Emtritsitabin

General characteristics. Structure:

Active ingredient: 200 mg of an emtritsitabin.

Excipients: cellulose microcrystallic, кросповидон, magnesium stearate, povidone.

Structure of a gelatin capsule: gelatin, titanium dioxide (Е 171), dye diamond blue (Е 133).

Pharmacological properties:

Pharmacodynamics. Emtritsitabin is a synthetic nucleoside, a cytidine analog, is phosphorylated by cellular enzymes to эмтрицитабин 5 triphosphates. Emtritsitabin 5 triphosphate inhibits activity of the return VICh-1 transcriptase, competing with natural substrate дезокситидин 5 triphosphate and through inclusions in the formed virus DNA that leads to break of a chain. Emtritsitabin 5 triphosphate is weak inhibitor α-, β-, ε-polymerases of DNA and a mitochondrial γ-polymerase of DNA.

Indications to use:

— treatment of VICh-1 of an infection at adults and children (as a part of the combined anti-retrovirus therapy).

Route of administration and doses:

Inside, irrespective of meal. Adults: the recommended dose - 1 capsule of 200 mg in 1 times/days.

Children weighing more than 33 kg who can swallow the whole capsule: the recommended dose - 1 capsule of 200 mg in 1 times/days.

At impossibility of a proglatyvaniye of the whole capsule, and also children are more senior than 3 months and weighing less than 33 kg have to receive эмтрицитабин in the form of solution for intake. Anti-retrovirus therapy is shown, as a rule, during all life. Therapy duration drug Emtritsitabin is defined by individually attending physician.

Correction of the mode of dosing. Renal failure. At purpose of an emtritsitabin to patients with a renal failure significant increase in influence of drug is observed. At patients with KK <the interval of administration of drug is recommended to increase 50 ml/min., using the recommendations stated in table 2.

Table 2. Dose adjustment of an emtritsitabin at patients with a renal failure

KK, ml/min.
	> 50 ml/min.	30-49 ml/min.	15-29 ml/min.	<15 ml/min. or hemodialysis
Capsules of 200 mg	200 mg each 24 h	200 mg each 48 h	200 mg each 72 h	200 mg each 96 h

Safety and efficiency of these recommendations about correction of intervals between administrations of drug at patients with a renal failure was not clinically estimated. At these patients it is necessary to carry out constant control of function of kidneys. At children correction of an interval of reception of capsules of an emtritsitabin has to be carried out by the same principles, as for adults.

Features of use:

Use at pregnancy and feeding by a breast. Increase in frequency of developing of malformations of a fruit in researches embrio-was not registered and fetotoksichnost of an emtritsitabin at mice on exposure (AUC) of drug are about 60 times higher, and rabbits have enough AUC at the person at reception of the recommended daily doses of an emtritsitabin. However adequate controlled researches of use of an emtritsitabin for pregnant women were not conducted. Considering impossibility of full extrapolation of data of in vivo on reproductive system of the person, it is possible to use эмтрицитабин at pregnant women only according to vital indications.

The women nursing. To HIV-positive women do not recommend to nurse for the purpose of the prevention of risk of post-natal transfer of HIV. It is not known whether gets эмтрицитабин into women's milk. Because of risk of transfer of HIV infection and possibility of heavy side reactions at the newborn, mothers should not nurse throughout therapy by drug.

Use at renal failures. At purpose of an emtritsitabin to patients with a renal failure significant increase in influence of drug is observed.

Increase in an interval between administrations of drug at patients with clearance of creatinine less than 50 ml/min. or with an end-stage of the renal failure demanding dialysis is recommended

Use for children. Children weighing more than 33 kg who can swallow the whole capsule: the recommended dose - 1 capsule of 200 mg in 1 times/days.

