Catalog of medicines. Interaction with other drugs
pharmachologic effect
Nucleoside analogue reverse transcriptase inhibitor. Possesses selective antiviral action in relation to human immunodeficiency virus types 1 and 2 (HIV-1 And HIV-2), including HIV-1 strains resistant to zidovudine, lamivudine, zalcitabine, didanosine, or nevirapine. In vitro studies have shown that the mechanism of action of abacavir is reverse transcriptase inhibition. HIV, which leads to the termination of the RNA chain and the cessation of viral replication. In vitro, a synergism of action was found in the combination of abacavir with nevirapine and zidovudine. Abacavir has an additive effect in combination with didanosine, zalcitabine, lamivudine and stavudine. Strains have been isolated in vitro HIV-1 resistant to abacavir. The development of resistance is associated with genotypic changes in a specific codon region of reverse transcriptase (codons M184V, K65R, L74V and Y115F). HIV resistance to abacavir in vitro and in vivo develops relatively slowly; multiple mutations are needed to increase the IC 50 concentration by 8 times compared to the "wild" strain of the virus, which may be clinically significant. In strains resistant to abacavir, sensitivity to lamivudine, zalcitabine and / or didanosine may be reduced, but sensitivity to zidovudine and stavudine remains. It is unlikely that cross-resistance will develop between abacavir and protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
IN clinical research demonstrated that treatment with Ziagen in combination with zidovudine and lamivudine was accompanied by a pronounced and sustained decrease in the concentration of the virus and a corresponding increase in the number of CD4+ cells in adults and children.
In patients who have not previously received antiretroviral drugs, Ziagen in combination with other drugs allows for highly effective initial therapy.
In patients who have previously received antiretroviral therapy, there are few data available that the addition of Ziagen to nucleoside reverse transcriptase inhibitors leads to an additional decrease in the concentration of the virus and increases the number of CD4+ cells. In such cases, the effectiveness of Ziagen depends on the nature and duration of previous therapy, which can lead to the formation of HIV strains with cross-resistance to abacavir.
Abacavir crosses the BBB and reduces the level of HIV-1 RNA in cerebrospinal fluid. In combination with others antiretroviral drugs Ziagen may slow down the development of resistance and may also play a role in preventing neurological complications associated with HIV infection.
Indications
Treatment of HIV infection in adults and children (as part of combination antiretroviral therapy).
Dosing regimen
Ziagen can be taken with or without food.
Ziagen should be prescribed by specialists with experience in the treatment of HIV infection.
Adults and teenagers over 12 years old
the drug is prescribed 300 mg 2 times / day.
Children aged 3 months to 12 years
the dose is calculated based on 8 mg/kg of body weight, but not more than 600 mg/day. Multiplicity of reception 2 times / day.
There are currently no data on the use of Ziagen in children under the age of 3 months.
Currently, there are no necessary clinical data on the use of the drug in patients with impaired liver function. Due to the fact that abacavir is metabolized primarily in the liver, a study is currently underway investigating the effect of impaired liver function. varying degrees severity on the pharmacokinetics of abacavir in order to develop recommendations on the dosing regimen in this category of patients.
Patients with impaired renal function
special selection dose is not required.
When prescribing the drug the elderly should take into account the higher incidence of decreased liver, kidney and heart function, the presence of concomitant diseases and taking other medications.
Side effect
Hypersensitivity reaction
In clinical studies, a hypersensitivity reaction developed in approximately 4% of patients treated with abacavir, and in rare cases led to lethal outcome. The hypersensitivity reaction was manifested by symptoms that indicated multiple organ/systemic lesions. In most cases, one of the manifestations of the hypersensitivity syndrome was fever and/or rash (usually maculopapular or urticarial), but the hypersensitivity reaction may not be accompanied by these symptoms. Symptoms usually develop during the first 6 weeks of treatment with the drug (average 11 days after the start of treatment).
Dermatological reactions:
>=10% - rash (maculopapular or urticarial).
>=10% - nausea, vomiting, diarrhea, abdominal pain, increased liver function tests; rarely - ulceration of the oral mucosa, impaired liver function.
From the side respiratory system:
rarely - shortness of breath, sore throat.
From the CNS and peripheral nervous system:
>=10% - headache; rarely - paresthesia.
From the hematopoietic system:
rarely - lymphopenia.
From the side musculoskeletal system:
>=10% - myalgia; rarely - myolysis, arthralgia, increased levels of CPK.
