Abacavir - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline - 384.11 mg, sodium carboxymethyl starch - 24.00 mg, silicon colloidal dioxide - 4.50 mg, magnesium stearate - 16.00 mg.

Tablet casing: Fill yellow (13K52177) - 20,000 mg: hypromellose (6cP) - 59.0%, titanium dioxide 26.0%, triacetin / glycerol 8.0%, iron oxide yellow 6.0%, polysorbate 80-1, 0%.

Description:

The capsule-shaped, biconvex tablets, coated with a film coating of yellow color,with a risk on both sides and with engraving "D"and" 88 "on both sides of the risks on the one hand.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.F.06 Abacavir

Pharmacodynamics:

Mechanism of action

Abacavir is a nucleoside analogue that inhibits HIV reverse transcriptase and selectively suppresses the replication of HIV-1 and HIV-2, including HIV-1 strains resistant to zidovudine, lamivudine, zalcitabine, didanosine and nevirapine.

Abacavir undergoes intracellular metabolism, becoming an active form of carbovir-5'-triphosphate (carbovir-TF). According to research in vitro, the antiviral effect of the drug is due to the inhibition of HIV reverse transcriptase, which leads to the breakdown of DNA synthesis on the viral RNA template and the stopping of HIV replication.

There was no antagonism in the antiviral activity of abacavir in cell culture when combined with nucleoside reverse transcriptase inhibitors didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, non-nucleoside reverse transcriptase inhibitors, nevirapine, or an HIV protease inhibitor amprenavir.

Pharmacodynamics

In the obtained in vitro strains of HIV 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 8-fold increase in 50% inhibitory concentration (IC₅₀) require multiple mutations of the viral genome.

Strains resistant to abacavir may have decreased sensitivity to lamivudine, zalcitabine and / or didanosine, but retain a sensitivity to zidovudine and stavudine. Cross-resistance to abacavir and HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely. Inefficiency of the combination of the first-line regime, including abacavir, lamivudine and zidovudine, is mainly associated with a single mutation - M184V, which preserves the possibility of a wide choice of regimens for the second-line therapy.

Abacavir penetrates into the cerebrospinal fluid (CSF) and reduces the content of HIV-1 RNA in it. In combination with other antiretroviral drugs, it can prevent the development of neurological complications of HIV infection and slow the emergence of resistant strains within the CNS.

Pharmacokinetics:

Suction

Abacavir is quickly and well absorbed when taken orally. Absolute bioavailability of abacavir for oral administration in adults is about 83%. The time to reach the maximum concentration (T_mOh) when taking abacavir orally in the form of tablets is about 1.5 h.

When taking abacavir orally at a dose of 300 mg 2 times a day, the maximum concentration in the blood plasma (C_mOh) on reaching the equilibrium state averages 3 μg / ml, and the area under the pharmacokinetic curve "concentration-time" (AUC) during 12hour period between doses - on average 6,02 μg * h / ml (during the day - about 12 μg * h / ml). After a single admission of abacavir tablets in a dose of 600 mg C_mOh averages about 4.26 μg / ml, a AUC - an average of 11.95 μg * h / ml.

According to the study, 20 HIV-infected patients abacavir in a dose of 300 mg twice a day and only one dose (300 mg) before the 24-hour sampling period for analysis, the geometric mean of the terminal half-life (T₁_/₂) of intracellular carbovir-TF at an equilibrium state is 20.6 h (the same index for the concentration of abacavir in serum is 2.6 h).Equilibrium pharmacokinetic indices when taking abacavir 600 mg once a day were similar to those with abacavir 300 mg twice daily in a cross-sectional clinical trial in 27 HIV-infected patients. The intracellular content of carbovir-TF in peripheral blood mononuclears was higher with abacavir at a dose of 600 mg 1 time per day compared with 300 mg twice a day for abacavir (AUC in 24-hour equilibrium (AUC₂₄_{, ss}) by 32%, the maximum daily concentration in the equilibrium state (C_{max 24, ss}) by 99%), which indicates the possibility of such a regimen of taking the drug by HIV-infected patients.

Eating slows the absorption of abacavir and reduces C_mOh, but does not affect AUC. therefore abacavir can be taken with or without food.

