Kivexa (Kivexa)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAbacavir + LamivudineAbacavir + Lamivudine
Dosage form: & nbspfilm-coated tablets
Composition:

Component

amount

mg / tablet

The core of the tablet


Abacavir Sulfate

7021

Lamivudine

300

Microcrystalline cellulose

309

Carboxymethyl starch of sodium type A

55

Magnesium stearate

9

Shell


Reward orange YS-1-13065-A

412,3

Purified water4

-

1 Equivalent to 600 mg of abacavir in 1 tablet (conversion factor 1.17).

2 The weight of the film jacket can vary depending on the efficiency of the coating process.

3 41 mg of film coating contains:

- 26.4 mg of hypromellose (E 464) - Heb. Farm.

- 9.2 mg of titanium dioxide (E 171, CI77891) - Heb. Farm.

- 3,3 mg of macrogol 400 - He. Farm.

- 0.4 mg of polysorbate 80 (E 433) - Hept. Farm.

- 1,7 mg of dye-yellow aluminum lacquer (Sunset Yellow aluminum lake , E - 110, Cl 15985)- domestic company specification.

4 Removed during production.

Description:

The tablet is elongated, biconvex, orange-coated, on one side of the tablet - engraving GS FC2, the other side has a smooth surface.

Pharmacotherapeutic group:Antiviral [HIV] agent
ATX: & nbsp

J.05.A.R.02   Abacavir + Lamivudine

Pharmacodynamics:

Mechanism of action

Abacavir and lamivudine belong to the group of nucleoside reverse transcriptase inhibitors (NRTIs) and are potent selective inhibitors of HIV-1 and HIV-2. Abacavir and lamivudine are subsequently metabolized under the action of intracellular kinases to the corresponding triphosphates (TF), which act as active metabolites. Lamivudine-TF and carbovir-TF (active triphosphate abacavir) act as a substrate and are competitive inhibitors of reverse transcriptase (RT) of HIV. However, the main antiviral effect of drugs is due to the insertion of monophosphate into a chain of viral DNA, which leads to the termination of replication. Triphosphates of abacavir and lamivudine have a much lower affinity for DNA polymerases of host cells.

According to the study, 20 HIV-infected patients abacavir at a dose of 300 mg twice a day and only one dose (300 mg) before the 24-hour sampling period for analysis, the geometric mean of the terminal intracellular half-life of the carbovir-TF half-life in the equilibrium state was 20.6 hours. The geometric mean half-life Abakavir from plasma in this study was 2.6 hours. Equilibrium pharmacokinetic indices when taking abacavir 600 mg once a day were the same with those with abacavir 300 mg twice daily in a cross-sectional clinical trial with involving 27 HIV-infected patients. The intracellular content of carbovir-TF in peripheral blood mononuclear cells was higher with the administration of abacavir in a dosage of 600 mg 1 once a day compared with the reception of abacavir 300 mg 2 times a day (an increase in the area under the pharmacokinetic curve "concentration-time" in a state of equilibrium in 24 hours (AUC24,ss) by 32%, the maximum daily concentration in the equilibrium state Cmah24ss - by 99% and the residual concentration - by 18%). In patients who took lamivudine 300 mg once a day, the terminal intracellular half-life of lamivudine-TF increased from 16 to 19 hours, and the half-life of lamivudine from plasma increased from 5 to 7 hours.A study of the pharmacokinetics of lamivudine, taken at a dose of 300 mg once a day for 7 days compared with 150 mg of lamivudine 2 times a day for 7 days, with 60 healthy volunteers, showed that the values AUC24,ss and Cmah24ss for the intracellular concentration of lamivudine-TF in mononuclear cells of peripheral blood were identical, but the residual concentration when taking lamivudine 300 mg once a day was lower than when taking lamivudine 150 mg twice a day. The variability of the concentration of lamivudine-TF within the cell was higher than the residual concentration of lamivudine in the blood plasma. These results are confirmed by data obtained with the administration of 300 mg of lamivudine and 600 mg of abacavir 1 once a day (the effectiveness and safety of this combination when taking drugs 1 once a day was also confirmed in the course of the basic clinical study CNA30021).

Pharmacodynamic effects

Antagonism of antiviral activity of abacavir in cell culture was not observed with the combination of the latter with NDTD didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or protease inhibitor (IP) amprenavir.There were no antagonistic effects in vitro with the simultaneous use of lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine).

