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

Combined antiviral (HIV), a nucleoside reverse transcriptase inhibitor, a potent selective inhibitor HIV-1 and HIV-2. Abacavir and lamivudine metabolized by the action of intracellular kinases to the corresponding triphosphates, which act as active metabolites. However, the main antiviral effect is due to the incorporation of monophosphate into the chain DNA, which as a result is broken. Abacavir and lamivudine triphosphates have significantly less affinity for DNA-polymerization of host cells.

Pharmacokinetics:

After oral administration lamivudine and abacavir It is quickly and well absorbed from GIT, the absolute bioavailability in adults is about 80-85% and 83%, respectively. Eating food reduces absorption of the drug (C_max decreases by an average of 18-32%) and increases T_max (approximately 1 hour), but does not affect the amount of absorption. The average volume of distribution for lamivudine and abacavir is 1.3 and 0.8 l / kg, respectively. Lamivudine has a linear pharmacokinetics in the entire range of therapeutic doses and a low ability to bind to plasma albumin (less than 36% in vitro). The binding to plasma proteins of abacavir is approximately 49%. This indicates that for the drug the probability of interaction with drugs by displacing them from binding sites with proteins is not high. Lamivudine and abacavir go through blood-brain barrier and are found in cerebrospinal fluid. The ratio of abacavir concentration in cerebrospinal fluid and plasma (AUC) is 30-44%. The mean concentration of abacavir in cerebrospinal fluid 1.5 hours after taking the dose of 300 mg was 0.14 μg / ml, after taking a dose of 600 mg in 0.5-1 hour, it was 0.13 μg / ml and after 3-4 hours it increased to 0.74 μg / ml.

Lamivudine is excreted from the body by the kidneys in unchanged form. Drug interactions of lamivudine are unlikely due to a small hepatic metabolism (5-10%) and weak binding to plasma proteins. Abacavir primary metabolized in the liver with the participation of alcohol dehydrogenase and through glucuronization formed its metabolites - 5'-carbolic acid and 5'-glucuronic acid, constituting 66% of the dose of the drug that is excreted in the urine, less than 2% of abacavir is excreted unchanged in the urine.

Half-life lamivudine - 5-7 hours. The prevalence of renal clearance (more than 70%), elimination is carried out using the transport system of organic cations, and the average system clearance is approximately 0.32 l / h / kg. Elimination of lamivudine is impaired in renal failure, so when ground clearance creatinine ≤ 50 mL / min, a dose reduction is necessary.

Average half-life Abacavir is approximately 1.5 hours. With repeated intake of 300 mg twice a day, significant cumulation of abacavir is not observed. Abacavir metabolized in the liver, the subsequent elimination of metabolites is carried out by the kidneys. Abacavir and its metabolites make up about 83% of the dose received in the urine, the rest is excreted with feces.

Patients with impaired liver function. The pharmacokinetics of lamivudine is not significantly impaired with moderate and severe hepatic insufficiency. Abacavir Primarily metabolized in the liver. With mild hepatic insufficiency, there is an average increase AUC in 1.89 times, and half-life - in 1,58 times. The rate of formation and excretion of its metabolites is reduced. Thus, with mild hepatic insufficiency, a reduction in the dose of abacavir is recommended, with moderate to severe - the use of abacavir is contraindicated.

Patients with impaired renal function. With renal failure, a decrease in renal clearance of lamivudine is observed and its elimination is disturbed. When ground clearance Creatinine less than 50 ml / min is recommended to reduce the dose of the drug. Abacavir metabolized in the liver and less than 2% of the drug is excreted unchanged in the urine. The pharmacokinetics of abacavir are the same in the final stage of renal failure and with preserved kidney function. When a dose adjustment of lamivudine is required (clearance creatinine less than 50 ml / min), it is preferable to prescribe lamivudine and abacavir apart.

Indications:

Infection caused by the human immunodeficiency virus (HIV), as part of combined antiretroviral therapy for adults and adolescents over 12 years of age.

ICD-10

I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified

Contraindications:

Hypersensitivity, liver failure, chronic renal failure (creatinine clearance less than 50 ml / min), simultaneous reception with zalcitabine, body weight less than 40 kg, children's age (up to 12 years), breast-feeding.

Carefully:

Age over 65, pregnancy (taking into account the expected benefit to the mother and possible risk to the fetus).

It is not recommended to use the drug to treat children under the age of 12 due to the lack of the possibility of dose adjustment. For the selection of therapy, physicians are advised to consult the instructions for the use of lamivudine and abacavir.

