Ziagen

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

Indications of the ziagen

It is used for children and adults as an integral part of complex treatment during ARVT - when treating HIV infection.

Release form

Release in the form of a solution for ingestion, in a polyethylene bottle with a volume of 240 ml. The package contains 1 bottle, complete with a syringe adapter and a dosing syringe.

[1], [2]

Pharmacodynamics

The active substance of drugs - abacavir, which is included in the category NRTI. This is a potent inhibitor of HIV-1 elements, as well as HIV-2 (this includes HIV-1 isolates that have a lower sensitivity for lamivudine with zidovudine, and in addition nevirapine with didanosine and zolcitabine). Once inside the cell, the substance is converted into an active degradation product (carbovir triphosphate), and its main mechanism of action is the slowing down of HIV reverse transcriptase processes, which destroys the virus-required bond inside the DNA strand and stops the replication process.

During the in vitro tests, the antiviral properties of abacavir showed no antagonism to NRTIs (such as lamivudine and zidovudine with didanosine, as well as stavudine with emtricitabine and zolcitabine with tenofovir), NNRTIs (such as viramun) or IP drugs (eg, amprenavir) as a result of their joint application.

[3], [4], [5], [6]

Pharmacokinetics

Abacavir, getting inside the gastrointestinal tract, is absorbed quickly enough, and the level of its bioavailability in an adult after oral administration reaches 83%. The serum maximum of the substance is observed after 1.5 hours after the use of the tablet or 60 minutes after the application of the oral solution.

The values of AUC are the same for both solution and tablets. After using the drug tablet in a 600 mg / day dose, the peak concentration reaches about 3 μg / ml, and the AUC level at a 12 hour interval between doses is 6 μg / h / ml. The peak values of the substance when using the solution will be higher (although not much) than with the use of tablets. The use of the drug together with food slows the time to reach the peak serum score, but does not affect the total plasma values of the drug. This allows you to eat Ziagen with food.

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

The drug passes the process of hepatic metabolism (primary), while less than 2% of the applied dosage is excreted through the kidneys (unchanged form). The main degradation products are the 5'-carboxylic acid, as well as 5'-glucuronide, which are formed with the participation of alcohol dehydrogenase or by the glucuronization process.

The half-life of the drug is 90 minutes. With a multiple dose of medicine at a rate of 300 mg twice a day, no significant accumulation of substance occurs. Unchanged abacavir with its decay products is excreted through the kidneys (83%), and the remainder - with feces.

[7], [8], [9]

Dosing and administration

Use of the medicine is allowed only under the supervision of a doctor who has extensive experience of therapy in people with HIV.

Before starting a treatment course with abacavir, screening is required to determine whether the HIV-infected person is the carrier of the HLA B * 5701 allele. Doing this is necessary regardless of the race of the patient. Prescribe medication to people who have found the HLA B * 5701 allele is prohibited.

The solution is used regardless of eating. The medicine is also released in tablet form.

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

Children weighing less than 25 kg.

Children older than 1 year are required to take 8 mg / kg per day (with a two-time intake) or 16 mg / kg (with a single dose). For a day is allowed to take no more than 600 mg (or 30 ml) of the drug.

Infants aged 3-12 months are required to give a medication in the amount of 8 mg / kg (twice a day). If two-time use of medicines is not possible, consider a one-time dose of 16 mg / kg per day. It should be borne in mind that information on the use of drugs in a single-use daily dosage for a given age category is very limited.

In case of switching to a one-time supplement with a 2-time intake, it is required to drink a one-off portion (indicated above) approximately 12 hours after the application of the daily dosage in 2 doses, and then continue to use the medication with the intervals required for a one-time use (24 hours). If you change the single-dose regimen to double, you must take the first part of a double dose approximately 24 hours after you use the last one-time dose.

[10], [11]

Use of the ziagen during pregnancy

Usually, if a decision is made 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 taken after animal tests is taken into account, and in addition, the existing clinical experience of using Ziagen in pregnant women.

Tests performed on animals showed embryotoxicity in rats, but rabbits were not found. The carcinogenic effect of drugs was observed in animal models, but the therapeutic significance of these data was not established. It was found that abacavir with its decay products can penetrate the placenta in humans.

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

Mitochondrial disorders: nucleoside as well as nucleotide analogues of drugs in in vitro or in vivo tests caused damage to the mitochondria. There is information on mitochondrial dysfunction in children with HIV-negative testing, whose mothers used analogues of a nucleoside-type drug during pregnancy or during the postnatal period.

