Abacavir Canon, 300 mg 60 pcs

Antiviral agent, synthetic carbocyclic analogue of nucleosides. Inside the cell abacavir is converted with the participation of cellular enzymes into the active metabolite carbovir triphosphate. Carbovir triphosphate is an analogue of deoxyguanosine-5′-triphosphate (dGTP). Carbovir triphosphate inhibits HIV-1 reverse transcriptase activity due to competition with the natural substrate dGTP and disruption of its incorporation into viral DNA. Loss of the 3′-OH group in the embedded nucleoside analogue prevents the formation of the 5′- and 3′-phosphorus-ether bonds required for DNA strand elongation. As a result, viral DNA growth stops.

Indications

Treatment of HIV infection (as part of combination therapy).

Pharmacological effect

Pharmacotherapeutic group

Antiviral [HIV] agent

ATX code

J05AF06

Pharmacodynamics:

Abacavir is a nucleoside analogue that inhibits HIV reverse transcriptase and selectively inhibits the replication of HIV-1 and HIV-2, including HIV-1 strains resistant to zidovudine, lamivudine, zalcitabine, didanosine and nevirapine. Abacavir undergoes intracellular metabolism, turning into the active form, carbovir 5′-triphosphate (carbovir-TF). According to in vitro studies, the antiviral effect of the drug is due to the inhibition of HIV reverse transcriptase, which leads to the termination of DNA synthesis on the RNA template and stops HIV replication. There was no antagonism in the antiviral activity of abacavir in cell culture when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (HIV PI) amprenavir.

In vitro-derived HIV-1 strains resistant to abacavir were found to have mutations in several codons of the reverse transcriptase gene

(OT) – M184V, K65R, L74V and Y115F. HIV resistance to abacavir in vitro and in vivo develops slowly. For a clinically significant increase of 50% inhibitory concentration (IC50) (8-fold increase in IC50 relative to the wild strain of the virus) multiple mutations are required. Strains resistant to abacavir may have reduced sensitivity to lamivudine, zalcitabine and/or didanosine, but fully retain sensitivity to zidovudine and stavudine. Cross-resistance between abacavir and HIV PIs or NNRTIs is unlikely. Failure of the first-line regimen, including abacavir, lamivudine and zidovudine, is predominantly associated with a single mutation – M184V, which retains the possibility of a wide choice of second-line treatment regimens.

Abacavir penetrates the cerebrospinal fluid (CSF) and reduces the content of HIV-1 RNA in it. When combined with other antiretroviral drugs, it may prevent the development of neurological complications of HIV infection and slow the emergence of resistant strains within the central nervous system (CNS).

Pharmacokinetics:

Suction

Abacavir is quickly and well absorbed when taken orally. The absolute bioavailability of abacavir when taken orally in adults is approximately 83%. The time to reach maximum concentration (Tmax) when taking abacavir orally in the form of tablets is about 1.5 hours, and in the form of an oral solution – about 1 hour. The area under the concentration-time pharmacokinetic curve (AUC) for the tablet form of abacavir is no different from that for abacavir oral solution. When taking the tablet form of abacavir orally at a dose of 300 mg 2 times a day, the maximum concentration in blood plasma (Cmax) upon reaching an equilibrium state averages 3 μg/ml, and AUC during the 12-hour interval between doses averages 6.02 μg/h/ml.

After a single dose of 600 mg abacavir tablets, Cmax averages about 4.26 mcg/ml, and AUC ∞ averages 11.95 mcg/h/ml.

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily and only one dose (300 mg) before a 24-hour sample collection period, the geometric mean terminal half-life (T1/2) of intracellular carbovir-TF at steady state was 20.6 hours (the same for abacavir serum concentration – 2.6 h). Steady-state pharmacokinetic parameters when taking abacavir 600 mg once daily were similar to those when taking abacavir 300 mg twice daily in a clinical study with a crossover design in 27 HIV-infected patients. The intracellular content of carbovir-TF in peripheral blood mononuclear cells was higher when using abacavir at a dose of 600 mg 1 time per day compared with taking abacavir 300 mg 2 times per day (increase in AUC at steady state for 24 hours (AUC24,ss) by 32%, maximum daily concentration at steady state (Cmax24,ss) by 99%), which indicates the possibility such a regimen for taking the drug by HIV-infected patients. The efficacy and safety of abacavir as a single daily dose was demonstrated in a clinical trial (CNA30021).