From the urinary system:
increased creatinine levels, impaired renal function.
Others:
>=10% - fever, fatigue, general malaise; rarely - edema, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions.
In some patients, the hypersensitivity reaction was initially regarded as a respiratory disease (pneumonia, bronchitis, pharyngitis), influenza-like illness, gastroenteritis, or a reaction to other drugs.
Other side effects
For many other side effects, it is not clear if they are caused by abacavir, other medicines or are complications of the HIV infection itself.
From the side digestive system:
nausea, vomiting, diarrhea, loss of appetite. There are reports of the development of pancreatitis, but the relationship with taking abacavir has not been established.
Others:
fever, headache, drowsiness, fatigue, rash (not accompanied by systemic manifestations). In clinical studies, changes in laboratory parameters were rarely observed; not noted significant differences in the frequency of changes in laboratory parameters between patients of the main and control groups.
Contraindications
Hypersensitivity to the components of the drug.
Pregnancy and lactation
If it is necessary to prescribe the drug during pregnancy, the intended benefit to the mother and the potential risk to the fetus should be carefully evaluated. When prescribing the drug during lactation, breastfeeding should be stopped.
The safety of abacavir during pregnancy has not yet been established.
IN experimental studies It has been shown in laboratory animals that abacavir and/or its metabolites can cross the placental barrier. Abacavir provided toxic effect on the development of the embryo and fetus only in rats at doses toxic to pregnant females (500 mg/kg of body weight or more). These doses are 32-35 times higher than therapeutic doses for a person. The identified disorders included edema and fetal abnormalities, resorption, weight loss of the fetus and an increase in the number of stillborn fetuses. Dose that does not adverse influence for pre- and postnatal development, was 160 mg/kg of body weight per day. This dose is approximately 10 times the human dose. Mentioned changes not found in rabbits.
A study in rats showed that abacavir at doses up to 500 mg/kg did not affect the fertility of males and females. The results of studies in animals are not always predictive for humans.
Abacavir and its metabolites pass into the milk of lactating rats. It can be assumed that they also penetrate the breast milk of lactating women, but there is currently no evidence for this. There are no data on the safety of abacavir in children under 3 months of age. Experts advise HIV-infected women to refrain from breastfeeding to prevent the child from becoming infected with HIV.
If symptoms of hypersensitivity appear, the patient should immediately consult a doctor. When the diagnosis of a hypersensitivity reaction is confirmed, Ziagen should be discontinued immediately. It is necessary to ask the patient to return all unused tablets / syrup to the doctor in order to avoid accidental use of the drug in the future. With continued treatment, the symptoms worsen, which can threaten the patient's life. With the abolition of Ziagen, the symptoms of hypersensitivity, as a rule, passed. In the event of a hypersensitivity reaction to abacavir, Ziagen or another drug containing abacavir should never be prescribed subsequently, because. most severe symptoms(including life-threatening arterial hypotension), resume within a few minutes and can be fatal.
For timely diagnosis hypersensitivity reactions and to minimize the risk of developing life-threatening hypotension, Ziagen should be discontinued if hypersensitivity reactions are suspected, even in cases where the possibility of another diagnosis (for example, respiratory diseases, influenza-like illness, gastroenteritis, or reactions to other drugs) cannot be ruled out . Therapy with Ziagen should not be restarted, even if symptoms reappear while taking other drugs.
If therapy with Ziagen has been suspended and a decision is made to continue it, the reasons for discontinuing the drug should be carefully analyzed to exclude the possibility of hypersensitivity symptoms. If symptoms of hypersensitivity are not excluded, Ziagen therapy should not be resumed.
There are isolated reports of the development of a hypersensitivity reaction after the resumption of Ziagen, when the temporary withdrawal of the drug was preceded by only one main symptom (for example, rash, fever, or gastrointestinal disturbances). In cases where the diagnosis of hypersensitivity is not confirmed in patients who have temporarily discontinued Ziagen (one symptom is present), it is recommended: to consider the possibility that a hypersensitivity reaction preceded the withdrawal of the drug; evaluate the ratio of risk and possible therapeutic effect resumption of Ziagen therapy; if a decision is made to resume therapy with Ziagen, it should be carried out in an appropriate medical institution.
