Akimasol - instructions for use, doses, side effects, contraindications

Active substanceAbacavir + Lamivudine + ZidovudineAbacavir + Lamivudine + Zidovudine

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Akimasol

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FARMASINTEZ, JSC (Irkutsk) Russia

Trizivir®

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VeeV Helsker United Kingdom Limited United Kingdom

Dosage form: & nbspfilm-coated tablets

Composition:

Composition per 1 tablet

Active substances:

Abacavir sulfate 351 mg

in terms of abacavir 300 mg

Zidovudine 300 mg

Lamivudine 150 mg

Excipients

Core: Giprolose low-substituted - 199.8 mg; hypromellose E15 - 3.2 mg; sodium carboxymethyl starch - 58.0 mg; magnesium stearate - 12.0 mg; cellulose microcrystalline - 216.0 mg.

Composition of water-soluble film shell: hypromellose E5 - 21.0 mg, macrogol 6000 - 2.7 mg, polysorbate 80 - 0.3 mg, titanium dioxide - 6.0 mg.

Description:The tablets covered with a film shell of white color, biconvex, oval. On a cross-section of a tablet of white or almost white color.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.R.04 Abacavir + Lamivudine + Zidovudine

Pharmacodynamics:

Mechanism of action

Lamivudine, zidovudine and abacavir - nucleoside analogs that inhibit HIV reverse transcriptase and selectively suppress the replication of HIV-1 and HIV-2. Lamivudine, zidovudine and abacavir pass consecutive stages of metabolism involving intracellular kinases and are converted to the corresponding 5'-triphosphate (TF). Lamivudine-TF.Abacavir-TF and zidovudine-TF are substrates and competitive inhibitors of HIV reverse transcriptase. Basic The antiviral effect of the active components of the preparation Akimasol lies in their ability to be built in the form of monophosphate in the HIV DNA synthesizing, leading to a break of replication. The affinity of lamivudine, abacavir and zidovudine to DNA polymerases of the host cell is much lower.

There was no antagonism in the antiviral activity of abacavir in cell culture when combined with neurotoxic reverse transcriptase inhibitors (NRTIs) didanosine, emitcitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or a protease inhibitor (PI) amprenavir. There were no antagonistic effects in vitro with the simultaneous use of lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine). There were no antagonistic effects in vitro with simultaneous use with zidovudine and other antiretroviral drugs (tested substances: abacavir, didanosine, lamivudine and interferon-alpha).

In the obtained in vitro HIV strains resistant to abacavir, mutations in several codons of the reverse transcriptase gene (RT) -M184V, K65R, L74V and Y115F. HIV resistance to abacavir in vitro and in vivo formed slowly. For a clinically significant increase in inhibitory concentration against 50% of strains IC50 (8 times the "wild" type virus) requires multiple mutations of the viral genome. Isolates resistant to abacavir may have reduced sensitivity to lamivudine, zalcitabine, and / or didanosine, but completely retain sensitivity to zidovudine and stavudine. Inefficiency of the combination of abacavir, lamivudine and zidovudine at the very beginning of treatment is usually due to only one mutation - M184V, so the use of this combination preserves the possibility of a wide choice of regimens for second-line therapy.

Cross-resistance to abacavir, zidovudine. lamivudine and HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely. HIV isolates with reduced sensitivity to abacavir were isolated in patients with uncontrolled viral replication, in which previous therapy with other nucleoside reverse transcriptase inhibitors was ineffective.

Pharmacokinetics:

Suction

Ingestion lamivudine, abacavir and zidovudine quickly and well absorbed in the gastrointestinal tract. Absolute bioavailability of lamivudine. Abacavir and zidovudine after oral administration in adults are respectively 80-85%, 83% and 60-70%.

Distribution

The volume distribution of lamivudine, abacavir and zidovudine for IV administration is 1.3, 0.8 and 1.6 l / kg, respectively. Binding lamivudine to the main protein of the blood plasma, albumin, slightly (in vitro less than 36% of serum albumin), the pharmacokinetics of lamivudine is linear. Zidovudine binds to blood plasma proteins by 34-38%. According to research in vitro, Abacavir in therapeutic doses is associated with serum proteins by approximately 49%. This indicates a low probability of interactions with other drugs through their displacement from the connection with blood proteins. Therefore, when using abacavir + zidovudine + lamivudine, no interaction with drugs is expected through their displacement from the association with plasma proteins. Thus, the preparation Akimasol also should not enter into such variant of interaction with medical products,which is mediated by their displacement from the connection with the proteins of the blood plasma.

Lamivudine, abacavir and zidovudine penetrate the blood-brain barrier and is found in the cerebrospinal fluid (CSF). The ratio of the concentration of lamivudine and zidovudine in the serum to the corresponding concentrations of preparations in the CSF 2-4 hours after oral administration averages about 0.12 for lamivudine and 0.5 for zidovudine. The true degree of lamivudine penetration into the central nervous system, as well as the clinical significance of this phenomenon, have not been established to date.

According to studies in HIV-infected patients, abacavir well penetrates into the CSF, while AUC Abacavir in CSF is 30-44% of AUC abacavir in plasma. In Phase 1 clinical trial to study the pharmacokinetics of abacavir shows that after 1.5 hours after administration of the dose of abacavir 300 mg 2 times a day, its concentration in CSF is 0.14 mcg / ml. When using abacavir in a dose of 600 mg twice a day, its concentration in the CSF increases from 0.13 μg / ml 0.5-1 hour after its administration, up to 0.74 μg / ml after 3-4 hours. Thus, even if concentration of abacavir in CSF 4 hours after its administration at a dose of 600 mg 2 times a day and does not reach a maximum, it exceeds IC50 (0.8 μg / ml or 0.6 μmol / L) approximately 9-fold.

Metabolism

Since only a small fraction of lamivudine is metabolized in the liver (5-10%), and also due to insignificant binding to plasma proteins, metabolic interactions of lamivudine with other drugs are unlikely. Lamivudine is excreted unchanged by renal excretion.