Eating slows down the absorption of abacavir and reduces Cmax, but does not affect AUC. Therefore, abacavir can be taken with or without food. Taking a crushed tablet with a small amount of semi-solid food or liquid does not affect pharmacokinetics and therefore clinical effectiveness. This conclusion is based on the physicochemical and pharmacokinetic parameters of the active substance and the water solubility of abacavir tablets, and it is assumed that the patient crushes and adds the entire tablet to food or liquid and ingests it immediately.

Distribution and binding to plasma proteins

The volume of distribution of abacavir when administered intravenously is about 0.8 l/kg, indicating its ability to easily penetrate tissue.

Studies in HIV-infected patients have shown that abacavir penetrates well into the CSF, with the ratio of abacavir AUC in CSF to abacavir AUC in plasma being 30-44%. In a phase I pharmacokinetic study, it was found that 1.5 hours after taking abacavir at a dose of 300 mg 2 times a day, its average concentration in the CSF was 0.14 μg/ml. When using abacavir at a dose of 600 mg 2 times a day, the concentration of the drug in the CSF increased from 0.13 μg/ml 0.5-1 hour after administration to 0.74 μg/ml when measured 3-4 hours after taking abacavir. Thus, even if the concentration of abacavir observed in the CSF 4 hours after taking the drug at a dose of 600 mg 2 times a day is not the same. the maximum achieved with this treatment regimen, it already exceeds IC50 (0.08 μg/ml or 0.26 μmol/l) by 9 times.

In vitro studies have found that in therapeutic doses, abacavir binds moderately (approximately 49%) to human plasma proteins. This indicates that the interaction of abacavir with other drugs by displacing them from plasma proteins is unlikely.

Metabolism

Abacavir is metabolized primarily in the liver, and less than 2% of the administered dose is excreted unchanged by the kidneys. In humans, abacavir is metabolized mainly by alcohol dehydrogenase to form 5′-carboxylic acid and by conjugation with glucuronic acid to form 5′-glucuronide, accounting for about 66% of the total administered dose of the drug. These metabolites are excreted by the kidneys.

Removal

On average, the half-life of abacavir is about 1.5 hours. Long-term oral administration of abacavir at a dose of 300 mg 2 times a day does not lead to significant accumulation of the drug. Abacavir is eliminated through metabolism in the liver, followed by excretion of metabolites primarily by the kidneys. About 83% of the administered dose is excreted by the kidneys in the form of metabolites and unchanged abacavir, and the remaining amount is excreted through the intestines.

Special patient groups

Children

Abacavir is well and quickly absorbed in the form of an oral solution and in tablet form when taken orally in children. Plasma exposure of abacavir was the same for both formulations at the same dosage. In children receiving abacavir oral solution according to the recommended dosing regimen, abacavir plasma exposure was similar to that in adults. Children receiving abacavir tablets according to the recommended dosing regimen had higher abacavir plasma exposure than children receiving abacavir oral solution due to higher mg/kg doses taken with tablets. Pharmacokinetic studies in children have shown that taking the drug once a day is equivalent in terms of AUC0-24 to taking the same dose of the drug divided into 2 times a day.

There is insufficient safety data to recommend the use of abacavir in children under 3 months of age. There are limited data showing that a dose of 2 mg/kg in neonates less than 30 days of age provides similar or greater AUC values ​​compared to a dose of 8 mg/kg in older children.

Elderly patients

The pharmacokinetics of abacavir in patients over 65 years of age have not been studied. When treating elderly patients, it is necessary to take into account the more frequent dysfunction of the liver, kidneys and heart at this age, as well as concomitant diseases and medications taken.

Patients with impaired renal function

Abacavir is metabolized primarily in the liver, less than 2% of it is excreted unchanged by the kidneys. The pharmacokinetics of abacavir in end-stage renal failure is approximately the same as in normal renal function. Therefore, if renal function is impaired, no dose adjustment is required.

Patients with liver dysfunction

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

Patients with mild liver dysfunction can take 200 mg of abacavir 2 times a day for therapeutic purposes.