Very rarely, a hypersensitivity reaction has been reported that developed after the resumption of therapy with Ziagen in patients without obvious previous symptoms of hypersensitivity. In a number of cases, documentary data were clearly insufficient. The clinical significance of these messages has not been established. If a decision is made to resume therapy with Ziagen, the patient should be able to receive urgent medical attention.
The patient must be informed about possible reactions hypersensitivity to abacavir, which may present with life-threatening or fatal symptoms, and the patient should be aware of the need immediate appeal see a doctor if you develop fever, nausea, vomiting, diarrhea or abdominal pain, respiratory disorders (shortness of breath, cough, sore throat). A special card for patients with information about hypersensitivity reactions is included in the Ziagen package, and patients should be reminded to carry it with them at all times.
In HIV-infected patients (mainly women) who took antiretroviral drugs from the group of nucleoside analogues as monotherapy or as part of complex therapy, including abacavir, rare cases of lactic acidosis and severe hepatomegaly with fatty liver (including fatal) are described. Caution should be exercised when treating Ziagen, especially if patients have risk factors for liver disease. In the event of clinical or laboratory signs lactic acidosis or liver dysfunction, Ziagen should be discontinued.
Despite taking Ziagen or other antiretroviral drugs, patients may develop infections caused by opportunistic pathogens, and other complications of HIV infection. Therefore, patients should be under constant surveillance physicians experienced in the treatment of HIV infection. Patients should be informed that treatment with antiretroviral drugs (including abacavir) does not prevent the risk of transmitting HIV to others through sexual intercourse or blood transfusion, so patients should take appropriate precautions.
The oral solution contains sorbitol, which can cause abdominal pain and diarrhea. In the process of metabolism, sorbitol is converted into fructose, therefore Ziagen in the form of an oral solution is not indicated for patients with congenital fructose intolerance.
Influence on the ability to drive vehicles and control mechanisms
There is no data to support the effect of abacavir on the ability to engage in potentially dangerous species activities requiring more attention.
Overdose
In clinical studies, patients received single doses of abacavir up to 1200 mg and daily doses up to 1800 mg. There were no reports of unexpected adverse reactions. Action over high doses abacavir is unknown.
Treatment:
it is necessary to monitor the patient's condition in order to identify signs of intoxication and, if necessary, carry out maintenance therapy. There are no data on the possibility of removing abacavir using hemodialysis and peritoneal dialysis.
drug interaction
Results from in vitro studies and data on the major pathways of abacavir metabolism indicate a low likelihood drug interactions with abacavir. Abacavir does not inhibit metabolic processes involving the CYP3A4 enzyme of the cytochrome P 450 system. In vitro studies have shown that abacavir does not interact with drugs that are metabolized by CYP3A4, CYP2C9 or CYP2D6. In clinical studies, there was no increase in hepatic metabolism under the influence of the drug. Therefore, interaction of abacavir with antiretroviral protease inhibitors and other drugs metabolized with the participation of enzymes of the cytochrome P 450 system is unlikely.
Clinical studies have not identified clinically significant interactions between abacavir, zidovudine and lamivudine.
Ethanol alters the metabolism of abacavir, resulting in an increase in the AUC of abacavir by approximately 41%. Given the safety profile of abacavir, these changes can be considered clinically insignificant. Abacavir does not affect the metabolism of ethyl alcohol.
In a pharmacokinetic study, the co-administration of abacavir at a dose of 600 mg 2 times / day and methadone led to a decrease in Cmax by 35% and an increase in the time to achieve it by 1 hour. At the same time, the AUC value did not change. It is believed that these data do not have clinical significance. In this study, abacavir increased the mean systemic clearance of methadone by 22%. For most patients, these changes are not clinically significant, but sometimes a further increase in the dose of methadone may be required.
Retinoids (such as isotretinoin) are inactivated by alcohol dehydrogenase. Interaction with abacavir is possible, however special studies was not carried out.
Terms and conditions of storage
The drug should be stored at a temperature not exceeding 30°C. Shelf life - 2 years.
Terms of dispensing from pharmacies
Ziagen is available by prescription.
Abacavir (abacavir)
Composition and form of release of the drug
Tablets, coated film sheath light yellow, round, biconvex.
Excipients: microcrystalline cellulose - 395.2 mg, sodium carboxymethyl starch - 48 mg, K25 - 36 mg, magnesium stearate - 12 mg, colloidal silicon dioxide - 6 mg.
