Ziagen - instructions for use, dose, side effects, contraindications

Components	Amount, mg
Active substance
Abacavir sulfate (in terms of abacavir)	23,4 (20,0)
Excipients
Sorbitol 70 % (non-crystalline)²	492,0
Saccharin sodium	0,3
Aromatic Strawberry	2,0
Aromatic Banana	2,0
Sodium citrate	10,0
Lemon acid	7,0
Methylparahydroxybenzoate	1,5
Propyl parahydroxybenzoate	0,18
Propylene glycol	50,0
Hydrochloric acid	to pH 4.1
A solution of sodium hydroxide	to pH 4.1
Purified water	up to 1.0 ml

Description:

Transparent or slightly opalescent slightly yellowish solution with a fruity smell.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.F.06 Abacavir

Pharmacodynamics:

Mechanism of action

Abacavir is a nucleoside analogue, which inhibits HIV reverse transcriptase and selectively suppresses replication of HIV-1 and HIV-2, including HIV-1 strains resistant to zidovudine. lamivudine, zalcitabine, didanosine and nevirapine. Abacavir is subject to intracellular metabolism, transforming into an active form, carbovir-5'-triphosphate (carbovir-TF). According to research in vitro, the antiviral effect of the drug is due to the inhibition of HIV reverse transcriptase, which leads to the breakdown of DNA synthesis on the RNA template and the stopping of HIV replication. There was no antagonism in the antiviral activity of abacavir in cell culture when combined with nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor (HIV-IP) amprenavir.

The obtained in vitro HIV-1 strains resistant to abacavir, mutations in several codons of the reverse transcriptase gene (RT) - M184V, K65R, L74V and Y1I5F. HIV resistance to abacavir in vitro and in vivo formed slowly. For a clinically significant increase in the 50% inhibitory concentration (IC50) (increase IC50 8 times the "wild" strain of the virus) requires multiple mutations. Strains resistant to abacavir may have decreased sensitivity to lamivudine, zalcitabine and / or didanosine, but retain a sensitivity to zidovudine and stavudine. Cross-resistance to abacavir and HIV or NNRTI is unlikely. Inefficiency of the first-line regime, including abacavir, lamivudine and zidovudine. is mainly associated with a single mutation - M184V, which preserves the possibility of a wide choice of regimens for second-line therapy.

Abacavir penetrates into the cerebrospinal fluid (CSF) and reduces the content of HIV-1 RNA in it. In combination with other antiretroviral drugs, it can prevent development neurological complications of HIV infection and slow resistant strains within the central nervous system (CNS).

Pharmacokinetics:

Suction

Abacavir is quickly and well absorbed when taken orally. Absolute the bioavailability of abacavir for oral administration in adults is about 83%.The time to reach the maximum concentration (T_m_Oh) when taking abacavir orally in the form of a solution for oral administration - about 1 hour. Area under the pharmacokinetic curve "concentration-time" (AUC) for the tablet form of abacavir does not differ from that for abacavir in the form of a solution for oral administration.

Food intake slows down absorption abacavir and decreases C_m_Oh, but does not affect AUC. therefore abacavir can be taken with or without food.

Distribution and binding to blood plasma proteins

Studies involving HIV-infected patients showed that abacavir well penetrates into the CSF, while the ratio of AAB abacavir in CSF to AUC abacavir in blood plasma is 30-44%. In the Phase I pharmacokinetic study, it was found that 1.5 hours after taking abacavir 300 mg twice daily, its mean concentration in the CSF was 0.14 μg / ml. When using abacavir in a dose of 600 mg 2 times a day, the concentration of the drug in the CSF increased from 0.13 μg / ml 0.5-1 hour after administration to 0.74 μg / ml when measured 3-4 hours after administration of abacavir . Thus, even if the concentration of abacavir, observed in the CSF 4 hours after taking the drug at a dose of 600 mg 2 times a day,is not the maximum achieved with this treatment regimen, it already exceeds IC50 (0.08 μg / ml or 0.26 μmol / l) 9-fold.

