Abavir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABAVIR (ABAVIR)

Composition:

Active substance: abacavir;

1 ml of solution contains 20 mg of abacavir (as sulfate);

Excipients: sorbitol, sodium saccharin, sodium citrate, citric acid anhydrous, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), propylene glycol, strawberry flavoring, banana flavoring, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear or slightly opalescent yellowish liquid with a strawberry-banana odor.

Pharmacotherapeutic group. Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors. ATC code J05A F06.

Pharmacological properties.

Pharmacodynamics.

Abacavir belongs to the group of nucleoside reverse transcriptase inhibitors (NRTIs) and is a potent inhibitor of HIV-1 and HIV-2, including HIV-1 isolates with reduced susceptibility to zidovudine, lamivudine, zalcitabine, didanosine or nevirapine. Within the cell, abacavir is converted into its active metabolite carbovir triphosphate, whose primary mechanism of action is inhibition of human immunodeficiency virus (HIV) reverse transcriptase, thereby disrupting the essential linkage in the viral DNA chain and halting its replication. In in vitro studies, the antiviral activity of abacavir was not antagonistic when co-administered with the NRTIs didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

Resistance in vitro

Abacavir-resistant HIV-1 isolates have been selected in vitro and are associated with specific genetic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V, and Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations to achieve a clinically significant increase in EC₅₀ compared to wild-type virus.

Resistance in vivo (therapy in treatment-naïve patients)

Demonstration of abacavir efficacy is primarily based on studies conducted with a twice-daily dosing regimen in previously untreated patients receiving combination therapy.

Isolates from most patients experiencing virological failure in the main clinical trials with abacavir-containing regimens showed either no NRTI-associated changes compared to baseline (45%) or selection of only M184V or M184I (45%). The overall frequency of M184V or M184I selection was high (54%), while selection of L74V (5%), K65R (1%), and Y115F (1%) was less common. The inclusion of zidovudine in the regimen reduced the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine: 0/40; without zidovudine: 15/192, 8%).

Thymidine analogue mutations (TAMs) need to be selected when thymidine analogues are combined with abacavir. In a meta-analysis of 6 clinical trials, TAMs were not selected in regimens containing abacavir without zidovudine (0/127), but were selected in regimens combining abacavir with the thymidine analogue zidovudine (22/86, 26%).

Resistance in vivo (therapy in previously treated patients)

Clinically significant reduction in abacavir susceptibility has been demonstrated in clinical isolates from patients with uncontrolled viral replication who were previously treated and resistant to other nucleoside inhibitors. In a meta-analysis of 5 clinical trials where abacavir was added to intensify therapy, among 166 individuals, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had M41L, 30 (18%) had K70R, and 25 (15%) had D67N. K65R was not observed, and L74V as well as Y115F were infrequent (≤3%). Regression modeling of predictive genotypic changes (adjusted for baseline HIV-1 RNA [vRNA] plasma levels, CD4+ cell count, number, and duration of prior antiretroviral treatments) showed that the presence of 3 or more NRTI resistance-associated mutations was associated with reduced response at week 4 (p=0.015), or 4 or more mutations at mid-week 24 (p≤0.012). In addition, the Q151M mutation complex, which is typically observed in combination with A62V, V75I, F77L, and F116Y, leads to a high level of resistance to abacavir.

Phenotypic resistance and cross-resistance

Phenotypic resistance to abacavir requires M184V plus at least one other abacavir-selected mutation or M184V in combination with multiple TAMs. Phenotypic cross-resistance to other NRTIs with a single M184V or M184I mutation is limited. Zidovudine, didanosine, stavudine, and tenofovir retain their antiretroviral activity against such HIV-1 variants. The presence of M184V together with K65R leads to increased cross-resistance between abacavir, tenofovir, didanosine, and lamivudine, while M184V combined with L74V results in cross-resistance between abacavir, didanosine, and lamivudine. The presence of M184V with Y115F causes increased cross-resistance between abacavir and lamivudine. Appropriate use of abacavir should consider existing resistance patterns.