The composition of the film shell: Opadry II 85F220118 yellow - 30 mg, including: polyvinyl alcohol - 12 mg, titanium dioxide - 7.392 mg, macrogol-3350 - 6.06 mg, talc - 4.44 mg, iron dye yellow oxide - 0.108 mg.
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pharmachologic effect
Means, synthetic carbocyclic analog 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 the activity of HIV-1 reverse transcriptase, which is due to competition with the natural substrate dGTP and disruption of its integration into viral DNA. The loss of the 3"-OH group in the embedded nucleoside analogue prevents formation of 5"- and 3"-phosphoroether bonds necessary for the elongation of the DNA chain. As a result, the growth of viral DNA stops.
Pharmacokinetics
After oral administration, absorption is high, bioavailability is 83%. C max - 3 μg / ml, T max - 1-1.5 hours. AUC (within 12 hours after administration) - 6 μg / ml / h. Food slows down the absorption of abacavir and reduces Cmax, but does not affect AUC. Penetrates through the BBB, the concentration of abacavir in the cerebrospinal fluid is 30-44% of that in. Plasma protein binding is low. Metabolized in the liver with the participation of acetaldehyderogenase and the formation of glucuronide conjugates (5"-carboxylic acid and 5"-glucuronide). T1 / 2 - 1.5 hours. Excreted by the kidneys - 83% as metabolites and 2% unchanged; the rest is excreted through the intestines. Does not accumulate.
Indications
Treatment of HIV infection (as part of combination therapy).
Contraindications
Moderate and severe liver dysfunction; childhood younger than 3 months and body weight less than 14 kg; hypersensitivity to abacavir.
Dosage
In combination with others antiviral agents inside adults 300 mg 2 times / day, children aged 3 months to 16 years - 8 mg / kg 2 times / day.
Side effects
From the skin and skin appendages: rash (usually maculopapular or urticarial); very rare - multiform exudative erythema including Stevens-Johnson syndrome and toxic epidermal necrolysis.
From the digestive system: loss of appetite, nausea, vomiting, diarrhea, ulceration of the oral mucosa, increased activity of liver enzymes, liver failure.
From the respiratory system: shortness of breath, cough, sore throat, respiratory distress syndrome adults, respiratory failure.
From the nervous system: headache, paresthesia, drowsiness.
From the hematopoietic and lymphatic systems: lymphopenia.
on the part of the urinary system: increased serum creatinine concentration, renal failure.
From the musculoskeletal system: often - hyperlactatemia; rarely - lactic acidosis, accumulation / redistribution of adipose tissue, myalgia, rhabdomyolysis, arthralgia, increased CPK activity.
Others: fever, fatigue, malaise, edema, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions.
drug interaction
According to pharmacokinetic studies, the use of abacavir at a dose of 600 mg 2 times / day in combination with methadone reduces Cmax of abacavir in serum by 35%, increases the time to reach Cmax in serum by 1 hour, but does not change AUC. Clinical relevance these changes are 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 you may need to change the dose of methadone.
Retinoids, such as isotretinoin, are eliminated by alcohol dehydrogenase, so they can interact with abacavir, but no special studies have been conducted at this time.
special instructions
Symptoms of hypersensitivity may appear any time after the start of treatment with abacavir, but most often they occur within the first 6 weeks.
If, with the development of a hypersensitivity reaction, patients continue to take abacavir, then clinical manifestations become more pronounced and may take life threatening character. In most cases, symptoms disappear when abacavir is stopped.
There are reports of the development of lactic acidosis, hepatomegaly and fatty degeneration of the liver, incl. with a fatal outcome due to antiretroviral therapy with nucleoside analogues, including abacavir, and zidovudine, taken either alone or in combination. In most cases, these complications occur in women.
Symptoms suggestive of lactic acidosis include general weakness loss of appetite, rapid weight loss unclear etiology, disorders of the gastrointestinal tract and disorders of the respiratory system (shortness of breath and tachypnea).
The use of abacavir in any patient requires caution, especially in the presence of risk factors for liver damage. If clinical or laboratory signs of lactic acidosis or hepatotoxicity appear (may manifest as hepatomegaly and fatty degeneration of the liver even in the absence of a pronounced increase in aminotransferase activity), treatment with abacavir should be discontinued.
Combination antiretroviral therapy may be accompanied by the development of lipodystrophy syndrome. At clinical examination patients during the treatment period, it is necessary to pay attention to the redistribution of subcutaneous fat. Laboratory examination should include determination of serum lipid concentration and blood concentration. In violation of lipid metabolism, appropriate treatment is prescribed.