The pharmacokinetics of abacavir in patients with moderate to severe hepatic impairment have not been studied; therefore, the use of abacavir is not recommended in these patient groups.

Special instructions

The drug should be prescribed by a doctor experienced in treating HIV infection.

Each patient should read the instructions for use.

Hypersensitivity

The use of the drug Abacavir Canon is associated with the risk of developing HSR, characterized by the appearance of fever and/or rash and other symptoms indicating multiple organ damage. HSR can be life-threatening and, in rare cases, when not treated appropriately, can be fatal. The risk of developing HSR when using Abacavir Canon is significantly increased in patients who test positive for the presence of the HLA-B*5701 allele. However, abacavir HSRs were observed with less frequency in patients who were not carriers of this allele.

The following rules should be followed.

– Testing for the presence of the HLA-B*5701 allele should be performed before initiating therapy with Abacavir Canon and also before resuming therapy with Abacavir Canon in patients with unknown HLA-B*5701 allele status who have previously tolerated abacavir therapy well.

– The use of Abacavir Canon is not recommended in patients with the HLA-B*5701 allele or in patients in whom HSR was suspected while using any other drug containing abacavir, regardless of HLA-B*5701 status.

– Each patient should be reminded to read the instructions for use included in the packaging of Abacavir Canon. Patients should also be reminded to carry the warning card that came with the drug with them at all times.

– In all patients receiving therapy with Abacavir Canon, the clinical diagnosis of suspected HSR should remain the basis for clinical decision making.

– If HSR is suspected, therapy with Abacavir Canon should be stopped immediately, even in the absence of the HLA-B*5701 allele. Delay in stopping therapy with Abacavir Canon after the occurrence of HSR may result in a life-threatening reaction.

– Patients who develop HSR should be advised to hand over remaining Abacavir Canon tablets to their healthcare provider to avoid restarting Abacavir.

– Reintroduction of abacavir-containing drugs following a suspected abacavir HSR may result in rapid return of symptoms within hours, which may include life-threatening hypotension and death.

– When considering restarting abacavir therapy after stopping treatment with any abacavir-containing drug for any reason, the reason for discontinuation of therapy should be established, regardless of whether the patient carries the HLA-B*5701 allele. If HSR cannot be excluded, use of Abacavir Canon or any other medicines containing abacavir should not be resumed.

– If HSR is excluded, it is possible to resume therapy with Abacavir Canon. In rare cases, patients who discontinued abacavir for reasons other than HSR symptoms have also experienced life-threatening reactions within a few hours of resuming abacavir therapy (see Selected Adverse Reactions section).

Patients should be informed of the possibility of developing HSR when resuming therapy with Abacavir Canon or other medicinal products containing abacavir should only be done if they have ready access to medical care.

Clinical picture of HSR to abacavir

Abacavir HSRs have been well studied in clinical trials and during post-marketing surveillance. Symptoms usually appear within the first 6 weeks (median time of onset of this reaction is 11 days) after starting abacavir therapy, but these reactions can develop at any time during therapy.

Almost all HSR reactions to abacavir include fever and or rash as part of the syndrome. Other signs and symptoms that are noted as a manifestation of HSR to abacavir include respiratory and gastrointestinal symptoms, which may lead to misdiagnosis of HSR as a respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis (see sections “Side effects”, “Description of selected adverse reactions”). Patients should be closely monitored with consultations every 2 weeks, especially during the first 2 months of therapy with Abacavir Canon.

If abacavir treatment is continued when HSR-related symptoms appear, they become more severe and may become life-threatening. In most cases, these symptoms disappear when you stop taking abacavir.

Lactic acidosis and severe hepatomegaly with steatosis

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

Symptoms that may indicate the development of lactic acidosis include general weakness, loss of appetite, rapid unexplained weight loss, gastrointestinal problems (nausea, vomiting and abdominal pain), respiratory problems (shortness of breath and tachypnea) or neurological symptoms (including motor symptoms).

Lactic acidosis has a high mortality rate if not treated promptly and may be associated with pancreatitis, liver failure, or kidney failure. Lactic acidosis usually appeared after several months of therapy. Treatment with nucleoside analogs should be discontinued in the event of symptomatic hyperlactatemia and metabolic or lactic acidosis, progression of hepatomegaly, or rapid increases in aminotransferase activity.