Cross-resistance between abacavir and antiretroviral drugs from other classes (e.g., PIs and NNRTIs) is unlikely.

Pharmacokinetics.

Absorption. Abacavir is rapidly and well absorbed from the gastrointestinal tract, with an absolute bioavailability of 83% after oral administration in adults. Maximum plasma concentration (C_max) of abacavir is reached within 1.5 hours after tablet intake and within 1 hour after oral solution intake. The area under the concentration-time curve (AUC) is equivalent for tablets and oral solution. After administration of 600 mg abacavir daily, C_max is approximately 3 µg/mL and AUC over a 12-hour dosing interval is 6 µg·h/mL. C_max after oral solution intake is slightly higher than after tablet intake. Administration of abacavir with food delays the time to peak concentration but does not affect the total plasma exposure. Therefore, the drug can be taken regardless of food intake.

Distribution. Abacavir readily distributes into various body tissues. Clinical studies in HIV-infected patients show that abacavir penetrates well into cerebrospinal fluid. The mean ratio of abacavir concentrations in cerebrospinal fluid to plasma is approximately 30–44%. At therapeutic doses, plasma protein binding is about 49%.

Metabolism. Abacavir undergoes primary hepatic metabolism, with less than 2% of the administered dose excreted unchanged by the kidneys. The main metabolites are 5’-carboxylic acid and 5’-glucuronide, formed via alcohol dehydrogenase or glucuronidation pathways.

Elimination. The mean elimination half-life of abacavir is 1.5 hours. No significant accumulation occurs after multiple doses of 300 mg twice daily. Metabolites and unchanged abacavir are excreted in urine (approximately 83% of the administered dose), with the remainder eliminated in feces.

Pharmacokinetics in patients with renal impairment. Abacavir is primarily metabolized by the liver, with approximately 2% of unchanged abacavir excreted by the kidneys. The pharmacokinetics of abacavir in patients with end-stage renal disease are similar to those in patients with normal renal function. Therefore, dose adjustment of abacavir is not required in patients with renal impairment. However, based on limited experience, abacavir should not be used for the treatment of patients with end-stage renal disease.

Carcinogenesis. In carcinogenicity studies in mice and rats, oral administration of abacavir was associated with an increased incidence of malignant and benign tumors. Malignant tumors occurred in the preputial glands of males and clitoral glands of females, as well as in the liver, urinary bladder, lymph nodes, and subcutaneous tissue in female rats.

In most cases, these tumors occurred at the highest doses of abacavir—330 mg/kg/day in mice and 600 mg/kg/day in rats. These doses are equivalent to systemic exposure levels 24–32 times higher than in humans. An exception is the development of tumors in preputial glands, which occurred at a dose of 110 mg/kg, 6 times the human systemic exposure. Humans lack anatomical equivalents of these glands. Although the carcinogenic potential of abacavir in humans is unknown, these data suggest that the potential clinical benefit of the drug outweighs the carcinogenic risk in humans.

Animal studies. Mild degrees of myocardial degeneration were observed in rats and mice after administration of abacavir for 2 years. Systemic exposures were 7 to 24 times higher than expected in humans. The clinical significance of these findings is not established.

Clinical characteristics.

Indications.

The medicinal product is indicated, as part of combination antiretroviral therapy, for the treatment of HIV infection in children and adults.

Contraindications.

Hypersensitivity to abacavir or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Based on in vitro experimental data and well-known metabolic pathways of abacavir, the potential for CYP450-mediated interactions with other medicinal products is low. CYP450 enzymes do not play a major role in abacavir metabolism; in turn, abacavir does not inhibit CYP3A4-mediated metabolism of the cytochrome P450 system. In vitro studies have demonstrated that abacavir, at clinically relevant concentrations, also does not inhibit the CYP3A4, CYP2C9, or CYP2D6 enzymes. No induction of hepatic metabolism has been observed in clinical studies; therefore, the potential for interactions with other antiretroviral protease inhibitors and other medicinal products metabolized by most P450 enzymes is minimal. Clinical studies have confirmed the absence of clinically significant interactions between abacavir, zidovudine, and lamivudine.