Zidovudine, in general, is metabolized in the liver. The main metabolite of zidovudine in blood plasma and urine is 5'-glucuronide of zidovudine, which is excreted by the kidneys and is approximately 50-80% of the accepted dose of the drug. Other zidovudine metabolites for parenteral administration are 3'-amino-3'-deoxythymidine (AMT).

Abacavir is predominantly metabolized in the liver, only 2% of the accepted dose is excreted unchanged by the kidneys. In humans abacavir is metabolized. basically, under the influence of alcohol dehydrogenase to form a 5'-carboxylic acid and by conjugation with glucuronic acid to form 5'-glucuronide, which is about 66% of the total amount released through the kidneys of the preparation.

Excretion

The half-life of lamivudine is 5-7 hours.The average systemic clearance of lamivudine is about 0.32 l / h kg, most of it is renal clearance (more than 70%), carried out through the system of organic cation transport. In studies involving patients with renal insufficiency, it was shown that impaired renal function affects the excretion of lamivudine. Patients with a creatinine clearance of 50 ml / min or less need a dose reduction.

According to studies with intravenous administration of zidovudine, its mean final half-life _and, blood plasma is an average of 1.1 hours, and the average systemic clearance is 1.6 l / kg / h. The estimated renal clearance of zidovudine is 0.34 l / h / kg, indicating glomerular filtration and active tubular secretion by the kidneys. In patients with severe renal dysfunction, the concentration of zidovudine in the blood plasma is increased.

The average half-life of abacavir is about 1.5 hours. After repeated administration of abacavir 300 mg orally 2 times a day, significant cumulation is not observed. Abacavir excretion is carried out by metabolism in the liver, followed by excretion of metabolites mainly by the kidneys.About 83% of the administered dose of abacavir is excreted by the kidneys in the form of metabolites and unchanged, the remaining amount is output through intestines.

Special patient groups

Elderly patients

Data on the pharmacokinetics of the drug in patients older than 65 years are absent.

Patients with impaired renal function

In studies involving patients with renal insufficiency, it was shaken that a disturbance in kidney function affects the excretion of lamivudine due to decreased renal clearance. Patients with a creatinine clearance of less than 50 mL / min require a dose reduction. It was also shown that in patients with severe renal dysfunction, the concentration of zidovudine in plasma was increased. Abacavir is metabolized mainly in the liver, less than 2% of it is excreted by the kidneys in an unchanged form. The pharmacokinetics of abacavir in patients with terminal stage of renal failure is similar to that of patients with normal renal function. Since patients with reduced renal function (creatinine clearance below 50 ml / min) may require a reduction in the dose of lamivudine and zidovudine, such patients are advised to use lamivudine, zidovudine and abacavir in the form of separate preparations.

Patients with impaired hepatic function

There are no data on the use of the drug Akimasol in patients with impaired liver function. Limited data obtained in patients with cirrhosis of the liver indicate the possibility of cumulation of zidovudine due to a decrease in the rate of formation of glucuronide. The data obtained with the use of lamivudine in patients with impaired liver function of moderate and severe degree, indicates that the violation of liver function does not have a significant effect on the pharmacokinetics of lamivudine.

Abacavir is metabolized mainly in the liver. The pharmacokinetics of abacavir has been studied in patients with mild liver function disorders (5-6 on the Child-Pugh scale). The results of the study indicate an increase AIJC Abacavir averages 1.89 times and an increase in the half-life of abacavir 1.58 times. The violation of liver function does not affect the value AUC metabolites of abacavir, however, the rate of their formation and excretion decreases. Therefore, in patients with mild liver function disorder, a reduction in the dose of abacavir is required.The pharmacokinetics of abacavir in patients with impaired liver function of an average degree has not been studied, therefore, the use of the drug Akimasol in these patient groups is not recommended.

Indications:

- Treatment of HIV infection in adults and children over 12 years of age as part of antiretroviral therapy.

Contraindications:

- Hypersensitivity to abacavir, lamivudine or zidovudine, or any other component of the drug.

- Hepatic insufficiency of medium and severe degree (class B and C on the Child-Pugh scale), due to the lack of clinical data and the recommended dosing regimen.

- Hepatic insufficiency of mild degree (class A on the Child-Pugh scale), due to the inability to provide a dosing regimen.

- Impaired renal function (creatinine clearance less than 50 ml / min).

- A marked decrease in the neutrophil count (less than 0.75 x 10⁹/ l) or hemoglobin concentration (less than 7.5 g / dL, or 4.65 mmol / L) due to the content of zidovudine.

- Age to 12 years (due to the lack of possibility of dose adjustment).

- Body weight less than 40 kg (due to lack of recommended dosing regimen).

Carefully:

- Oppression of bone marrow hematopoiesis (with a hemoglobin concentration of less than 9 g / L (5.59 mmol / L) or a neutrophil count of less than 1.0 x 10⁹/ l), a dose adjustment of zidovudine may be required. when these unwanted reactions develop abacavir, zidovudine and lamivudine are used as separate preparations.

- Pancreatitis (including in history).

- Hepatomegaly, hepatitis, any risk factors for liver disease.

- Presence of risk factors for the development of coronary heart disease.

- Elderly age.

Pregnancy and lactation:

Fertility

The effects of abacavir, lamivudine and zidovudine on fertility in women have not been studied to date. With respect to zidovudine, it is shown that its use in men does not affect the number, morphology and motility of spermatozoa.

Pregnancy

The safety of Akimasol in women during pregnancy has not been studied to date. There are research data on the effects of abacavir, lamivudine and zidovudine on fetal development in animals. Therefore, during pregnancy, the drug Akimasol is prescribed only if the intended use for the mother exceeds the potential risk to the fetus.

There is evidence of a slight transient increase in lactate concentration in the blood plasma, possibly due to mitochondrial disorders,in newborns and infants whose mothers during pregnancy and in the perinatal period received nucleoside reverse transcriptase inhibitors. The clinical significance of this enhancement is not currently established.

In addition, there are some reports of developmental delay, convulsive seizures and other neurological disorders, such as increased muscle tone. However, the causal relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established. These data do not abolish existing recommendations for antiretroviral treatment during pregnancy to prevent vertical transmission of HIV.

