Elpida® (Elpida®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceElsulphavirinElsulphavirin
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  • Elpida®
    capsules inwards 
    Viriom, Open Company     Russia
    • Dosage form: & nbspcapsules
    Composition:

    1 capsule contains:

    active substance: sodium alesulfavirin 20.7 mg (in terms of ilsulfavirin 20.0 mg);

    Excipients: lactose monohydrate, croscarmellose sodium, povidone-K30, magnesium stearate;

    hard gelatin capsule: titanium dioxide (E171), dye crimson [Ponso 4R] (E124), iron dye oxide red (E172), gelatin.

    Description:

    Hard gelatin capsules No. 1 with a white body and a red lid. The contents of capsules are white or almost white powder.

    Pharmacotherapeutic group:Antiviral (HIV) agent
    ATX: & nbsp

    J.05.A.G.   Non-nucleosides - reverse transcriptase inhibitors

    Pharmacodynamics:

    Elsulfavirin sodium is rapidly metabolized in the liver to form an active metabolite, which is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus 1 (HIV-1). The active metabolite inhibits HIV-1 reverse transcriptase and does not inhibit the reverse transcriptase of HIV-2 and human DNA polymerase (α, β, γ and δ).

    Antiviral activity in vitro

    The concentration of active metabolite, in which in vitro 50% inhibition of activity is observed (IR50) of the recombinant HIV-1 (HIV-OT) wild-type reverse transcriptase enzyme (strain HXB2) is 1.2 nmol. The main mutations of recombinant HIV-OT (L100I, K103N, V106A, E138K, Y181C, G190A, M230L, L101I/K103N, K103N/Y181C, V179F/Y181C), resistant to other NNRTIs, were sensitive to Elpid's drug. In experiments in vitro on cultures of MT-4 cells infected with HIV-1 for four mutant viruses with mutations in the coding portion of the HIV-OT gene (V106A, G190A) and double mutants (L100I/K103N and K103N/Y181 C), the corresponding IR values50 were close to those that were obtained for wild-type HIV-1 (strain HXB2). The average indicator of the multiplicity of shifts from HXB2 to inhibit the replication of mutants V106A, G190A, L100I/K103Nand K103N/Y181C did not exceed 1.0.

    The effect of human serum proteins on the antiviral activity of the active metabolite was determined on MT-4 cell culture in the presence of 40% human serum. Replication of wild-type HIV-1 (strain HXB2) was inhibited by an active metabolite, with the mean IR50 in a standard culture medium was 1.3 nmol; in a medium containing 40% human serum, the mean IR50 was 13.8 nmol, which corresponds to an increase of 10.6 times.

    Resistance

    In experiments in vitro on cultures of MT-4 cells infected with wild-type HIV-1 (strain HXB2D) variants of the virus with a decreased sensitivity to the Elpid preparation were selected. The most common was a double mutation V106I/A + F227C, which also greatly reduced the viability of the virus (by 94%). This combination was often accompanied by one or more additional mutations: A98G, VI081, E138K, M230L, P236L. Another common combination was the double mutation VI061 + Y188L, often with one or more additional mutations: L1001, E138K, Y181C.

    Experiments in vitro showed that the drug Elpida has a higher genetic barrier to the emergence of resistance in comparison with other NNRTIs. For the emergence of significant resistance to the drug Elpida requires not one mutation, but a combination of at least two, often three or more mutations.

    Cross-resistance

    The antiviral activity of the Elpid preparation was determined on a panel of 50 recombinant viruses obtained from plasma samples of patients infected with HIV infection and previous antiretroviral therapy coursesApt) based on the NNRTI. The frequency of mutations in the coding sequence of the HIV-OT gene associated with the emergence of resistance to the NNRTIs used in the studied panel of 50 viruses was similar to the values ​​recorded in the current versions of the databases on the HIV-OT gene. The most common in this panel were mutations K103N (54%), Y181C (41 %), G190A (41%), K101E (17%), A98G/S (37%), V108I (24%), L100I (9%), P225H (9%), V179I (15%), K103R(11%), K103S, G190S, V179D, V106A, V106I, Y188L (4-7%) and M230L (2%). All 50 viruses were highly resistant to the inhibitory effect of efavirenz. Elpida inhibited the replication of 46 of the 50 efavirenz-resistant viruses with IC values50 below 10 nmol. With allowances for protein binding in the presence of 40% human serum, Elpida inhibited the replication of 92% of the tested viruses with IR50 below 100 nmol. On the contrary, reference compounds efavirenz and etravirine inhibited replication in 0% and 62% of the tested viruses, respectively, with IR values50 below 10 nmol.