Resistance of HIV-1 to lamivudine is due to a mutation in the codon M184V. located close to the active center of viral OT. This mutation is observed both in conditions in vitro, and in HIV-1-infected patients who underwent combined therapy, including lamivudine. In case of mutation in the codon M184V significantly reduces the sensitivity to lamivudine and significantly reduces the ability of the virus to replicate according to research data in vitro. In studies in vitro it is established that zidovudine-resistant isolates of the virus can become susceptible to its action if these isolates develop resistance to lamivudine simultaneously. However, the clinical significance of such changes has not been determined to date.

Abacavir-resistant isolates of HIV-1 were isolated under conditions in vitro. These isolates are characterized by certain genotypic changes in the codons OT (codons M184V, K65R, L74V and Y115F).

HIV resistance to abacavir in vitro and in vivo formed slowly.For a clinically significant increase IC50 (inhibitory concentration against 50% of the strains) in 8 times with respect to the "wild" strain of the virus), multiple mutations of the viral genome are required. Resistant to abacavir isolates may also have a decreased sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and / or didanosine, but remain sensitive to zidovudine and stavudine.

The development of cross-resistance between abacavir and lamivudine and antiretroviral drugs of other classes (eg, IP and NNRTI) unlikely. HIV isolates with reduced sensitivity to abacavir were isolated in patients with uncontrolled viral replication, in which previous treatment with other NRTIs was ineffective.

It is unlikely that clinical isolates of the virus that have three or more mutations associated with resistance to NRTIs will be sensitive to abacavir. Cross-resistance, due to M184V a mutation of OT. is limited to the class of nucleoside inhibitors of antiretroviral drugs. Zidovudine, stavudine, abacavir and tenofovir retain their antiretroviral activity against HIV-1 lamivudine-resistant isolates that carry only M184V mutation.

Pharmacokinetics:

The drug Kiveksa in the form of tablets is bioequivalent to abacavir and lamivudine, used as monopreparations. This was confirmed by a comparative study of bioequivalence, in which healthy volunteers (n = 30) once took a Kivexa (fasting) or 2 tablet of 300 mg of abacavir and 2 tablets of 150 mg of lamivudine (fasted), or a Kivex drug after meals, containing a large amount of fat.

When taking an empty stomach, there were no significant differences in the degree of absorption (area under the pharmacokinetic curve "concentration-time" (AUC)) and the maximum concentration (CmOh) of each of the components. Also, there were no clinically significant changes in pharmacokinetic parameters due to the administration of the Kivex drug on an empty stomach or with food. These data indicate that the drug can be taken regardless of food intake.

The pharmacokinetic properties of lamivudine and abacavir are described below.

Suction

Abacavir and lamivudine quickly and well absorbed after oral administration. Absolute bioavailability of abacavir and lamivudine in adults with oral administration is 83% and 80-85%, respectively. Mean time to maximum serum concentration (tmax) is about 1.5 h and 1.0 h for abacavir and lamivudine, respectively. After a single oral intake of 600 mg of abacavir, the average CmOh is 4.26 μg / ml, and the mean AUCss- 11.95 μg / ml. After repeated oral administration of lamivudine 300 mg once a day for seven days, the average equilibrium CmOh is 2.04 μg / ml, and the mean AUC24 - 8.87 μg h / ml.

Distribution

In conditions in vitro it was found that when administered at therapeutic concentrations abacavir slightly (~ 49%) binds to human plasma proteins. Lamivudine demonstrates a linear change in pharmacokinetic parameters when using therapeutic doses and is slightly associated with blood plasma proteins (less than 36%). This indicates a low probability of interaction with other drugs, in which there is a replacement of drugs from the connection with plasma proteins.

The available data indicate that abacavir and lamivudine penetrate into the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). It was found that the relation AUC for CSF and blood plasma is from 30 to 44%.The peak concentration of abacavir in CSF when taken at a dose of 600 mg twice a day is 9 times higher IC50 abacavir. which is 0.08 μg / ml or 0.26 μmol / l. The average ratio of lamivudine concentration in CSF to its serum concentration after 2-A h after oral administration of the drug is approximately 12%. The true extent of lamivudine penetration into the central nervous system, as well as the clinical significance of this phenomenon, have not been established to date.

Metabolism

Abacavir is metabolized, mainly in the liver, in an unchanged form is released by the kidneys of less than 2% of the accepted dose of the drug. In humans abacavir is metabolized mainly by the action of alcohol dehydrogenase with the formation of the 5'-carboxylic acid and by conjugation with glucuronic acid to form 5'-glucuronide constituting about 66 % of the total administered dose of the drug. These metabolites are excreted by the kidneys.