Breastfeeding period

Specialists do not recommend breastfeeding to HIV-infected patients to avoid HIV transmission to the child. Because the abacavir, its metabolites and HIV penetrate into breast milk, breastfeeding is contraindicated.

Dosing and Administration:

The drug Akimasol is intended for oral administration.

Therapy should be performed by a physician with experience in the treatment of HIV infection.If it is necessary to cancel or reduce the dose of one of the active ingredients of the preparation Akimasol, they are used as separate preparations of abacavir, lamivudine and zidovudine.

Adults and children over 12 years of age

The recommended dose of the drug for adults and children over 12 years - 1 tablet 2 times a day, regardless of food intake.

If the weight of the body of a teenager or an adult is less than 40 kg, the preparation of Akimasol is not used, since the dose of each active ingredient in the pill is fixed, that is, the dose reduction for each active substance alone is impossible.

Special patient groups

Elderly patients

Data on the pharmacokinetics of the drug Akimasol in persons older than 65 years are absent. In connection with the possibility of age-related changes, including a decrease in kidney function and hematological disorders, the administration of Akimasol to persons of this age group requires special care.

Patients with impaired renal function

Impaired renal function may require a reduction in the dose of lamivudine or zidovudine. In this regard, patients with impaired renal function (creatinine clearance less than 50 ml / min) is recommended to use abacavir, lamivudine and zidovudine in the form of separate preparations.

Patients with impaired hepatic function

Patients with mild liver function disorders (grade A on the Child-Pugh scale) may need a dose adjustment for abacavir and zidovudine. In connection with the impossibility of reducing the dose with the use of the drug Akimasol, monotherapy drugs such as abacavir, lamivudine and zidovudine should be used, if necessary. The drug Akimasol is contraindicated in patients with impaired liver function.

Correction of dose in the development of hematological adverse reactions

At a hemoglobin concentration of less than 9 g / dl (5.59 mmol / L) or a neutrophil count of less than 1.0 x 10'7 l, a dose adjustment of zidovudine may be required. When these unwanted reactions develop abacavir, zidovudine and lamivudine prescribe as separate preparations.

Side effects:

As the composition of the drug Akimasol includes abacavir. lamivudine and zidovudine, it can cause the same undesirable reactions as these three active substances alone (see Table 1). For many of the undesirable reactions listed below, it remains unclear,whether their occurrence is associated with one of the active substances or with other broad-spectrum medicines for the treatment of HIV infection, or they are caused by a major disease. In clinical trials, the safety profile of Akimasol has not been evaluated to date.

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: Often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10,000 and <1/1000) and rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical trial data and post-registration surveillance.

Table 1. Adverse reactions of each of the active ingredients Akimasol drug (unwanted reactions occurring is not less than 5% of patients, bold)

WARNING: For information on hypersensitivity to abacavir, see "Special instructions"

	Abacavir	Lamivudine	Zidovudine
Heart Disease			Rarely: cardiomyopathy.
Disorders from the gastrointestinal tract	Often: nausea, vomiting, diarrhea. Rarely: pancreatitis.	Often: nausea, vomiting, diarrhea, pain in the upper abdomen. Rarely: increased serum amylase, pancreatitis.	Very often: nausea. Often: vomiting, diarrhea, abdominal pain. Infrequent: flatulence. Rarely: pigmentation of the oral mucosa, a taste disorder, dyspepsia, pancreatitis.
Violations of the blood and lymphatic system		Infrequent: anemia, neutropenia, thrombocytopenia. Very rarely: true erythrocyte aplasia.	Often: anemia, neutropenia, leukopenia. Infrequent: thrombocytopenia, pancytopenia (due to bone marrow hypoplasia). Rarely: true erythrocytic aplasia. Very rarely: aplastic anemia.
Immune system disorders	Often: hypersensitivity.
Disorders from the metabolism and nutrition	Often: anorexia.		Rarely: anorexia, lactic acidosis without hypoxemia.
Disorders of the psyche			Rarely: anxiety, depression.
Disturbances from the liver and bile ducts		Infrequently: transient increase in activity of hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), increased serum amylase activity. Rarely: hepatitis.	Often: increased bilirubin concentration and hepatic enzyme activity in the blood. Rarely: liver damage, including severe hepatomegaly with steatosis.
Disorders from the kidneys and urinary tract			Rarely: frequent urination.
Violations of the genitals and mammary gland			Rarely: gynecomastia.
Disturbances from musculoskeletal system and connective tissue		Often: myopathy, arthralgia. Rarely: rhabdomyolysis.	Often: myalgia. Infrequent: myopathy.
Disturbances from the nervous system	Often: headache.	Often: headache, insomnia. Very rarely: peripheral neuropathy (paresthesia).	Very often: headache. Often: dizziness. Rarely: insomnia, paresthesia, drowsiness, decreased mental abilities, cramps, anxiety.
Disturbances from the respiratory system, organs of the chest and mediastinum		Often: cough, nasal symptoms	Infrequent: shortness of breath. Rarely: cough.
Disturbances from the skin and subcutaneous tissues.	Often: a rash without systemic manifestations. Very rarely: polymorphic erythema, including Stevens-Johnson syndrome and toxic epidermal necrolysis.	Often: rash, alopecia.	Infrequent: rash, itching. Rarely: pigmentation of nails and skin, hives, sweating.
General disorders and disorders at the site of administration	Often: fever, drowsiness, fatigue.	Often: fever, malaise, fatigue.	Often: malaise. Infrequently: fever, generalized pain, asthenia. Rarely: chills, chest pain, flu-like syndrome.

Description of individual adverse reactions

Hypersensitivity reactions to abacavir

Many of the above unwanted reactions associated with taking abacavir (nausea, vomiting, diarrhea, fever, fatigue, rash) usually develop as manifestations of hypersensitivity reactions to abacavir. Therefore, if any of these symptoms appear, a thorough examination of the patient is shown to confirm the development of a hypersensitivity reaction. If the drug Akimasol was canceled due to the appearance of any of the above symptoms and the decision was made to resume therapy with Akimasol, it should be started only under direct medical supervision. Careful medical supervision is necessary during the first 2 months with consultations every 2 weeks.