Potential enzyme inducers such as rifampicin, phenobarbital, and phenytoin may slightly reduce plasma concentrations of abacavir through their effect on uridine diphosphate-glucuronosyltransferase.

Effect of abacavir on the pharmacokinetics of other substances

In vitro studies show that abacavir does not inhibit or only weakly inhibits organic anion transporting polypeptides 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP), or P-glycoprotein (Pgp), and has minimal inhibition of organic cation transporter 1 (OCT1), OCT2, and multidrug and toxin extrusion protein 2K (MATE-2K). Therefore, abacavir is not expected to affect plasma concentrations of medicinal products that are substrates of the aforementioned transporters. In vitro studies indicate that abacavir is an inhibitor of MATE1; however, abacavir has a low potential to affect plasma concentrations of MATE1 substrates at therapeutic exposure levels (up to 600 mg).

Effect of other substances on the pharmacokinetics of abacavir

In vitro studies show that abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein 2 (MRP2), or MRP4. Therefore, medicinal products that modulate these transporters are not expected to influence abacavir plasma levels.

Abacavir is also a substrate of BCRP and Pgp in in vitro studies. Clinical studies indicate no significant changes in abacavir pharmacokinetics when administered concomitantly with lopinavir/ritonavir (inhibitors of BCRP and Pgp).

Interactions related to abacavir

Ethanol. Abacavir metabolism is affected by ethanol—AUC increases by approximately 41%. These changes are not considered clinically significant. Abacavir does not affect ethanol metabolism.

Methadone. Pharmacokinetic study data show that concomitant administration of 600 mg abacavir twice daily and methadone reduced abacavir Cmax by 35% and delayed its time to peak concentration by one hour, but AUC remained unchanged. These pharmacokinetic changes of abacavir are not considered clinically significant. According to this study, abacavir increased the mean systemic clearance of methadone by 22%. Therefore, induction of drug-metabolizing enzymes cannot be excluded. Patients receiving methadone therapy should be closely monitored for withdrawal symptoms. In such cases, re-adjustment of the methadone dose may be necessary.

Retinoids. Retinoid components are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.

Special precautions.

Abacavir is associated with a high risk of hypersensitivity reactions (HSR) (see section "Adverse Reactions"), characterized by fever and/or rash accompanied by other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir use, some of which may be life-threatening and, in rare cases without appropriate management, fatal.

The risk of HSR to abacavir is higher in patients who are HLA B*5701-positive. However, there have been reports (less frequently) of HSR to abacavir in patients who do not carry this allele.

Therefore, the following recommendations must be followed:

• HLA B*5701 status must be documented prior to initiating abacavir therapy in every HIV patient, regardless of race;
• Abacavir-containing therapy must never be prescribed to patients who are HLA B*5701-positive, or to patients with HLA B*5701-negative status who previously experienced suspected HSR to abacavir when treated with other abacavir-containing medicinal products;
• Abacavir therapy must be discontinued immediately upon suspicion of HSR, even in patients lacking the HLA B*5701 allele; delay in stopping treatment after onset of hypersensitivity may lead to life-threatening conditions;
• After discontinuation of Abacavir due to suspected hypersensitivity reaction, Abacavir or any other abacavir-containing medicinal product must never be restarted;
• Regardless of HLA B*5701 status, if treatment with an abacavir-containing medicinal product has been discontinued for any reason and reinitiation is considered, the reasons for discontinuation must be carefully evaluated to ensure that HSR was not the cause; if HSR cannot be ruled out, Abacavir or any other abacavir-containing medicinal product must not be restarted;
• Reinitiating abacavir therapy after a hypersensitivity reaction leads to rapid recurrence of symptoms within hours; this recurrence is usually more severe than the initial reaction and may include life-threatening hypotension and death;
• To prevent re-exposure to Abacavir, any remaining medication should be discarded in patients with suspected hypersensitivity to abacavir;
• Patients must be informed of the necessity to remove and read this instruction leaflet and the special "Warning Card," and to carry the latter with them at all times.