The use of Abacavir Canon and other abacavir-containing drugs requires caution in any patient (especially overweight women) with hepatomegaly, hepatitis or other known risk factors for liver damage and hepatic steatosis (including the use of certain drugs and alcohol). Patients with co-occurring hepatitis C receiving interferon alfa and ribavirin therapy may be at particular risk. Patients at increased risk require careful monitoring.

If clinical or laboratory signs of lactic acidosis with or without hepatitis appear (may manifest as hepatomegaly and steatosis even in the absence of a marked increase in aminotransferase activity), treatment with Abacavir Canon should be suspended.

Mitochondrial dysfunction

In vitro and in vivo studies have shown that nucleoside and nucleotide analogues are capable of causing varying degrees of mitochondrial damage. Cases of mitochondrial dysfunction have been reported in HIV-negative children receiving nucleoside analogues in utero and/or after birth. The main adverse reactions were hematological disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These adverse reactions are often transient. Some late-onset neurological disorders (increased muscle tone, seizures, behavioral disturbances) have been reported. Whether these neurological disorders are transient or permanent is currently unknown. Any child, even HIV-negative, exposed in utero to nucleoside and nucleotide analogues should undergo clinical and laboratory evaluation to rule out mitochondrial dysfunction if signs or symptoms are detected. These data do not change current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV infection.

Redistribution of subcutaneous fat tissue

Some patients receiving combination antiretroviral therapy may experience redistribution and/or accumulation of subcutaneous fat, including central obesity, dorsocervical fat deposition (“buffalo hump”), decreased subcutaneous fat on the face and extremities, breast enlargement, increased serum lipid concentrations and increased blood glucose concentrations.

Although one or more of the above adverse reactions associated with the general syndrome, which is often referred to as lipodystrophy, can be caused by all drugs of the HIV PI and NRTI classes. Data indicate that there are differences between individual members of these drug classes in their ability to cause these adverse reactions.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, stage of HIV infection, advanced age, and duration of antiretroviral therapy play important, possibly synergistic, roles.

The long-term consequences of these adverse reactions are currently unknown.

When clinically examining patients, it is necessary to pay attention to the redistribution of subcutaneous fat. Laboratory testing should include determination of serum lipid concentrations and blood glucose concentrations. If lipid metabolism is disrupted, appropriate treatment is prescribed.

Pancreatitis

Cases of pancreatitis have been reported, although a causal relationship with abacavir use has not been clearly established.

Triple nucleoside reverse transcriptase inhibitor (NRTI) therapy

In patients with a high viral load (> 100,000 copies/ml), the administration of a triple combination containing abacavir, lamivudine and zidovudine requires special consideration.

High rates of virological failure and early resistance have been reported when the combination of abacavir with tenofovir desoproxil fumarate and lamivudine was used as a once-daily regimen.

Liver diseases

The efficacy and safety of abacavir have not been established in patients with significant concomitant liver disease. Abacavir Canon is contraindicated in patients with moderate to severe liver dysfunction.

Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combination antiretroviral therapy and should be monitored according to established practice. It is necessary to consider the possibility of suspending or discontinuing treatment if the disease worsens in such patients.

Concomitant hepatitis B or C

Patients with concomitant chronic hepatitis B or C who are receiving combination antiretroviral therapy are at increased risk of severe and potentially fatal hepatic adverse reactions. In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the corresponding instructions for the use of these drugs.

Caution must be exercised when prescribing abacavir and ribavirin simultaneously.

Kidney diseases

Abacavir Canon should not be prescribed to patients with end-stage chronic renal failure.

Immune reconstitution syndrome

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy, such therapy may lead to increased symptoms of opportunistic infections or other serious consequences. These reactions usually occur within the first weeks or months after starting antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (formerly P. 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) have been observed in the setting of immune reconstitution, but the timing of initial manifestations varies and the disease may occur many months after the start of therapy and have an atypical course.

Osteonecrosis

Although the etiology of this disease is multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis most often occurred in patients at an advanced stage of HIV infection and/or on long-term combination antiretroviral therapy. Patients should consult a doctor if they experience joint pain and stiffness or difficulty moving.