The pharmacokinetics of abacavir and lamivudine in patients older than 65 years have not been studied. In treating elderly patients, the increased incidence of liver, kidney, heart, and other comorbid conditions, as well as the use of other medications, should be considered.

While patients with renal dysfunction are not required to adjust the dose of abacavir, the dose of lamivudine should be reduced in proportion to the decrease in creatinine clearance. In this regard, it is not recommended to use the drug when creatinine clearance is less than 50 ml / min.

Pregnancy and lactation:

The action category for fetus by FDA is C.

Safety of use of the drug in pregnant women is not established. Data were obtained in the reproductive studies of lamivudine and abacavir in animals. In this regard, the question of prescribing the drug during pregnancy should be considered only if the benefit to the mother exceeds the possible risk to the fetus. The drug should be used in accordance with current recommendations on the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

As HIV enters the breast milk, it is not recommended for women to breast-feed to prevent the transmission of the virus to the baby through breast milk.

Lamivudine is excreted with milk in a concentration close to the concentration in the blood serum. Expected that abacavir will also be excreted with milk, although this is not confirmed.

Dosing and Administration:

Therapy should be performed by a doctor with experience in HIV treatment.

Due to the impossibility of dose adjustment when using combined tablets with fixed dosages of ingredients, the drug should not be administered to adults and adolescents whose body weight is less than 40 kg.

The drug can be taken regardless of food intake.

Combination preparations with fixed doses of ingredients should not be used when there may be a need for dose adjustment, for example, when creatinine clearance is less than 50 ml / min, as well as in liver failure. In case of discontinuation of the drug or, if necessary, dose adjustment should be administered as mono preparations abacavir or lamivudine. In such situations, the doctor should become familiar with the instructions for the use of these medications.

Adults and children 12 years of age and older drug is prescribed 1 tablet once a day every day.

Side effects:

Since the drug is combined, it is possible to display side effects, characteristic of abacavir and lamivudine.For many of the side effects listed below, it remains unclear whether their appearance is related to the action of the active substances of the drug, the simultaneous use of other drugs (used to treat HIV), or they are manifestations of the underlying disease.

Hypersensitivity to abacavir

In clinical studies conducted before the screening for the presence of the HLA-B * 5701 allele, approximately 5% of patients taking abacavir, a hypersensitivity reaction developed, which in rare cases led to a fatal outcome. This reaction is characterized by the appearance of symptoms that indicate a multiple organ failure.

Almost all patients who develop hypersensitivity reactions experience an increase in body temperature and / or rash (usually maculopapular or urticaria), but there have been cases of a hypersensitivity reaction that was not accompanied by the appearance of a rash and an increase in body temperature.

Symptoms of hypersensitivity reactions can occur at any time during treatment with abacavir, but they usually appear within the first six weeks of the start of the drug (the average is 11 days).

The signs and symptoms of a hypersensitivity reaction are listed below.

From the skin: rash (usually maculopapular or urticarum).

From the digestive tract: nausea, vomiting, diarrhea, abdominal pain, ulceration in the oral cavity.

From the respiratory system: dyspnoea, cough, sore throat, respiratory distress syndrome, respiratory failure.

From the nervous system: headache, paresthesia.

On the part of the blood system: lymphopenia.

From the hepatobiliary system: increase in liver function tests, liver failure

From the musculoskeletal system: myalgia, rarely - myolysis, arthralgia, increased level creatine phosphokinase.

From the urinary system: increased creatinine, kidney failure.

Other: a fever, a feeling of fatigue, malaise, edema, lymphadenopathy, lowering of arterial pressure, conjunctivitis, anaphylaxis.

Overdose:

Symptoms: increased side effects.

Treatment: in case of an overdose, the patient should be under the supervision of a doctor (in order to identify signs of toxic effects of the drug).If necessary, conduct a standard maintenance therapy. Due to lamivudine can be removed from the body by dialysis, treatment of an overdose should include continuous hemodialysis (although studies to study the possibility of hemodialysis during drug overdose have not been performed). At present, it is not known whether peritoneal dialysis and hemodialysis contribute to the excretion of abacavir from the body.

Interaction:

The spectrum of drug interactions is determined by the nature of the interactions of abacavir and lamivudine, among which there are no clinically significant ones to date. Abacavir and lamivudine are slightly metabolized by enzymes of the cytochrome P450 system (for example: CYP3A4, CYP2C9 or CYP2D6) and do not have an inhibitory or inductive effect on this enzyme system. Therefore, the probability of drug interaction with antiretroviral non-nucleoside protease inhibitors and other drugs whose metabolism occurs with the participation of the main enzymes of the cytochrome P450 system is small.

