Ziagen

Ziagen is an antiviral systemic drug. It is an inhibitor of nucleotide and nucleoside reverse transcriptase.

Indications Ziagen

It is used for children and adults as part of complex treatment during ART – therapy for HIV infection.

Release form

Released as a solution for oral administration, in a polyethylene bottle with a volume of 240 ml. The package contains 1 bottle complete with a syringe adapter and a dosing syringe.

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Pharmacodynamics

The active substance of the drug is abacavir, which is included in the NRTI category. It is a powerful inhibitor of HIV-1 elements, as well as HIV-2 (this includes HIV-1 isolates that have reduced sensitivity to lamivudine with zidovudine, as well as nevirapine with didanosine and zalcitabine). Once inside the cell, the substance is converted into an active decay product (carbovir triphosphate), and its main mechanism of action is to slow down the processes of HIV reverse transcriptase, which destroys the bond required for the virus within the DNA chain and stops the process of its replication.

In vitro antiviral testing of abacavir did not show antagonism of NRTIs (such as lamivudine and zidovudine with didanosine, as well as stavudine with emtricitabine and zalcitabine with tenofovir), NNRTIs (such as viramune), or PI drugs (such as amprenavir) when co-administered.

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Pharmacokinetics

Abacavir, when it enters the gastrointestinal tract, is absorbed fairly quickly, and its bioavailability in adults after oral administration reaches 83%. The serum maximum of the substance is observed after 1.5 hours after taking the tablet or after 60 minutes after taking the oral solution.

The AUC values are the same for both the solution and the tablets. After taking a tablet of the drug in a dose of 600 mg/day, the peak concentration reaches approximately 3 mcg/ml, and the AUC level at an interval of 12 hours between doses is 6 mcg/hour/ml. Peak values of the substance when using the solution will be higher (although not much) than when using tablets. Using the drug with food slows down the time to reach the peak serum value, but does not affect the total plasma values of the drug. This allows Ziagen to be taken with food.

The drug easily penetrates into various tissues. Clinical tests have shown that in people with HIV infection, the drug passes well into the CSF. The average proportions of the active component of the drug in the cerebrospinal fluid and blood serum are approximately 30-44%. After taking the drug in a medicinal dose, the protein binding index is about 49%.

The drug undergoes hepatic metabolism (primary), with less than 2% of the applied dose excreted through the kidneys (unchanged form). The main breakdown products are 5'-carboxylic acid and 5'-glucuronide, which are formed with the participation of alcohol dehydrogenase or through the process of glucuronidation.

The half-life of the drug is 90 minutes. With repeated administration of the drug in the amount of 300 mg twice a day, there is no noticeable accumulation of the substance. Unchanged abacavir with its decay products is excreted through the kidneys (83%), and the remainder - with feces.

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Dosing and administration

The drug may only be used under the supervision of a doctor with extensive experience in treating people with HIV.

Before starting a course of treatment with abacavir, screening is required to determine whether an HIV-infected person is a carrier of the HLA B*5701 allele. This must be done regardless of the patient's race. Prescribing the drug to people who have been found to have the HLA B*5701 allele is prohibited.

The solution is used regardless of food intake. The medicine is also available in tablet form.

Dosage sizes for children weighing more than 25 kg and adults: it is recommended to take 600 mg of the drug (or 30 ml) per day - either in 2 doses (300 mg/15 ml), or the entire daily dose in 1 dose.

Children weighing less than 25 kg.

Children over 1 year of age are required to take 8 mg/kg per day (with two doses) or 16 mg/kg (with a single dose). No more than 600 mg (or 30 ml) of the medicine is allowed per day.

Infants aged 3-12 months should be given the drug in the amount of 8 mg/kg (twice a day). If it is not possible to use the drug twice a day, the option of taking a single dose of 16 mg/kg per day should be considered. It should be taken into account that information regarding the use of the drug in a single daily dose for this age category is very limited.

When switching from twice daily to a single dose, you should take the single dose (designated above) approximately 12 hours after taking the daily dose in 2 doses, and then continue taking the medicine at the intervals required for single use (24 hours). When changing from a single dose to a twice daily dose, you should take the first part of the twice daily dose approximately 24 hours after taking the last single dose.

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Use Ziagen during pregnancy

Typically, when deciding on the use of antiretroviral drugs for HIV therapy in pregnant women and to reduce the risk of vertical transmission of the disease to the child, information obtained from animal tests is taken into account, as well as existing clinical experience with the use of Ziagen in pregnant women.

Animal tests have shown embryotoxicity in rats, but none in rabbits. Carcinogenic effects have been noted in animal models, but the medicinal significance of these data has not been established. It has been found that abacavir and its breakdown products can cross the human placenta.

In pregnant women who took the drug in the 1st trimester (more than 800 cases), as well as in those who took it in the 2nd and 3rd trimesters (more than 1000 cases), no neonatal/fetal reactions or congenital anomalies in the fetus were observed. This information allows us to conclude that the risk of a congenital anomaly in humans is very low.