The hypersensitivity reaction (MRI) to abacavir was defined as a general undesirable reaction in the treatment with drugs containing abacavir. The signs and symptoms of MRI are listed below. These signs and symptoms were identified during clinical trials or post-marketing follow-up. Symptoms and symptoms that occur in at least 10% of patients with WGH are highlighted in bold.

Practically all patients with HGV develop fever and / or a rash (usually maculopapular or urticaria) as part of the syndrome, but reactions can also occur without rash or fever. Other major symptoms include symptoms from the gastrointestinal tract, respiratory system, or constitutional symptoms such as drowsiness and malaise.

Disturbances from the skin and subcutaneous tissues: rash (usually maculopapular or urticaria).

Disorders from the gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, ulceration of the mucous membrane of the mouth.

Disturbances from the respiratory system, chest and mediastinal organs: shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Violations from the nervous system / psyche: headache, paresthesia, fatigue.

Violations from the blood and lymphatic system: lymphopenia. lymphadenopathy.

Disorders from the liver and bile ducts: increase of biochemical parameters of liver function, hepatitis, hepatic insufficiency.

Disturbances from the musculoskeletal system and connective tissue: myalgia, rarely myolysis, arthralgia, increased activity of creatine phosphokinase.

Disorders from the kidneys and urinary tract: an increase in the concentration of creatinine in the blood plasma, kidney failure.

Immune system disorders: anaphylactic reactions.

Disturbances on the part of the organ of sight: conjunctivitis.

Vascular disorders: arterial hypotension.

General disorders and disorders at the site of administration: fever, malaise, swelling. Resumption of the drug Akimasol after MRI on abacavir leads to a rapid appearance of symptoms within a few hours. Repeated MRI usually proceeds more severely than the original MRI, and may include life-threatening arterial hypotension and death. In rare cases, reactions also occur with the resumption of therapy with Akimasol after its withdrawal, caused by the appearance of only one of the main symptoms of hypersensitivity (see.above), and in very rare cases, this reaction occurs when the Akimaxol drug is resumed by patients who did not have any MRI symptoms prior to discontinuation of the drug (i.e., in patients previously thought to be abacavir-tolerant).

For detailed information on clinical management in case of suspicion of an MRSV for abacavir, see "Special instructions".

Unwanted reactions to zidovudine on the part of the blood

Treatment with zidovudine may lead to the development of anemia, neutropenia, leukopenia and aplastic anemia. These complications were more common with higher doses of zidovudine (1200-1500 mg / day) and in patients with advanced HIV infection (in particular, with a reduced reserve of bone marrow before the start of treatment), especially in patients with a number Cd4 cells less than 100 / mm³. Neutropenia is also more common in patients with a reduced neutrophil count, hemoglobin concentration and serum vitamin B concentration12 at the beginning of zidovudine therapy. In this regard, patients taking the drug Akimasol, it is necessary to carefully assess the hematological parameters. With the development of anemia, neutropenia and leukopenia, a dose reduction or discontinuation of therapy with Akimasol may be required.With the development of anemia, a blood transfusion may be required.

Lactic acidosis

There are reports of the development of lactic acidosis, including fatal, usually accompanied by severe hepatomegaly with steatosis. as a result of antiretroviral therapy with nucleoside analogues.

Metabolic disorders

Use of combination antiretroviral therapy (Apt) was accompanied by metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia. Lipodystrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat, which was most pronounced on the face, extremities and buttocks. During therapy with Akimasol, patients should be examined regularly for signs of lipoatrophy, and if therapy is suspected for lipoatrophy, the drug Akimasol should be discontinued.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, an inflammatory response may occur against asymptomatic opportunistic infections or their residual effects.However, cases of autoimmune diseases (for example, Graves' disease) were registered 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.

Osteonecrosis

Osteonecrosis has been documented, especially in patients with known risk factors, late HIV infection, or long-term use of combined Apt. The frequency of this phenomenon is unknown.

Overdose:

Symptoms

There were no cases of overdose with Akimasol. Specific symptoms of acute overdose of zidovudine and lamivudine. other than dose-dependent adverse reactions for these drugs, is not described. There were no cases of a lethal outcome with an overdose of zidovudine and lamivudine. Clinical studies of abacavir, when used in single doses not exceeding 1200 mg, and in daily doses not exceeding 1800 mg, did not reveal unforeseen undesirable reactions. The effects of abacavir in higher doses have not been studied to date.

Treatment

In the case of an overdose of Akimasol, the patient is monitored forsymptoms of poisoning and. if necessary, conduct a standard maintenance therapy. Because the lamivudine is withdrawn by means of dialysis, with an overdose of Akimasol, one can resort to continuous hemodialysis, although its effectiveness in this situation has not been studied. Although hemodialysis and peritoneal dialysis are ineffective for the excretion of zidovudine, they accelerate the elimination of its metabolite - glucuronide. How effective are hemodialysis and peritoneal dialysis for the removal of abacavir, is still unknown.

For more information, the physician should read the instructions for using individual lamivudine, zidovudine and abacavir preparations.

Interaction:

Clinical studies have not shown clinically significant interactions between abacavir, lamivudine and zidovudine. As the composition of the drug Akimasol includes abacavir, lamivudine and zidovudine, he can enter into the same drug interactions as each of them individually.

The list of interactions listed below should not be considered exhaustive, but it reflects interactions for drug classes,at which care must be taken.

The effect of abacavir on the pharmacokinetics of other substances

In vitro Abacavir demonstrated a lack or a weak ability to inhibit mediators (the transporter of organic anions 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp)) and minimal inhibition of the transporter of organic cations 1 (OST1), OCT2 and protein extrusion of drugs and toxins 2-K (MATE2-K). Thus, it is not expected that abacavir will affect the concentration in the blood plasma of drugs that are substrates of these carrier proteins.

Abicavir is an inhibitor of the protein MATE1 in vitro, but has a weak ability to influence the concentration of MATE1 protein substrates in the blood plasma at therapeutic exposure levels (up to 600 mg).