WARNING CARD

(must carry this card at all times)

ABACAVIR

Oral solution, 20 mg/mL

Since Abacavir contains abacavir, patients receiving Abacavir may experience hypersensitivity reactions (serious allergic reactions), which may be life-threatening if Abacavir treatment is continued. Seek immediate medical advice regarding further use of the medicine if:

1. You develop a skin rash

OR

1. You experience one or more symptoms from at least TWO of the following groups:
   • fever;
   • shortness of breath, sore throat, or cough;
   • nausea, vomiting, diarrhea, or abdominal pain;
   • sudden weakness, fatigue, or general malaise.

If you have stopped Abacavir due to a hypersensitivity reaction, YOU MUST NEVER AGAIN USE Abacavir oral solution or any other abacavir-containing medicine (Trizivir, Ziagen), as this may result in life-threatening hypotension or death within hours.

Clinical manifestations of abacavir hypersensitivity reactions

Hypersensitivity reactions to abacavir have been well documented in clinical trials and post-marketing experience. Symptoms typically appear within the first six weeks (median onset: 11 days) after starting abacavir therapy, although these reactions may occur at any time during treatment.

Almost all cases of hypersensitivity reactions include fever and/or rash. Other symptoms and signs associated with abacavir HSR are described in detail in the "Adverse Reactions" section, including respiratory and gastrointestinal symptoms. Importantly, such symptoms may lead to misdiagnosis as respiratory tract illnesses (pneumonia, bronchitis, pharyngitis) or gastroenteritis instead of a hypersensitivity reaction.

Symptoms related to hypersensitivity worsen with continued therapy and may be life-threatening. These symptoms usually resolve after discontinuation of abacavir.

Rarely, in patients who discontinued abacavir for reasons unrelated to HSR symptoms, life-threatening reactions occurred within hours of reinitiating therapy (see section "Adverse Reactions"). Reinitiation of abacavir in such patients should only occur if immediate medical care is available if needed.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues may cause mitochondrial dysfunction of varying severity, particularly when used concomitantly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors in utero and/or postnatally, primarily in regimens containing zidovudine. The main adverse reactions reported include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Rare reports of neurological disorders (hypertension, seizures, behavioral changes) occurring after delayed exposure have been reported. Whether these neurological disorders are transient or permanent is currently unknown. These disorders should be considered in any child exposed to nucleoside and nucleotide analogues in utero who presents with severe clinical disorders of unknown etiology, particularly neurological. These data do not affect current national guidelines for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Lactic acidosis

Cases of lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, have been reported with nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign gastrointestinal symptoms (nausea, vomiting, abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including muscle weakness).

Lactic acidosis has a high mortality rate and may be associated with pancreatitis, hepatic, or renal failure.

Lactic acidosis typically develops after several months of treatment.

If symptomatic hyperlactatemia, metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur, treatment with nucleoside analogues should be discontinued.

Nucleoside analogues should be used with caution in any patient (particularly obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medications and alcohol). Patients co-infected with hepatitis C and receiving alpha-interferon and ribavirin are at particular risk.

Patients at increased risk require close monitoring.

Body weight and metabolic parameters

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Contributing factors may also include disease control and lifestyle changes. Evidence supports a treatment effect on increased lipid levels in some cases, whereas increased body weight lacks such confirmation. Monitoring of serum lipid and blood glucose levels should follow established HIV treatment protocols. Treatment of lipid disorders should be based on clinical indications.

Pancreatitis

Cases of pancreatitis have been reported, but a causal relationship with abacavir therapy has not been established.