Lamivudine is almost not metabolized and is mainly excreted unchanged by the kidneys. The likelihood of metabolic interactions with lamivudine is low, since a small proportion of the liver is metabolized (less 10%) of the accepted dose of the drug.

Excretion

The mean half-life of abacavir is approximately 1.5 hours. After repeated oral administration of abacavir (300 mg twice daily), there is no significant accumulation of abacavir. Abacavir excretion is carried out by metabolism in the liver with subsequent excretion of metabolites predominantly kidneys. In urine, approximately 83% of the accepted dose of abacavir is detected in the form of metabolites and unchanged. The rest is removed through the intestine.

The half-life of lamivudine is from 5 to 7 hours. The average total clearance of lamivudine is approximately 0.32 L / h / kg, most of which is renal clearance (> 70%), which is realized by active tubular secretion through the system of organic cation transport.

Special patient groups

Dysfunction of the liver

There are data on the pharmacokinetics of abacavir and lamivudine, obtained with separate use of drugs. The pharmacokinetics of abacavir has been studied in patients with mild liver function disorders (5-6 on the Child-Pugh scale). The study found that AUC Abacavir increased by an average of 1.89 times, and the half-life increased 1.58 times. With liver diseases AUC the individual metabolites of the drug did not change. However, the rate of formation and excretion of these metabolites decreased.

Patients with mild liver function disorders need to reduce the daily dose of abacavir. To treat such patients, a drug containing only abacavir (preparation Ziagen ®). Studies of the pharmacokinetics of abacavir in patients with violations of liver function of medium and severe degree have not been conducted. It is assumed that in such patients the concentration of abacavir in plasma will be characterized by variability and will be significantly increased. In this regard, the use of the drug Kivexa is not recommended in patients with impaired liver function.

The data obtained with the use of lamivudine in patients with violations of the liver function of moderate and severe degree, indicate that significant changes in the pharmacokinetic parameters of the drug in the violation of liver function does not occur.

Renal impairment

There are data on the pharmacokinetics of abacavir and lamivudine, obtained with separate use of drugs. Abacavir it is metabolized mainly in the liver.Approximately 2% of abacavir is excreted unchanged by the kidneys. The pharmacokinetic indices of abacavir in patients with terminal stage of renal dysfunction and normal renal function are virtually indistinguishable. Studies have shown that patients with impaired renal function concentration AUC lamivudine in plasma increases due to lower clearance. In connection with the need to reduce the dose of lamivudine in patients with creatinine clearance less than 50 ml / min, such patients should be prescribed lamivudine mono drug (Epivir ® preparation).

Indications:

Treatment of HIV infection as part of combined antiretroviral therapy for adults and adolescents over 12 years of age and weighing more than 40 kg.

Contraindications:

- Hypersensitivity to abacavir or lamivudine or any other component in the formulation;

- hepatic failure secondary to severe (grade B and C Child-Pugh (in the absence of clinical data and the recommended dosing regimen));

- hepatic insufficiency of mild degree (class A on the Child-Pugh scale (due to the lack of a recommended dosing regimen));

- impaired renal function (creatinine clearance less than 50 ml / min (due to lack of recommended dosing regimen));

- age up to 12 years (due to the lack of possibility of dose adjustment);

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

Carefully:

- Caution should be exercised when using Kivex, especially in patients with hepatomegaly, hepatitis, or other known risk factors for developing liver disease and steatosis of the liver (including certain drugs and alcohol).

- When prescribing antiretroviral therapy, including abacavir, it is necessary to take into account the existing risk of coronary heart disease.

Pregnancy and lactation:

Fertility

Animal studies have shown that neither abacavir, nor lamivudine do not affect fertility.

Pregnancy

The safety of the use of Kivex in women during pregnancy has not been studied to date. There is evidence of studies on the effects of abacavir and lamivudine on fetal development in animals. Therefore, during pregnancy, Kivexa is used only if the intended benefit to the mother exceeds the potential risk to the fetus.

There is evidence of a slight transient increase in lactate concentration in the blood plasma, possibly due to mitochondrial disorders in newborns and infants whose mothers took NRTIs during pregnancy and in the perinatal period. The clinical significance of this enhancement is not currently established. In addition, there are some reports of developmental delay, convulsive seizures and other neurological disorders, such as increased muscle tone. However, the causal relationship of these disorders to the effect of NRTIs during the intrauterine and perinatal periods has not been established. These data do not abolish existing recommendations for antiretroviral therapy (Apt) during pregnancy to prevent vertical transmission of HIV.