Distribution and binding to blood plasma proteins

The volume of distribution of abacavir with intravenous administration is about 0.8 l / kg, which indicates its ability to easily penetrate into tissues.

In studies in HIV-infected patients, it has been shown that abacavir well penetrates into the cerebrospinal fluid (CSF), with the ratio AUC abacavir in CSF and AUC Abacavir in plasma is 30-44%.It was found that 1.5 hours after taking abacavir at a dose of 300 mg twice a day, its concentration in the CSF was 0.14 μg / ml. When using abacavir in a dose of 600 mg twice a day, the concentration of the drug in the CSF increased from 0.13 μg / ml when measured 0.5-1 hour to 0.74 μg / ml when measured 3-4 hours after taking abacavir . Thus, even if the abacavir concentration observed in the CSF is 4 hours after taking the drug at a dose of 600 mg 2 once a day, is not the maximum achieved with this mode of therapy, it already exceeds IC₅₀ (0.08 μg / ml or 0.26 μmol / L) 9-fold.

In studies in vitro it was found that in therapeutic doses abacavir moderately (approximately 49%) binds to human plasma proteins. This indicates that the interaction of abacavir with other drugs by their displacement from the compound with plasma proteins is unlikely.

Metabolism

Abacavir is metabolized predominantly in the liver. Less than 2% of the accepted dose of the drug is excreted by the kidneys unchanged. In the human body abacavir is metabolized mainly by the action of alcohol dehydrogenase to form the 5'-carboxylic acid and by conjugation with glucuronic acid to form 5'-glucuronide,accounting for about 66% of the total amount of the administered dose of the drug. These metabolites are excreted by the kidneys.

Excretion

On average, the half-life of abacavir is about 1.5 hours. Prolonged intake of abacavir orally at a dose of 300 mg 2 times a day does not lead to significant cumulation of the drug. Abacavir excretion is carried out by metabolism in the liver, followed by excretion of metabolites mainly through the kidneys. About 83% of the administered dose is excreted by the kidneys in the form of metabolites and abacavir in unchanged form, and the remaining amount - through the intestine.

Special patient groups

Children

Abacavir is well and rapidly absorbed when ingested in children. All pharmacokinetic parameters in children are comparable to those in adults with slightly greater variability in plasma concentrations. Pharmacokinetic studies in children showed that taking the drug 1 time per day is equivalent in terms of indices AUC₀_-24Reception of the same dose of the drug, divided into 2 times per day, for existing dosage forms (oral solution and film-coated tablets).

There is insufficient safety data to recommend the use of abacavir in children younger than 3 months.

Elderly people

The pharmacokinetics of abacavir in patients older than 65 years have not been studied. In the treatment of elderly patients, it is necessary to take into account more frequent violations of the liver, kidney and heart function at this age, as well as concomitant diseases and medications taken.

Patients with impaired renal function

Abacavir is metabolized predominantly in the liver, less than 2% it is excreted by the kidneys unchanged. The pharmacokinetics of abacavir in the terminal stage of renal failure is about the same as with normal kidney function. Therefore, if the renal function is impaired, dose adjustment is not required.

Patients with impaired hepatic function

Abacavir is metabolized mainly in the liver. The results of a study of the pharmacokinetics of abacavir in patients with mild liver function disorder (5-6 points on the Child-Pugh scale) indicate an AUC increase of 1.89 times on average and a half-life of 1.58 times. The index of AUC metabolites of abacavir is not affected by liver dysfunction, however, the rate of their formation and excretion decreases.

Patients with a mild liver function disorder show the administration of the drug in another dosage form.

The pharmacokinetics of abacavir in patients with impaired liver function of moderate and severe severity has not been studied, thus, the use of abacavir is contraindicated in these patient groups.

Indications:

Treatment of HIV infection in adults and children weighing more than 14 kg as part of combined antiretroviral therapy.

Contraindications:

- Hypersensitivity to abacavir or any other component included in the preparation;

- children and adolescents with a body weight of less than 14 kg (for this dosage form).

- the period of breastfeeding;

- a violation of the liver function (for a given dosage form) according to the Child-Pugh class A, B and C (due to the lack of clinical data and the recommended dosing regimen).

Carefully:

Patients with a possible risk of coronary heart disease, joint use of abacavir and ribavirin (see section "Interaction").