Opportunistic infections

The use of Abacavir Canon or other antiretroviral drugs does not exclude the possibility of developing opportunistic infections or other complications of HIV infection, therefore patients should remain under the supervision of a physician experienced in treating HIV-associated diseases.

HIV transmission

Carrying out antiretroviral therapy, including the drug Abacavir Canon, does not exclude the possibility of HIV transmission through sexual contact or contact with infected blood and therefore does not eliminate the need to take appropriate precautions.

Myocardial infarction

A prospective observational epidemiological study examining the incidence of myocardial infarction in patients receiving combination antiretroviral therapy found that prior use of abacavir within 6 months was associated with an increased risk of myocardial infarction. According to a pooled analysis of clinical studies, there was no increase in the risk of myocardial infarction associated with taking abacavir. The biological mechanisms explaining the potentially increased risk are unknown. In general, the available data from observational cohorts and controlled clinical trials do not allow a definitive determination of the association between abacavir therapy and the risk of myocardial infarction.

However, antiretroviral therapy, including drugs containing abacavir, should be prescribed with caution to patients at possible risk of coronary heart disease. Every effort must be made to minimize all modifiable risk factors (such as hypertension, dyslipidemia, diabetes mellitus and smoking).

Impact on the ability to drive vehicles and machinery:

There is no data confirming the effect of abacavir on the ability to engage in potentially hazardous activities that require increased attention. However, patients should be informed about the possible development of adverse reactions such as fatigue during treatment with abacavir. They should be advised to be careful when driving a car and operating machinery.

Active ingredient

Abacavir

Composition

1 film-coated tablet 300 mg contains:

Active ingredient: abacavir sulfate 351.4 mg, equivalent to abacavir 300 mg.

Excipients: sodium carboxymethyl starch 35 mg, colloidal silicon dioxide 7 mg, magnesium stearate 7 mg, povidone K-30 28 mg, microcrystalline cellulose 291.6 mg.

Film coating composition: Opadry II yellow 22 mg, including: hypromellose (hydroxypropyl methylcellulose) 7.48 mg, lactose monohydrate 6.16 mg, macrogol (polyethylene glycol) 2.64 mg, titanium dioxide 4.62 mg, iron dye yellow oxide 1.1 mg.

1 film-coated tablet 600 mg contains:

Active ingredient: abacavir sulfate 702.8 mg, equivalent to abacavir 600 mg.

Excipients: sodium carboxymethyl starch 58 mg, colloidal silicon dioxide 11 mg, magnesium stearate 11 mg, povidone K-30 46 mg, microcrystalline cellulose 391.2 mg.

Film shell composition: Opadry II yellow 38 mg, including: hypromellose (hydroxypropyl methylcellulose) 12.92 mg, lactose monohydrate 10.64 mg, macrogol (polyethylene glycol) 4.56 mg, titanium dioxide 7.98 mg, iron dye yellow oxide 1.9 mg.

Pregnancy

Pregnancy

The use of abacavir during pregnancy and after childbirth has been studied in more than 2000 women. Data available from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major congenital malformations associated with abacavir use compared with the incidence of malformations in the comparison group. However, there are no adequate and well-controlled studies in pregnant women, and the safety of abacavir in women during pregnancy has not yet been established. There is evidence of the effects of abacavir in animal reproductive studies. If it is necessary to use abacavir during pregnancy, the ratio of the expected benefit to the mother and the potential risk to the fetus should be assessed. There is evidence of a slight transient increase in plasma lactate concentrations in newborns and infants whose mothers took NRTIs during pregnancy and childbirth. This may be due to mitochondrial disorders. The clinical significance of this phenomenon has not yet been established. In addition, there are extremely rare reports of developmental delay, seizures, and other neurological abnormalities (eg, increased muscle tone) in newborns, although the causal relationship of these abnormalities to maternal use of NRTIs during pregnancy and labor has not been established. These data do not change existing recommendations for the use of antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Breastfeeding period

Experts do not recommend breastfeeding for HIV-infected patients to avoid transmitting HIV infection to the child. Since abacavir, its metabolites and HIV pass into breast milk, breastfeeding is contraindicated.