The effect of other substances on the pharmacokinetics of abacavir

In vitro abacavir is not a substrate of OATP1B1, OATP1B3, OST1, OST2, OAT1, MATE1, MATE2-K, associated with multiple drug resistance of protein 2MRP2) or MRP4. Therefore, it is not expected that the drugs that affect the activity of these vectors,will affect the concentration of abacavir in the blood plasma.

Although in vitro abacavir is a substrate BCRP and P-gp, clinical studies showed no clinically significant changes in the pharmacokinetics of abacavir when used concurrently with lopinavir / ritonavir (P-gp and BCRP).

Drug Interactions Associated with Abacavir

Research in vitro and analysis of the main metabolic pathways of abacavir indicate that its interaction with other drugs mediated by cytochrome P450 is unlikely. Abacavir does not suppress metabolic reactions involving isoenzyme ZA4 cytochrome P450. In studies in vitro shown, that abacavir does not reduce the activity of isoenzymes CYP3A4, CYP2C9 and CYP2D6. Clinical studies have not revealed induction of hepatic metabolism. Thus, the interaction of abacavir with antiretroviral protease inhibitors and other drugs metabolized with the participation of the main isoenzymes of cytochrome P450 is unlikely.

Ethanol

Ethanol, when combined, affects the metabolism of abacavir, leading to an increase AUC abacavir by 41%. These results are not considered clinically relevant. Abacavir does not affect the metabolism of ethanol.

Methadone

According to the pharmacokinetic study using abacavir in a dose of 600 mg twice a day in combination with methadone C_m_Oh abacavir by 35% and delay T_mfor 1 hour, however AUC did not change. Changes in the pharmacokinetics of abacavir were not considered clinically significant. In this study abacavir increased the average systemic clearance of methadone by 22%. These changes were not considered clinically significant in most patients, however, in some cases, there may be a need for a methadone dose adjustment.

Retinoids

Retinoid compounds, such as isotretinoin, are derived with the participation of alcohol dehydrogenase. Interaction with abacavir is possible, but has not been studied to date.

Rifampicin

The interaction has not been studied. It may slightly increase the concentration of abacavir in the blood plasma by the induction of UDP-glucuronyl transferase (UDF-HT). There is not enough data to recommend a dose adjustment.

Phenobarbital

The interaction has not been studied. It may slightly increase the concentration of abacavir in the blood plasma due to the induction of UDF-HT. There is not enough data to recommend a dose adjustment.

Phenytoin

The interaction has not been studied. May slightly increase the concentration of abacavir plasma by induction of UDP-YY. There is not enough data to recommend a dose adjustment. It is necessary to monitor the concentration of phenytoin.

Ribavirin

Due to abacavir and ribavirin have the same path phosphorylation supposed interaction between these materials, which can lead to a decrease in phosphorylation of intracellular metabolites of ribavirin and potentially leading to a decrease in the probability of achieving sustained virologic response in HIV-infected patients with hepatitis C virus confection, treated with pegylated interferon and ribavirin. Controversial data have been published on the simultaneous use of abacavir and ribavirin. According to some data, it is assumed that HIV-infected patients receiving abacavir-containing drugs may have a low risk of responding to antiviral therapy with pegylated interferon and ribavirin. Care should be taken when taking these medications at the same time.

The effect of lamivudine on the pharmacokinetics of other substances

In vitro lamivudine demonstrated the absence or weak ability to inhibit the carriers of the drugs OATP1B1, OLTR1B3, BCRP or P-gp. MATE1, MATE2-K or OST3. Thus, it is not expected that lamivudine will affect the concentration in the blood plasma of drugs that are substrates of these protein mediators.

In vitro lamivudine is an inhibitor of OST1 and OCT2 proteins with values IC50 17 and 33 μM, respectively, but lamivudine has a weak ability to influence the concentration of substrates of proteins OST1 and OST2 in blood plasma under therapeutic exposure conditions (up to 300 mg).

The effect of other substances on the pharmacokinetics of lamivudine

In vitro lamivudine is a substratum of proteins MATE1, MATE2-K and OST2. It has been shown that trimethoprim (an inhibitor of medication data) increases the concentration of lamivudine in blood plasma, but this interaction is not considered clinically significant and a dose adjustment of lamivudine is not required.

Lamivudine is the substrate of the OSTE transporter protein that provides absorption in the liver. Since excretion by the liver plays a minimal role in the clearance of lamivudine, it is unlikely that drug interactions,The inhibition of OSTE is clinically important.

Lamivudine is a substrate P-gp and BCRP, but due to its high bioavailability, it is unlikely that these carriers play a significant role in the absorption of lamivudine. Therefore, it is unlikely that simultaneous use of drugs that are inhibitors of these efflux vectors will affect the distribution and excretion of lamivudine.

Drug Interactions, associated with lamivudine

Metabolic interactions with lamivudine are unlikely in connection with limited metabolism and binding to plasma proteins, and almost complete renal clearance. Nevertheless, with the joint use of lamivudine with other drugs, it is necessary to consider the possibility of drug interactions, especially if these drugs are excreted mainly by the kidneys.

Trimethoprim

The combination of trimethoprim and sulfamethoxazole at a dose of 160 + 800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40% due to trimethoprim. However, in patients with normal renal function, such a change does not require correction of the dose of lamivudine.On the pharmacokinetics of trimethoprim and sulfamethoxazole lamivudine does not affect. Joint use of lamivudine with higher doses of co-trimoxazole, used to treat pneumonia caused by Pneumocystis jiroveci (R. carinii), and toxoplasmosis, is not recommended.

Zalcitabine

With simultaneous application lamivudine can suppress intracellular phosphorylation of zalcitabine, therefore, the drug Akimasol is not recommended for use with zalcitabine.

Emtricitabine

With simultaneous application lamivudine can inhibit intracellular phosphorylation of emtricitabine. In addition, the mechanism of viral resistance to lamivudine and emtricitabine is associated with the same mutation of the reverse transcriptase gene (MI84V), so the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or drugs with fixed combinations of doses containing emtricitabine, Not recommended.

Cladribine

The interaction has not been studied. In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when combined in clinical practice.Some clinical data also confirm the interaction between lamivudine and cladribine. Thus, the simultaneous use of lamivudine and cladribine is not recommended.