Efficiency and safety of use of an emtritsitabin for patients aged from 3 months till 21 year was studied in 3 open nonrandomized clinical trials. The drug was administered to 169 infected patients. The pharmacokinetics of an emtritsitabin was studied also on 20 newborns from HIV-positive mothers. All newborns were HIV-negative upon termination of a research. However these data are not enough for assessment of efficiency of an emtritsitabin as prevention of transfer of a virus from mother to the child, and also treatments of HIV-positive newborn children.

Use for elderly patients. Enough persons at the age of 65 years did not participate in clinical trials of an emtritsitabin and is more senior for definition of distinctions in the response to therapy between them and persons of younger age. It is necessary to select with care a dose for elderly patients, considering the big frequency of abnormal liver functions, kidneys or heart, and also associated diseases or reception of other medicines.

Special instructions. The general. Emtritsitabin it is not necessary to appoint along with drugs which contain эмтрицитабин or with drugs which contain ламивудин (because of his similarity with emtritsitabiny). These are such drugs as Emtriva (эмтрицитабин), Atripla (efavirenz/emtritsitabin/tepofovir), Kombivir (ламивудин / a zidovudine), Epivir (ламивудин), Epivir-HBV (ламивудин), Epziky (abakavir/lamivudin), Trizivir (абакавир/ламивудин/зидовудин).

Lactacidemia/hepatomegalia with a steatosis. At use of analogs of nucleosides, including an emtritsitabina, in the form of monotherapy or together with other anti-retrovirus drugs, there were messages on emergence of a lactacidemia and the expressed increase in a liver with a steatosis, including lethal cases. The majority of such cases was observed at women. Obesity and use of nucleosides of long action can be risk factors. With extra care it is necessary to apply analogs of nucleosides at patients with the known risk factors at a liver disease, however such cases were registered at patients and without existence of the known risk factors. At emergence in the patient of clinical or laboratory signs of a lactacidemia or explicit hepatotoxic (which can include increase in a liver and a steatosis even in the absence of the expressed increase in level трансамииаз), treatment by drug should be stopped.

The patients who are at the same time infected with HIV and a virus of hepatitis B. All HIV-positive patients before anti-retrovirus therapy are recommended to carry out the analysis on existence of chronic hepatitis V. Emtritsitabin is not approved for treatment of the persistent infection caused by a virus of hepatitis B (HBV) and also safety and efficiency of an emtritsitabin and for the patients who are at the same time infected with a virus of hepatitis B and HIV are not established. It was reported about the expressed sharp exacerbation of hepatitis B at the patients who are at the same time infected with HIV and HBV which stopped applying эмтрицитабин. At some patients who received treatment emtritsitabiny the exacerbation of hepatitis B was followed by a hepatic decompensation and injury of a liver. At the patients who are at the same time infected with HIV and HBV which stopped use of an emtritsitabin function of a liver should be controlled by clinical and laboratory methods, at least, for several months. If necessary it is necessary to begin treatment of hepatitis B.

Distribution of fatty tissue. At the patients receiving anti-retrovirus therapy observed redistribution / accumulation of fatty tissue of a body, including obesity in a stomach, a dorsotservikalny adiposity ("a bison hump"), loss of fatty tissue on extremities, loss of fatty tissue on a face, increase in a breast and "a cushingoid look". The mechanism of development and long-term effects of these changes are not known. Relationship of cause and effect is not established.

Syndrome of immune recovery. It was reported about a syndrome of immune recovery at the patients receiving the combined anti-retrovirus therapy including эмтрицитабин. In an initial phase of the combined anti-retrovirus treatment at patients whose immune system reacts to treatment development of inflammatory reaction to the slowed-down or residual opportunistic infections (the infection caused by Mycobacterium avium, a Cytomegaloviral infection, the pneumonia caused by Pneumocystis jirovecii (RSR), or tuberculosis) is possible that can demand further inspection and treatment.

Also was reported about autoimmune diseases (for example, Greyvs's disease, a polymiositis, a syndrome to Giyena-Barra) which developing happened in the conditions of immune recovery. However time of emergence of these diseases considerably varies and can be observed in many months after an initiation of treatment.