In in vitro studies, it has been found that in therapeutic doses abacavir moderately (approximately 49%) binds to human plasma proteins. This indicates that the interaction of abacavir with other drugs by their displacement from the compound with plasma proteins is unlikely.

Metabolism

Abacavir is metabolized mainly in the liver, in an unchanged form, less than 2% of the accepted dose of the drug is excreted by the kidneys. In the human body, abacavir is metabolized mainly by the action of alcohol dehydrogenase with the formation of 3'-carboxylic acid and by conjugation with glucuronic acid to form 3'-glucuronide, which is about 66% of the total amount of the administered dose of the drug. These metabolites are excreted by the kidneys.

Excretion

On average, the half-life of abacavir is about 1.5 hours. Prolonged intake of abacavir orally at a dose of 300 mg 2 times a day does not lead to significant cumulation of the drug. Abacavir excretion is carried out by metabolism in the liver, followed by excretion of metabolites mainly by the kidneys.About 83% of the administered dose is excreted by the kidneys in the form of metabolites and abacavir in unchanged form, and the remaining quantity is excreted through the intestine.

Special patient groups

Children

Abacavir is absorbed well and quickly in the form of a solution for oral administration and in tablet form when taken orally the children. Exposure of abacavir in blood plasma was the same for both forms of release at the same dosage. In children receiving abacavir in the form of a solution for oral administration in according to the recommended dosing regimen, exposure abacavir in plasma was similar to that of adults. In children, receiving abacavir in the form of tablets in accordance with the recommended dosing regimen, exposure Abacavir in plasma was higher than in children receiving abacavir in the form of a solution for oral administration, in connection with the administration of higher doses in mg / kg with the administration of tablets. Pharmacokinetic studies the children They showed, that preparation 1 time at day is equivalent by indicators AUC_0-24receiving the same dose drug, divided 2 times in day, for existing dosage forms preparation Ziagen® (oral solution and coated tablets shell).

There is insufficient safety data to recommend the use of abacavir in children younger than 3 months. There are limited data showing that a dose of 2 mg / kg in newborns under 30 days provides similar or more value of indicators AUC compared with a dose of 8 mg / kg in older children.

Elderly patients

The pharmacokinetics of abacavir in patients older than 65 years have not been studied. In the treatment of elderly patients, it is necessary to take into account more frequent violations of the liver, kidney and heart function at this age, as well as concomitant diseases and medications taken.

Patients with impaired renal function

Abacavir is metabolized predominantly in the liver, less than 2% of it theKidneys in unchanged form. Pharmacokinetics of abacavir in end-stage renal disease insufficiency is about the same as with normal kidney function. Therefore, if the renal function is not corrected, dose adjustment is not required.

Patients with impaired hepatic function

Abacavir is metabolized mainly in the liver.The results of a study of the pharmacokinetics of abacavir in patients with mild liver function disorder (5-6 on the Child-Pugh scale) indicate an increase AUC an average of 1.89 times and a half-life of 1.58 times. On the metric AUC metabolites of abacavir a violation of liver function is not affected, but the rate of their formation and excretion is reduced.

Patients with a mild liver function disorder may receive 200 mg of abacavir 2 times a day for therapeutic purposes.

The pharmacokinetics of abacavir in patients with impaired liver function of medium and severe degree has not been studied, thus, the use of abacavir is not recommended in these patient groups.

Indications:Treatment of HIV infection in adults and children in combination antiretroviral therapy.

Contraindications:

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

- age before 3 months, since the experience of using Ziagen ® in this age group is limited;

- hepatic insufficiency of moderate and severe degree (class B and C on the Child-Pugh scale), due to the lack of clinical data and the recommended dosing regimen.

Pregnancy and lactation:

Pregnancy

The use of abacavir during pregnancy and after childbirth evaluated according to the Registry of the use of antiretroviral drugs during pregnancy more than 2000 women. The data available in the Registry on the use of antiretroviral drugs during pregnancy do not indicate an increased risk of developing major congenital malformations associated with abacavir use compared to the frequency of developmental defects in the comparison group. However, adequate and well-controlled studies in pregnant women are not available, the safety of abacavir in women during pregnancy has not yet been established.