If HIV-infected patients with severe immunodeficiency have asymptomatic or low-symptom opportunistic infections at the time of initiation of antiretroviral therapy (ART), such therapy may lead to an increase in the symptoms of opportunistic infections or other grave consequences. These reactions usually occur within the first weeks or months after starting ART. Typical examples are cytomegalovirus retinitis, generalized 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.
The use of abacavir 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 experienced in the treatment of these diseases.
Antiretroviral therapy, including drugs containing abacavir, should be used with caution in patients with possible risk occurrence of IBS. All measures should be taken to minimize all modifiable risk factors (such as arterial hypertension, dyslipidemia, diabetes and smoking).
Pregnancy and lactation
Adequate and well-controlled clinical studies of the safety of the use of abacavir during pregnancy and lactation have not been conducted.
If necessary, use during pregnancy should weigh the expected benefit of therapy for the mother and the potential risk to the fetus.
It is not known whether abacavir is excreted from breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.
Application in childhood
Children aged 3 months to 16 years - 8 mg / kg 2 times / day.
Description of the active ingredient
pharmachologic effect
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 the activity of HIV-1 reverse transcriptase, which is due to competition with the natural substrate dGTP and disruption of its integration into viral DNA. The loss of the 3"-OH group in the embedded nucleoside analogue prevents formation of 5"- and 3"-phosphoroether bonds necessary for the elongation of the DNA chain. As a result, the growth of viral DNA stops.
Indications
Treatment of HIV infection (as part of combination therapy).
Dosing regimen
In combination with other antiviral agents inside adults 300 mg 2 times / day, children aged 3 months to 16 years - 8 mg / kg 2 times / day.
Side effect
From the skin and skin appendages: rash (usually maculopapular or urticarial); very rarely - erythema multiforme exudative, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
From the digestive system: loss of appetite, nausea, vomiting, diarrhea, abdominal pain, ulceration of the oral mucosa, increased activity of liver enzymes, liver failure.
From the respiratory system: shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.
From the nervous system: headache, paresthesia, drowsiness.
From the hematopoietic and lymphatic systems: lymphopenia.
From the side of the liver and pancreas:
From the musculoskeletal system: myalgia, rarely - rhabdomyolysis, arthralgia, increased CPK activity.
From the urinary system: increased serum creatinine concentration, renal failure.
From the musculoskeletal system: often - hyperlactatemia; rarely - lactic acidosis, accumulation / redistribution of adipose tissue. The frequency of these adverse reactions depends on many factors, incl. from antiretroviral drugs used in combination with abacavir.
Others: fever, fatigue, malaise, edema, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions.
Contraindications
Moderate and severe liver dysfunction; children under 3 months of age and body weight less than 14 kg; hypersensitivity to abacavir.
Pregnancy and lactation
Adequate and well-controlled clinical studies of the safety of the use of abacavir during pregnancy and lactation have not been conducted.
If necessary, use during pregnancy should weigh the expected benefit of therapy for the mother and the potential risk to the fetus.
It is not known if abacavir is excreted in breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.
Application for children
Children aged 3 months to 16 years - 8 mg / kg 2 times / day.
special instructions
Symptoms of hypersensitivity may appear any time after the start of treatment with abacavir, but most often they occur within the first 6 weeks.
If, with the development of a hypersensitivity reaction, patients continue to take abacavir, the clinical manifestations become more pronounced and may become life-threatening. In most cases, symptoms disappear when abacavir is stopped.
There have been reports of lactic acidosis, hepatomegaly, and fatty liver disease, including fatal cases, following antiretroviral therapy with nucleoside analogues, including abacavir, lamivudine, and zidovudine, taken alone or in combination. In most cases, these complications occur in women.
Symptoms indicative of lactic acidosis include general weakness, loss of appetite, rapid weight loss of unknown etiology, gastrointestinal tract and disorders of the respiratory system (dyspnea and tachypnea).
The use of abacavir in any patient requires caution, especially in the presence of risk factors for liver damage. If clinical or laboratory signs of lactic acidosis or hepatotoxicity appear (may manifest as hepatomegaly and fatty degeneration of the liver even in the absence of a pronounced increase in aminotransferase activity), treatment with abacavir should be discontinued.
