Indinavir sulfate
When ATH:
J05AE02
HIV protease inhibitor. White or almost white hygroscopic crystalline powder. It is soluble in water and methanol.
Pharmacological action.
Antiviral, inhibiting HIV protease.
Application.
According to Physicians Desk Reference (2003), indinavir sulfate in combination with antiretroviral agents is indicated for the treatment of HIV infection.
Hypersensitivity; should not be administered concurrently with terfenadine, cizapridom, astemizolom, triazolamom, midazolam or preparations based on extracts of ergot (indinavir inhibition of CYP3A4 may lead to increased concentrations of these drugs in the blood, which can cause serious or life-threatening reactions).
Pregnancy, lactation, childhood (safety and effectiveness in children have not identified).
When pregnancy is possible, only if the effect of therapy outweighs the potential risk to the fetus (adequate and well-controlled studies in pregnant women have not performed).
Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)
The ability of indinavir excreted in the milk of nursing women is not defined. In experimental studies have shown, indinavir that passes into breast milk in lactating rats. At the time of treatment should stop breastfeeding (due to the possibility of serious adverse effects in infants, breastfed).
Unknown, usilivaet you indinavir, his mother received in the perinatal period, physiological hyperbilirubinemia in neonates.
Side effects, associated with indinavir sulfate and observe more than 2% patients (on a double-blind, multicenter, randomized, the finished testing, проведенного в Бразилии — Study 028), are presented in Table 1.
No clinically significant side effects of moderate or severe severity, occurs in ≥2% of patients (Study 028)
| Body systems / Side Effects | Incidence, % | ||
Indinavira culьfat (n=332) | Indinavir sulfate + zidovudine (n=332) | Zidovudine (n=332) | |
| Body as a Whole | |||
| Abdominal pain | 16,6 | 16,0 | 12,0 |
Weakness / fatigue | 2,1 | 4,2 | 3,6 |
Fever | 1,5 | 1,5 | 2,1 |
Malaise | 2,1 | 2,7 | 1,8 |
| Gastrointestinal tract | |||
Nausea | 11,7 | 31,9 | 19,6 |
Diarrhea | 3,3 | 3,0 | 2,4 |
Vomiting | 8,4 | 17,8 | 9,0 |
| Brash | 2,7 | 5,4 | 1,8 |
Anorexia | 2,7 | 5,4 | 3,0 |
| Increased appetite | 2,1 | 1,5 | 1,2 |
Dyspepsia | 1,5 | 2,7 | 0,9 |
Jaundice | 1,5 | 2,1 | 0,3 |
| Cardiovascular system and blood | |||
Anemia | 0,6 | 1,2 | 2,1 |
| Locomotor apparatus | |||
| Backache | 8,4 | 4,5 | 1,5 |
| Nervous system and sense organs | |||
| Headache | 5,4 | 9,6 | 6,0 |
Dizziness | 3,0 | 3,9 | 0,9 |
Drowsiness | 2,4 | 3,3 | 3,3 |
| Dysgeusia | 2,7 | 8,4 | 1,2 |
| Skin | |||
Itch | 4,2 | 2,4 | 1,8 |
Rash | 1,2 | 0,6 | 2,4 |
| Genito-urinary system | |||
| Nephrolithiasis (including how much počečnuû, flank pain with / without haematuria) | 8,7 | 7,8 | 8,1 |
Dizurija | 1,5 | 2,4 | 0,3 |
In a series of clinical trials in approximately 12,4% (301/2429) patients, receiving indinavir sulfate at recommended doses, It was marked nephrolithiasis, incl. flank pain with hematuria (including microhematuria) with or without (in the range of 4,7% to 34,4% in various studies); Medium term clinical trials was 47 Sun (in the range of 1 day before 242 Sun, 2238 patients completed the study). In clinical trials during the double-blind phase of the development of nephrolithiasis during treatment with indinavir sulfate in 2,8% (7/246) patients developed hydronephrosis, in 4,5% (11/246) — установлен стент. After sharp attacks in 4,9% (12/246) treated patients was canceled.