Contraindications

– Hypersensitivity to abacavir or any other component of the drug;

– Children weighing less than 14 kg (for this dosage form);

– Moderate and severe liver failure (class B and C on the Child-Pugh scale), due to the lack of clinical data and the recommended dosage regimen;

– Mild liver failure (class A on the Child-Pugh scale), due to the inability to provide the dosage regimen;

– Breastfeeding period;

– Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution:
Patients with a possible risk of coronary heart disease; combined use of abacavir and ribavirin (see section “Interaction”).

Side Effects

The nature of other adverse reactions other than HSR, but observed in patients taking Abacavir Canon, is not completely clear. Whether these adverse reactions are a consequence of the use of the drug Abacavir Canon or a wide range of other drugs simultaneously prescribed for the treatment of HIV infections, or whether they are caused by the disease itself, has not yet been established.

Many of the following adverse reactions associated with taking Abacavir Canon (nausea, vomiting, diarrhea, fever, fatigue, rash) are usually observed with the development of HSR to abacavir. therefore, if any of these symptoms occur, careful evaluation of the patient is indicated to confirm the development of HSR. If Abacavir Canon was discontinued due to the appearance of the above symptoms and a decision is made to resume therapy with Abacavir Canon, this can only be done under direct medical supervision.

Very rare cases of erythema multiforme exudative, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in which HSR to abacavir could not be excluded. In such cases, it is necessary to permanently stop taking medications containing abacavir.

Most of the adverse reactions listed below are not treatment limiting. The frequency of occurrence is determined as follows:

very often – >1/10,

often – from >1/100 to <1/10,

uncommon – from >1/1000 to <1/100,

rarely – from >1/10000 to <1/1000,

very rarely – <1/10000.

Clinical trial data

Metabolic and nutritional disorders

Common: loss of appetite.

Nervous system disorders

Often: headache.

Disorders of the gastrointestinal tract

Common: nausea, vomiting, diarrhea.

General and administration site disorders

Common: fever, drowsiness, fatigue.

Controlled clinical studies have shown that changes in laboratory parameters during treatment with abacavir are observed infrequently, as in the control group of patients who did not receive abacavir.

Children

Safety data supporting single-dose abacavir in children were obtained from the ARROW study (COL 105677), in which 669 HIV-1-infected children received abacavir and lamivudine once or twice daily. No additional safety signals were identified in children receiving abacavir once or twice daily compared with adults.

Post-marketing surveillance data

Metabolic and nutritional disorders

Common: hyperlactatemia.

Rarely: lactic acidosis, accumulation and/or redistribution of adipose tissue. The incidence of these adverse reactions depends on many factors, including the antiretroviral drugs used in combination with abacavir.

Gastrointestinal disorders

Rarely: pancreatitis (a cause-and-effect relationship with the use of abacavir has not been clearly established).

Skin and subcutaneous tissue disorders

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

Very rare: erythema multiforme, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and fatty liver, have been reported with the use of nucleoside analogues.

Combination antiretroviral therapy has been associated with redistribution of fat tissue (lipodystrophy) in patients with HIV, including decreased subcutaneous fat in the face and extremities, increased intra-abdominal and visceral fat, breast enlargement, 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, inflammatory reactions to asymptomatic or residual opportunistic infections may occur during initiation of combination antiretroviral therapy. Autoimmune diseases (eg, Graves’ disease) occurring in the setting of immune reactivation have also been reported, but the reported timing of disease manifestation is more variable and may occur many months after initiation of therapy.

Cases of osteonecrosis have been reported, especially in patients with well-known risk factors, advanced HIV infection, or long-term use of combination antiretroviral therapy. The frequency of this phenomenon is unknown.

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity reaction (HSR) to abacavir has been defined as a common adverse reaction during treatment with drugs containing abacavir. The signs and symptoms of HSR are listed below. These signs and symptoms were identified during clinical trials or post-marketing surveillance. Symptoms and signs that occur in at least 10% of patients with HSR are highlighted in bold. Almost all patients with HSR develop fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, but reactions can occur without rash or fever. Other major symptoms include gastrointestinal, respiratory, or constitutional symptoms such as drowsiness or malaise.