There is evidence of the effects of abacavir in reproductive studies in animals. If it is necessary to use Ziagen® during pregnancy, the ratio the potential benefit to the mother and the potential risk to the fetus.

There is evidence of a slight transient increase in the concentration of lactate in the blood plasma of newborns and infants whose mothers during pregnancy and childbirth took NRTIs. Perhaps this is due to mitochondrial disorders.

The clinical significance of this phenomenon has not been established to date. In addition, there are extremely rare reports of developmental delay, epileptic seizures and other neurological disorders (eg, muscle tone increase) in newborns, although the cause-and-effect relationship of these disorders to NRTIs in mothers during pregnancy and childbirth is not established. These data do not abolish existing recommendations for use antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Breastfeeding period

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

Dosing and Administration:

The drug Ziagen ® is taken orally, regardless of food intake.

The drug should be prescribed by a doctor with experience in the treatment of HIV infection.

Children and adults who do not receive Ziagen® in tablets are not indicated, or patients who swallow the tablet are difficult to prescribe Ziagen® as an oral solution.

Adults, adolescents and children weighing not less than 25 kg

The recommended dose of Ziagen ® is 600 mg / day. The drug is given in a dose of 300 mg (15 ml) 2 times a day or 600 mg (30 ml) once a day.

Special patient groups

Children

Children aged 3 months and older with a body weight of up to 25 kg

The recommended dose is 8 mg / kg 2 times a day or 16 mg / kg once a day at a maximum daily dose of 300 mg twice a day or 600 mg once a day (30 ml). Children up to 3 months old

Data on the use of Ziagen ® in this age group is very limited.

Patients with impaired renal function

In patients with impaired renal function, dose adjustment of Ziagen® is not required.

Patients with impaired hepatic function

Abacavir is metabolized predominantly in the liver. The recommended dose of Ziagen ® for patients with mild liver function disorders (5-6 points on the Child-Pugh scale) is 200 mg (10 ml of solution) 2 times a day. Considering the need to use smaller doses of Ziagen ® in patients with mild liver function disorders, it is prescribed as a solution for oral administration to correctly dispense the drug. There is no data on the pharmacokinetics and safety of abacavir in patients with moderate or severe liver dysfunction. In this way.The use of abacavir in patients with impaired liver function of medium and severe degree is contraindicated.

Side effects:

The nature of other undesirable reactions, other than MIRV, but observed in patients taking Ziagen®, is not completely clear. Whether these unwanted reactions result from the use of Ziagen® or a wide range of other drugs concomitantly prescribed for the treatment of HIV infections or caused by the disease itself has not been established to date.

Many of the undesirable reactions associated with taking Ziagen® (nausea, vomiting, diarrhea, fever, fatigue, rash) are usually observed in developing MIRVs to abacavir. Therefore, if any of these symptoms appear, careful examination of the patient for confirmation development of the MIRV. If the drug Ziagen ® was canceled due to the appearance of the above symptoms and the decision was made to resume therapy with Ziagen ®, then this can only be done under direct medical supervision.

Very rare cases of polymorphic exudative erythema, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported. in which it was impossible to exclude MIRVs to abacavir.In such cases, you must permanently stop taking medication containing abacavir.

Most of the undesirable reactions listed below are not are the limiting treatment. 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 <1/1000), rarely (< 1/10 000).

Clinical Trials Data

Disorders from the metabolism and nutrition

Often: loss of appetite.

Disturbances from the nervous system

Often: headache.

Disorders from the gastrointestinal tract

Often: nausea, vomiting, diarrhea.

General disorders and disorders at the site of administration

Often: fever, drowsiness, fatigue.

In controlled clinical trials, it was shown that the change in laboratory parameters in the treatment with Ziagen® was observed infrequently, as in the control group of patients who did not receive the drug.

Children

Safety data confirming a single dose of abacavir in children were obtained in the study ARROW (COL 105677), in which 669 children infected with HIV-1 received abacavir and lamivudine 1 or 2 times a day. No additional safety signals were identified in children who took abacavir 1 or 2 times a day compared with adults.

Post-registration data

Disorders of metabolism and nutrition

Often: hyperlactatemia.