    Elpida has a broad spectrum of antiviral activity against various strains and clinical isolates of HIV infection, including those resistant to other NNRTIs.

    Elpida specifically inhibits the DNA polymerase activity of HIV-OT in vitro, including mutations V106A, G190A, L100I/K103N and K103N/Y181C. Cross-resistance of Elpida with other NNRTIs in experiments in vitro was not observed.

    Pharmacokinetics:

    Suction

    After ingestion, Elpida is quickly absorbed into the systemic circulation. The maximum concentration (CmOh) of the active metabolite with a single administration of Elpida in a dose of 20 mg averages 98 ng / ml and is achieved within 3.5 hours. With repeated administration of the drug Elpida at a dose of 20 mg / day CmOh the active metabolite in blood plasma is 164 ng / ml and is achieved in 7-8 days.

    Effect of food on absorption

    Eating lowers the absorption of Elpid, which leads to a decrease in CmOh active metabolite in 4-5 times and coefficient of variation for the indicator area under the curve "concentration-time" (AUC) in 1,5-2 times. In this case, an increase in the time to reach the maximum concentration (TmOh) 2 times indicates a slowdown in absorption. In this regard, the drug Elpida is recommended to be taken on an empty stomach 15 minutes before meals.

    Distribution

    The active metabolite is deposited in the blood cells, where its content is significantly higher than in the plasma. The value of CmOh active metabolite in the formed elements of blood is 1041 ng / ml and is achieved after 6 days of taking the drug Elpida in a dose of 20 mg / day.

    Metabolism

    The metabolic stability of elsulfavirin in liver microsomes and hepatocytes of rats, dogs, monkeys and humans was assessed as sufficiently low, in the fraction S9 Elsulfavirin quickly turned into an active metabolite.

    Metabolic stability of the active metabolite in liver microsomes and hepatocytes of rats, dogs, monkeys and humans was assessed as sufficiently high, which indicates its insignificant level of metabolism. Its main metabolites in hepatocytes were hydroxylation products with subsequent glucuronation, as well as acid and aminosulfonamide.

    Elpida practically has no inhibitory effect on cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4) in concentrations> 50 μmol in microsomes of human liver.

    Elpida is an inducer of mRNA expression of isoenzymes CYP2B6 and CYP3A4, and also strongly induces activity CYP3A4. Degree of induction of enzyme CYP3A4 and mRNA expression by the active metabolite is significantly higher than the inducing action of efavirenz and rifampicin. The maximum inducing effect of the active metabolite of the drug Elpida on CYP3A4 in a concentration of 0.1 μmol was comparable to efavirenz and rifampicin in a concentration of 10 μmol.

    In this regard, it should be used with caution in conjunction with drugs, the metabolism of which occurs with the participation of isoforms CYP2B6 and CYP3A4 cytochrome P450 (see section "Interaction with other drugs").

    Excretion

    The drug Elpida is excreted mainly with bile in the form of glucuronide metabolites. The half-life (T1 / 2) of the active metabolite from the blood plasma is 7-9 days.

    Pharmacokinetics in specific patient groups

    Impaired liver function

    The pharmacokinetics of Elpida in patients with impaired liver function has not been studied.

    Impaired renal function

    The pharmacokinetics of Elpida in patients with a glomerular filtration rate (GFR) of less than 60 ml / min has not been studied.

    Sex and race

    In both men and women, as well as in patients of different racial affinities, similar pharmacokinetic parameters were observed.

    Elderly patients

    The pharmacokinetics of Elpida in patients older than 65 years has not been studied.

    Children

    Pharmacokinetics in patients younger than 18 years of age have not been studied.

    Indications:

    Treatment of HIV-1 infection in adults as part of combined antiretroviral therapy.

    Contraindications:

    - Hypersensitivity to sodium eslsulfavirin or any other component of the drug.

    - Lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome (the drug contains lactose).

    - Children under 18 years.

    - Pregnancy and the period of breastfeeding.

    - Patients with impaired renal function of medium and severe degree (GFR <60 ml / min).

    - Patients with impaired liver function of moderate and severe degree (class B and C by Child-Pugh).

    Carefully:

    - Patients with severe anemia and pancytopenia.

    - Simultaneous reception with drugs, the metabolism of which occurs with the participation of isoenzymes CYP2B6 and CYP3A4 cytochrome P450 (see section "Interaction with other medicinal products").

    - Patients with mild liver function disorder (Child-Pugh class A) (see section "Special instructions").

    Pregnancy and lactation:

    The use of Elpida during pregnancy and during breastfeeding is contraindicated.

    Pregnancy

    Currently, there are no data on the use of Elpida in pregnant women. In preclinical studies, signs of embryotoxicity and teratogenicity Elpid was not found. When treating the drug Elpida should avoid pregnancy.It is necessary to use reliable methods of barrier contraception in combination with other methods. Since the Elpida preparation has a long half-life, it is necessary to use reliable contraceptive methods for 12 weeks after discontinuation of treatment with the drug. Before starting treatment with Elpida, women who are capable of giving birth should undergo a pregnancy test. Elpida should not be given during pregnancy, except when the potential benefit to the mother exceeds the possible risk to the fetus, and there are no other alternative therapies. If a woman takes Elpida during the first trimester of pregnancy or if pregnancy occurs during the use of the drug, she should be warned about the potential harm to the fetus.

    Breastfeeding period

    It is not known whether Elpida is excreted in breast milk. Women who take the drug Elpida during lactation, breast-feeding is not recommended. Under all circumstances, HIV-infected mothers are not recommended to breast-feed to avoid the transmission of HIV infection.

    Dosing and Administration:

    The drug Elpida is ingested. It is recommended to take the drug on an empty stomach 15 minutes before eating. Capsule swallowed whole, without chewing, squeezed with enough water.

    Therapy with Elpid should be prescribed by a doctor who has experience in the treatment of HIV infection.

    The drug Elpida should be administered in combination with other antiretroviral drugs.

    Adults

    The drug Elpida is prescribed in a dose of 20 mg once a day in combination with other antiretroviral drugs.

    In case of missing the next dose of the drug

    If the patient has not taken the Elpid medication at the usual time, and less than 6 hours have elapsed since the prescribed time of admission, you should take the missed capsule as soon as possible. The next capsule must be taken at the set time.

    If more than 6 hours have elapsed since the established time of reception, continue reception at the next day at the set time.

    Dose correction

    Correction of doses of Elpid or concomitant therapy is not provided.

    Patients with impaired renal function

    The drug Elpida is contraindicated in patients with impaired renal function of medium and severe degree (GFR <60 ml / min).

    Patients with impaired hepatic function

    Elpid medication is contraindicated in patients with moderate and severe liver dysfunction (Child-Pugh class B and C).

    Side effects:

    The frequency of unwanted drug reactions in organs and systems is given according to the classification of the World Health Organization (WHO) and taking into account the size of the general population of HIV patients treated with Elpid in clinical trials: very often (≥ 1/10) - more than 10 cases; often (≥ 1/100, <1/10) - from 2 to 10 cases, infrequently (≥ 1/1000, <1/100) - single case, rarely (≥ 1/10000, <1/1000) - not applicable , very rarely (<1/10000) - not applicable.

    Infectious and parasitic diseases: often - herpes simplex; infrequently - genital herpes, oral cavity herpes, fungal infection.

    Violations from the blood and lymphatic system: often - leukopenia, neutropenia.

    Disorders from the endocrine system: infrequently - an autoimmune thyroiditis.

    Disorders of the psyche: often - sleep disorder, depressive conditions (depressed mood), anxiety, apathy, irritability; infrequently - aggression, mood changes, attention violation, obsessive thoughts, nightmares.

    Impaired nervous system: very often - headache; often - dizziness, unusual dreams, drowsiness; infrequently - reduced concentration of attention, memory impairment, insomnia, decreased quality of sleep, a violation of taste sensitivity, paresthesia.