Pregnancy and lactation:

Pregnancy

Data available in the Registry of the use of antiretroviral drugs during pregnancy,do not indicate an increase in the risk of developing major congenital malformations associated with the use of abacavir, compared with the frequency of malformations in the comparison group. However, adequate and well-controlled studies involving pregnant women are not available, the safety of abacavir in women during pregnancy has not been established to date. There is evidence of the effects of abacavir in reproductive studies in animals. If it is necessary to use the drug Abacavir During pregnancy, the ratio of expected benefit to the mother and the potential risk to the fetus should be assessed.

There is evidence of a slight transient increase in the concentration of lactic acid in the blood plasma of newborns and infants whose mothers during pregnancy and childbirth were receiving nucleoside reverse transcriptase inhibitors. Perhaps this is due to mitochondrial disorders. The clinical significance of this phenomenon has not been established to date. In addition, there are extremely rare reports of developmental delay, epileptic seizures and other neurological disorders in newborns (eg, muscle tone increase).However, the causal relationship of these disorders with the intake of nucleoside reverse transcriptase inhibitors by mothers during pregnancy and in childbirth has not been established. These data do not abolish existing recommendations on the use of antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Lactation

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:

Inside, regardless of food intake.

The drug should be prescribed by a doctor with experience in the treatment of HIV infection.

Adults, children and adolescents with a body weight of at least 25 kg

The recommended dose of the drug Abacavir - 600 mg / day. The drug is prescribed in a dose of 300 mg (1 tablet) 2 times a day or 600 mg (2 tablets) once a day.

Special patient groups

Children with a body weight of 14 to 25 kg

- Children with body weight from 14 to 20 kg: recommended dose of the drug Abacavir - 1/2 tablets (break exactly as per the risk) 2 times a day or 300 mg (1 tablet) once a day;

- Children with a body weight of more than 20 kg, but less than 25 kg: recommended dose of the drug Abacavir - 1/2 tablets (break accurately at risk) in the morning and 1 tablet in the evening or 1½ tablets once a day.

Patients with impaired renal function

In patients with impaired renal function, dose adjustment Abacavir not required.

Patients with impaired hepatic function

The use is contraindicated (for this dosage form, due to the lack of clinical data and the recommended dosage regimen).

Side effects:

Hypersensitivity

According to clinical studies conducted before the screening for the presence of an allele HLA-B* 5701, in about 5% of patients taking abacavir, there was a reaction of hypersensitivity, in rare cases with fatal outcome. Hypersensitivity to abacavir is characterized by the appearance of symptoms that indicate a multiple organ failure.

Almost the majority of patients with hypersensitivity develop fever and / or a rash (usually maculopapular or urticaria), although in some cases these manifestations are absent.

Symptoms of hypersensitivity reactions may appear at any time after initiation of abacavir treatment, but most often they occur during the first 6 weeks of treatment (median time of onset of this reaction is 11 days).Patients should be closely monitored with advice every 2 weeks, especially during the first 2 months of abacavir therapy.

The hypersensitivity reactions are shown below. Symptoms that occur in at least 10% of patients with hypersensitivity are in bold.

Disturbances from the skin and subcutaneous fat

Rash (usually maculopapular or urticaria).

From the gastrointestinal tract

Nausea, vomiting, diarrhea, abdominal pain, ulceration of the oral mucosa.

Disturbances from the respiratory system, chest and mediastinal organs

Shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Disturbances from the nervous system

Headache, paresthesia.

Disturbances from the hematopoietic and lymphatic system

Lymphopenia.

Disorders from the liver and pancreas

Increase in biochemical parameters of liver function, hepatitis, hepatic insufficiency.

Disorders from the musculoskeletal system

Myalgia; rarely - myolysis, arthralgia, increased activity of creatine phosphokinase.

Disorders from the kidneys and urinary system

Increased serum creatinine, renal failure.

Other

Fever, fatigue, malaise, swelling, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions.

Patients with a hypersensitivity reaction may initially take it for respiratory disease (pneumonia, bronchitis, pharyngitis), flu-like syndrome, gastroenteritis, or for unwanted reactions associated with taking other drugs. Late diagnosis of a hypersensitivity reaction leads to the continuation or resumption of abacavir, resulting in a more severe hypersensitivity reaction or death.