Rarely: lactic acidosis, accumulation and / or redistribution of adipose tissue. The frequency of this unwanted reaction depends on many factors, including antiretroviral drugs used in combination with abacavir.

Disorders from the gastrointestinal tract

Rarely: pancreatitis (a cause-and-effect relationship with the use of abacavir is not exactly established).

Disturbances from the skin and subcutaneous tissues

Often: rash (in the absence of systemic manifestations).

Very rarely: polymorphic erythema exudative, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Lactoacidosis, sometimes fatal, has been reported, usually associated with severe hepatomegaly and fatty liver dysfunction, using nucleoside analogues.

The use of combination antiretroviral therapy has been 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 (the "buffalo hump").

The use of combination antiretroviral therapy has been 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 antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections may occur. Cases have also been reported autoimmune diseases (eg, Graves' disease) occurring under conditions of immune reactivation, however, the presented terms of the disease manifestation are more various and these phenomena can occur many months after the initiation of therapy.

Osteonecrosis has been documented, especially in patients with well-known risk factors, advanced HIV infection, or long-term use of combined antiretroviral therapy. The frequency of this phenomenon is unknown.

Description of individual adverse reactions

Hypersensitivity

The hGH to abacavir was defined as a general undesirable reaction in the treatment with drugs containing abacavir. The signs and symptoms of MRI are listed below. These signs and symptoms were identified during clinical trials or postgistratsionnom supervision. Symptoms and signs that occur in at least 10% of patients with MRSV are indicated in bold type. Practically all patients with HGV develop fever and / or a rash (usually maculopapular or urticaria) as part of the syndrome, but reactions can also occur without rash or fever. Other major symptoms include symptoms from the gastrointestinal tract, respiratory system, or constitutional symptoms, such as drowsiness or malaise.

Disturbances from the skin and subcutaneous tissues:

rash (usually maculopapular or urticarum).

Disorders from the gastrointestinal tract:

nausea, vomiting, diarrhea, abdominal pain, ulceration of the oral mucosa.

Disturbances from the respiratory system, organon of the thorax and mediastinum:

shortness of breath, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Impaired nervous system:

headache, paresthesia.

Violations from the blood and lymphatic system:

lymphopenia.

Disorders from the liver and bile ducts:

increase of biochemical parameters of liver function, hepatitis, hepatic notadequacy.

Disturbances from the musculoskeletal and connective tissue:

myalgia, myolysis, arthralgia, increased activity of creatine phosphokinase.

Disorders from the kidneys and urinary tract:

increased serum creatinine concentration, renal failure.

General disorders and disorders at the site of administration:

fever, fatigue, malaise, swelling, lymphadenopathy, arterial hypotension, conjunctivitis, anaphylactic reactions. Renewal of the drug Ziagen® after the MIRV on abacavir leads to a rapid return of symptoms within a few hours. Repeated MRI usually proceeds more severely than the first, and may include life-threatening arterial hypotension and death. In rare cases, reactions also occur with the resumption of therapy with the drug Ziagen® After its cancellation, caused by the emergence of just one of the main symptoms of hypersensitivity (seeabove), and in very rare cases, this reaction occurs when the drug is resumed Ziagen® patients who did not have any MRI symptoms prior to discontinuation (i.e., in patients previously thought to be abacavir-tolerant). Detailed information on the clinical management of the case of a suspected MRSV abacavir see "Special instructions".

Overdose:

Symptoms

In clinical studies, no undesirable reactions were observed with the use of Ziagen ® in single doses up to 1200 mg and diurnal up to 1800 mg. The effect of the drug in higher doses has not been studied to date.

Treatment

In the case of an overdose of Ziagen®, patients are monitored for symptoms of poisoning and timely treatment. If necessary, perform symptomatic treatment. The efficacy of peritoneal dialysis and hemodialysis for abacavir removal is unknown.