Breastfeeding period

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

In the study, after repeated oral administration of 150 mg of lamivudine 2 times a day (in combination with zidovudine 300 mg twice a day) or 300 mg of lamivudine 2 times a day, lamivudine was excreted in breast milk (0.5 to 8.2 μg / ml), in similar concentrations lamivudine was found in the serum. In other studies, after repeated oral administration of 150 mg lamivudine 2 times a day (as in combination with zidovudine 300 mg and in Combivir® or Trizivir®), the ratio of lamivudine concentration in breast milk and maternal blood plasma was between 0.6 and 3.3. In studies after repeated oral administration of 300 mg of abacavir 2 times a day (taken in the form of Trizivir®), the concentration ratio in the maternal plasma and breast milk was 0.9. For oral administration of abacavir, pharmacokinetic studies were not performed once a day. The average serum concentration of lamivudine in infants was between 18 and 28 ng / ml and was not determined in one of the studies (sensitivity of the assay was 7 ng / ml). Most infants (8 of 9) had undetectable levels of abacavir (sensitivity of analysis - 16 ng / ml). The content of intracellular lamivudine-TF and carbovir-TF (active metabolites lamivudine and abacavir) were not measured in infants with breastfeeding, so the clinical significance of the measurement of the serum concentration of the parent compound is unknown.

Dosing and Administration:

Therapy should be performed by a physician with experience in the treatment of HIV infection.

Kivex should not be given to adults and adolescents weighing less than 40 kg due to the impossibility of dose adjustment.

The drug Kiveksa can be taken regardless of food intake.

Kivex should not be used in cases where it may be necessary to adjust the dose, for example, when creatinine clearance is less than 50 ml / min. In the event of discontinuation of the drug Kiveksa, or if necessary, dose adjustment should be given mono drugs abacavir (Ziagen ®) or lamivudine (Epivir ®). In such situations, the doctor should become familiar with the instructions for the use of these medications.

Adults and children 12 years and older

The recommended dose of Kivexa is 1 tablet once a day.

Special patient groups

Children under 12 years old

It is not recommended to use Kivexa for the treatment of children under the age of 12 due to the lack of dose correction capability. For the selection of therapy for therapies, it is recommended to consult the instructions for the use of lamivudine (Epivir®) and abacavir (Ziagen®).

Elderly patients

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. Special care must be taken when using the drug in this age group because of age-related changes such as decreased kidney function and changes in blood parameters.

Patients with impaired renal function

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 Kivexa when creatinine clearance is less than 50 ml / min.

Patients with impaired hepatic function

Patients with a mild liver function disorder (degree A on the Child-Pugh scale) may need a reduction in the dose of abacavir. In connection with the impossibility of reducing the dose with the use of the drug Kiveksa, you should use individual drugs abacavir (Ziagen ®) and lamivudine (Epivir ®).The drug Kiveksa is not recommended for patients with impaired liver function.

Side effects:

Since the drug Kiveksa is a combined drug, it is possible the manifestation of unwanted reactions, characteristic of abacavir and lamivudine. For many of the undesirable reactions 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 a manifestation of the underlying disease.

Hypersensitivity to abacavir

In clinical studies conducted before the screening for the presence of an allele HLA- B * 5701, 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 spotty-papular or urticaria), however, 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. The signs and symptoms marked not less than 10 % patients with a hypersensitivity reaction, are highlighted in bold.

From the skin: rash (usually spotty-papular or urticaria).

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

From the respiratory system: shortness of breath, 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: increased indicators of functional liver samples, hepatitis, hepatic failure.

From the musculoskeletal system: myalgia, rarely myolysis, arthralgia, increased activity of creatine phosphokinase.

From the urinary system: increase in creatinine concentration, renal failure.

Other: a fever, a feeling of fatigue, malaise, edema, lymphadenopathy, lowering of arterial pressure, conjunctivitis, anaphylaxis. Patients with a hypersensitivity reaction at first can take it for respiratory disease (pneumonia, bronchitis, pharyngitis), respiratory viral infection, gastroenteritis, or for unwanted reactions associated with taking other drugs. Continuation of the drug Kiveksa with the development of a hypersensitivity reaction, as well as the resumption of its administration after the symptoms subsided, is fraught with serious consequences, even fatal. Therefore, if any of these symptoms appear, a thorough examination of the patient is necessary to exclude the hypersensitivity reaction. If you can not exclude a hypersensitivity reaction, then you should not re-prescribe Kivex or other drugs containing abacavir (such as Ziagen®, Trizivir®).