Combination antiretroviral therapy may be accompanied by the development of lipodystrophy syndrome. During the clinical examination of patients during the treatment period, it is necessary to pay attention to the redistribution of subcutaneous fat. Laboratory examination should include determination of serum lipid concentration and blood glucose concentration. In violation of lipid metabolism, appropriate treatment is prescribed.
If HIV-infected patients with severe immunodeficiency have asymptomatic or oligosymptomatic opportunistic infections at the time of initiation of antiretroviral therapy (ART), the introduction of such therapy may lead to an increase in the symptoms of opportunistic infections or other serious consequences. These reactions usually occur within the first weeks or months after starting ART. Typical examples are cytomegalovirus retinitis, generalized 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.
The use of abacavir 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 experienced in the treatment of these diseases.
Caution should be given to antiretroviral therapy, including drugs containing abacavir, in patients with a possible risk of coronary artery disease. All measures should be taken to minimize all modifiable risk factors (such as arterial hypertension, dyslipidemia, diabetes mellitus and smoking).
Pharmacological group: Reverse transcriptase inhibitors from the group of nucleoside analogues.
Pharmacological action: It has a selective antiviral effect against human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), including HIV-1 strains resistant to Zidovudine, Zalcitabine, Didanosine or Nevirapine. In vitro studies have shown that the mechanism of action of Abacavir is the inhibition of HIV reverse transcriptase, which leads to the termination of the RNA chain and the termination of viral replication.
Systematic (IUPAC) name: ((1S, 4R)-4-cyclopent-2-en-1-yl) methanol
Trade names: Ziagen
Legal Status: Available by prescription only
Application: orally (solution or tablets)
Bioavailability: 83%
Metabolism: liver
Half-life: 1.54 ± 0.63 h
Excretion: renal (1.2% abacavir, 30% 5"-carboxylic acid metabolite, 36% 5" glucuronide metabolite, 15% unknown minor metabolites). Fecal (16%)
Formula: C 14 H 18 N 6 O
Mol. mass: 286.332 g/mol
Melting point: 165°C (329°F)
Abacavir is a nucleoside analog reverse transcriptase inhibitor used to treat HIV and AIDS. It is available under trade name Ziagen (ViiV Healthcare) and as part of combined drugs Trizivir (Abacavir, Zidovudine and) and Kivexa / Epzicom (Abacavir and). The drug is well tolerated side effect is hypersensitivity, which can be very serious, and in rare cases can be fatal. Genetic testing can be used to find out if a person will have hypersensitivity; Abacavir is safe for over 90% of patients. However, in a separate study, the drug was shown to increase the risk heart attack by almost 90%. Viral strains that are resistant to Zidovudine or are generally sensitive to Abacavir, however, there are a number of exceptions.
Clinical indications
Abacavir in the form of tablets and oral solution, in combination with other antiretroviral drugs, is indicated for the treatment of HIV-1 infection. Abacavir must be used in combination with other antiretroviral drugs. Abacavir should not be used as monotherapy when changing antiretroviral regimens due to loss of virological response.
Side effects of Abacavir (Ziagen)
Are common adverse reactions include nausea, headache, fatigue, vomiting, hypersensitivity reactions, diarrhea, fever/chills, depression, rash, anxiety, increased levels of URI, aspartate aminotransferase, alanine aminotransferase, hypertriglyceridemia, and lipodystrophy. Serious adverse reactions include hypersensitivity reactions, severe anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, myocardial infarction, lactic acidosis, hepatomegaly/steatosis, pancreatitis, immune reconstitution syndrome, and autoimmune disorders.
Warnings
Patients with liver disease should exercise caution when using Abacavir, as this may worsen the patient's condition. The use of nucleoside drugs such as abacavir can, in very rare cases, cause lactic acidosis. Resistance to Abacavir develops in laboratory versions of HIV that are also resistant to other HIV-specific antiretrovirals such as Didanosine and Zalcitabine. HIV strains that are resistant to protease inhibitors are not likely to be resistant to Abacavir. In people taking antiviral medicines, lipodystrophy (redistribution or accumulation of fat) may develop, leading to central obesity, wasting of the face, arms, legs, and/or buttocks, breast enlargement, and fat accumulation at the base of the neck ("bull's hump"). Abacavir is contraindicated for use in children under the age of 3 months.
Overdose
Little is known about the effects of an overdose of Abacavir. Overdose victims must be taken to a hospital emergency room for treatment.