Mitochondrial disorders: Nucleoside and nucleotide analogs of drugs have been shown to cause mitochondrial damage in vitro or in vivo tests. There is information on mitochondrial dysfunction in HIV-negative children whose mothers used nucleoside analogs of drugs during pregnancy or during the postnatal period.

Tests on rats showed that abacavir and its metabolites penetrate into their milk. The active component of the drug can also be excreted into human breast milk. There is no information on the use of the drug by infants under 3 months. In this regard, it is recommended to refrain from breastfeeding during treatment with Ziagen. In general, mothers with HIV are advised to refrain from breastfeeding in any case to avoid the risk of transmitting the infection to the child.

Contraindications

Main contraindications:

• hypersensitivity to abacavir or other components of the drug;
• moderate to severe liver failure;
• There is no information on the safety of using the drug for infants under 3 months of age, so it is prohibited to prescribe it for this age category.

Side effects Ziagen

The origin of many side effects has not yet been explained - it is not known whether they are related to the use of Ziagen specifically or other drugs, or whether they arose as a consequence of the disease itself. The main disorders:

• problems with the gastrointestinal tract and metabolic processes: hyperlactatemia or anorexia is often observed. Lactic acidosis occasionally develops;
• lesions in the nervous system: headaches often appear;
• manifestations from the digestive system: vomiting, diarrhea or nausea often occur. Pancreatitis is occasionally observed, but it has not been possible to establish that its development is associated with the use of drugs;
• lesions of the subcutaneous layers and the surface of the skin: a rash often appears (without systemic manifestations). Stevens-Johnson syndrome, erythema multiforme or TEN develops occasionally;
• Systemic disorders: a feeling of lethargy or fatigue, as well as a fever, are often noted.

Overdose

Clinical trials have been conducted with single doses of up to 1.2 g of the drug (and up to 1.8 g of the drug per day) and no new adverse reactions have been identified other than those reported with standard doses. There is no information on the use of higher doses of the solution.

If intoxication develops, the patient requires constant monitoring to determine the manifestations of toxicity. If necessary, supportive treatment procedures should be carried out. There is no information on the possibility of removing abacavir using hemodialysis or peritoneal dialysis procedures.

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Interactions with other drugs

In vitro experimental testing has shown that the potential for interactions with other drugs via element 450 is quite low for abacavir. Element 450 is not a major participant in the metabolism of the substance, and abacavir itself does not inhibit metabolic processes via the CYP3A4 enzyme, which is part of the P450 hemoprotein system. It was found that in vitro tests showed that the drug in medicinally active concentrations does not inhibit CYP3A4, CYP2C9, or CYP2D6 enzymes. In clinical tests, no induction of metabolic processes in the liver occurred, therefore the likelihood of interactions with other antiretroviral protease inhibitors, as well as with other drugs, the metabolism of which is carried out via many P450 enzymes, is extremely low. Studies have also shown that there is no significant interaction for therapeutic processes between Ziagen and lamivudine or zidovudine.

Drugs that have the potential to induce enzymes (eg, phenobarbital with rifampicin or phenytoin), by affecting UFDGT, may slightly decrease plasma levels of abacavir.

The metabolism of the drug changes under the influence of ethyl alcohol - there is an increase in the AUC level - by approximately 41%. But this indicator is not considered significant. In turn, abacavir does not affect the metabolism of ethyl alcohol.

Data obtained from pharmacokinetic tests show that the combination of 600 mg (twice daily) of Ziagen with methadone reduces the peak values of abacavir by 35% and delays the time to reach them by 60 minutes, but the AUC level remains the same. Changes in the pharmacokinetic properties of the drug have no clinical significance. Tests also showed that the drug increases the average values of total clearance of methadone by 22%. Because of this, induction of enzymes that metabolize drugs may occur. People treated with methadone should be constantly monitored by doctors - for signs of withdrawal that occur during dosing. If such a situation develops, a new change in the methadone dosage may be required.

Retinoids are excreted with the participation of the element alcohol dehydrogenase. Interactions with the drug may develop, although they have not been studied.

Because ribavirin and abacavir are phosphorylated in similar ways, intracellular interactions between them are expected. This may result in a decrease in the intracellular phosphorylated degradation products of ribavirin, which may subsequently reduce the chances of achieving a sustained virological response in individuals infected with the hepatitis C virus (in the case of therapy with pegylated interferon/ribavirin). The medical literature provides conflicting information regarding the combination of Ziagen with ribavirin. Some sources suggest that individuals coinfected with HIV and hepatitis C virus, taking antiretroviral drugs that contain abacavir, are at risk of having a weakened response to therapy with pegylated ribavirin/interferon. Therefore, caution should be exercised when combining these drugs.

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Storage conditions

Ziagen should be kept in a place where small children cannot reach, at a temperature of no more than 30°C.

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Shelf life

Ziagen must be used within 2 years from the date of manufacture of the drug. However, an opened bottle has a shelf life of no more than 2 months.

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