Information for patients. In order to avoid complications Emtritsitabin apply under control of the doctor having experience of maintaining HIV-positive patients.

Patients need to be warned that they should not use other drugs at the same time independently. Irregular administration of drug can lead to development of stability of a virus and decrease in efficiency of treatment.

Patients should be informed that therapy by Emtritsitabin does not reduce risk of transfer of HIV to other people at sexual contacts or hemotransfusion and therefore does not cancel need of observance of the appropriate measures of precaution.

Influence on ability to driving of motor transport and to control of mechanisms. Researches of influence of drug on ability to manage motor transport or other mechanisms were not conducted. Patients have to be informed on possible dizziness at treatment emtritsitabiny.

Side effects:

More than 2000 HIV-positive patients accepted эмтрицитабин as monotherapy or in a combination with other anti-retrovirus drugs during from 10 days to 200 weeks within clinical trials.

As conditions of conduct of clinical trials vary in considerable limits, the frequency of observed by-effects in clinical testing of medicine cannot be directly compared to the frequency of the side reactions observed in clinical trials of other medicine and can not correspond to the level of the undesirable phenomena observed in practice. In an otnogeniya of a large number from the listed below phenomena it is authentically unknown whether they are connected with action of a wide range of usually appointed drugs for treatment of HIV infection, or the registered undesirable reactions are result of the pathological processes which are the cornerstone of a disease.

The most frequent side effects (> 10%, irrespective of severity) which were observed at the patients receiving эмтрицитабин in combination with other aitiretrovirusiy drugs in 3 large-scale controlled clinical trials were a headache, diarrhea, nausea, fatigue, dizziness, a depression, sleeplessness, pathological dreams, rash, an abdominal pain, an adynamy, strengthening of cough and rhinitis.

Researches 301A and 303. The most frequent side reactions observed at patients who received эмтрицитабин in combination with other anti-retrovirus means included a headache, diarrhea, nausea and rash which, as a rule, were easy or moderate severity. About 1% of patients stopped administration of drug in connection with these side reactions. All undesirable phenomena were registered with an identical frequency at the patients receiving a combination therapy with emtritsitabiny or other schemes of anti-retrovirus therapy except for skin discoloration which was observed with higher frequency at the patients accepting эмтрицитабин. The skin discoloration which is shown a hyperpegmentation of palms and/or soles was moderate and asymptomatic. Origins of this phenomenon and clinical value are unknown.

Table 3. The side reactions observed at ≥3% of patients in various groups of treatment in researches 301A and 303.

	Research 303		Research 301A
	Etritsitabin + zidovudine or ставудин + NNIOT1 or IP2 (n=294)	Lamivudin + zidovudine or ставудин + NNIOT1 or IP2 (n=146)	Etritsitabin + диданозин + эфавиренз (n=286)	Stavudin + диданозин + эфавиренз (n=285)
Organism in general
Fatigue	16%	10%	12%	17%
Headache	13%	6%	22%	25%
Frustration from a GIT
Diarrhea	23%	18%	23%	32%
Dyspepsia	4%	5%	8%	12%
Nausea	18%	12%	13%	23%
Vomiting	9%	7%	9%	12%
Abdominal pain	8%	11%	14%	17%
Frustration from a musculoskeletal system
Arthralgia	3%	4%	5%	6%
Mialgiya	4%	4%	6%	3%
Frustration from a nervous system
Pathological dreams	2%	<1%	11%	19%
Depressive frustration	6%	10%	9%	13%
Dizziness	4%	5%	25%	26%
Sleeplessness	7%	3%	16%	21%
Neuropathy / переферический neuritis	4%	3%	4%	13%
Parasthesias	5%	7%	6%	12%
Frustration from a respiratory organs
Strengthening of cough	14%	11%	14%	8%
Rhinitis	18%	12%	12%	10%
Disturbances from skin and hypodermic cellulose
Syp3	17%	14%	30%	33%

^{1 -} nenkukleozidny inhibitor of the return transcriptase

^{2 -} protease inhibitor

^{3 -} cases of rash included an itch, spotty and papular rash, a small tortoiseshell, vezikulo-violent rash, pustular rash and allergic reactions

Laboratory deviations in these researches were observed with an identical frequency at the patients receiving эмтрицитабин and in groups of comparison (tab. 4).