When indinavir sulfate have been cases of asymptomatic hyperbilirubinemia (общий билирубин ≥2,5 мг/дл), which is manifested mainly increase indirect bilirubin (about 14%) and less than 1% cases accompanied by an increase of ALT or AST.
Hyperbilirubinemia and nephrolithiasis occurred with greater frequency when receiving doses, exceeding 2,4 g / day (по сравнению с приемом доз ≤2,4 г/сут).
The data of laboratory tests of severe or life-threatening severity (Study 028)
Indicators | Frequency, % | |||
Indinavir sulfate (n=329) | Indinavir sulfate + zidovudine (n=320) | Zidovudine (n=330) | ||
Gematologiya | ||||
| Lowering of hemoglobin less 70 g / l | 0,6 | 0,9 | 3,3 | |
| Понижение числа тромбоцитов менее 50·109/l | 0,9 | 0,9 | 1,8 | |
| Понижение числа нейтрофилов менее 0,75·109/l | 2,4 | 2,2 | 6,7 | |
| Biochemistry of blood | ||||
| Increased ALT more 500% VGN * | 4,9 | 4,1 | 3,0 | |
| Increased AST more 500% VGN | 3,7 | 2,8 | 2,7 | |
| Total serum bilirubin more 250% VGN | 11,9 | 9,7 | 0,6 | |
| Increased serum amylase more 200% VGN | 2,1 | 1,9 | 1,8 | |
| Increased glucose more 13,875 mmol / l | 0,9 | 0,9 | 0,6 | |
| Increased creatinine 300% VGN | 0 | 0 | 0,6 | |
* VGN – the upper limit of normal
Body as a Whole: Redistribution / accumulation of fat in the neck, chest, abdominal and retroperitoneal region.
Cardiovascular system and blood: cardiovascular diseases, incl. myocardial infarction, angina, cerebrovascular disorders, increased frequency of spontaneous bleeding in patients with hemophilia, acute hemolytic anemia (cm. Precautions).
Gastrointestinal tract: abnormal liver function, hepatitis, hepatic failure (cm. Precautions), pancreatitis, abdominal distention, jaundice, dyspepsia.
Allergic reactions: anaphylactoid reactions, hives, vasculitis.
Nervous system and sense organs: oralynaya paresthesia, depression.
The skin and its appendages: rash, incl. многоформная эритема и синдром Стивенса — Джонсона, giperpigmentatsiya, alopecia, ingrown toenail and / or paronychia, itch.
Genito-urinary system: nephrolithiasis, incl. with impaired renal function, including acute renal failure (cm. Precautions), pyelonephritis with or without bacteremia, kristallurija; interstitial nephritis, sometimes with the deposition of crystals of indinavir; some patients have interstitial nephritis did not stop after taking indinavir sulfate; leucocyturia, dizurija.
Other: newly diagnosed diabetes, exacerbation of existing diabetes, giperglikemiâ (cm. Precautions), arthralgia, increase in serum triglycerides, increase in serum cholesterol.
It should not be administered concurrently with terfenadine, cizapridom, astemizolom, triazolamom, midazolam or preparations based on extracts of ergot (indinavir inhibition of CYP3A4 enzyme cytochrome P450 can lead to increased concentrations of the drug in the blood and the development of severe or life-threatening reactions).
Rifampicin is a potent inducer of CYP3A4, and significantly reduces the concentration of indinavir plasma (should not be administered simultaneously).
The interaction of indinavir with drugs, that are less potent inducers of CYP3A4, Cem rifampicin, eg, phenobarbital, phenytoin, carbamazepine and dexamethasone not studied; by sharing a caution should be exercised (possible reduction in plasma concentration of indinavir).
Preparations, containing St. John's wort, reduce the plasma levels of indinavir (may decrease the effectiveness of treatment).
Co-administration of rifabutin and indinavir is accompanied by increased concentrations of rifabutin and a decrease in plasma concentrations of indinavir (you need to decrease the dose of rifabutin and dose increase of indinavir).
Due to the increased plasma concentration of indinavir, while the appointment of indinavir and ketoconazole should consider reducing the dose of indinavir.