Rifampicin

The interaction has not been studied. There is not enough data to recommend a dose adjustment.

Phenobarbital

The interaction has not been studied. There is not enough data to recommend a dose adjustment.

Phenytoin

The interaction has not been studied. There is not enough data to recommend a dose adjustment. It is necessary to monitor the concentration of phenytoin.

Drug interactions associated with zidovudine

The excretion of zidovudine is carried out mainly by conjugation in the liver with the formation of an inactive glucuronated metabolite. In this regard, drugs that are excreted primarily by metabolism in the liver, especially through glucuronation, may have the ability to inhibit zidovudine metabolism.

Atovahon

It was found that zidovudine does not affect the pharmacokinetics of atovahona. However, based on pharmacokinetic data, it has been shown that atovahon can reduce the rate of zidovudine metabolism to its glucuronated metabolite (AUC zidovudine in the equilibrium state was increased by 33%, the maximum concentration of glucuronide in the plasma was reduced by 19%). It is unlikely that the combined use of zidovudine at a dosage of 500 or 600 mg per day and atovahona for 3 weeks to treat acute PCP may lead to an increased incidence of adverse reactions due to a higher concentration of zidovudine in the blood plasma. Special monitoring is required for patients receiving long-term therapy with atavahone.

Clarithromycin

Clarithromycin in the form of tablets reduces the absorption of zidovudine. This can be avoided with the use of clarithromycin and zidovudine with at least a two-hour interval.

Lamivudine

Simultaneous use of zidovudine and lamivudine leads to an increase in zidovudine exposure by 13% and an increase in peak plasma concentrations by 28%, but the total exposure (AUC) did not change significantly. This phenomenon is not considered significant for the safety of patients, so correction of the dosing regimen is not required. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin

There have been reports of a decreased concentration of phenytoin in some patients receiving zidovudine, while in one patient, on the contrary, the concentration was increased. These observations indicate the need for careful monitoring of the concentration of phenytoin in patients in the case of its combination with the drug Akimasol.

Probenecid

There are limited data indicating an increase in the mean half-life of zidovudine and its area under the concentration-time curve under the influence of probenecid by decreasing glucuronidation. The excretion of glucuronide (and, possibly, zidovudine in a free form) by kidneys in the presence of probenecid decreases.

Rifampicin

Restricted data indicate that with simultaneous application of zidovudine and rifampicin AUC zidovudine decreased by 48% ± 34%. The clinical significance of this phenomenon is not established.

Stavudine

Zidovudine can inhibit the intracellular phosphorylation of stavudine in a joint application, so the use of stavudine in combination with the drug Akimasol is not recommended.

Phenobarbital

The interaction has not been studied. It may slightly increase the concentration of zidovudine in blood plasma by induction of UDF-HT. There is not enough data to recommend a dose adjustment.

The concomitant use of valproic acid, fluconazole or methadone with zidovudine may lead to an increase AUC zidovudine and a corresponding decrease in its clearance. Despite the fact that the clinical significance of this phenomenon is unknown, it is necessary to provide thorough medical observation regarding possible manifestations of zidovudine toxicity.

There are other drugs that can influence zidovudine metabolism by competitive inhibition of glucuronation or direct inhibitory action on hepatic microsomal metabolism, including acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam. cimetidine, clofibrate, dapsone and isoprinosine. Careful evaluation of the possibility of drug interactions before the use of these drugs, in particular, for long-term therapy, in conjunction with the drug Akimasol.

The simultaneous use of potentially nephrotoxic and myelosuppressive drugs (such as pentamidine for systemic use, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine. ganciclovir, interferon, vincristine, vinblastine and doxorubicin), especially for short-term therapy, may also increase the risk of unwanted reactions to zidovudine. If you need to use any of these drugs in combination with the drug Akimasol, you should closely monitor kidney function and hematological parameters, and, if necessary, reduce the dose of one or more drugs.

The concomitant use of ribavirin and zidovudine in some cases led to an increased risk of anemia, a fact that is especially important for patients who had an anemia of zidovudine-induced anemia.

Since treatment with Akimasol does not exclude the risk of opportunistic infections, it may be necessary to consider the possibility of simultaneous preventive antimicrobial therapy with co-trimoxazole, pentamidine in the form of aerosol, pyrimethamine and acyclovir. Limited data from clinical trials do not indicate a significant increase in the risk of adverse reactions to zidovudine when using these medications.

The drug Akimasol should not be taken with other medications containing lamivudine, or medicinal products containing emtricitabine.

Special instructions:

Hypersensitivity to abacavir

The use of the drug Akimasol is associated with the risk of developing MRSV, characterized by the appearance of fever and / or rash and other symptoms that indicate a multiple organ failure. The MRI may be life threatening and in rare cases, if not treated properly, can lead to death. The risk of developing MRI with the use of the drug Akimasol is significantly increased in patients with a positive test for the presence of an allele HLA-B* 5701. However, abacavir were observed with a lower frequency in patients who are not carriers of this allele.

Follow the following rules

- A study should be conducted for the presence of an allele HLA-B* 5701 before the beginning of therapy with the drug Akimasol and also before the resumption of therapy with the drug Akimasol in patients with unknown status with respect to the allele HLA-B* 5701, who previously tolerated abacavir well.

- It is not recommended to use the drug Akimasol in patients with an allele HLA-B* 5701 or in patients who have been suspected of having an MRI during any other drug containing abacavir, regardless of the status of the allele HLA-B*5701.

- Each patient should be reminded that it is necessary to read the instructions for use, enclosed in the packaging of the drug Akimasol. Also, patients should be reminded that it is necessary to constantly carry a warning card attached to the drug.

- In all patients receiving therapy with Akimasol, the clinical diagnosis of a suspected MRS should remain the basis for making a clinical decision.

- If MRI is suspected, therapy with Akimasol should be stopped immediately, even if there is no allele HLA-B* 5701. The delay in discontinuing therapy with Akimasol after the occurrence of MRI may lead to a life-threatening reaction.

