Kivexa, 600 mg+300 mg 30 pcs

Abacavir and lamivudine belong to the group of nucleoside reverse transcriptase inhibitors and are potent selective inhibitors of HIV-1 and HIV-2. Abacavir and lamivudine are sequentially metabolized by intracellular kinases to their respective triphosphates (TFs), which act as active metabolites.

Lamivudine TF and carbovir TF (active abacavir triphosphate) act as substrates and are competitive inhibitors of HIV reverse transcriptase (RT). However, the main antiviral effect of the drugs is due to the incorporation of monophosphate into the DNA chain, which leads to an interruption of replication. Abacavir and lamivudine triphosphates have much less affinity for host cell DNA polymerases.

A study in which 20 HIV-infected patients took abacavir (300 mg 2 times daily and once 24 hours before sampling) showed that the geometric mean terminal intracellular T1/2 of carbovir-TF at equilibrium was 20.6 hours.

The geometric mean geometric T1/2 of abacavir from plasma in this study was 2.6 h. The equilibrium pharmacokinetic values for abacavir 600 mg once daily were similar to those for abacavir 300 mg twice daily in a cross-sectional clinical study in 27 HIV-infected patients.

. The intracellular content of carbovir triphosphate in peripheral blood mononuclear cells was higher when abacavir was taken at a dose of 600 mg once daily compared with abacavir 300 mg twice daily (a 32% increase in the area under the concentration-time curve at equilibrium over 24 h ( AUC24,ss) of the maximum daily concentration at equilibrium ( Cmax 24,ss)-99%).

In patients taking lamivudine 300 mg once daily, the terminal intracellular T1/2 of lamivudine-TF increased from 16 to 19 h, and the T1/2 of lamivudine from plasma increased from 5 to 7 h.

. A study of the pharmacokinetics of lamivudine taken at a dose of 300 mg once daily for 7 days compared to taking lamivudine 150 mg twice daily for 7 days, conducted on 60 healthy volunteers, showed that the AUC 24, ss and Cmax 24, ss for the intracellular concentration of lamivudine-TF in peripheral blood mononuclear cells were similar, but the minimum values were lower with lamivudine 300 mg once daily than with lamivudine 150 mg twice daily.

The variability of lamivudine metabolite concentrations within the cell is higher than in plasma. These results are supported by data obtained with lamivudine 300 mg and abacavir 600 mg once daily (the efficacy and safety of this combination when taking the drugs once daily was also confirmed in the CNA 30021 reference clinical trial).

Lamivudine acts synergistically with zidovudine to effectively suppress HIV replication in cell culture. Under in vitro conditions, abacavir acts synergistically in combination with amprenavir, nevirapine and zidovudine and additively with didanosine, zalcitabine, stavudine and lamivudine.

The resistance of HIV-1 to lamivudine is due to a mutation in the M184V codon located close to the active center of the viral OT. This mutation is observed in both in vitro and HIV-1-infected patients who have received combination therapy that includes lamivudine.

Mutation in the M184V codon significantly reduces sensitivity to lamivudine and significantly decreases the ability of the virus to replicate according to in vitro studies.

It has also been found in in vitro studies that zidovudine-resistant virus isolates can become susceptible to the drug if lamivudine resistance develops in these isolates subsequently. However, the clinical significance of such changes has not yet been conclusively determined.

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

HIV resistance to abacavir in vitro and in vivo develops slowly. Multiple mutations of the viral genome are required for a clinically meaningful increase in inhibitory concentration against 50% of IC 50 strains (8% increase in IC 50 (inhibitory concentration in 50% of cases) relative to the “wild” strain of the virus).

Abacavir-resistant isolates may also have reduced sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and/or didanosine, but retain sensitivity to zidovudine and stavudine.

The development of cross-resistance between abacavir and lamivudine and other classes of antiretrovirals (e.g.: protease inhibitors [PIs] and non-nucleoside reverse transcriptase inhibitors [NNRTIs]) is unlikely. Isolates of HIV with reduced sensitivity to abacavir have been isolated in patients with uncontrolled viral replication in whom prior treatment with other nucleoside reverse transcriptase inhibitors was ineffective.

The clinical isolates of the virus with three or more mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) are also likely to be resistant to abacavir. Cross-resistance due to the M184V OT mutation is limited to the class of OT nucleoside inhibitors. Zidovudine, stavudine, abacavir, and tenofovir retain their antiretroviral activity against lamivudine-resistant HIV-1 isolates carrying only the M184V mutation.

Indications

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

Active ingredient

Composition

1 tablet contains abacavir sulfate 702 mg, which corresponds to the content of abacavir 600 mg,

lamivudine 300 mg.

Auxiliary substances:

Microcrystalline cellulose 309 mg,

sodium carboxymethyl starch (type A) 55 mg,

Magnesium stearate 9 mg.

How to take, the dosage

Therapy should be given by a physician experienced in treating HIV.