The likelihood of metabolic interactions with lamivudine is low, as it is poorly metabolized, poorly bound to plasma proteins and excreted almost exclusively by the kidneys. Lamivudine is derived mainly through active organic cationic secretion. Consideration should be given to the possibility of interaction with other drugs, especially in cases where the kidneys are the main way of excretion.

Drug interactions due to the presence of abacavir

Ethanol: the metabolism of abacavir is disturbed by simultaneous administration with ethanol, which leads to an increase in AAC of abacavir by approximately 41%. Given the safety profile of abacavir, these data are not considered clinically relevant. Abacavir does not affect the metabolism of ethanol.

Methadone: in the study of pharmacokinetics of drugs with concomitant administration of abacavir (600 mg twice daily) and methadone, there was a decrease in C_max abacavir by 35% and a decrease in the time to reach C_max for 1 h, however AUC remained unchanged. Changes in the pharmacokinetics of abacavir have not been clinically significant. In this study abacavir increased the average total methadone clearance by 22%. This change was not clinically significant in most patients, but there may sometimes be a need for a methadone dose adjustment.

Drug interactions due to the presence of lamivudine

Trimethoprim: taking trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim. However, except for patients with renal failure, a dose adjustment of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. Joint use of lamivudine with higher doses of co-trimoxazole used to treat pneumonia (caused by Pneumocystis carinii) and toxoplasmosis, has not been studied.

Zalcitabine: lamivudine can inhibit intracellular phosphorylation of zalcitabine with simultaneous administration of these drugs. In this regard, it is not recommended to take the drug in combination with zalcitabine.

Special instructions:

Treatment should be performed by a doctor who has experience with the drug.

The drug should not be used in cases where dose adjustment is required (creatinine clearance less than 50 ml / min, hepatic insufficiency) due to the presence of fixed doses of individual components in one tablet. In such cases, monotherapy with abacavir or lamivudine.

In 5% of patients receiving abacavir, a hypersensitivity reaction (more often in the first 6 weeks), which in rare cases leads to a lethal outcome. When there are symptoms of multiple organ damage (fever and / or rash, weakness, malaise, nausea, vomiting, diarrhea, abdominal pain, shortness of breath, sore throat, cough, x-ray signs of chest damage (infiltrates)), stop and never resume taking the drug, as well as other medicinescontaining abacavir. The recurrence of the hypersensitivity reaction is more severe (compared with the first reaction) and may be accompanied by a decrease blood pressure (up to a lethal outcome).

The risk of developing a hypersensitivity reaction to abacavir is determined by the genetic factor (presence of the HLA-B5701 allele), which is present in 50% of the patients of the Caucasian race, in 8% of the patients of the Negroid race and in 22% of the patients of the Spanish ethnicity. However, the basis of diagnosis is the presence of clinical symptoms of a hypersensitivity reaction, regardless of whether there is an allele of HLA-B5701 or not.

When taking the drug, it is possible to develop lactic acidosis, severe hepatomegaly with steatosis, including with a lethal outcome.The drug should be stopped even if there is no significant increase in the activity of transaminases.

Some patients have a redistribution of fat in the body: the increase on the back of the neck and back ( "buffalo hump"), breast enlargement, reduction of fat in the periphery and in the facial area. Perhaps the development of lipodystrophy, hyperglycemia and hyperlipidemia.

In appointing the drug in patients with concomitant hepatitis B should monitor liver function tests and markers of replication of hepatitis B.

When taking the drug, opportunistic infections and other complications can develop HIV.

Abacavir-resistant patients have reduced sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and / or didanosine, but remain sensitive to AZT and stavudine.

The development of cross-resistance between abacavir, lamivudine and antiretrovirals drugs other classes is unlikely.

Hypersensitivity to abacavir

According to clinical studies conducted prior to the screening for the allele HLA-B * 5701, approximately 5% of patients,host abacavir, hypersensitivity to the drug develops, in rare cases with a fatal outcome.