Triple nucleoside therapy

In patients with high viral load (over 100,000 copies/mL), the choice of triple combination therapy including abacavir, lamivudine, and zidovudine requires special consideration. High rates of early virological failure and resistance emergence have been reported with the combination of abacavir, tenofovir disoproxil fumarate, and lamivudine in once-daily regimens.

Liver disease

The safety and efficacy of abacavir in patients with significant liver disease have not been established. The drug is not recommended for patients with moderate to severe hepatic impairment (see section "Dosage and Administration").

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to current standard recommendations. If signs of worsening liver disease occur, interruption or discontinuation of therapy should be considered.

Patients co-infected with chronic hepatitis B or C

Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions. When used concomitantly with antiviral agents for hepatitis B or C, refer to the prescribing information for those agents.

Kidney disease

The drug should not be used in patients with end-stage renal disease.

Immune Reconstitution Syndrome

In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy may lead to an inflammatory response to asymptomatic or residual opportunistic infections, potentially resulting in severe clinical conditions or symptom exacerbation. These reactions typically occur within the first weeks or months of therapy. Examples include cytomegalovirus retinitis, generalized or focal mycobacterial infections, or Pneumocystis jirovecii pneumonia (commonly known as PCP). Any inflammatory conditions should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution, although their onset is more variable and may occur months after starting treatment.

Osteonecrosis

Although its etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, and high body mass index), cases of osteonecrosis have been reported in patients with advanced HIV disease and long-term use of combination antiretroviral therapy. Patients should be advised to seek medical consultation if they experience joint pain, joint stiffness, or difficulty moving.

Opportunistic infections

Opportunistic infections and other complications of HIV infection may occur in patients treated with Abacavir or other antiretroviral agents. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.

Transmission of infection

While effective viral suppression with antiretroviral therapy significantly reduces the risk of sexual HIV transmission, the risk cannot be completely excluded. Preventive measures to reduce infection transmission should be applied according to national guidelines.

Cardiovascular events

Although clinical and observational data on abacavir are conflicting, some studies suggest an increased risk of cardiovascular events (particularly myocardial infarction) in patients receiving abacavir. Therefore, when prescribing Abacavir, measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia). Additionally, alternative treatment options to abacavir-containing regimens should be considered in patients with high cardiovascular risk.

Excipients

Abacavir oral solution contains sorbitol. When used as recommended, each 15 mL of the product contains approximately 5 g of sorbitol. Patients with rare hereditary fructose intolerance should not use this medicine. Sorbitol may have a mild laxative effect. The caloric value of sorbitol is 2.6 kcal/g.

The product also contains methylparahydroxybenzoate and propylparahydroxybenzoate, which may cause allergic reactions (possibly delayed).

The product contains at least 81 mg of sodium per 30 mL (maximum daily dose). Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Decisions regarding the use of antiretroviral drugs for treating HIV infection in pregnant women and reducing the risk of vertical transmission to the newborn are generally based on data from animal studies and clinical experience in pregnant women.

Animal studies with abacavir indicate embryotoxicity in rats but not in rabbits. Abacavir has shown carcinogenic properties in animal models. The clinical relevance of these findings in humans is unknown. Transplacental passage of abacavir and/or its metabolites in humans has been demonstrated.

Data from over 800 cases of abacavir use during the first trimester and over 1,000 cases during the second and third trimesters in pregnant women indicate no increased risk of congenital malformations or fetal/neonatal effects. Based on these data, the risk of congenital malformations in humans is unlikely.

Mitochondrial dysfunction: nucleotide and nucleoside analogues cause mitochondrial damage in vitro and in vivo. Reports of mitochondrial dysfunction have occurred in HIV-negative newborns and infants whose mothers received nucleoside analogues during pregnancy or postnatally (see section "Special Precautions").

Lactation. Abacavir and its metabolites are excreted in rat milk. Abacavir is also excreted in human breast milk. There are no data on the safety of abacavir in infants under 3 months of age. Therefore, women should not breastfeed while receiving abacavir therapy. Additionally, HIV-infected women are advised to avoid breastfeeding under any circumstances to prevent transmission of HIV to their infants.