Because of the inability to adjust the dose with fixed-dose combination tablets, Kivexa should not be given to adults and adolescents whose body weight is less than 40 kg.

Kivexa tablets can be taken regardless of meals.

Combination drugs with fixed-dose ingredients should not be used when a dose adjustment may be necessary, such as when CK is less than 50 ml/min and when there is hepatic impairment. Abacavir (Ziagen) or lamivudine (Epivir) should be administered as monotherapies if Quivex is discontinued or if a dose adjustment is necessary. In these situations, the doctor should read the instructions for use for these medications.

Adults and children 12 years of age and older take 1 tablet. 1 time daily.

Kivexa is not recommended for children under 12 years of age because there is no possibility of dose adjustment. Prescribers are advised to refer to the guidelines for lamivudine and abacavir for therapy.

The pharmacokinetics of abacavir and lamivudine in patients older than 65 years have not been studied. When treating elderly patients, the increased frequency of liver, kidney and heart disorders, other comorbidities and the use of other medications should be taken into account.

While in patients with impaired renal function no dose adjustment of abacavir is required, 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 in patients with CKR less than 50 ml/min.

Patients with hepatic impairment

Patients with mild hepatic impairment may need to reduce the dose of abacavir. Because it is not possible to reduce the dose with Kivex, a drug containing only abacavir should be used. The drug is contraindicated in patients with moderate to severe liver dysfunction.

Interaction

The spectrum of interactions of the drug Kivex is due to the nature of interactions between abacavir and lamivudine, among which, to date, no clinically significant interactions have been identified. Abacavir and lamivudine are slightly metabolized by enzymes of cytochrome P450 system (for example: CYP3A4, CYP2C9 or CYP2D6) and have no inhibitory or inducing effect on this enzyme system.

This is why there is little chance of interaction of the drug with antiretroviral non-nucleoside protease inhibitors and other medications whose metabolism occurs with the participation of major enzymes of the cytochrome P450 system.

The probability of metabolic interactions with lamivudine is low because it is little metabolized, poorly bound to plasma proteins and excreted almost exclusively by the kidneys. Lamivudine is excreted mainly through active organic cationic secretion. The possibility of interaction with other drugs should be taken into account, especially in cases when the kidneys are the main route of drug excretion.

Drug interactions due to the presence of abacavir

Ethanol: The metabolism of abacavir is impaired when taken concomitantly with ethanol, resulting in an increase in abacavir AUC of approximately 41%. Given the safety profile of abacavir, these data are not considered clinically relevant. Abacavir has no effect on ethanol metabolism.

Methadone: In a drug pharmacokinetics study, concomitant administration of abacavir (at a dose of 600 mg 2 times daily) and methadone showed a 35% decrease in C max of abacavir and a 1 h decrease in time to reach Cmax, but AUC remained unchanged. Changes in abacavir pharmacokinetics were not found to be clinically significant.

In this study, abacavir increased mean total methadone clearance by 22%. This change was not found to be clinically significant in most patients, but occasionally it may be necessary to adjust the methadone dose.

Drug interactions due to the presence of lamivudine

Trimethoprim: Trimethoprim/sulfamethoxazole 160 mg/800 mg (co-trimoxazole) administration causes a 40% increase in lamivudine exposure due to the presence of trimethoprim. However, with the exception of patients with renal impairment, no dose adjustment of lamivudine is required.

Lamivudine has no effect on the pharmacokinetics of trimethoprim and sulfamethoxazole. Co-administration of lamivudine with higher doses of co-trimoxazole used to treat pneumonia (caused by Pneumocystis carinii ) and toxoplasmosis has not been studied.

Zalcitabine: Lamivudine may inhibit intracellular phosphorylation of zalcitabine when these drugs are taken simultaneously. Therefore, it is not recommended to take Kivexa in combination with zalcitabine.

Special Instructions

Hypersensitivity to abacavir

According to clinical studies conducted before screening for the HLA-B*5701 allele, approximately 5% of patients taking abacavir develop hypersensitivity to the drug, rarely 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 developing a hypersensitivity reaction to abacavir. In the CNA106030 (PREDICT-1) prospective clinical trial, patients with the HLA-B*5701 allele were not prescribed abacavir, 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

Clinicians are encouraged to screen for carriage of the HLA-B*5701 allele in HIV-infected patients who were not previously prescribed abacavir-containing medications.

HLA-B*5701 carrier screening is recommended before re-prescribing abacavir-containing medication in patients with unknown HLA-B*5701 status who have previously tolerated abacavir-containing therapy well.

The use of abacavir-containing medications is not recommended in these patients and should be considered only in exceptional cases with careful medical monitoring when the potential benefit exceeds the risk of using the drug.

The clinical diagnosis of a suspected hypersensitivity reaction should remain the basis for the decision to use abacavir-containing drugs in all patients. Even in the absence of the HLA-B*5701 allele, abacavir must be discontinued and not restarted in all cases where a hypersensitivity reaction cannot be excluded based on clinical data because of the potential risk of serious adverse effects or even death.