Risk factors

In clinical studies, carriage of the HLA-B * 5701 allele has been shown to significantly increase the risk of a hypersensitivity reaction to abacavir. In the prospective clinical trial CNA106030 (PREDICT-1), patients with the presence of the HLA-B * 5701 allele were not given abacavir preparations, which significantly reduced the incidence of clinically suspected hypersensitivity reactions from 7.8% (66 patients out of 847) to 3.4% (27 patients out of 803), as well as the incidence of hypersensitivity reactions confirmed by the skin-application test from 2.7% (23 patients out of 842) to 0.0% (0 patients from 802). Thus, based on the results of this study, it was shown that hypersensitivity reactions to abacavir develop in patients carrying the HLA-B * 5701 allele at a frequency of 48-61% compared to patients who do not have this allele (frequency of hypersensitivity reactions 0 -4 %).

Clinicians are advised to screen for carriage of the HLA-B * 5701 allele in HIV-infected patients who have not previously been prescribed drugs containing abacavir.

Screening for the carriage of the HLA-B * 5701 allele is recommended before reassignment of the abacavir-containing drug in patients with an unknown HLA-B * 5701-status who previously had a good abacavir-containing drug.

The use of abacavir drugs is not recommended in such patients and should be considered only in exceptional cases with careful medical supervision when the potential benefit exceeds the risk of using the drug.

The clinical diagnosis of suspected hypersensitivity reactions should remain the basis for deciding the use of drugs containing abacavir, in all patients. Even in the absence of the HLA-B * 5701 allele 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 is characterized by the appearance of symptoms of multiple organ failure. Most patients have fever and / or rash.

Other possible symptoms of hypersensitivity include weakness, malaise, symptoms of the gastrointestinal tract (such as nausea, vomiting, diarrhea, abdominal pain), respiratory symptoms (such as shortness of breath, sore throat, cough), as well as radiologic signs lesions of the chest (mainly, limited infiltrates). Symptoms of hypersensitivity reactions in the treatment of abacavir can be observed at any time, however, usually appear within the first six weeks of taking the drug. With the continuation of treatment, the severity of the symptoms increases, and they can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Some patients with hypersensitivity initially believed that they suffer from respiratory (pneumonia, bronchitis, pharyngitis) or flu-like diseases, gastroenteritis or reactions to other medications. In this regard, the hypersensitivity reaction was not diagnosed immediately, and patients continued (or resumed) the drug. This entailed the development of a more severe hypersensitivity reaction (up to a lethal outcome).Taking this into account, it is necessary to take into account the possibility of developing such a reaction and to exclude it in patients who have symptoms of these diseases. If it is impossible to exclude the presence of a hypersensitivity reaction, resume taking the drug or any other drug containing abacavir, do not do it.

Symptoms caused by hypersensitivity reactions increased with continued treatment and usually disappeared after discontinuation of abacavir.

The resumption of abacavir after a hypersensitivity reaction for several hours leads to a rapid return of symptoms. Recurrence of hypersensitivity reactions may be more severe, compared with the first reaction, and accompanied by life-threatening lowering of blood pressure (up to a lethal outcome). Patients who have experienced this hypersensitivity reaction should stop and never resume taking the drug, as well as any other medications containing abacavir.

There are isolated reports of the development of a hypersensitivity reaction after the resumption of taking abacavir,canceled with the appearance of certain key symptoms of hypersensitivity (rash, fever, weakness / malaise, gastrointestinal disorders or symptoms of respiratory damage). In very rare cases, the development of a hypersensitivity reaction has been reported after resumption of treatment with patients who have not previously experienced hypersensitivity symptoms.

Treatment

Patients, regardless of HLA-B * 5701-status, who have signs and symptoms of hypersensitivity, MUST immediately contact their doctor for advice. When making a diagnosis of hypersensitivity, SHOULD immediately stop taking the drug. NEVER SHOULD RESUME TREATMENT OF THE MEDICINE AND OTHER MEDICINES CONTAINING abacavir (such as Ziagen, Trizivir), after the occurrence of a hypersensitivity reaction. This is due to the threat of appearance within a few hours after the resumption of taking the drug of severe symptoms (including life-threatening hypotension), which can lead to death.

To prevent delayed detection and reduce the risk of life-threatening hypersensitivity,should completely stop taking the drug if it is impossible to exclude hypersensitivity, even with the potential presence of other diseases (respiratory diseases, flu-like diseases, gastroenteritis, reactions to taking other medications). Do not resume treatment with medication and other medications containing abacavir (such as Ziagen, Trizivir), even in the case of hypersensitivity symptoms when re-taking other medications.