Table 4. Significant deviations of laboratory indicators (3 and 4 severity) observed at ≥1% of patients in various groups of treatment of researches 301A and 303.

 

	Research 303		Research 301A
	Etritsitabin + zidovudine or ставудин + NNIOT1 or IP2 (n=294)	Lamivudin + zidovudine or ставудин + NNIOT1 or IP2 (n=146)	Etritsitabin + диданозин + эфавиренз (n=286)	Stavudin + диданозин + эфавиренз (n=285)
Laboratory deviations ≥3 severity	31%	28%	34%	38%
ALT (> 5 VGN1)	2%	1%	5%	6%
NUCLEAR HEATING PLANT (> 5 VGN)	3%	<1%	6%	9%
Bilirubin (> 2.5 VGN)	1%	2%	<1%	<1%
Creatine kinase (> 4 VGN)	11%	14%	12%	11%
Neutropenia (<750/mm)	5%	3%	5%	7%
Pancreatic amylase (> 2 VGN)	2%	2%	<1%	1%
Serumal amylase (> 2 VGN)	2%	2%	5%	10%
Glucose level in serum (<40 or> 25 g/l)	3%	3%	2%	3%
Serumal lipase (> 2 VGN)	<1%	<1%	1%	2%
Triglycerides (> 750 mg/dl)	10%	8%	9%	6%

^{1 -} VGN - the upper bound of norm

Research 934. In a research 934 took part 511 earlier not treated anti-retrovirus drugs of the patients receiving эмтрицитабин and тенофовир in a combination with efavirenzy (п =257) or a zidovudine / ламивудин in a combination with efavirenzy (п =254). The side effects observed in this research, as a rule, will be coordinated with data of other researches of the patients who were earlier not treated by antiretroviruspy drugs or already receiving treatment (tab. 5).

Table 5. The collateral ^{reaktsii1 2-4} severity observed at ≥5% of patients in various groups of treatment of a research 934 (0-144 weeks).

 

	Etritsitabin + тенофовир + efavirenz2 (n=257)	Zidovudine / ламивудин + эфавиренз (n=254)
Frustration from a GIT
Diarrhea	9%	5%
Nausea	9%	7%
Vomiting	2%	5%
From an organism in general - the general side reactions:
Fatigue	9%	8%
Infections and invasions
Sinusitis	8%	4%
Upper respiratory tract infections	8%	5%
Nasopharyngitis	5%	3%
Frustration from a nervous system
Headache	6%	5%
Dizziness	8%	7%
Mental disorders
Depression	9%	7%
Sleeplessness	5%	7%
Disturbances from skin and hypodermic cellulose
Syp3	7%	9%

^{1 -} frequency of by-effects is based on data of all undesirable phenomena connected with treatment, irrespective of communication with the studied drug

^{2 -} during the period from 96 to 144 weeks of a research patients received the combined drug in one tablet containing a tenofovir dizoproksit fumarating and эмтрицитабин, instead of two of these means in separate dosage forms

^{3 -} rash was observed exfoliative, generalized, spotty, spotty and papular, pruritic and vesicular character

The significant laboratory deviations observed in this research are reflected in table 6.