Therefore, if any of these symptoms appear, a thorough examination of the patient is necessary to exclude the hypersensitivity reaction. If you can not exclude hypersensitivity reaction, then re-appointment of the drug Abacavir or other abacavir-containing drugs is strictly contraindicated.

It is likely that interruption of therapy may increase the risk of developing sensitization and, consequently, the occurrence of clinically significant hypersensitivity reactions.Therefore, patients should be warned about the importance of regular intake of the drug Abacavir.

If the hypersensitivity reaction develops, patients continue to take the drug Abacavir, the clinical manifestations become more pronounced, and with the withdrawal of the drug Abacavir they are usually subjected to reverse development. Renewal of the drug Abacavir patients with a history of hypersensitivity reaction lead to the development of a second reaction within a few hours.

Repeated hypersensitivity reactions can occur more severely than the first, and manifest life-threatening arterial hypotension, up to a lethal outcome. When developing a hypersensitivity reaction to abacavir, regardless of the carriage of the HLA-B * 5701 allele, the drug should be withdrawn and never administered again, as with other drugs containing abacavir.

Sometimes the hypersensitivity reaction develops when the drug is resumed Abacavir after its withdrawal, caused by the appearance of just one of the main symptoms of this reaction (rash, fever, malaise, fatigue, disorders of the gastrointestinal tract or respiratory system).

In rare cases, this reaction occurs when the drug is resumed Abacavir patients who had no previous symptoms of hypersensitivity reaction prior to discontinuation of the drug.

The nature of other adverse events other than the hypersensitivity reaction, but observed in patients receiving the drug Abacavir, to the end is not clear. Whether these undesirable phenomena result from the use of the drug Abacavir or other drugs simultaneously prescribed with it, or they are caused by the disease itself, has not been established to date.

Many of the undesirable effects associated with taking the drug Abacavir (nausea, vomiting, diarrhea, fever, fatigue, rash) may also occur with the development of a hypersensitivity reaction. Therefore, when any of these symptoms appear, a thorough examination of the patient is performed to confirm or exclude a hypersensitivity reaction. If the drug Abacavir was canceled due to suspicion of a hypersensitivity reaction, resumption of the drug is prohibited. Resume drug therapy Abacavir after interruption in connection with the appearance of the above symptoms can only be after the elimination of the hypersensitivity reaction and under direct medical supervision.

Very rare cases of polymorphic exudative erythema, Stevens-Johnson syndrome, or toxic epidermal necrolysis were reported in which the hypersensitivity reaction to abacavir could not be ruled out. In such cases, you should always stop taking medication containing abacavir.

Most of the undesirable reactions listed below do not limit the use of the drug Abacavir.

Depending on the frequency of detection, they can be divided into the following categories: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely > 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Clinical Trials Data

Disorders from the metabolism and nutrition

Often: anorexia.

Disturbances from the nervous system

Often: headache.

Violations from the groan of the gastrointestinal tract

Often: nausea, vomiting, diarrhea.

Systemic manifestations and local reactions

Often: fever, drowsiness, fatigue.

In controlled clinical trials, it was shown that the change in laboratory parameters during drug treatment Abacavir is observed as rarely as in the control group of patients who did not receive the drug.

Post-registration data

Metabolic and nutritional disorders

Often: hyperlactatemia, hypertriglyceridemia, hypercholesterolemia, insulin resistance.

Rarely: lactic acidosis (possibly fatal, usually associated with severe hepatomegaly and steatosis of the liver), accumulation and / or redistribution of adipose tissue (lipodystrophy).

The frequency of these adverse reactions depends on many factors, including antiretroviral drugs used in combination with abacavir.

Disorders from the central nervous system: headache, dizziness, migraines, sleep disorders, depressive disorders, malaise, fatigue.

Disorders from the cardiovascular system: myocardial infarction.

Disorders from the gastrointestinal tract

Rarely: nausea, vomiting, diarrhea, abdominal pain, gastritis, pancreatitis (cause-and-effect relationship with abacavir is not exactly established), hepatomegaly, fatty liver.

Rarely: pancreatitis (a cause-and-effect relationship with the use of abacavir is not exactly established).