Interaction:

In vitro studies and analysis of the main metabolic pathways of abacavir indicate that its interaction with other drugs, mediated by cytochromeP450 is unlikely. Abacavir does not suppress metabolic reactions involving isoenzyme 3A4 cytochrome P450. In studies in vitro shown, that abacavir Do not enter into interactions with drugs that are metabolized by isoenzymes CYP3A4, CYP2C9, CYP2D6. Clinical studies have not revealed the induction of hepatic metabolism of exogenous substances under the action of abacavir. Thus, the interaction of abacavir with HIV protease inhibitors and other drugs, metabolized with the participation of the main isoenzymes of cytochrome P450, unlikely.

Clinical studies have shown no clinically relevant interactions between abacavir, zidovudine and lamivudine.

Powerful inducers of enzymes, such as rifampicin, phenobarbital and phenytoin when exposed to UDP-glucuronyl transferase, can slightly reduce the concentration of abacavir in plasma.

Ethanol: ethanol slows metabolism abacavir, which leads to an increase in AUC on 41%. However, the clinical significance of this change is small. On the metabolism of ethanol abacavir does not affect.

Methadone: according to pharmacokinetic studies, the use of abacavir in a dose 600 mg twice a day in combination with methadone reduces C_m_Oh abacavir in serum blood by 35%, increases T_m_Ohfor 1 hour in the serum, but does not change AUC. The clinical significance of these changes is small. The same study found that abacavir increases the systemic clearance of methadone by 22%. In most cases, these changes are also considered clinically insignificant, but in certain situations, a dose change in methadone may be required.

Retinoids: retinoids, for example isotretinoin; are eliminated with the participation of alcohol dehydrogenase, so they can interact with abacavir, but to date no special studies have been conducted.

Ribavirin: due to abacavir and ribavirin have the same phosphorylation pathways, an interaction between these substances is suggested that can lead to a reduction 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 published for 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.

Special instructions:

Hypersensitivity

The use of Ziagen ® is associated with the risk of developing MRI, characterized by fever and / or rash and other symptoms that indicate multiple organ failure. The MRI may be life threatening and in rare cases, when no appropriate treatment is prescribed, it can lead to death. The risk of developing MRI with Ziagen®significantly increased in patients with a positive test for the presence of an allele HLA-B* 5701. However, abacavir were observed with a lower frequency in patients who are not carriers of this allele.

The following rules should be observed.

- A study should be conducted for the presence of an allele HLA-B* 5701 prior to initiation of Ziagen therapy, and also before resumption of Ziagen therapy in patients with unknown status for the allele HLA-B* 5701, who previously tolerated abacavir well.

- It is not recommended to use Ziagen ® in patients with an allele HLA-B* 5701 or in patients who were suspected of having an MRI during any other drug containing abacavir (eg, Kivex, Trizivir®) regardless of status in relation to HLA-B*5701.

- Each patient should be reminded that it is necessary to read the instructions for use, enclosed in the Ziagen® package. Also, patients should be reminded that it is necessary to constantly carry a warning card attached to the drug.

- Have of all patients receiving Ziagen®, the clinical diagnosis of a suspected MRI should remain the basis for making a clinical decision.

- If MRI is suspected, Ziagen® therapy should be discontinued immediately even if there is no allele HLA- B * 5701. The delay in stopping therapy with Ziagen® after the occurrence of MRI may lead to a life-threatening reaction.

- Patients who developed MRIs should be informed of the need to transfer the remaining Ziagen® tablets to the treating physician in order to avoid the resumption of abacavir.

- Renewal of the use of drugs containing abacavir, after the suspected MRI on abacavir can lead to a rapid return of symptoms within a few hours, which may include life-threatening arterial hypotension and death.

- When considering the resumption of therapy with abacavir after discontinuation of treatment by anyone containing abacavir but for any reason, the reason for discontinuing therapy should be established regardless of the patient's carriage of the allele HLA-B* 5701. If the MRI can not be ruled out, the use of Ziagen® or any other medications containing abacavir (for example, Kivexa, Trizivir®).

- If the MRI is excluded, it is possible to resume therapy with Ziagen®. In rare cases, patients who discontinued abacavir use for reasons other than the symptoms of MRSV. also noted the development of life-threatening reactions for several hours after the resumption of therapy abacavir (cm. "Description of individual undesired reactions"). Patients should be informed of the possibility of developing an MRI with the resumption of therapy with Ziagen® or other medications containing abacavir (eg, Kivex, Trizivir®), and that the resumption of therapy with Ziagen® or other medications containing abacavir (eg, Kivex, Trizivir®), should only be carried out with quick access to medical care.