    Hearing disorders and labyrinthine disturbances: infrequently - a hyperacusion, a noise in the ears.

    Disturbances from the respiratory system, chest organs and mediastinum: infrequently - cough, shortness of breath, pain in the oropharynx, rhinorrhea, smell disorder.

    Disorders from the gastrointestinal tract: often - nausea, diarrhea, dry mouth. vomiting; infrequently - discomfort in the abdomen, abdominal pain, belching, glossalgia, colitis.

    Disturbances from the skin and subcutaneous tissues: often - a rash, itching; infrequently - loss of hair, furunculosis.

    Disturbances from the musculoskeletal and connective tissue: infrequently - arthralgia.

    Disorders from the kidneys and urinary tract: often - mild proteinuria, polyuria; infrequently - urolithiasis, leukocyturia.

    Violations of the genitals and mammary gland: infrequently - delay of menstruation, polymenorrhea, sexual dysfunction.

    General disorders and disorders at the site of administration: often - asthenia, weakness, decreased appetite, fever; infrequently - a pain in the chest.

    Laboratory and instrumental data: very often - increased activity of gamma-glutamyl transferase (GGT); often - increased activity of alanine aminotransferase (ALT), increased activity of creatine phosphokinase (CK), increased blood glucose levels; infrequently - increased activity of aspartate aminotransferase (ACT), increased blood pressure, weight loss. If any of the side effects listed in the manual are aggravated or you notice any other side effects not listed in the instructions, inform the doctor about it.

    Overdose:

    In clinical trials, patients took Elpida once in a dose up to 80 mg and repeatedly (at least 12 weeks) at a dose of 40 mg. The use of the drug Elpida at a dose of 40 mg per day led to a more frequent (compared with the recommended dose) development of adverse reactions from the nervous system and the psyche, as well as the appearance of reactions from the skin (rash).

    In case of an overdose, treatment should consist of taking measures to reduce absorption of the drug (gastric lavage, intake of adsorbents),the control of vital signs and a condition of the basic bodies and systems. To accelerate the removal of unabsorbed preparation, one can use Activated carbon. There is no specific antidote.

    Interaction:

    Antiretroviral drugs

    As part of a clinical study of Phase 3, Elpida was used as part of an integrated Apt with a fixed combination of 2 NRTIs - tenofovir and emtricitabine. This combination of drugs was well tolerated by patients.

    In the clinical study on the evaluation of inter-drug interaction, the use of Elpida in combination with HIV protease inhibitors darunavir and ritonavir, as well as the integrase inhibitor raltegravir, has been studied. In general, joint taking of drugs was well tolerated. Changes in pharmacokinetic parameters and drug exposure are insignificant and do not require a change in the standard dosage regimen of these drugs. The administration of atazanavir after completion of therapy with Elpida in another clinical study led to the development of severe adverse reactions from the gastrointestinal tract (nausea, vomiting),specific for atazanavir.

    Other medications

    The drug Elpida induces the activity of isoenzymes CYP2B6 and CYP3A4 and can reduce the concentration in the plasma and, consequently, reduce the activity of drugs that are substrates of these isoenzymes. Joint use of these drugs should be done with caution.

    Substrates of isoenzymes CYP2B6 and CYP3A4, whose activity can be reduced by joint admission with the drug Elpida

    Substrates CYP2B6 and CYP3A4:

    Immunosuppressors (ciclosporin, tacrolimus, sirolimus).

    Chemotherapeutic drugs (docetaxel, tamoxifen, paclitaxel, cyclophosphamide, doxorubicin, erlotinib, etoposide, ifosfamide, teniposide, vinblastine, vincristine, vindesine, imatinib, sorafenib, sunitinib, vemurafenib, tessirolimus, anastrozole, genfatinib).

    Azole antifungal drugs (ketoconazole, itraconazole).

    Macrolides (clarithromycin, erythromycin, telithromycin; except for azithromycin). Tricyclic antidepressants (amitriptyline, clomipramine, imipramine, cyclobenzaprine).

    Selective serotonin reuptake inhibitors (citalopram, norfluoxetine, sertraline).