Skin and subcutaneous tissue disorders

Rash (usually maculopapular or urticarial).

Gastrointestinal disorders

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

Respiratory, thoracic and mediastinal disorders

Dyspnea, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Nervous system disorders

Headache, paresthesia.

Blood and lymphatic system disorders

Lymphopenia.

Disorders of the liver and biliary tract

Increased biochemical indicators of liver function, hepatitis, liver failure.

Musculoskeletal and connective tissue disorders

Myalgia, myolysis, arthralgia, increased activity of creatine phosphokinase.

Renal and urinary tract disorders

Increased serum creatinine concentration, renal failure.

General and administration site disorders

Fever, fatigue, malaise, edema, lymphadenopathy, hypotension, conjunctivitis, anaphylactic reactions. Resumption of Abacavir Canon after abacavir HSR results in a rapid return of symptoms within a few hours. Repeated HSR is usually more severe than the first and may include life-threatening hypotension and death. In rare cases, reactions also occur when Abacavir Canon is restarted after discontinuation due to the onset of just one of the major hypersensitivity symptoms (see above) and in very rare cases, when Abacavir Canon is reintroduced in patients who had not experienced any symptoms of HSR prior to discontinuation of the drug (i.e., in patients who were previously considered tolerable to Abacavir therapy).

For detailed information on the clinical management of suspected abacavir HSR, see the “Special Instructions” section.

Interaction

In vitro studies 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 the cytochrome P450 isoenzyme CYP3A4.

In vitro studies have shown that – abacavir does not interact with drugs that are metabolized by isoenzymes CYP3A4, CYP2C9 and CYP2D6. Clinical studies have not revealed any induction of hepatic metabolism of exogenous substances by abacavir. Thus, the interaction of abacavir with HIV protease inhibitors and other drugs metabolized by major cytochrome P450 isoenzymes is unlikely.

Clinical studies have shown the absence of clinically significant interactions between abacavir, zidovudine and lamivudine. Potent enzyme inducers such as rifampicin, phenobarbital and phenytoin, when acting on UDP-glucuronyltransferase, may slightly reduce the plasma concentration of abacavir.

Ethanol: Ethanol slows the metabolism of abacavir, resulting in a 41% increase in AUC. However, the clinical significance of this change is small. Abacavir does not affect ethanol metabolism.

Methadone: according to pharmacokinetic studies, the use of abacavir at a dose of 600 mg 2 times a day in combination with methadone reduces the Cmax of abacavir in the blood serum by 35%, increases the Tmax in the serum for 1 hour, but does not change the AUC. The clinical significance of these changes is small.

The same study found that abacavir increased the systemic clearance of methadone by 22%. In most cases, these changes are also regarded as clinically insignificant, but in certain situations it may be necessary to change the dose of methadone.

Retinoids: Retinoids, such as isotretinoin, are eliminated by alcohol dehydrogenase and may interact with abacavir, but no specific studies have been conducted to date.

Ribavirin: Due to the fact that abacavir and ribavirin share the same phosphorylation pathways, an interaction between these substances is expected, which may lead to a decrease in the intracellular phosphorylation of ribavirin metabolites and potentially leads to a decrease in the likelihood of achieving a sustained virological response in hepatitis C-coinfected HIV-infected patients receiving pegylated interferon and ribavirin therapy. Conflicting data have been published regarding the concomitant use of abacavir and ribavirin. Some data suggest that HIV-infected patients receiving abacavir-containing drugs may be at risk of poor response rates to antiviral therapy with pegylated interferon and ribavirin. Caution should be exercised when taking these drugs concomitantly.

Overdose

Symptoms

In clinical studies, no adverse reactions were identified when using abacavir in single doses up to 1200 mg and daily doses up to 1800 mg. The effect of the drug in higher doses has not yet been studied.

Treatment

In case of overdose, the patient is monitored to identify symptoms of poisoning and timely initiation of treatment. If necessary, carry out symptomatic treatment. The effectiveness of peritoneal dialysis and hemodialysis for the removal of abacavir is unknown.

Storage conditions

At a temperature not exceeding 25 °C in the manufacturer’s packaging.

Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

Kanonpharma production CJSC, Russia