Disturbances from the respiratory system: bronchitis.

Disturbances from the skin

Often: rash (in the absence of systemic manifestations).

Very rarely: polymorphic erythema exudative, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the side of the musculoskeletal system: musculoskeletal pain.

Laboratory changes: an increase in the activity of creatine phosphokinase, amylase, alanyl aminotransferase (ALT), aspartate aminotransferase (ACT), gamma glutamyltranspeptidase (GGT), hypertriglyceridemia, hypercholesterolemia, neutropenia, anemia, thrombocytopenia, leukopenia, hyperglycemia.

Other: fever, lethargy, chills, opportunistic infections, immune reconstitution syndrome, autoimmune diseases.

Lactoacidosis, sometimes fatal, has been reported, usually associated with severe hepatomegaly and fatty liver dysfunction, using nucleoside analogues.

The use of combination antiretroviral therapy has been associated with the redistribution of adipose tissue (lipodystrophy) in patients with HIV, including a reduction in the subcutaneous fat layer on the face and extremities,increase in mammary glands and dorsocervical fat deposition ("buffalo hump").

The use of combination antiretroviral therapy has been associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency, the onset of combined antiretroviral therapy may result in inflammatory responses to asymptomatic or residual opportunistic infections.

There have also been cases of autoimmune diseases (eg, Graves' disease) occurring under conditions of immune reactivation, but the presented terms of the disease manifestation are more diverse and these phenomena can occur many months after the initiation of therapy.

Cases of osteonecrosis have been reported, especially in patients with well-known risk factors, advanced stage of HIV infection or long-term use of combination antiretroviral therapy.

The frequency of this phenomenon is unknown.

Overdose:

Symptoms

In clinical trials, no undesirable reactions were observed with the use of the drug Abacavir in single doses up to 1200 mg and daily up to 1800 mg. The effect of the drug in higher doses has not been studied to date.

Treatment

In case of drug overdose Abacavir the patient is monitored for symptoms of poisoning and timely treatment. If necessary, perform symptomatic treatment. The efficacy of peritoneal dialysis and hemodialysis for abacavir removal is unknown.

Interaction:

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 3A4 cytochrome P450. In studies in vitro shown, that abacavir Do not enter into interactions with drugs that are metabolized by isoenzymes CYP3A4, CYP2C9 and CYP2D6. Clinical studies have not revealed the induction of hepatic metabolism of exogenous substances under the action of abacavir. Thus, the interaction of abacavir with HIV protease inhibitors and other drugs metabolized with the participation of the main cytochrome P450 isoenzymes is unlikely.

Clinical studies have shown no clinically relevant interactions between abacavir, zidovudine and lamivudine.

Powerful inducers of cytochrome P450 isoenzymes, such as rifampicin, phenobarbital and phenytoin when exposed to UDP-glucuronyl transferase, the plasma concentration of abacavir can be slightly reduced.

Ethanol: ethanol slows the metabolism of abacavir, which leads to an increase AUC at 41%. However, the clinical significance of this change is small. On the metabolism of ethanol abacavir does not affect.

Methadone: according to pharmacokinetic studies, the use of abacavir at a dose of 600 mg twice a day in combination with methadone reduces the maximum concentration (C_mOh) of abacavir in serum by 35%, increases the time to reach the maximum concentration in serum (T_mOh) for 1 hour, but does not change AUC.

The clinical significance of these changes is small. The same study found that abacavir increases the systemic clearance of methadone by 22%. In most cases, these changes are also considered clinically insignificant, but in certain situations, a dose change in methadone may be required.

Retinoids: retinoids, for example isotretinoin, are eliminated with the participation of alcohol dehydrogenase, so they can interact with abacavir, but to date no special studies have been conducted.

Ribavirin: as in abacavir, ribavirin has the same pathways of intracellular phosphorylation. The interaction between these drugs can lead to a decrease in the concentration of intracellular phosphorylated metabolites of ribavirin and, as a consequence, reduce the likelihood of achieving a stable virologic response (SVR) in HIV-infected patients infected with hepatitis C who received pegylated interferon and ribavirin. Clinical evidence suggests that HIV / HCV-infected patients receiving abacavir containing antiretroviral regimens may be at risk of a lower response to PEG-interferon / ribavirin therapy. Caution should be exercised in the combined use of abacavir and ribavirin.