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

In the event of discontinuation of treatment with the drug, regardless of the carriage of the HLA-B * 5701 allele, the reason for refusing the drug should be carefully studied before resumption of the drug and that the patient does not have symptoms of a hypersensitivity reaction. Do not resume taking the drug and other medications containing abacavir, if it is impossible to exclude the hypersensitivity reaction.

A few cases of the development of a hypersensitivity reaction with the resumption of treatment with abacavir after its withdrawalin connection with the emergence of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue, gastrointestinal disturbances and violations of the respiratory system). 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 or other abacavir containing drug in these patients is not recommended.

The hypersensitivity reaction was noted, although very rarely, even with the resumption of treatment with this drug by patients who had not previously experienced symptoms of this reaction, and a break in receiving the abacavir drug was associated with other causes. In this case, the resumption of taking the drug is possible, but requires the patient or people around him to have quick access to medical care.

Screening for carriage of the HLA-B * 5701 allele is recommended before re-administration of an abacavir-containing drug in patients with unknown HLA-B * 5701 status who previously tolerated therapy abacavir containing drug.

The re-administration of an abacavir-containing drug to patients carrying the HLA-B * 5701 allele is not recommended and can only be considered in exceptional cases under close medical supervision, when the potential benefit of drug treatment outweighs all possible risks.

Lactic acidosis, hepatomegaly and fatty liver disease

When using antiretroviral nucleoside analogues (including abacavir and lamivudine), taken either individually or in combination, development of lactic acidosis, hepatomegaly and severe fatty liver disease, including cases that ended in a fatal outcome, was noted. Similar phenomena were noted mainly among women.

Clinical signs of developing lactic acidosis are: general weakness, anorexia, sudden, uncaused weight loss, symptoms of respiratory damage (shortness of breath, rapid breathing) and gastrointestinal tract.

Care should be taken when prescribing the drug to all patients, especially those who have risk factors for liver damage. The drug should be discontinued when there are clinical or laboratory signs of lactic acidosis or hepatotoxicity (which include hepatomegaly and steatosis,even in the absence of a significant increase in the level of aminotransferase).

Lipodystrophy

In some patients who underwent combined antiretroviral therapy, there was a redistribution / accumulation of fat in the body, an increase in the amount of fat on the back of the neck and back ("buffalo buffalo"), a reduction in the amount of peripheral fat deposits, emaciation of the face, enlargement of the mammary glands, and lipid levels in serum.

Lipodystrophy can develop when taking any medication from a class of protease inhibitors or nucleoside reverse transcriptase inhibitors. However, the available data indicate that the risk of developing these side effects when taking different preparations of these classes is not the same.

In addition, many factors contribute to the development of lipodystrophy. The presence of HIV infection, the elderly age and the duration of antiretroviral therapy play an important and possibly mutually potent role.

During the clinical examination, attention should be paid to the signs of fat redistribution in the body.It is necessary to closely monitor serum lipids and blood glucose levels. If necessary, appropriate treatment for violations of fat metabolism.

Patients with concomitant viral hepatitis B

Clinical studies and post-marketing data on the use of lamivudine suggest that some patients with concomitant viral hepatitis B may develop clinical or laboratory signs of hepatitis relapse after stopping lamivudine. Discontinuation of lamivudine may have more severe consequences in patients with decompensated liver damage. Therefore, in patients with concomitant viral hepatitis B, when the drug is withdrawn, it is necessary to monitor the performance of functional liver samples and regularly determine the level of replication of the hepatitis B virus.

Immunodeficiency Syndrome

If HIV-infected patients with severe immunodeficiency are asymptomatic or asymptomatic opportunistic infections at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences.Usually, these reactions occur within the first weeks or months after the onset antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized 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.

Opportunistic infections

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

Transmission of infection

Modern antiretroviral therapy, including the drug, does not prevent the transmission of HIV during sexual intercourse or contact with infected blood. It is necessary to remember the need to comply with appropriate security measures.

Myocardial infarction

As a result of a prospective, observational, epidemiological study to study the incidence of myocardial infarction in patients receiving combination antiretroviral therapy,the connection of the previous, within 6 months, reception of abacavir with the increased risk of development of a myocardial infarction was found out. According to the generalized analysis of clinical studies, there was no increase in the risk of myocardial infarction associated with abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data from observing cohorts and controlled clinical studies do not allow one to unequivocally determine the relationship between abacavir therapy and the risk of myocardial infarction.

However, 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 arterial hypertension, dyslipidemia, diabetes and smoking).

Instructions

Abacavir + Lamivudine (Abacavirum + Lamivudinum)