Abacavir hypersensitivity syndrome
Hypersensitivity to Abacavir is associated with a single nucleotide polymorphism in the human leukocyte antigen B*5701 locus. There is a relationship between the prevalence of HLA-B*5701 and heredity. The prevalence of this allele is estimated to be 3.4 to 5.8% on average in populations of European ancestry, 17.6% in American Indians, 3.0% in Hispanic Americans, and 1.2% in Chinese Americans. There is significant variability in the prevalence of HLA-B*5701 among African population. Among African Americans, prevalence is estimated at an average of 1.0%, 0% in the Yoruba of Nigeria, 3.3% in Luhya of Kenya, and 13.6% in the Masai of Kenya, although averages are derived from highly variable frequencies within sample groups. . Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea and diarrhea, some patients may also present with skin rash. Symptoms of abacavir hypersensitivity syndrome usually appear within six weeks of treatment with abacavir, although they can be confused with symptoms of HIV, a syndrome immune recovery, hypersensitivity syndrome associated with other drugs, or infections. On July 24, 2008, the FDA issued a warning regarding Abacavir and medicines containing Abacavir. It is recommended to screen for the HLA-B*5701 allele before starting treatment, and in patients with this allele to use alternative methods treatment. Genetic testing of the HLA-B*5701 allele is recommended before starting or restarting treatment with abacavir or abacavir-containing drugs. The transdermal patch test method can be used to determine if a person will experience hypersensitivity reactions to abacavir, although some patients susceptible to hypersensitivity may not respond to the patch test at all. If hypersensitivity reactions to Abacavir are suspected, Abacavir should be discontinued immediately in all patients, including those without the HLA-B*5701 allele. On March 1, 2011, the FDA informed the public of the ongoing safety review of abacavir and possible increase the risk of heart attack associated with the use of this drug.
Immunopathogenesis
The mechanism underlying the abacavir hypersensitivity syndrome is associated with a change in HLA-B*5701 protein product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This leads to a change in immunological tolerance and subsequent activation of abacavir-specific cytotoxic T cells, which produce systemic reaction known as "Abacavir hypersensitivity syndrome".
Mechanism of action of Abacavir
ABC is an analogue of guanosine (purine). Its target is the viral reverse transcriptase enzyme.
Pharmacokinetics
Abacavir is taken orally and has a high bioavailability (83%). It is metabolized mainly by alcohol dehydrogenase or glucuronyl transferase. Abacavir can cross the blood-brain barrier.
Story
On December 18, 1998, Abacavir was approved by the US FDA and thus is the fifteenth approved antiretroviral drug in the United States. His patent expired in the US on December 26, 2009.
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Manufacturers: GlaxoSmithKline C.A. (Venezuela)
Active ingredients
Abacavir
Dihydrotachysterol
Disease class
Not indicated. See instructionsClinical and pharmacological group
Not indicated. See instructionsPharmacological action
Not indicated. See instructionsPharmacological group
Means for the treatment of HIV infectionTablets oral Abacavir (Abacavir)
Instructions for medical use drugContent
Description pharmacological action
Indications for use
Release form
Pharmacodynamics of the drug
Pharmacokinetics of the drug
Use during pregnancy
Use in impaired renal function
Contraindications for use
Side effects
Dosage and administration
Overdose
Interactions with other drugs
Precautions for use
Special instructions for admission
Storage conditions
Best before date
Description of the pharmacological action
Inhibits HIV-1 and HIV-2 reverse transcriptase. Causes RNA chain termination and stops virus replication. Rapidly and fairly completely absorbed after oral administration. Absolute bioavailability - 83%. Cmax is reached after 1-1.5 hours and is about 3 μg / ml. Eating slows down absorption.
In the blood, it binds to proteins, easily passes histohematic barriers (except for the BBB) and penetrates tissues, the volume of distribution is 0.8 l / kg. It is metabolized in the liver with the participation of alcohol dehydrogenase and glucuronyl transferase. About 66% of the dose is excreted in the form of glucuronide conjugates (only 2% unchanged) mainly by the kidneys (over 80%), partly with faeces; T1 / 2 - 1.5 hours. Does not accumulate.
As part of combination therapy (combination with Azidothymidine and Epivir), it slows down the progression of HIV infection, reduces the frequency and severity of AIDS-associated diseases, and improves the function of the immune system.
Indications for use
Treatment of HIV infection (as part of combination therapy.