Special instructions:

The drug should be prescribed by a doctor with experience in the treatment of HIV infection.

Each patient should read the instructions for use.

Hypersensitivity

According to clinical studies conducted before the screening for the presence of an allele HLA-B* 5701, in about 5% of patients receiving abacavir, hypersensitivity to the drug develops, in rare cases with a fatal outcome.

Risk factors

In clinical studies, it has been shown that the carriage of an allele HLA-B* 5701 significantly increases the risk of developing a hypersensitivity reaction to abacavir. In a prospective clinical study CNA106030 (PREDICT-1) patients with an allele HLA-B* 5701 preparations containing abacavirwere not administered, which significantly reduced the incidence of a clinically suspected hypersensitivity reaction from 7.8% (66 patients out of 847) to 3.4% (27 patients out of 803) (p <0.0001), and the incidence of hypersensitivity reaction , confirmed by the skin-application sample, from 2.7% (23 patients out of 842) to 0.0% (0 patients from 802) (p <0.0001). Thus, the results of this study showed that 48-61% patients-carriers of the allele HLA-B* 5701 a hypersensitivity reaction develops compared to 0-4 % patients who do not have this allele.

It is recommended that doctors screen for carriage of an allele HLA-B* 5701 in HIV-infected patients who have not previously been prescribed drugs containing abacavir. Screening is also recommended before the re-administration of abacavir to patients with unknown HLA-B* 5701-status, who previously tolerated abacavir well.

The use of abacavir-containing drugs is not recommended in patients carrying an allele HLA-B* 5701 and should be considered only in exceptional cases under close medical supervision, when the potential benefit exceeds the risk associated with the use of the drug.

Clinical diagnosis of suspected hypersensitivity reactions should remain the basis for deciding whether to use drugs containing abacavir, in all patients. Even in the absence of an allele HLA-B*5701 abacavir it is necessary to cancel and not to resume its reception in all cases when the hypersensitivity reaction can not be ruled out, guided by clinical data, because of the potential risk of serious adverse effects or even death.

Clinical picture

The reaction of hypersensitivity to abacavir is characterized by the appearance of symptoms indicating multiorgan lesion.The most common symptoms - fever and / or rash - are noted in most patients. Other symptoms of hypersensitivity to abacavir include fatigue, malaise, gastrointestinal disturbances, including vomiting, nausea, diarrhea and abdominal pain, respiratory system disorders, including dyspnea, sore throat, cough, lung damage (mainly in the the form of local infiltrative changes detected by chest x-ray).

Symptoms may be hypersensitive at any time after starting treatment with abacavir, but most often they occur within the first six weeks of use. Patients should be closely monitored with advice every 2 weeks, especially during the first 2 months of therapy with the drug Abacavir.

If, when hypersensitivity symptoms appear, abacavir treatment continues, they become more pronounced and can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Treatment

When hypersensitivity symptoms to abacavir appear, the patient, regardless of the carriage of the allele HLA-B* 5701, MUST immediately contact your doctor for advice.The diagnosis of a hypersensitivity reaction to abacavir requires immediate withdrawal of the drug. NEVER SHOULD RESUME MEDICATION Abacavir or other preparation containing abacavir, after the occurrence of a hypersensitivity reaction. This is due to the threat of even more severe symptoms (including life-threatening arterial hypotension) occurring within a few hours after the resumption of the drug, which can lead to death.

To prevent late detection and reduce the risk of developing a life-threatening hypersensitivity reaction, you should completely stop taking the drug Abacavir if it is impossible to exclude hypersensitivity, even with the potential presence of other diagnoses (respiratory diseases, influenza-like diseases, gastroenteritis, reactions to taking other medications). It is necessary to observe special care for those patients who simultaneously started taking the drug Abacavir and other drugs known to cause skin reactions (eg, non-nucleoside reverse transcriptase inhibitors - NNRTIs).This is due to the fact that at present it is difficult to differentiate the rash caused by these drugs and the hypersensitivity reaction to abacavir.

Do not resume drug treatment Abacavir or other preparation containing abacavir, even in the case of the appearance of symptoms of hypersensitivity in the re-admission of alternative medications.