Itraconazole is an inhibitor CYPZA4, which increases the concentration of indinavir plasma (while the appointment is required a dose reduction of indinavir).
When concomitant administration of indinavir and efavirenz due to enzyme induction decreases the concentration of indinavir in the blood plasma (We need to increase the dose of indinavir).
According to one published study, HIV-positive men (n=6) concomitant use of indinavir and sildenafil citrate leads to a mutual increase in the concentration of indinavir (incl. AUC в интервале 0–8 ч после приема — на 11%, Cmax - On 48%) sildenafil and (AUC повышалось на 340%) in blood (Be particularly careful in view of the increased risk of adverse effects of sildenafil).
Concomitant use of indinavir sulfate with lovastatin or simvastatin is not recommended. Caution must be exercised when taking protease inhibitors (including indinavir sulfate) simultaneously with other inhibitors of HMG-reductase KoA, metabolized with the participation of CYP3A4 (eg, atorvastatin calcium, cerivastatin sodium, or), tk. This combination of drugs may increase the risk of myopathy, including rhabdomyolysis.
In studies no clinically significant interactions with the following drugs: zidovudine, zidovudine / lamivudine, trimethoprim / sulfamethoxazole, fluconazole, Isoniazid, clarithromycin, methadone, cimetidine, quinidine, norethisterone / ethinylestradiol-containing contraceptive.
Overdose.
There are more than 60 reports of acute or chronic overdose in humans (incl. when receiving doses up 23 times the recommended daily dose 2,4 g). In most cases, the symptoms observed kidney (nephrolithiasis, pain in the side, hematuria) and gastrointestinal symptoms (nausea, vomiting, diarrhea).
Inside, for 1 hours before or after 2 ч после приема пищи с небольшим количеством воды или др. liquids (skimmed milk, juice, coffee, tea) or simultaneously with the reception of a light meal (corn flakes with skim milk and sugar, and others.). The recommended dose - 2,4 g / day (by 800 mg every 8 no).
When treatment with indinavir nephrolithiasis develops. In some cases, nephrolithiasis accompanied by renal impairment or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis, including flank pain with hematuria (incl. mikrogematuriâ) with or without, should consider a temporary suspension (eg, 1-3 days) or discontinuation of therapy. All patients during treatment is recommended adequate hydration (no less 1,5 liters per day).
During postmarketing surveillance in patients, indinavir, It was marked by rare cases of interstitial nephritis with medullary calcification and cortical atrophy, observed in patients with asymptomatic severe leukocyturia (more 100 cells / field of view). Patients with severe asymptomatic leukocyturia require further examination.
There are reports of the development of acute hemolytic anemia, incl. fatal (After confirmation of the diagnosis should begin activities hemolytic anemia treatment, among which may include removal of the drug, and).
Cases of development during treatment with indinavir sulfate hepatitis, accompanied by liver failure and death. However, most of these patients had other diseases and / or simultaneously and they received another treatment, therefore a causal relationship between indinavir sulfate and these events has not been established.
There are reports, received post-marketing studies, of the primary detection of diabetes or hyperglycemia, as well as exacerbation of existing diabetes in HIV-infected patients, treated with protease inhibitors. Some patients for the correction of these disorders require appointment or dose adjustments of insulin or oral hypoglycemic agents. In some cases, developing diabetic ketoacidosis. In some patients, after the abolition of the protease inhibitor hyperglycemia persisted. The frequency and the causal relationship between these events and the protease inhibitor therapy has not been established.
There have been reports of spontaneous bleeding in patients with hemophilia A and B, treated with protease inhibitors. Some patients required additional administration of factor VIII. In many of these cases, treatment with protease inhibitors has been continued or resumed. A causal relationship between protease inhibitor therapy and similar episodes has not been established.
In patients with hepatic insufficiency, caused by cirrhosis, Dosage should be reduced due to decreased metabolism of indinavir sulfate.
При необходимости совместного применения индинавира и диданозина следует принимать их на пустой желудок с интервалом не менее 1 no, tk. for optimum absorption of indinavir requires normal (sour) environment in the stomach, and when receiving didanosine pH in the stomach is increased.