    Other antidepressants (mirtazapine, nefazodone, reboxetine, venlafaxine, trazodone). Antipsychotics (haloperidol, aripiprazole, risperidone, ziprasidone, pimozide).

    Opioid analgesics (alfentanil, buprenorphine, codeine, fentanyl, hydrocodone, methadone, levacetylmetadol, tramadol).

    Benzodiazepines (alprosolam, midazolam, triazolam, diazepam).

    Sleeping Pills (zopiclone, zaleplon, zolpidem).

    Statins (atorvastatin, lovastatin, simvastatin, cerivastatin; except pravastatin and rosuvastatin).

    Calcium channel blockers (diltiazem, felodipine, nifedipine, verapamil, amlodipine, lercanidipine, nitrendipine, nisoldipine, bepridil).

    Antiarrhythmics (amiodarone, droperedon, quinidine).

    Inhibitors of phosphodiesterase-5 (sildenafil, tadalafil).

    Agonists and antagonists of sex hormones (finasteride, estradiol, progesterone, ethinyl estradiol, testosterone, toremifene, bicalutamide).

    H1-receptor antagonists (terfenadine, astemizole, chlorphenamine).

    HIV protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir).

    Some glucocorticosteroids (budesonide, hydrocortisone, dexamethasone).

    Other Substrates CYP2B6:

    Bupropion, valproic acid, methoxetamine, propofol, efavirenz.

    Other Substrates CYP3A4:

    Aprepitant, buspirone, warfarin, dapsone, domperidone, donepezil, caffeine, clopidogrel, lidocaine, montelukast, nateglinide, nevirapine, omeprazole, ondansetron, propranolol, salmeterol, cisapride, eplerenone, ergot alkaloids (ergotamine, dihydroergotamine, ergonovin, methylergonovine).

    Special instructions:

    Patients should be warned that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV infection to other people with blood or during sexual intercourse. During treatment with Elpida, patients should continue to observe appropriate precautions.

    Elpida is not used as a monotherapy for the treatment of HIV infection (may lead to the development of virus resistance) or as the only drug added to ineffective treatment. Treatment should be performed by a physician with sufficient experience in the treatment of HIV infection.

    Given the tropicity of the active metabolite to the blood elements, it is necessary to carefully prescribe the drug Elpida to patients with severe anemia and pancytopenia.

    Accompanying Apt

    If taking any antiretroviral drug as part of a combination Apt is canceled in connection with suspicion of intolerance, it is necessary to consider the possibility of simultaneous cancellation of all antiretroviral drugs. Admission of all antiretroviral drugs that have been canceled should be resumed immediately after the disappearance of symptoms of intolerance. It is not recommended interrupted monotherapy and sequential re-administration of antiretroviral drugs because of the increased likelihood of the emergence of a resistant to therapy virus.

    Effect of food

    Food intake affects the kinetics of absorption of the drug Elpida, significantly reducing the extent of its absorption, so the use of Elpida is recommended on an empty stomach.

    Allergic reactions

    In the clinical studies conducted with the use of the drug Elpida, allergic reactions were not recorded.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency at the onset of combined Apt An inflammatory reaction may occur in response to the activation of pathogens of asymptomatic or residual opportunistic infections, which can lead to serious clinical conditions or increased symptoms.Usually, these reactions occur within the first weeks or months after the onset of the complex Apt. Typical examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumonia caused by Pneumocystis jiroveci (R. carinii). The appearance of any symptoms of inflammation requires examination and, if necessary, treatment. Autoimmune diseases (such as Graves' disease) were also observed against the background of restoration of immunity, but the time of primary manifestations varied and the disease could occur many months after the initiation of therapy.

    Body weight and metabolic parameters

    Against the background of the Apt there may be an increase in body weight and an increase in the concentration of glucose and lipids in the blood. These changes may be partly related to the disease itself and the way of life. In some cases, the effect of the therapy on the increase in lipid concentration has been proven, but there is no conclusive evidence of the effect of therapy on weight gain. Monitoring of the concentration of glucose and lipids in the blood should be carried out, guided by the recommendations for the treatment of HIV infection.Disorders of lipid metabolism should be adjusted in case of clinical necessity.