Special instructions for treatment after a break in therapy with the drug Abacavir

Regardless of the carriage of the allele HLA-B* 5701, if after discontinuation of the drug Abacavir the resumption of treatment with this drug is expected, it is necessary to find out the reason for the cancellation and make sure that the patient does not have symptoms of hypersensitivity. If you can not exclude a hypersensitivity reaction, then the resumption of treatment with the drug Abacavir or other preparation containing abacavir, forbidden.

A few cases of development of a hypersensitivity reaction during the resumption of treatment with abacavir after its withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue, gastrointestinal disturbances and respiratory system disorders) are described.The most common isolated symptom of a hypersensitivity reaction was a skin rash.

Since in all such cases it is impossible to exclude the hypersensitivity reaction and, taking into account the data on its more severe course with the repeated use of abacavir, the resumption of therapy with the drug Abacavir or other abacavir-containing drug in these patients is not recommended. However, if in such cases the question of re-appointment of abacavir is resolved positively, then treatment is carried out only under direct medical supervision.

The hypersensitivity reaction is noted, although extremely rare, even with the resumption of treatment with an abacavir-containing drug in patients who have not previously experienced symptoms of this reaction and who have a break in taking the drug containing abacavir, was associated with other causes. In this case, the resumption of taking the drug is possible, but it is necessary to have quick access to medical care from the patient or those around him.

Screening for carriage of an allele HLA-B * 5701 is recommended before reassignment of abacavir in patients with unknown HLA-B* 5701-status, previously well tolerated with abacavir therapy. Re-administration of abacavir to allele-bearing patients HLA-B* 5701 is not recommended and can only be considered in exceptional cases under careful medical supervision, when the potential benefit of drug treatment outweighs all possible risks.

Necessary information for patients

The doctor prescribing the drug, should familiarize patient with the following information about the hypersensitivity reaction:

- the patient should be aware of the possibility of life-threatening symptoms of hypersensitivity and the risk of death, as well as the increased risk of hypersensitivity reactions in the carriers of the allele HLA- B * 5701;

- the patient must be warned that even in the absence of the HLA-B * 5701 allele, a hypersensitivity reaction may develop. Thus, ALL patients with the appearance of symptoms that may be due to a hypersensitivity reaction, MUST IMMEDIATELY contact your doctor;

- Patients with hypersensitivity to abacavir should be warned about the inadmissibility of resuming the use of the drug Abacavir or other drugs containing abacavir, regardless HLA-B* 5701-status;

- to avoid repeated use of the drug Abacavir patients who have had a hypersensitivity reaction, they are recommended to return the remaining tablets of the drug Abacavir to the doctor;

- patients who for any reason interrupted treatment with the drug Abacavir (especially in connection with possible unwanted reactions or complications of treatment), before, resumption of the drug should consult a doctor.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal, due to antiretroviral therapy with nucleoside analogues, including abacavir, lamivudine and zidovudine, taken either individually or in combination. In most cases, these complications occur in women.

Symptoms that indicate the development of lactic acidosis include general weakness, loss of appetite, rapid weight loss of unknown etiology, disorders of the gastrointestinal tract (nausea, vomiting and abdominal pain), disorders of the respiratory system (dyspnea and tachypnea) or neurological symptoms ( including motor).

Lactic acidosis has a high mortality in the absence of emergency treatment and can be associated with pancreatitis, hepatic or renal insufficiency. Lactic acidosis, as a rule, manifests itself after several months of therapy. It is necessary to stop therapy with nucleoside analogues in case of symptomatic manifestations of hyperlactatemia and metabolic or lactic acidosis, progression of hepatomegaly or rapid increase in aminotransferase activity.

Application of the drug Abacavir and other abacavir-containing drugs in any patient requires caution for any patient (especially overweight women) with hepatomegaly, or hepatitis or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol).

Patients with co-infected hepatitis C receiving interferon alfa and ribavirin therapy can be a particular risk group. Patients with an increased risk require careful monitoring.

When there are clinical or laboratory signs of lactic acidosis or hepatotoxicity (it can be manifested by hepatomegaly and steatosis,even in the absence of a marked increase in the activity of aminotransferases) treatment with the drug Abacavir it is necessary to stop.