- Patients who developed MRI. should be informed about the need to transfer the remaining tablets of the drug Akimasol to the treating doctor in order to avoid the resumption of taking abacavir.

- Renewal of the use of drugs containing abacavir after the suspected MRI on abacavir, can lead to a rapid return of symptoms within a few hours, which may include life-threatening arterial hypotension and death.

- When considering the resumption of abacavir therapy after discontinuation of treatment with any drug containing abacavir for any reason, the reason for discontinuing therapy should be established regardless of the patient carrying the alga HGA-B * 5701. If the MRI can not be ruled out, the use of Akimasol or any other medications containing abacavir.

- If the MRI is excluded, it is possible to resume therapy with the drug Akimasol. In rare cases, patients who discontinued abacavir use for reasons other than MRS symptoms also reported the development of life-threatening reactions within a few hours after resumption of abacavir therapy (see section "Description of individual adverse reactions"). Patients should be informed of the possibility of developing an MRI with the resumption of therapy with Akimasol or other medications containing abacavir, and that the resumption of therapy with Akimasol or other medications containing abacavir. Should be carried out only with the availability of quick access to medical care.

Clinical picture of MRI on abacavir

MIRVs on abacavir were well studied in clinical trials and during post-registration follow-up. Symptoms usually appear within the first 6 weeks (median time of onset of this reaction-I1 days) after initiation of abacavir therapy, however these reactions can develop at any time during therapy.

Virtually all of the responses of the WGS to abacavir include fever and / or rash, as part of the syndrome.

Other signs and symptoms that are noted as a manifestation of WGS on abacavir, include symptoms on the part of the respiratory and gastrointestinal tract, which can lead to incorrect diagnosis of MRI as a respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis. If, with the emergence of symptoms associated with MRI, treatment with abacavir continues, they become more pronounced and can take a life-threatening character.In most cases, these symptoms disappear when discontinuing abacavir.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal outcomes, due to antiretroviral therapy with nucleoside analogues in the form of individual drugs, including abacavir. lamivudine and zidovudine, or combinations thereof. Similar phenomena were noted mainly among women. Clinical symptoms that may indicate the development of lactic acidosis include general weakness, anorexia, lack of appetite, rapid weight loss of unclear etiology, gastrointestinal disorders (nausea, vomiting and abdominal pain), respiratory system disorders (shortness of breath and tachypnea) or neurologic symptoms (including motor weakness).

Caution should be exercised when using the drug Akimasol, especially patients with hepatomegaly, hepatitis or other risk factors for liver damage and steatosis of the liver (including certain drugs and alcohol). Patients with hepatitis C virus infection and patients who receive treatment with alpha interferon and ribavirin may be at a particular risk group.Use of the drug is necessary to suspend the appearance of clinical or laboratory signs of lactic acidosis with hepatitis with or without (which include hepatomegaly and steatosis even in the absence of a significant increase in activities of aminotransferases) Symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly or the rapid increase activities of aminotransferases.

Mitochondrial dysfunction

Research in vitro and in vivo showed that the analogues of nucleosides and nucleotides can cause a different degree of damage to the mitochondria. Mitochondrial dysfunction was observed in HIV-negative children who received intrauterine and / or post-nucleoside analogues. The main undesirable reactions were hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions are often transient. Some neurological disorders with late onset have been reported (muscle tone increase, convulsions, behavioral disorders).Whether these neurological disorders are transient or permanent, is currently unknown. Any child, even HIV-negative, exposed to prenatal exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the corresponding signs or symptoms. These data do not affect the current national recommendations for use Apt in pregnant women for the prevention of vertical transmission of HIV infection.

Lipoatrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat. The frequency of occurrence and severity of lipoatrophy are related to the total exposure. Such a loss of fat, which is most pronounced on the face, extremities and buttocks, can only be reversed, and improvement can only come a few months after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and other drugs containing zidovudine, patients should be regularly examined for signs of lipoatrophy,and if you suspect a development of lipoatrophy, you should, if possible, switch to an alternative therapy regimen.

Serum lipids and blood glucose

Concentrations of serum lipids and blood glucose may increase during antiretroviral therapy. Control of the disease and lifestyle changes can also contribute to this process. The need to determine the concentration of serum lipids and blood glucose should be considered. Disorders of lipid metabolism should be treated, guided by their clinical manifestations.

Undesirable reactions from the hematopoiesis system

In patients receiving zidovudine. can be observed anemia, neutropenia and leukopenia (usually secondary to neutropenia). Most often, these phenomena occur with the use of high doses of zidovudine (1200-1500 mg / day), as well as in cases when, before the start of treatment, the patient experienced oppression of hematopoiesis, in particular, in the late stages of HIV infection. Neutropenia is also more common in those patients whose neutrophil count, serum hemoglobin and vitamin B12 concentration were reduced even before the initiation of zidovudine therapy.Therefore, in patients taking the drug Akimasol, it is necessary to carefully monitor hematologic indices.

These haematological disorders usually occur no earlier than 4-6 weeks after initiation of therapy. In the late stages of HIV infection during the first three months of treatment, a blood test is recommended at least every 2 weeks, then at least monthly. For therapy initiated in the early stages of HIV infection, hematological adverse reactions are rare. Depending on the general condition of the patients, a blood test can be performed less often, for example, every 1-3 months.

With the development of severe anemia and severe myelosuppression under the influence of the preparation Akimasol, as well as in the presence of hematologic disorders prior to treatment, for example, with a hemoglobin concentration below 9 g / dl (5.59 mmol / L) or a neutrophil content below 1.0 x 10⁹/ l, a dose adjustment of zidovudine may be required. Since the dose of zidovudine in the composition of the drug Akimasol can not be changed, such patients should use separate preparations of zidovudine. abacavir and lamivudine.

Pancreatitis

On a background of treatment with abacavir, lamivudine and zidovudine, pancreatitis is rare in rare cases, although it is still unclear whether it is caused by the action of these drugs or is a consequence of HIV infection. When clinical signs, symptoms or laboratory signs of pancreatitis appear, treatment with Akimasol should be stopped immediately.