If hypersensitivity reactions develop, patients continue to take the drug Kivexa, then the clinical manifestations become more pronounced, and with the withdrawal of the Kivex drug, they usually undergo a reverse development.

Renewal of taking Kivexa by patients with a history of hypersensitivity reaction leads to the development of a second reaction within a few hours. Repeated hypersensitivity reactions can occur more severely than the first, and manifest life-threatening arterial hypotension, up to a lethal outcome. When a hypersensitivity reaction develops, the patient, regardless of the carrier of the allele HLA-B*5701, should permanently abandon the use of Kivex and other drugs containing abacavir (such as Ziagen®, Trizivir®).

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

In rare cases, this reaction occurs when the patient resumes taking Kivexa in patients who did not have any hypersensitivity symptoms before the drug was discontinued.

Characteristic for the administration of abacavir or lamivudine, the adverse reactions listed below are listed in accordance with organ and organ damage and frequency of occurrence.Frequency of occurrence is defined as follows: Often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.

Many of the unwanted reactions (nausea, vomiting, diarrhea, fever, apathy, rash) often occur in patients with hypersensitivity to abacavir. Therefore, patients with any of these symptoms should be carefully screened to exclude hypersensitivity reactions. If taking Kivexa was stopped due to the onset of one of these symptoms, and then it was decided to resume taking abacavir, it should be started only under the direct supervision of a doctor.

In addition to the undesirable reactions described in the clinical studies, the table below shows the undesirable reactions found in the post-marketing application of abacavir and lamivudine. These reactions were selected for inclusion in the table due to a possible causal relationship with abacavir and / or lamivudine.

Clinical research data and post-registration data

Body System

Abacavir

Lamivudine


Violations

with


Infrequently: neutropenia,


sides of the blood

and


anemia,


lymphatic



thrombocytopenia


systems



Rarely: true





erythrocyte aplasia *


Violations

with

Often: hypersensitivity



the immune side

to the drug



systems




Disorders from the metabolism and nutrition

Often: anorexia, hyperlactatemia *

Rarely: lactic acidosis *

Often: hyperlactatemia Rarely: lactic acidosis *


Disturbances from the nervous system

Often: headache

Often: headache Very rarely: paresthesia, peripheral neuropathy is described (cause-effect relationship with treatment not established) *


Disorders from the gastrointestinal tract

Often: nausea, vomiting, diarrhea Rarely: pancreatitis, but the cause-and-effect relationship with abacavir is not established *

Often: nausea, vomiting, pain in the upper abdomen, diarrhea Rarely: increased activity

serum amylase, pancreatitis (cause-and-effect relationship with lamivudine not established) *


Disturbances from the liver and bile ducts


Infrequently: a temporary increase in the activity of liver enzymes (ACT, ALT)


Disturbances from the skin and subcutaneous tissues

Often: rash (without systemic symptoms) *

Very rare: exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis *

Often: rash, alopecia *


General disorders and disorders at the site of administration

Often: fever, apathy, fatigue

Often: feeling tired, malaise, fever

Disturbances from musculoskeletal and connective tissue *


Often: arthralgia, muscle damage *

Rarely: rhabdomyolysis *

* adverse reactions described in clinical studies.

There are reports of the development of lactic acidosis, including fatal, usually accompanied by severe hepatomegaly with steatosis, due to Apt analogues of nucleosides.

Application of combined Apt was associated with the redistribution of adipose tissue (lipodystrophy) in patients with HIV, including a reduction in the subcutaneous fat layer on the face and extremities, an increase in intra-abdominal and visceral fat, an increase in mammary glands and dorsocervical fat deposition (buffalo hump). Application of combined Apt was associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency during the onset of combined Apt there may be inflammatory responses to asymptomatic or residual opportunistic infections. There have also been cases of autoimmune diseases (eg, Graves' disease) occurring under conditions of immune reactivation, but the timing of the manifestation of the disease is more diverse, and these phenomena can occur many months after the initiation of therapy.

Cases of osteonecrosis have been reported, especially in patients with recognized risk factors, late HIV infection or long-term combined Apt. The frequency of occurrence of this phenomenon is unknown.

Overdose:

Symptoms

There were no specific symptoms or signs of acute overdose of abacavir and lamivudine, except for the symptoms listed in the "Side effect" section.