The clinical picture of MRI on abacavir

MIRVs on abacavir were well studied in clinical trials and during post-registration follow-up. Symptoms usually appear during the first 6 weeks (median time of onset of this reaction is 11 days) after initiation of abacavir therapy, however, these reactions can develop at any time during therapy.

Virtually all of the responses of the WGS to abacavir include fever and / or rash, as part of the syndrome.

Other signs and symptoms that are noted as a manifestation of WGS on abacavir, include symptoms on the part of the respiratory and gastrointestinal tract, which can lead to incorrect diagnosis of the MRI as a respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis (see sections "Side effect", "Description of individual adverse reactions"). Patients should be closely monitored with advice every 2 weeks, especially during the first 2 months of therapy with Ziagen®.

If, when symptoms appear, related to MIRV, treatment with abacavir continues, they become more pronounced and can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.

Lactic acidosis and expressed hepatomegaly with steatosis

There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis. including fatal, due to antiretroviral therapy with nucleoside analogues, including abacavir, taken either individually or in combination. In most cases, these complications occur in women. Symptoms that may indicate the development of lactic acidosis include general weakness, lack of appetite, rapid weight loss of unclear etiology, gastrointestinal disturbances (nausea, vomiting and abdominal pain), respiratory system disorders (dyspnea and tachypnea), or neurologic symptoms (including movement).

Lactic acidosis has a high mortality and can be associated with pancreatitis. hepatic or renal insufficiency. Lactic acidosis, as a rule, manifested itself after several months of therapy. It is necessary to stop therapy with nucleotide analogues in case of symptomatic manifestations of hyperlactatemia and metabolic / lactic acidosis, progression of hepatomegaly or rapid increase in aminotransferase activity.

Application of the drug Ziagen® requires caution for any patients (especially women with overweight) with hepatomegaly. hepatitis or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol). Patients with co-infected hepatitis C receiving interferon alfa and ribavirin therapy can be a particular risk group. Patients with high risk require careful monitoring.

At the appearance of clinical or laboratory signs of lactic acidosis with or without hepatitis (hepatomegaly and steatosis may appear even in the absence of a pronounced increase in aminotransferase activity), drug treatment Ziagen® it is necessary to suspend.

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 beginning (increased muscle tone, convulsions, behavioral disorders). Whether these neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, who was exposed to intrauterine effects of analogues of nucleosides and nucleotides, should undergo a clinical and laboratory examination to mitochondrial dysfunction in the event of the identification of the relevant signs or symptoms.These data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

Redistribution of subcutaneous fat

In some patients receiving combined antiretroviral therapy. Can be observed redistribution and / or accumulation of subcutaneous fat, including obesity by the central type, dorsocervical fat deposition ("buffalo fish"), a reduction in the subcutaneous fat layer on the face and limbs, an increase in the mammary glands, an increase in serum lipid concentrations, and a concentration of glucose in the blood.

Although one or more of the following above unwanted reactions associated with a common syndrome, which is often referred to as lipodystrophy. may cause all drugs of HIV and NRTI classes, the data indicate the existence of differences between individual representatives of these classes of drugs in the ability to cause 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 the duration of antiretroviral therapy play an important role. Perhaps a synergistic role.

The long-term effects of these undesirable reactions are currently unknown.

When clinically examining patients, attention should be paid to the redistribution of subcutaneous fat. Laboratory examination should include the determination of serum lipid concentrations and blood glucose concentrations. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.

Pancreatitis

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

Therapy containing three NRTIs

In patients with high viral load (> 100,000 copies / ml), the appointment of a triple combination containing abacavir, lamivudine and zidovudine, requires special consideration.

There were recorded cases of high rates of virological failure and the emergence of resistance in the early stages, when a combination of abacavir with tenofovir, dizoproxil fumarate and lamivudine was used as a regimen of therapy once a day.