    Lipodystrophy and metabolic disorders

    Combined Apt is associated with the redistribution of subcutaneous fat body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of this phenomenon are still unknown and the mechanism of its development has not been studied sufficiently. The connection of visceral lipomatosis with the use of HIV protease inhibitors and lipoatrophy using NRTIs is suggested. The increased risk of lipodystrophy may be due to both individual factors, such as advanced age, hack and factors associated with taking medications, such as prolonged Apt and associated metabolic disorders. In this regard, a clinical examination of the patient should be a physical examination, paying attention to the redistribution of subcutaneous fat, as well as determine the concentration of lipids in the blood serum and the concentration of glucose in blood plasma on an empty stomach. Infringements should be corrected according to clinical displays.

    Osteonecrosis

    Although the etiology of this disease is recognized as multifactorial (including the use of glucocorticosteroids, alcohol abuse, severe immunosuppression, increased body mass index), cases of osteonecrosis have been observed predominantly in patients with long-term HIV infection and / or in patients who received long-term combined Apt. Patients should immediately consult a doctor if joint pain occurs, joint mobility is reduced, or walking difficulties occur. In clinical studies of the drug Elpida, these reactions were not recorded.

    Special patient groups

    Patients with liver disease

    The pharmacokinetics of Elpida in patients with impaired liver function has not been studied. Elpida is contraindicated in patients with moderate and severe liver dysfunction (Child-Pugh class B and C) (see "Contraindications", "Pharmacological properties"). Due to the metabolism of Elpida with the cytochrome P450 system and the limited clinical experience of the drug in patients with chronic liver disease, caution should be exercised when administering Elpida to patients with mild liver disease (Child-Pugh class A).Thus patients should be under supervision for timely revealing dose-dependent undesirable reactions, especially from nervous system. Also, at certain intervals, laboratory tests should be performed to assess the liver condition.

    The safety and efficacy of Elpida are not confirmed in patients with cirrhosis of any etiology. Studies of Elpida in patients with co-infection with HIV-1 and hepatitis B and / or C viruses have not been carried out. Patients with chronic hepatitis B or C taking a combined Apt, are at risk of developing severe adverse reactions from the liver, which can lead to death. In patients with a history of liver failure, including chronic hepatitis, the incidence of liver function disorders increases with combined Apt, so these patients should be monitored in accordance with the standard scheme. In patients with worsening liver disease or with a sustained increase in serum aminotransferase activity exceeding the upper limit of the norm by more than 5 times, the benefit of continuing therapy with Elpid should be compared with the possible risk of hepatotoxicity.In respect of such patients, consideration should be given to the desirability of interrupting or canceling Apt. With the simultaneous use of other drugs with known hepatotoxicity, it is recommended to monitor the activity of serum aminotransferases.

    Patients with renal insufficiency

    In studies of Elpida, patients with GFR <60 ml / min did not participate. The pharmacokinetics of Elpida in patients with renal insufficiency has not been studied, but renal dysfunction should not have a significant effect on drug clearance (see section "Pharmacological properties"). The experience of using the drug Elpida in patients with moderate and severe renal failure is absent, and therefore, the use of the drug in such patients is contraindicated (see section "Contraindications").

    Patients with co-infection

    Studies of the drug Elpida in patients with co-infection with HIV-1 and hepatitis B, C and / or tuberculosis were not carried out.

    Elderly patients

    Studies of the drug Elpida in elderly patients were not conducted.

    Children

    Studies of Elpida in children under the age of 18 years have not been conducted (see the section "Contraindications").

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

    There have been no studies of the Elpid drug to assess the effect on the ability to drive vehicles, mechanisms. Patients need to warn that if they have insomnia, dizziness and other undesirable reactions from the central nervous system, they should avoid the management of vehicles, mechanisms.

    Form release / dosage:

    Capsules 20 mg.

    Packaging:

    For 30 capsules in a polyethylene bottle, capped with a lid with a desiccant and control of the first autopsy.

    1 bottle together with the instruction for use is placed in a pack of cardboard.

    Storage conditions:

    In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004360
    Date of registration:30.06.2017
    Expiration Date:30.06.2022
    The owner of the registration certificate:Viriom, Open CompanyViriom, Open Company Russia
    Manufacturer: & nbsp
    Information update date: & nbsp28.07.2017
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