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 interactions of the drug Kiveksa is due to the nature of the interactions of abacavir and lamivudine. Clinical studies have shown that clinically significant interactions between abacavir and lamivudine are absent. Abacavir and lamivudine slightly metabolized by isoenzymes of the cytochrome P450 system (for example: CYP AP4, CYP 2C9 or CYP 2D6) and do not have an inhibitory or inductive effect on this enzyme system. Therefore, the probability of drug interaction with antiretroviral drugs from the classes of NNRTI and PI, and other drugs, the metabolism of which 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 not metabolized very much, slightly binds to plasma proteins and is excreted almost exclusively by the kidneys. Lamivudine is excreted mainly through active tubular secretion through the transport system of organic cations. Consideration should be given to the possibility of interacting with other medicinal products, 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 AUC 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 a study of the pharmacokinetics of drugs with simultaneous administration of abacavir (at a dose of 600 mg once, then 600 mg twice a day) and methadone (from 40 mg to 90 mg once a day), a decrease in CmOh abacavir by 35% and a decrease tmax for 1 hour, 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.There is no need to correct the dose of Kivexa.

Didanosine

The interaction has not been studied. No dose adjustment is required.

Zidovudine

The interaction has not been studied. No dose adjustment is required.

Rifampicin

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

Cimetidine

The interaction has not been studied. No dose adjustment is required.

Retinoid compounds (eg, isotretinoin)

The interaction has not been studied. Perhaps interaction, given the general pathway of elimination under the influence of alcohol dehydrogenase. There is not enough data to recommend a dose adjustment.

Ribavirin

The interaction has not been studied. Theoretically, a decrease in the intracellular concentration of phosphorylated metabolites is possible. Care is required when using these medicines together.

Phenobarbital

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

Phenytoin

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

Drug interactions due to the presence of lamivudine

Trimethoprim

Acceptance of trimethoprim / sulfamethoxazole 160 mg / 800 mg (co-trimoxazole) causes an increase in exposure to lamivudine by 40 %, which is due to the presence of trimethoprim. However, except for patients with renal insufficiency, correction of the dose 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 suppress intracellular phosphorylation of zalcitabine while simultaneously taking these drugs. In this regard, it is not recommended to take the drug Kivexa in combination with zalcitabine.

Emtricitabine

With simultaneous application lamivudine can inhibit intracellular phosphorylation of emtricitabine.In addition, the mechanism of development of resistance to both lamivudine and emtricitabine is associated with a mutation in the same codon of the reverse transcriptase gene (M184V), and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended.

Didanosine

The interaction has not been studied. No dose adjustment is required.

Zidovudine

Zidovudine in a dose of 300 mg once, lamivudine in a dose of 150 mg once. Lamivudine: AUC without changes. Zidovudine: AUC without changes. No dose adjustment is required.

Rifampicin

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

Cimetidine

The interaction has not been studied. Clinically significant interaction is not expected. Cimetidine is partially excreted by the renal organic cationic transport system. No dose adjustment is required.

Cladribine

The interaction has not been studied.

In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when combined in clinical practice.Some clinical data also confirm the interaction between lamivudine and cladribine.

Thus, the simultaneous use of lamivudine and cladribine is not recommended.

Retinoid compounds (for example, isotretinoin)

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

Methadone

The interaction has not been studied. It is not necessary to correct the dose of the drug Kivexa. For most patients, methadone dose adjustment is not required, in rare cases, it may be necessary to repurpose.

Special instructions:

This section contains guidelines for abacavir and lamivudine. There are no additional specific indications related to a fixed combination of doses of abacavir and lamivudine (Kivexa preparation).

Hypersensitivity to abacavir

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

Risk factors

In clinical studies, it has been shown that the carriage of an allele HLA-B*5701 significantly increases the risk of developing a hypersensitivity reaction to abacavir. In a prospective clinical study CNA106030 (PREDICT-1) for patients with presence of an allele HLA-B*5701 drugs abacavir were not assigned, 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) (p <0.0001), as well as the incidence of hypersensitivity reactions, confirmed by the skin-application test with 2.7% (23 patients out of 842) to 0.0% (0 patients from 802) (p <0.0001). Thus, based on the results of this study, it was shown that hypersensitivity reactions to abacavir develop in patients with allele carriers HLA-B*5701 with a frequency of 48-61% compared with patients in whom this allele is absent (frequency of occurrence of hypersensitivity reactions 0-4%).

Before starting treatment, it is recommended to carry out screening for carriage of an allele HLA- B * 5701 in HIV-infected patients who were not previously assigned abacavir. Screening for carriage of an allele HLA-B*5701 It is recommended that prior to re-administration of abacavir in patients with unknown HLA-B*5701-Status, previously well tolerated abacavir therapy.