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 persistent 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 influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

Redistribution of subcutaneous fat

In some patients receiving combined antiretroviral therapy, there may be a redistribution and / or accumulation of subcutaneous fat, including central obesity, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and extremities, enlargement of the mammary glands , increased serum lipid concentrations and glucose concentrations in the blood.

Although all preparations from classes of protease inhibitors and NRTIs can cause one or more of the abovementioned unwanted reactions associated with a common syndrome, often called lipodystrophy, the accumulated evidence suggests that there are differences between individual representatives of these classes of drugs in the ability to induce these undesirable reactions.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology: for example, the stage of HIV infection,the elderly age and duration of antiretroviral therapy play an important, possibly synergistic role in the development of this complication.

The long-term consequences of these undesirable phenomena are still unknown.

During the clinical examination, attention should be paid to the signs of redistribution of subcutaneous fat. It is necessary to closely monitor the serum lipids concentration and blood glucose concentration. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

Pancreatitis: Possible development of pancreatitis. A causal relationship with the use of abacavir has not been established.

Therapy with three nucleoside reverse transcriptase inhibitors: patients with high viral load (> 100,000 copies / ml) triple therapy with nucleoside analogues (combination of abacavir, lamivudine and zidovudine) needs special consideration. There have been reports of virologic failure and development of resistance at an early stage, with the combination of abacavir and tenofovir with disoproxil fumarate and lamivudine once a day.

Liver diseases: Abacavir is contraindicated in patients with impaired liver function (this dosage form) grade A, B and C on the Child-Pugh scale.Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiviral therapy, and should be monitored in accordance with accepted practice.

Patients with concomitant hepatitis B or C: Patients with concomitant chronic hepatitis B or C taking combination antiretroviral therapy are at increased risk for serious and potentially deadly adverse reactions from the liver. In the case of concomitant antiviral therapy for hepatitis B or C, it is also necessary to familiarize yourself with the relevant information for these drugs. Caution should be exercised in the combined use of abacavir and ribavirin.

Kidney diseases: Abacavir should not be used in patients with terminal stage of chronic renal failure.

Immunodeficiency Syndrome

In the presence of asymptomatic opportunistic infections or their residual events in HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy (APT),the conduct of such therapy may 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 the onset of APT. Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (P. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (for example, Graves' disease, polymyositis, and Guillain-Barre syndrome) can also manifest themselves in conditions of immune system restoration. However, the time of onset is more variable and can occur several months after the start of treatment.

Osteonecrosis: Although the etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported in patients with advanced HIV infection and / or long-term exposure to combined antiretroviral therapy.Patients should be advised to see a doctor if they have experienced joint pain, joint stiffness, or difficulty in moving.

Opportunistic infections

Application of the drug Abacavir 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 physician with experience in the treatment of HIV-associated diseases.

Transmission of HIV infection

Antiretroviral therapy, including the drug Abacavir, does not exclude the possibility of sexual transmission of HIV or in contact with infected blood, and therefore does not negate the need for 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 6-month course of abacavir was detected with an increased risk of myocardial infarction.According to the generalized analysis of clinical studies, there was no increased 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 studies do not allow one to unequivocally determine the relationship of abacavir therapy with the risk of developing myocardial infarction.

Nevertheless, care should be taken to prescribe antiretroviral therapy, including drugs containing abacavir, patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize risk factors (such as hypertension, dyslipidemia, diabetes and smoking).

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

Studies on the effects of abacavir on the ability to drive vehicles and work with mechanisms have not been conducted. When assessing a patient's ability to drive and work with machinery, his condition and the full range of unwanted reactions of Abacavir should be taken into account.

Form release / dosage:

Film-coated tablets, 300 mg.

Packaging:

For 60 tablets in bottles of high density polyethylene of white color, sealed with a screwed polypropylene cover with protection from opening by children, and sealed with aluminum foil.

1 bottle with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003447

Date of registration:04.02.2016

Expiration Date:04.02.2021

The owner of the registration certificate:Bright Pharmaceuticals Operation SenteBright Pharmaceuticals Operation Sente China

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp16.01.2017

Illustrated instructions

Instructions

Abacavir (Abacavir)