Fertility. Animal studies showed no evidence of impaired fertility with abacavir.

Ability to affect reaction speed while driving or operating machinery.

No specific studies have been conducted on the effect of abacavir on reaction speed while driving or operating machinery.

Method of Administration and Dosage

Treatment with this medicinal product should be initiated only by a physician experienced in managing HIV-infected patients.

Before initiating therapy with abacavir, screening for HLA-B*5701 allele carriage must be performed in every HIV-infected patient, regardless of race (see section "Special Warnings and Precautions for Use").

Abacavir must not be administered to patients who are carriers of the HLA-B*5701 allele.

The medicinal product may be taken regardless of food intake.

Abacavir is also available in tablet form.

Adults and children (with body weight ≥25 kg): The recommended daily dose of abacavir is 600 mg (30 mL), which can be administered either as 300 mg (15 mL) twice daily or 600 mg (30 mL) once daily.

Children (with body weight <25 kg).

Children aged 1 year and older: The recommended dose is 8 mg/kg twice daily or 16 mg/kg once daily, with a maximum daily dose of 600 mg (30 mL).

Children aged 3 months to less than 1 year: The recommended dose is 8 mg/kg twice daily. If twice-daily administration is not feasible, once-daily administration at a dose of 16 mg/kg/day may be considered. However, data on once-daily dosing in this age group are very limited.

Children under 3 months of age: Experience with abacavir use in children under 3 months of age is limited.

When switching from twice-daily to once-daily dosing, the first single dose (as specified above) should be taken approximately 12 hours after the last dose of the twice-daily regimen, followed by continued administration of the recommended once-daily dose every 24 hours. When switching from once-daily to twice-daily dosing, treatment with the recommended twice-daily dose of abacavir (as specified above) should be initiated approximately 24 hours after the last dose of the once-daily regimen.

Renal Impairment

Dosage adjustment is not required when administering abacavir to patients with renal impairment. However, abacavir is not recommended for patients with end-stage renal disease.

Hepatic Impairment

Abacavir is primarily metabolized in the liver. Dosage adjustment is not required in patients with mild hepatic impairment (Child-Pugh score 5–6). There are no clinical data available for patients with moderate or severe hepatic impairment; therefore, abacavir is not recommended in these patients, except when clearly needed. If abacavir is used in patients with mild hepatic impairment, careful monitoring for safety is required, including monitoring of plasma abacavir levels if possible.

Elderly Patients

Currently, there are no pharmacokinetic data available for abacavir in patients aged 65 years and older.

Children.

Safety data for abacavir use in children under 3 months of age are lacking. Abacavir is indicated for treatment of children aged 3 months and older.

Overdose.

In clinical studies, single doses of abacavir up to 1200 mg and daily doses up to 1800 mg have been administered. No additional adverse effects were observed beyond those listed with normal dosing. The effects of higher doses are unknown. In case of overdose, the patient should be closely monitored for signs of toxicity (see section "Adverse Reactions"), and standard supportive therapy should be administered as needed. It is unknown whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Adverse Reactions

For many adverse reactions, it remains unclear whether they are related to abacavir administration, to the broad range of other drugs used in the treatment of HIV infection, or to the underlying disease itself.

Many of the symptoms listed below (nausea, vomiting, diarrhoea, fever, malaise, rash) commonly occur as part of an abacavir hypersensitivity reaction. Therefore, patients presenting with any of these symptoms should be carefully evaluated for the presence of hypersensitivity reactions (see section "Special Warnings and Precautions for Use"). There have been isolated reports of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis when abacavir hypersensitivity could not be ruled out. In such cases, the use of any abacavir-containing product must be permanently discontinued.

Most of the adverse reactions listed below do not necessitate discontinuation of treatment. The frequency of adverse effects is classified according to the following scale: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000).