Release form
coated tablets 300 mg;
Pharmacodynamics
An antiviral agent from the group of nucleoside analogues. It has a selective effect on HIV-1 and HIV-2 (including strains of HIV-1 resistant to zidovudine, lamivudine, zalcitabine, didanosine and nevirapine). By inhibiting reverse transcriptase, it leads to RNA chain termination and the termination of viral replication. Possible development resistance is associated with genotypic changes in a specific codon region of reverse transcriptase (codons M184V, K65R, L74V and Y115F). HIV resistance develops relatively slowly; multiple mutations are needed to increase the IC50 concentration by 8 times. The development of cross-resistance is unlikely. Increases the number of CD4 cells in the blood and reduces the concentration of viral RNA (including in the cerebrospinal fluid).
Pharmacokinetics
Absorption - high, bioavailability - 83%. Cmax - 3 μg / ml, the time to reach Cmax - 1–1.5 hours (after oral administration of the solution and tablets, respectively). AUC (within 12 hours after ingestion) - 6 mcg / h / ml. Food slows down the absorption of abacavir and reduces Cmax, but does not affect AUC. Penetrates through the BBB, the ratio of AUC in the cerebrospinal fluid and plasma is 30-44%. Communication with proteins - low. It is metabolized in the liver with the participation of alcohol dehydrogenase and the formation of glucuronide conjugates (5"-carboxylic acid and 5"-glucuronide). T1 / 2 - 1.5 hours. Excretion by the kidneys - 83% (as metabolites) and 2% (unchanged), the rest is excreted through the intestines.
Use during pregnancy
Adequate and well-controlled clinical studies of the safety of the use of abacavir during pregnancy and lactation have not been conducted.
If necessary, use during pregnancy should weigh the expected benefit of therapy for the mother and the potential risk to the fetus.
It is not known if abacavir is excreted in breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.
Use in impaired renal function
Side effects: rarely - kidney failure.
Contraindications for use
Hypersensitivity; children's age (up to 3 months).
With caution - pregnancy, lactation.
Side effects
Allergic reactions, fever, drowsiness, fatigue, nausea, vomiting, diarrhea, abdominal pain; myalgia, arthralgia, shortness of breath, headache, paresthesia; lymphadenopathy, conjunctivitis, ulceration of the oral mucosa; increased activity of "liver" transaminases, increased activity of CPK, hypercreatininemia; lactic acidosis, hepatomegaly, fatty degeneration liver (mainly in women).
Special instructions. During the period of treatment, the development of infections caused by opportunistic microorganisms is possible. Patients should be informed that treatment with antiretroviral drugs does not prevent the risk of transmission of HIV to others through sexual intercourse or blood transfusion, so patients should take appropriate precautions.
Dosage and administration
Inside, adults and children over 12 years old - 300 mg 2 times a day. Children from 3 months to 12 years - 8 mg / kg 2 times a day; maximum dose- 600 mg / day.
Overdose
In clinical studies, patients received single doses of abacavir up to 1200 mg and daily doses up to 1800 mg. There were no reports of unexpected adverse reactions. The effect of higher doses of abacavir is unknown.
Treatment: it is necessary to monitor the patient's condition in order to identify signs of intoxication and, if necessary, carry out maintenance therapy. There are no data on the possibility of removing abacavir using hemodialysis and peritoneal dialysis.
Interactions with other drugs
Does not inhibit metabolic processes involving CYP3A4, CYP2C9 and CYP2D6 isoenzymes. Additive action in combination with didanosine, zalcitabine, lamivudine and stavudine. Ethanol increases AUC by 41%.
Precautions for use
Monotherapy is not allowed. Only a specialist with experience in the treatment of HIV infection can prescribe the drug. Before starting active antiretroviral therapy, a complete clinical and laboratory examination of the patient is carried out, incl. the level of viral load on plasma and the number of CD4 + T-lymphocytes are determined. During treatment, regular (every 3–6 months) assessment of the level of the replication process, plasma viral load (determination of bDNA and RT-PCR) and the level of CD4+ cells is shown.
In the presence of clinical symptoms of HIV infection, it is necessary to start therapy without taking into account the number of CD4 + cells and the level of viral load on plasma. The appearance of any signs of a hypersensitivity reaction (usually occurring in the first 6 weeks of treatment) due to their potential danger for life requires discontinuation (and further use of the drug is unacceptable). The patient should be warned that treatment does not reduce the risk of passing HIV to others.