Hypersensitivity reactions are characterized by the occurrence of symptoms of multi-organ failure. At the same time, most patients experience the appearance of fever and/or rash.

Contraindications

Hypersensitivity to abacavir or lamivudine or other components of the drug;

A age less than 12 years (no possibility of dose adjustment); impaired liver function.

Side effects

Because Kivexa is a combination drug, side effects typical of abacavir and lamivudine are possible.

For many of the side effects listed below, it remains unclear whether they are related to the active ingredients of the drug, to the concomitant use of other medications (used to treat HIV), or to the underlying disease.

Hypersensitivity to abacavir

In clinical studies conducted prior to screening for the HLA-B*5701 allele, approximately 5% of patients taking abacavir developed a hypersensitivity reaction that was rarely fatal. This reaction is characterized by the onset of symptoms suggestive of multiple organ failure.

Almost all patients who have a hypersensitivity reaction have increased body temperature and/or a rash (usually patchy-papular or urtic), but there have been cases of hypersensitivity reactions without a rash or increased body temperature.

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

The signs and symptoms of hypersensitivity reactions are listed below. Signs and symptoms seen in at least 10% of patients with hypersensitivity reactions are in bold.

Skin: rash (usually maculopapular or urtic)

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, ulceration in the mouth

Respiratory system: Shortness of breath, cough, sore throat, respiratory distress syndrome, respiratory failure

Nervous system: headache, paresthesias.

Blood system disorders: lymphopenia.

Hepatobiliary system: increase of liver function tests, liver failure

Muscular system: myalgia, rarely – myolysis, arthralgia, increased CPK level.

Urinary system disorders: increase in creatinine level, renal failure.

Others: fever, fatigue, malaise, edema, lymphadenopathy, decreased blood pressure, conjunctivitis, anaphylaxis.

Patients with hypersensitivity reactions may initially mistake them for respiratory disease (pneumonia, bronchitis, pharyngitis, respiratory viral infection), gastroenteritis, or adverse reactions associated with taking other drugs. Continued use of the drug Kivex while developing hypersensitivity reaction, as well as resumption of its use after the symptoms have subsided, is fraught with serious consequences, up to and including death.

If any of the above symptoms occur, therefore, the patient must be examined carefully to rule out a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, reapplication of Kivex or other abacavir-containing drugs (such as Ziagen, Trisivir) is strictly contraindicated.

If patients continue to take Kivex while developing a hypersensitivity reaction, clinical manifestations become more severe and usually reverse when Kivex is withdrawn.

Resumption of Quivex in patients with a history of hypersensitivity reactions leads to development of a second reaction within a few hours. A second hypersensitivity reaction may be more severe than the first one, and manifest as life-threatening arterial hypotension, up to and including death.

If a patient develops a hypersensitivity reaction, regardless of HLA-B*5701 allele carriage, they should permanently discontinue Kyvex and other drugs containing abacavir (such as Ziagen, Trisivir).

Sometimes a hypersensitivity reaction will develop when resuming therapy with the drug after discontinuation, triggered by the appearance of just one of the main symptoms of this reaction (rash, fever, malaise, fatigue, gastrointestinal or respiratory disturbances).

In rare cases, this reaction occurs when patients who have not had any symptoms of hypersensitivity before discontinuation of the drug resume taking Kivex.

The side effects of abacavir or lamivudine are tabulated below and grouped by body system and absolute frequency. Side effects are divided into: very common (> 1/10), common (> 1/100, < 1/10), not common (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1000) and very rare (< 1/10,000).

Many of the side effects presented (nausea, vomiting, diarrhea, fever, apathy, rash) often occur in patients with hypersensitivity to abacavir. Therefore, patients with any of these symptoms should be carefully evaluated to rule out a hypersensitivity reaction. If Kivex has been discontinued due to the onset of one of these symptoms and, subsequently, the decision has been made to resume abacavir, it should only be started under the direct supervision of a physician.

Overdose

Symptoms: Symptoms of acute abacavir and lamivudine overdose correspond to the symptoms of side effects of the drug (see section “Side effects”).

Treatment: In case of overdose, the patient should be monitored by a physician (to detect signs of toxic effects of the drug). If necessary the standard supportive therapy is carried out.

In connection with the fact that lamivudine can be eliminated from the body by dialysis, treatment of overdose should include continuous hemodialysis (although there have been no studies to study the possibility of hemodialysis in overdose of the drug).

It is not currently known whether peritoneal dialysis and hemodialysis contribute to abacavir excretion.

Pregnancy use

The safety of Kivex in pregnant women has not been established. Data have been obtained in reproductive studies of lamivudine and abacavir in animals. Therefore, the prescription of 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 according to current recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Because HIV passes into breast milk, women should not breastfeed to avoid transmitting the virus to the baby through breast milk.

Lamivudine is excreted with milk at a concentration close to the serum concentration. Abacavir is also expected to be excreted with milk, although this has not been confirmed.