2C19 led to decrease in concentration of a vorikonazol and atazanavir in a blood plasma. Combined use of a vorikonazol (200 mg 2 times a day) with a combination of Reataz®/ritonavir at patients without functional allele of an isoenzyme of CYP2C19 led to increase in concentration of a vorikonazol and decrease in concentration of an atazanavir in a blood plasma.

Combined use of a vorikonazol and combination of Reataz®/ritonavir is recommended only when the potential advantage of use of a vorikonazol exceeds risk. At use of such combination therapy it is necessary to carry out careful monitoring of side effects of a vorikonazol, and also efficiency of a vorikonazol and an atazanavir who can decrease.

Anticoagulants: Warfarin: because of strengthening of activity of warfarin simultaneous use with the drug Reataz® can cause heavy and/or life-threatening bleeding. It is recommended to control the international normalized relation (INR).

Inhalation / nasal glucocorticosteroids (interaction with ritonaviry): at combined use of a ritonavir from a flutikazon propionate by healthy volunteers concentration of cortisol considerably decreased due to substantial increase of concentration of a flutikazon in plasma. Combined use of a combination of Reataz®/ritonavir from a flutikazon propionate can result in similar effect.

At combined use of a ritonavir and inhalation (or intranasal) drugs of a flutikazon of propionate development of system side effects of glucocorticosteroids (an Icenco-Cushing syndrome, oppression of bark of adrenal glands) was noted. Similar effects are possible also at combined use with other glucocorticosteroids, CYP3A4 which are metabolized an isoenzyme, for example, with budesonidy. In this regard use of a combination of Reataz®/ritonavir together with a flutikazon the propionate or other glucocorticosteroids which are metabolized CYP3A4 isoenzyme is justified only if the potential advantage of therapy exceeds risk of system effects of glucocorticosteroids. At combined use of the drug Reataz® (without ritonavir) and a flutikazona of propionate concentration of the last in a blood plasma can increase. It is necessary to be careful and, whenever possible, to use the drugs which are not containing a flutikazon propionate, especially at prolonged use.

Substrates of other isoenzymes of P450 (CYP) cytochrome: Clinically essential interactions between atazanaviry and substrates of isoenzymes CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2 or CYP2E1 are not expected. Atazanavir - weak inhibitor of an isoenzyme CYP2C8. It is necessary to be careful when sharing drug Reataz® (without ritonavir) and the drugs which to a large extent are depending on an isoenzyme of CYP2C8 and having a narrow therapeutic profile (for example, paklitakset, репаглинид). When using a combination of Reataz®/ritonavir together with substrates of an isoenzyme CYP2C8 of clinically significant interactions it is not expected.

Narcotic analgetics: Buprenorphine: in connection with inhibition of isoenzymes of CYP3A4 and UGT1A1 at combined use of the drug Reataz® or a combination of Reataz®/ritonavir and buprenorphine of concentration of buprenorphine and a norbuprenorfin raised. At use of a combination of Reataz®/ritonavir with buprenorphine of essential change of concentration of an atazanavir in plasma it is not revealed; use of the same combination, but without ritonavir, can lead to considerable decrease in concentration of an atazanavir in plasma. At simultaneous use of a combination of Reataz®/ritonavir and buprenorphine careful monitoring of a condition of the patient (assessment of sedative action and cognitive functions) is necessary. The buprenorphine dose decline can be required.

For the drugs given below clinically significant interactions are not expected in this connection dose adjustment of drugs is not required: Lamivudin + zidovudine: at combined use with the drug Reataz® in a dose of 400 mg of significant changes of concentration of a lamivudin and a zidovudine it was not observed. Also significant change of pharmacokinetic parameters of nukleozidny inhibitors of the return transcriptase under the influence of a ritonavir is not expected, Considering these data, significant change of concentration of a lamivudin and a zidovudine at combined use with a combination the drug Reataz®/ritonavir is not expected.

Abakavir. At combined use with a combination the drug Reataz®/ritonavir is not expected significant change of concentration of an abakavir.

Raltegravir. At combined use with a combination the drug Reataz®/ritonavir increase in values of the area under curve (AUCs) for a raltegravir for 41%, the maximum equilibrium concentration of a raltegravir (Cmax) for 24%, equilibrium concentration of a raltegravir in 12 h (From 12 h) for 77% was observed. Dose adjustment of a raltegravir is not required.

Flukonazol. At combined use with a combination the drug Reataz®/ritonavir of significant changes of concentration of an atazanavir and flukonazol it was not observed. Dose adjustment is not required.

Contraindications:

- Hypersensitivity to an atazanavir or any other component of drug;

- A liver failure of heavy degree (9 and more points/classes With on classification of Chayld-Pyyu) at any modes of dosing;

- A combination of Reataz®/ritonavir at patients with a liver failure of average and heavy degree;

- Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption;

- Реатаз® in a combination with astemizoly, terfenadiny, tsizapridy, Pimozidum, bepridily, quinidine (including for the drug Reataz® together with ritonaviry), triazolamy, midazolam (for intake), ergotamine derivatives (especially ergotamine, dihydroergotamine, ergometrine, methylergometrine), drugs of the St. John's Wort which is made a hole GMG-KOA-reduktazy inhibitors (simvastatiny, lovastatiny), indinaviry, irinotekany, rifampicin, alfuzoziny, sildenafily (at its appointment for treatment of pulmonary arterial hypertension), salmeteroly;

- Children's age up to 6 years.

With care: a diabetes mellitus, a hyperglycemia, a dislipidemiya, a hyperbilirubinemia, a nephrolithiasis, a viral hepatitis, chronic active hepatitis, a liver failure of easy and average degree (for an atazanavir), a liver failure of easy degree (for a combination atazanavir/ritonavir), hemophilia And yes In, a syndrome of inborn lengthening of an interval of PR and P-Q, combined use of drug with the drugs extending PR and P-Q an interval (for example, атенолол, diltiazem, verapamil), a syndrome of inborn lengthening of an interval of Q-T, the lowered acidity of a gastric juice (increase in PH value of a gastric juice), combined use with not Virapinum, efavirenzy, glucocorticosteroids, vorikonazoly.

Overdose:

During clinical tests reception by healthy volunteers of doses of drug to 1200 mg once was not followed by any undesirable phenomena. The only case of overdose of drug by the HIV-positive patient who accepted 29.2 g of drug (the dose by 73 times exceeding the recommended dose of 400 mg) was followed by asymptomatic blockade of both legs of a ventriculonector and lengthening of an interval of PR. These signs according to an ECG disappeared spontaneously. The expected symptoms of overdose of drug are jaundice without changes of results of hepatic tests (because of increase in concentration of an indirect bilirubin) and disturbance of a cordial rhythm (lengthening of an interval of PR).

There is no specific antidote. At overdose of the drug Reataz® it is necessary to exercise control of the main physiological indicators, to observe the general condition of the patient, to control an ECG, to appoint a gastric lavage, to cause vomiting for removal of the remains of drug; reception of absorbent carbon is recommended.

Dialysis is inefficient for removal of drug from an organism as it атазанавир is characterized by intensive metabolism in a liver and high extent of linkng with proteins.

Storage conditions:

To store at a temperature from 15 to 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to accept drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules of 150 mg, 200 mg. Packaging: on 6 capsules in the A1/A1 blister. On 10 blisters together with the application instruction in a pack cardboard.