Table 6. The significant deviations of laboratory indicators observed at ≥1% of patients in various groups of treatment of a research 934 (0-144 weeks)

 

	Etritsitabin + тенофовир + efavirenz2 (n=257)	Zidovudine / ламивудин + эфавиренз (n=254)
Laboratory deviations ≥3 severity	30%	26%
Cholesterol (> 240 mg/dl)	22%	24%
Creatine kinase (men:> 990 Pieces/l) (women:> 845 Pieces/l)	9%	7%
Serumal amylase (> 175 Pieces/l)	8%	4%
Alkaline phosphatase (> 550 Pieces/l)	1%	0%
NUCLEAR HEATING PLANT (men:> 180 Pieces/l) (women:> 170 Pieces/l)	3%	3%
ALT (men:> 215 Pieces/l) (women:> 170 Pieces/l)	2%	3%
Hemoglobin with	0%	4%
Hyperglycemia (> 25 g/l)	2%	1%
Hamaturia (> 75 erythrocytes under review)	3%	2%
Glucosuria (≥3+)	<1%	1%
Neutropenia (<750/mm3)	3%	5%
Triglycerides (> 750 mg/dl)	4%	2%

^{1 -} during the period from 96 to 144 weeks of a research patients received the combined drug in one tablet containing a tenofovir dizoproksit fumarating and эмтрицитабин, instead of two of these means in separate dosage forms.

Children. Assessment of side reactions is based on data of an open uncontrollable research 203 in which 116 VICh-1 infected children received эмтрицитабин within 48 weeks. In total, the profile of side reactions at children was comparable to that at adult patients. The hyperpegmentation was observed more often at children. To the additional undesirable phenomena, registered at children, anemia belongs.

At children who received therapy emtritsitabiny within 48 weeks the undesirable phenomena, irrespective of a causal relationship, included the following: infections (44%), hyperpegmentation (32%), strengthening of cough (28%), vomiting (23%), average otitis (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pains (10%), anemia (7%). Changes of laboratory indicators 3-4 severity which arose during treatment were observed at 9% of children and included increase in level of amylase> 2 VGN (п =4), a neutropenia <^750/mm3 (п =3), increase in the ALT level> 5 VGN (п =2), kreatinfosfokinaza> 4 VGN (п =2) and in one case of increase in content of bilirubin (> 3 VGN), gammaglutamiltranspeptidaza (> 10 VGN), lipases (> 2.5 VGN), decrease in hemoglobin (<70 g/l), and also decrease in level of glucose (<4 g/l).

Interaction with other medicines:

In concentration of in vitro, by 14 times exceeding concentration of in vivo эмтрицитабин did not suppress metabolism of drugs which is carried out through one of human isoforms of CYP cytochrome: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Emtritsitabin did not inhibit the process of a glyukuronization which is carried out by means of enzyme uridine-5-difosfoglyukuroniltransferazy. On the basis of these data and the known way of removal of an emtritsitabin the possibility of potential interaction of an emtritsitabin with other medicines through the CYP system is small.

In the researches conducted on healthy volunteers clinically significant medicinal interactions between emtritsitabiny and famtsikloviry, indinaviry, stavudiny were not observed, the tenofovira dizoproksit fumaraty, a zidovudine.

Contraindications:

— hypersensitivity to drug components;

— lactation period;

— children weighing less than 33 kg (for this dosage form).

With care:

— advanced age;

— the renal failure with KK is less than 50 ml/min.

Overdose:

The antidote is not known. There is a limited clinical experience of use of an emtritsitabin in the doses exceeding therapeutic. In one of pharmacological researches of 11 patients received эмтрицитабин in a dose 1200 mg. About development of heavy side reactions it was not reported.

The effect of reception of higher doses of an emtritsitabin is not known. In case of overdose the patient has to be under observation for identification of possible signs of toxicity at which emergence the standard maintenance therapy is carried out.

By means of a hemodialysis about 30% of an emtritsitabin during the 3-hour period of the hemodialysis begun in 1.5 h after reception of an emtritsitabin (speed of a blood-groove of 400 ml/min., a flow rate of dialyzate of 600 ml/min.) are removed. The possibility of removal of an emtritsitabin by means of peritoneal dialysis is not studied.

Storage conditions:

Drug is stored in dry protected from light, the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

10 pieces - planimetric strip packagings (3) - packs cardboard.