Diseases of the liver

The efficacy and safety of the drug Akimasol have not been established in patients with severe concomitant liver disease. The drug Akimasol is contraindicated in patients with impaired liver function. In patients with an initially present impaired hepatic function, including an active form of chronic hepatitis, there is an increase in the incidence of liver dysfunction in combination Apt. Such patients need to be monitored in accordance with standard clinical practice. With worsening of liver function in such patients should consider the possibility of suspension or withdrawal of the drug.

In patients with chronic hepatitis B or C receiving a combined Apt, increased risk of serious and deadly adverse reactions from the liver. In case of concomitant use of antiviral therapy for hepatitis B or C, the instructions for the use of these drugs should be consulted. With the cancellation of the drug Akimasol, patients with concomitant viral hepatitis B should monitor the performance of functional liver samples and regularly determine the viral load, since a possible relapse of hepatitis after stopping lamivudine. which can have more severe consequences in patients with decompensated liver damage.

Concomitant Hepatitis B

The results of clinical trials and post-registration data indicate that in some patients with chronic hepatitis B, lamivudine can be withdrawn from clinical and laboratory signs of hepatitis recurrence, which may have more severe consequences in patients with decompensated liver disease. In the case of cancellation of the drug Akimasol in patients with concomitant viral hepatitis B should consider the possibility of periodic monitoring of liver function and markers of replication of the hepatitis B virus.

Concomitant Hepatitis C

When zidovudine was used as part of the HIV treatment regimen, cases of exacerbation of anemia with ribavirin were recorded, the exact mechanism of this phenomenon remains unknown. In this regard, the simultaneous use of zidovudine with ribavirin is not recommended. If zidovudine already included in the scheme of combined antiretroviral therapy, should consider the possibility of its replacement. This is especially important for patients with a history of anemia-induced zidovudine anemia.

Immunodeficiency Syndrome

In the presence of HIV-infected patients with severe immunodeficiency of asymptomatic opportunistic infections or their residual phenomena at the time of initiation of antiretroviral therapy, it can intensify the inflammatory process and lead to an increase in the symptoms of opportunistic infections or other severe consequences. Typically, these reactions occur within the first weeks or months after initiation of antiretroviral therapy. As an example, cytomegalovirus retinitis, generalized or focal mycobacterial infection and pneumonia caused by Pneumocystis jiroveci (R. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after initiation of therapy and meticulous treatment.

Onopportunistic infections

The use of the drug Akimasol or other antiretroviral drugs does not exclude the possibility of developing opportunistic infections or other complications of HIV infection, so patients should remain under the supervision of a doctor who has experience in the treatment of these diseases.

Osteonecrosis

Despite the fact that the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often encountered in patients at a late stage of HIV infection and / or long-term combined Apt. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

Transmission of HIV infection

Patients should be warned that treatment with antiretroviral drugs, including Akimasol, does not prevent the risk of HIV transmission to other people by sexual contact and blood contamination. Therefore, patients should take appropriate precautions.

Myocardial infarction

As a result of a prospective, observational, epidemiological study in order to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, a previous association of abacavir was detected, within 6 months, with an increased risk of myocardial infarction. According to the generalized analysis of clinical studies, there was no increase in the risk of myocardial infarction associated with abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data obtained from observational cohort and controlled clinical trials do not allow one to unequivocally determine the relationship of abacavir therapy with the risk of myocardial infarction.

Nevertheless, caution should be given to antiretroviral therapy, including abacavir. patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize the modifiable risk factors (such as arterial hypertension, hyperlipidemia, diabetes and smoking).

Concomitant treatment

Patients should be cautioned against self-medication with any form of medication.

Correction of dose

If individual dosing is necessary, separate preparations of abacavir, lamivudine and zidovudine are used. In this case, the doctor should read the instructions for using each of these drugs.

Use with other antiretroviral drugs

At present, there is insufficient data on the efficacy and safety of simultaneous application of the drug Akimasol with non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

The drug Akimasol should not be used with drugs containing lamivudine or emtricitabine.

You should avoid the simultaneous use of stavudine and zidovudine.

The use of lamivudine with cladribine is not recommended.

Patient Warning Card

Attention!

Akimasol, film-coated tablets abacavir zidovudine+ 3TC

Always carry this card with you!

Because the drug Akimasol contains abacavir, in some patients receiving Akimasol, can develop a hypersensitivity reaction (a serious allergic reaction), often life-threatening, if not abolish the drug. IMMEDIATELY CONTACT YOUR DOCTOR DOCTOR for advice on the possibility of further taking the drug Akimasol if:

- you have a skin rash OR

- you have one or more of the following symptoms:

- fever;

- shortness of breath, sore throat, or cough;

- nausea or vomiting, abdominal pain, diarrhea;

- increased fatigue, pain or general malaise.

If you stop taking the drug Akimasol as a result of this reaction, DO NOT take any more Akimasol or any other preparation containing abacavir (Ziagen, Kivexa), as this can immediately lead to life-threatening drop in blood pressure or death.

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

Studies of the effect of the drug Akimasol and its active ingredients (abacavir, lamivudine and zidovudine) on the ability to drive vehicles and work with mechanisms have not been conducted.The pharmacological properties of the active substances do not allow to predict the effect of the drug Akimasol on these activities. When assessing a patient's ability to drive and work with machinery, his clinical condition and the full range of adverse reactions of the drug Akimasol should be considered.

Form release / dosage:

Film-coated tablets, 300 mg + 300 mg + 150 mg.

Packaging:

Primary packaging of medicinal product

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30, 60, 90, 120 tablets in a polymer jar of low-pressure polyethylene with a cover pulled with the control of the first opening. Pa banks glue labels from paper label or writing, or from polymer materials, self-adhesive.

Secondary packaging of medicinal product

By 3, 6, 9 contour mesh packages together with the instruction for use and a warning card are placed in a pack of cardboard. The packets are placed in a group package.

On 1 bank together with instructions on application and the precautionary card place in a pack from a cardboard. The packets are placed in a group package.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004660

Date of registration:25.01.2018

Expiration Date:25.01.2023

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp01.03.2018

Illustrated instructions

Instructions

Akimasol (Akimasol)