Diseases of the liver

Efficacy and safety of the drug Ziagen® have not been established in patients with severe concomitant liver diseases. A drug Ziagen®contraindicated in patients with impaired liver function of moderate and severe degree.

Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiretroviral therapy, and should be monitored in accordance with accepted practice. It is necessary to consider the possibility of suspension or termination of treatment, in the case of manifestations of worsening liver disease in such patients.

Concomitant Hepatitis B or C

Patients with concomitant chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially legal adverse reactions from the liver. In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the appropriate instructions for the use of these drugs.

Care should be taken when concurrent administration of abacavir and ribavirin.

Kidney Diseases

The drug Ziagen ® should not be given to patients with terminal chronic renal failure.

Excipients

The drug Ziagen ® in the form of a solution for oral administration contains 340 mg / ml sorbitol. When the drug is administered in accordance with the recommended dosing regimen, every 15 ml of Ziagen® contains approximately 5 g of sorbitol, which can cause abdominal pain and diarrhea. Sorbitol is metabolized to fructose, therefore it should not be administered to patients with hereditary intolerance fructose. Energy value sorbitol 2,6 kcal / g.

A drug Ziagen® in the form of a solution for oral administration also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, which can cause allergic reactions (possibly delayed type).

Immunodeficiency Syndrome

If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences. Typically, these reactions occur within the first weeks or months after initiation of antiretroviral therapy.Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (formerly P. 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 also observed against the background of restoration of immunity, however, the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

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 the late stage of HIV infection in the Nazis and / or in the long-term combined antiretroviral therapy. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

Opportunistic infections

Application of the drug Ziagen® 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 with experience in the treatment of HIV-associated diseases.

Transmission of HIV infection

Antiretroviral therapy, including the drug Ziagen®, does not exclude the possibility of sexual transmission of HIV or in contact with infected blood and therefore not precludes the need for appropriate precautions.

Myocardial infarction

As a result of a prospective observational epidemiological study to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, 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 developing myocardial infarction associated with the use of abacavir. Biological mechanisms that explain a potentially increased risk are unknown.In general, available data from cohort observations and controlled clinical studies do not allow one to unequivocally determine the relationship between abacavir therapy and the risk of myocardial infarction. However, care should be taken to prescribe antiretroviral therapy, including drugs containing abacavir. patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize all modifiable risk factors (such as hypertension, hyperlipidemia, sugar diabetes and smoking).

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

Patient Warning Card

Attention!

Ziagen®, solution for oral administration

Abacavir

Always carry this card with you

Because the drug Ziagen® contains abacavir, in some patients taking the drug Ziagen®, can develop a hypersensitivity reaction (a serious allergic reaction), often life-threatening, if not abolish the drug. IMMEDIATELY CONTACT YOUR DOCTOR DOCTOR for advice on the possibility of further taking the drug Ziagen® if:

3) you have a skin rash

4) you have one or more symptoms from at least two of the following groups:

- fever;

- shortness of breath, sore throat, or cough;

- nausea or vomiting or diarrhea or abdominal pain;

- increased fatigue or pain or general malaise.

If you stop taking Ziagen ® as a result of this reaction, MORE NEVER NEVER ACCEPT the Ziagen® preparation or any other preparation containing abacavir (Trizivir®, Kivexa), since within a few hours it can lead to a life-threatening drop in blood pressure or death.

Effect on the ability to drive transp. cf. and fur:Data on the effects of abacavir on the ability to drive vehicles and handle mechanisms are not available.

Form release / dosage:Solution for oral administration, 20 mg / ml.

Packaging:For 240 ml of the drug in a bottle of high-density polyethylene with a screw cap, equipped with protection from opening by children. One bottle together with an adapter, a dispensing syringe and instructions for use in a cardboard pack.

Storage conditions:

At a temperature not higher than 30 ° C. Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N011612 / 02

Date of registration:05.05.2010 / 12.11.2012

Expiration Date:Unlimited

The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom

Manufacturer: & nbsp

GlaxoSmithKline, Inc. Canada

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp11.04.2017

Illustrated instructions

Instructions

Ziagen® (Ziagen®)