When tests on rats it was found out that abacavir, along with its metabolites, penetrates into their milk. The active component of the drug is excreted in human breast milk. Information on taking medication by infants younger than 3 months is not available. In this regard, in the treatment with Ziagen, it is recommended to abandon breastfeeding. In general, mothers with HIV are recommended in any case to refuse breastfeeding in order to avoid the risk of transmission of infection to the child.

Contraindications

The main contraindications:

• hypersensitivity to abacavir or other elements of the drug;
• liver failure in medium or severe form;
• there is no information on the safety of use of drugs for infants until 3 months, so it is forbidden to assign it for this age category.

Side effects of the 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 or other medications, or as a consequence of the disease itself. Main violations:

• problems with the work of the gastrointestinal tract and metabolic processes: often there is hyperlactatemia or anorexia. Occasionally, lactic acidosis develops;
• lesions in the NA area: headaches often occur;
• manifestations of the digestive system: often there is vomiting, diarrhea or nausea. Occasionally, pancreatitis is noted, but it has not been possible to establish that its development is associated with the use of drugs;
• damage to the subcutaneous layers and skin surface: often there is a rash (not having systemic manifestations). The Stevens-Johnson syndrome, the erythema multiforme, or the TEN is sometimes developed;
• systemic disorders: often there is a feeling of inhibition or fatigue, as well as a state of fever.

Overdose

Clinical tests were performed with a single dose of up to 1.2 grams of medication (and up to 1.8 grams per day), in which no new adverse reactions were identified other than those indicated as side effects from taking standard dosages. There is no information on the use of higher portions of the solution.

With the development of intoxication, the victim needs constant monitoring to determine the manifestations of toxicity. If necessary, supportive care procedures should be carried out. There is no information on the possibility of excretion of abacavir by hemodialysis or peritoneal dialysis.

[12], [13]

Interactions with other drugs

Experimental in vitro tests have shown that the potential for interactions with other drugs, carried out with element 450, in abacavir is quite low. Element 450 is not a major participant in the metabolism of the substance, and abacavir itself does not inhibit the metabolic processes performed with the enzyme CYP3A4, which is part of the P450 hemoprotein system. It was found that, in in vitro tests, the medicament in medicinally active concentrations does not suppress the enzymes CYP3A4, and also CYP2C9 or CYP2D6. In clinical tests, induction of metabolic processes within the liver did not occur, and therefore the likelihood of developing interaction with other antiretroviral-type protease inhibitor drugs, as well as with other drugs, metabolized by many P450 enzymes, is extremely low. Also, studies have shown that there is no significant interaction between Ziagen, as well as lamivudine or zidovudine, for treatment processes.

Drugs that are potentially capable of inducing enzymes (eg, phenobarbital with rifampicin or phenytoin), acting on UDPGT, may slightly lower the plasma values of abacavir.

Metabolism of the drug is altered by exposure to ethyl alcohol - an increase in the level of AUC is approximately 41%. But this indicator is not considered significant. In turn, abacavir does not affect the metabolism of ethyl alcohol.

The data obtained after pharmacokinetic tests show that the combination of 600 mg (two-time daily intake) of Ziagen with methadone reduces the peak values of abacavir by 35% and slows the period of their achievement by 60 minutes, but the AUC level remains the same. Changes in the pharmacokinetic properties of drugs do not have clinical significance. Tests also showed that the drug increases by 22% the average values of total methadone clearance. Because of this, induction of enzymes that metabolize drugs may occur. People who are treated with methadone should be constantly monitored by doctors - for signs of withdrawal that occur during dosing. In the development of such a situation, there may be a need for a new change in the dosage of methadone.

Elimination of retinoids is carried out with the participation of the element alcohol dehydrogenase. It is possible to develop interactions with the drug, although they have not been studied.

Because ribavirin with abacavir is phosphorylated by analogous routes, it is believed that it is possible to expect the appearance of intracellular interactions between them. As a result, the phosphorylated degradation products of ribavirin may be reduced inside the cells, which can subsequently reduce the chances of a sustained virologic response in persons infected with the hepatitis C virus (in the case of pegylated interferon / ribavirin therapy). Medical literature gives conflicting information about the combination of Ziagen and ribavirin. Some sources suggest that people who are coinfected with HIV, as well as a type C hepatitis virus, who take antiretroviral drugs that contain the abacavir component, risk getting a weakened response to therapy with pegylated ribavirin / interferon. Therefore, in the case of a combination of drugs, caution must be exercised.

[14],

Storage conditions

Ziagen is required to be kept in a place where small children can not penetrate, with a maximum temperature of 30 ° C.

[15], [16], [17]

Shelf life

Ziagen is required to be used in the period of 2 years from the date of manufacture of the medicinal product. In this case, the opened bottle has a shelf life of no more than 2 months.

[18], [19]