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

The clinical diagnosis of a suspected hypersensitivity reaction should remain the basis for deciding the use of abacavir in all patients. Even in the absence of an allele HLA-B*5701 abacavir you must cancel and not to renew his appointment in all cases where a hypersensitivity reaction can not be excluded, guided by clinical data, due to the potential risk of serious adverse reactions or even death.

Skin and application test, used for research purposes as one of the methods in the study PREDICT-1, has no clinical significance, and therefore should not be used in clinical practice.

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), symptoms of respiratory damage (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, but, as a rule, appear during 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.

Treatment

Patients, regardless of HbA-B * 5701-status, who have signs and symptoms of hypersensitivity, MUST immediately contact their doctor for advice. When making a diagnosis of hypersensitivity, patients SHOULD immediately stop taking the drug Kivex. NEVER SHOULD RESUME TREATMENT OF KIVEX AND OTHER MEDICINES THAT CONTAIN abacavir (such as Ziagen®, Trizivir®), after a hypersensitivity reaction has occurred.This is due to the threat of even more severe symptoms (including life-threatening arterial hypotension) that may lead to death within a few hours after the resumption of the drug.

To prevent late detection and reduce the risk of developing a life-threatening hypersensitivity reaction, Kivex should be completely discontinued if hypersensitivity can not be excluded, even with the potential for other diagnoses (respiratory diseases, flu-like illnesses, gastroenteritis, reactions to other medications). Do not resume treatment with Kivexa and other medications containing abacavir (such as Ziagen®, Trizivir®), even if hypersensitivity symptoms appear when re-ingesting alternative medications.

A warning card with information for patients about the hypersensitivity reaction is in the package.

Special instructions for treatment after a break in therapy with Kivexa

In the event of discontinuation of treatment with any drug containing abacavir, regardless of the carriage of the allele HLA-B*5701, Before the resumption of taking Kivexa, one should carefully study the reason for refusing the drug and make sure that the patient has no symptoms of a hypersensitivity reaction. Do not resume taking Kivex and other medicines. preparations containing abacavir (such as Ziagen ®, Trizivir ®), 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 withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue, gastrointestinal disturbances or disorders of the respiratory system) are described. If a decision is made to resume treatment with Kivexa in these patients, then treatment under direct medical supervision is necessary.

A hypersensitivity reaction was noted, although extremely rare, even with the resumption of treatment with these drugs in patients who had not previously experienced symptoms of this reaction.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 an allele HLA-B*5701 It is recommended that prior to re-administration of abacavir in patients with unknown HLA-B*5701 -Status, previously well tolerated abacavir therapy. The re-administration of abacavir to allele-bearing patients HLA-B*5701 is not recommended and can be considered only in exceptional cases under careful medical supervision, when the potential benefit from drug treatment exceeds all possible risks.

Important information for patients

The doctor prescribing the drug should make sure that the following information about the hypersensitivity reaction has been brought to the attention of the patient in full:

- patients should be cautioned about the risk of developing a hypersensitivity reaction to abacavir, which can lead to life-threatening complications or death, as well as an increased risk of hypersensitivity reactions in the carriers of the allele HLA-B*5701;

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

- patients with hypersensitivity to abacavir should never take Kivex and other medications containing abacavir (such as Ziagen®, Trizivir®), regardless of HLA-B*5701 -Status;

- To avoid the risk of resumption of the drug, patients who have a hypersensitivity reaction should return the remaining pills to the doctor who prescribed the drug;

- patients who discontinued taking Kivexa for any reason (especially in connection with the possible development of side effects or disease) before recommencing the drug should consult with their doctor;

- each patient should familiarize themselves with the instructions for use that apply to the drug. Also, patients should be reminded that they should always carry a warning card attached to the drug.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis, severe hepatomegaly with steatosis, including fatal Apt analogues of nucleosides in the form of individual preparations, including abacavir, lamivudine or a combination thereof. Similar phenomena were observed, mainly, in women.

The clinical signs of developing lactic acidosis are gastrointestinal symptoms (nausea, vomiting and abdominal pain), general weakness, anorexia, loss of appetite, rapid unexplained weight loss, symptoms of gastrointestinal and respiratory damage (dyspnea and tachypnea), or neurological symptoms (including motor weakness).

Caution should be exercised when prescribing Kivex, especially in patients with hepatomegaly, hepatitis, or other risk factors for liver damage and steatosis of the liver (including certain drugs and alcohol). Patients with co-infection with hepatitis C and patients who receive treatment with alpha interferon and ribavirin may constitute a special risk group. The drug should be discontinued when clinical or laboratory signs of lactic acidosis occur with or without hepatitis (which include hepatomegaly and steatosis,even in the absence of a significant increase in aminotransferase activity) under conditions of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly, or with a rapid increase in aminotransferase activity.