Metabolism and Nutrition Disorders

Common: anorexia, hyperlactataemia.

Very rare: lactic acidosis (see section "Special Warnings and Precautions for Use").

Nervous System Disorders

Common: headache.

Gastrointestinal Disorders

Common: nausea, vomiting, diarrhoea.

Rare: pancreatitis, although a causal relationship with abacavir has not been established.

Skin and Subcutaneous Tissue Disorders

Common: rash (without systemic symptoms).

Very rare: erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

General Disorders

Common: fever, malaise, fatigue.

Description of Selected Adverse Reactions

Hypersensitivity (see also section "Special Warnings and Precautions for Use")

Signs and symptoms of hypersensitivity reactions are listed below. Reports of these reactions were received from clinical trials and post-marketing experience.

Those occurring with a frequency greater than 10% are indicated in bold.

Although hypersensitivity reactions typically involve fever and/or rash (maculopapular or urticarial) in almost all patients, such reactions have also occurred in the absence of rash and fever. Other key symptoms include gastrointestinal, respiratory, or systemic symptoms such as malaise and fatigue.

Skin: rash (typically maculopapular or urticarial).

Gastrointestinal: nausea, vomiting, diarrhoea, abdominal pain, mouth ulcers.

Respiratory: dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure, radiological changes in the chest (mainly infiltrates, which may be localised).

Other manifestations: fever, malaise, fatigue, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis.

Nervous system: headache, paraesthesia.

Haematological reactions: lymphopenia.

Hepatic/pancreatic: elevated liver function test results above normal, hepatitis, hepatic failure.

Musculoskeletal: myalgia, isolated cases of rhabdomyolysis, arthralgia, elevated creatine phosphokinase.

Renal: elevated creatinine, renal failure.

Symptoms associated with hypersensitivity reactions may worsen with continued therapy, can be life-threatening, and occasionally result in death.

Resuming abacavir therapy after a hypersensitivity reaction leads to a rapid return of symptoms within hours. This recurrence is usually more severe than the initial reaction and may include life-threatening hypotension and fatal outcomes. Similar reactions have also been observed, albeit rarely, in patients who restarted abacavir after experiencing only one of the key symptoms of hypersensitivity (listed above) prior to discontinuation, and very rarely in patients who restarted therapy without prior symptoms of hypersensitivity (e.g., patients previously considered tolerant to abacavir).

Lactic Acidosis

Lactic acidosis, sometimes fatal, has been reported with nucleoside analogues, often in association with severe hepatomegaly and steatosis (see section "Special Warnings and Precautions for Use").

Metabolic Parameters

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy (see section "Special Warnings and Precautions for Use").

Immune Reconstitution Syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur. Immune reconstitution has also been associated with autoimmune disorders (such as Graves’ disease and autoimmune hepatitis), although the onset of these conditions is more variable and may occur many months after initiation of treatment (see section "Special Warnings and Precautions for Use").

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with well-known risk factors, advanced HIV disease, or long-term use of combination antiretroviral therapy. The frequency of such events is unknown (see section "Special Warnings and Precautions for Use").

Laboratory Test Changes

According to data from controlled clinical trials, laboratory abnormalities occurred infrequently, with no significant difference in frequency between the abacavir-treated group and the control group.

Paediatric Population

In a clinical trial involving HIV-infected children aged 3 to 17 years, some of whom received abacavir and lamivudine once or twice daily, no additional safety concerns were identified in paediatric patients receiving once- or twice-daily dosing compared to adults.

Shelf Life. 2 years. After first opening of the bottle – 28 days.

Storage Conditions.

Store in the original packaging at a temperature not exceeding 30°C, in a place inaccessible to children.

Packaging. 240 ml of solution in a bottle; 1 bottle with a syringe (10 ml) and adapter in a cardboard box.

Prescription Category. Prescription only.

Manufacturer. Hetero Labs Limited, India.

Manufacturer's Address and Place of Business.

Unit III, Formulation Plot No. 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.