Lipodystrophy

In some patients receiving combined Apt, redistribution and / or accumulation of subcutaneous fat can be observed, including obesity in the central type, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and extremities, enlargement of the mammary glands, increased serum lipid concentrations and glucose concentration in the blood, both individually and together.

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

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

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

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

Immunodeficiency Syndrome

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

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

Opportunistic infections

The use of Kivex 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 HIV infection

Patients should be warned that treatment with antiretroviral drugs, including Kivex, does not prevent the risk of HIV transmission to other people during sexual intercourse or blood contamination. Therefore, patients should take appropriate precautions.

Myocardial infarction

As a result of a prospective observational epidemiological study to study the incidence of myocardial infarction in patients receiving a combined Apt, The association of the previous administration of abacavir within 6 months with an increased risk of myocardial infarction was found. 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 of abacavir therapy with the risk of myocardial infarction. Nevertheless, caution should be given to Apt, including preparations containing abacavir. patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize risk factors (such as hypertension, hyperlipidemia, diabetes and smoking).

Pancreatitis

Cases of pancreatitis have been documented, although the cause-and-effect relationship with lamivudine and abacavir has not been established.

Kidney Diseases

The drug Kivexa should not be administered to patients with creatinine clearance less than 50 ml / min.

Diseases of the liver

The efficacy and safety of the Kivexa drug have not been established in patients with severe concomitant liver disease. The drug Kiveksa is not recommended for patients with impaired liver function.

In patients with an initially present impaired liver function, including an active form of chronic hepatitis, there is an increase in the incidence of abnormalities on the part of the liver with combined Apt. Such patients need to be monitored in accordance with standard clinical practice.

Patients with chronic hepatitis B or FROM

Clinical studies and post-registration data on the use of lamivudine suggest that in some patients with concomitant viral hepatitis B (HBV) Clinical or laboratory signs of hepatitis recurrence may appear after stopping lamivudine, which may have more severe consequences in patients with decompensated liver disease. Therefore, in patients with concomitant viral hepatitis B, when quiescent drug is discontinued, it is necessary to monitor the performance of functional hepatic samples and regularly determine the viral load.

Due to abacavir and ribavirin have the same phosphorylation pathways, an interaction between these substances is suggested that can lead to a decrease in intracellular phosphorylation of ribavirin metabolites and potentially leads to a decrease in the likelihood of achieving a stable virologic response in HIV-infected patients infected with pegylated interferon and ribavirin. Controversial data have been published on the simultaneous use of abacavir and ribavirin. According to some data, it is assumed that HIV-infected patients receiving abacavir-containing drugs may have a low risk of responding to antiviral therapy with pegylated interferon and ribavirin. Care should be taken when taking these medications at the same time.

Mitochondrial dysfunction

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

Osteonecrosis

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

Risk of virological failure

Triple Nucleoside Therapy: a high incidence of virological failure and early-onset stability was noted with the simultaneous administration of abacavir and lamivudine with tenofovir dizoproxil fumarate under the dosing regimen once a day.

The risk of virologic failure with the use of the drug Kivexa may be higher than in the case of other possible therapies.

The drug Kiveksa should not be taken together with other medicines containing lamivudine, or medicinal products containing emtricitabine.

The combination of lamivudine and cladribine is not recommended.

The drug Kivexa contains a colorant of a sun-yellow aluminum varnish, which can cause allergic reactions.

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

Special studies of the effects of abacavir or lamivudine on the ability to drive vehicles or mechanisms have not been conducted. In addition, the negative impact on such activities can not be predicted, based on the pharmacology of these drugs.When assessing a patient's ability to drive vehicles or mechanisms, his general condition, as well as the profile of unwanted reactions of the Kivex drug, should be taken into account.

Form release / dosage:Film-coated tablets, 600 mg + 300 mg.
Packaging:

For 10 tablets in a blister of PVC / PVDC / aluminum foil. By 3 blisters with instructions for use and an individual patient card with information on hypersensitivity reactions in a cardboard box.

For 30 tablets in high-density polyethylene bottles, sealed with caps and a device against opening the bottle by children. For 1 bottle with instructions for use and an individual patient card with information on hypersensitivity reactions in a cardboard pack.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

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

Terms of leave from pharmacies:On prescription
Registration number:LSR-000078
Date of registration:28.05.2007
The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom
Manufacturer: & nbsp
Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO
Information update date: & nbsp05.11.2014
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