Abalam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABALAM (ABALAM)

Composition:

Active substances: abacavir (as sulfate), lamivudine;

1 tablet contains 600 mg of abacavir (as abacavir sulfate) and 300 mg of lamivudine;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, Opadry orange YS-1-13065-A coating: hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol (E 1521), polysorbate (E 433), yellow azo dye FCF (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, orange-colored, modified capsule-shaped, biconvex, with the inscription "H" on one side and "A1" on the other.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of HIV infection, combinations. Lamivudine and abacavir.

ATC code J05AR02.

Pharmacological properties.

Pharmacodynamics.

Abacavir and lamivudine belong to the group of nucleoside reverse transcriptase inhibitors and are potent selective inhibitors of HIV-1 and HIV-2. Abacavir and lamivudine are sequentially metabolized by intracellular kinases into their respective triphosphates (TP), which act as active metabolites. Lamivudine-TP and carbovir-TP (the active triphosphate of abacavir) act as substrates and competitive inhibitors of HIV reverse transcriptase (RT). However, the main antiviral effect of these drugs is due to the incorporation of the monophosphate into the DNA chain, resulting in chain termination. The triphosphates of abacavir and lamivudine have significantly lower affinity for host cell DNA polymerases.

No antagonistic effect has been observed in vitro when lamivudine is used concomitantly with other antiretroviral agents (substances studied: didanosine, nevirapine, and zidovudine). In vitro studies have shown that the antiviral activity of abacavir is not antagonistic when used concomitantly with nucleoside reverse transcriptase inhibitors (NRTIs) such as didanosine, emtricitabine, stavudine, tenofovir, or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

A study involving 20 HIV-infected patients who received abacavir (300 mg twice daily and once 24 hours before sampling) showed that the mean geometric terminal intracellular half-life of carbovir-TP at steady state was 20.6 hours. The mean geometric plasma half-life of abacavir in this study was 2.6 hours. Similar intracellular pharmacokinetic profiles are expected with abacavir 600 mg once daily. In patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP increased from 16 to 19 hours, and the plasma half-life of lamivudine increased from 5 to 7 hours. These findings are supported by data from studies using 300 mg lamivudine and 600 mg abacavir once daily (the efficacy of this combination when administered once daily has also been confirmed in the pivotal clinical trial CNA30021). Resistance of HIV-1 to lamivudine is caused by a mutation at codon M184V located near the active site of viral RT. This phenomenon has been observed both in vitro and in HIV-1-infected patients receiving antiretroviral therapy containing lamivudine. The M184V mutation significantly reduces susceptibility to lamivudine and decreases viral replicative capacity in vitro. In vitro studies indicate that zidovudine-resistant viral isolates may become more susceptible to the drug when resistance to lamivudine develops. However, the clinical significance of these changes has not been fully established.

HIV-1 isolates resistant to abacavir have been selected in vitro. These isolates have specific genotypic changes in codons near RT (codons M184V, K65R, L74V, and Y115F). Resistance to abacavir develops relatively slowly both in vitro and in vivo: multiple mutations are required to achieve an eightfold increase in the half-maximal inhibitory concentration (IC50) compared to wild-type virus, which may have clinical significance. Abacavir-resistant isolates may also exhibit reduced susceptibility to lamivudine, zalcitabine, tenofovir, emtricitabine, and/or didanosine, but remain sensitive to zidovudine and stavudine.

Cross-resistance between abacavir and lamivudine and antiretroviral drugs of other classes (e.g., protease inhibitors [PIs] and nucleoside reverse transcriptase inhibitors [NRTIs]) is unlikely. Decreased susceptibility to abacavir has been observed in clinical isolates from patients with uncontrolled viral replication who previously received other nucleoside inhibitors and developed resistance to drugs in this class.

Clinical isolates with three or more nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations are unlikely to remain susceptible to abacavir. Cross-resistance due to the M184V RT mutation is limited to nucleoside inhibitors. Zidovudine, stavudine, abacavir, and tenofovir retain their antiretroviral activity against lamivudine-resistant HIV-1 carrying only the M184V mutation.

Pharmacokinetics.

It has been demonstrated that abacavir/lamivudine tablets, as a fixed-dose combination, are bioequivalent to abacavir and lamivudine administered as individual agents. This has been confirmed by data from a comparative bioequivalence study in which healthy volunteers (n = 30) received a single dose of abacavir/lamivudine tablets (fasting), or two 300 mg abacavir tablets and two 150 mg lamivudine tablets (fasting), or abacavir/lamivudine tablets after a high-fat meal. When administered fasting, there was no significant difference in extent of absorption (area under the plasma concentration-time curve [AUC]) or maximum peak concentration (Cmax) for each component. No clinically significant food effect was observed with abacavir/lamivudine tablets, indicating that the drug can be taken regardless of food intake.

Absorption: abacavir and lamivudine are rapidly and well absorbed from the gastrointestinal tract. Absolute bioavailability after oral administration in adults is 83% for abacavir and 80–85% for lamivudine. The median time to reach maximum serum concentration (tmax) is 1.5 hours for abacavir and 1 hour for lamivudine. After a single oral dose of 600 mg abacavir, the mean Cmax is 4.26 µg/mL, and the mean AUC∞ is 11.95 µg·h/mL. After repeated oral administration of 300 mg lamivudine once daily for 7 days, the mean steady-state Cmax is 2.04 µg/mL, and the mean AUC24 is 8.87 µg·h/mL.

Distribution: studies have shown that the mean volume of distribution after intravenous administration is 0.8 L/kg for abacavir and 1.3 L/kg for lamivudine. In vitro studies on plasma protein binding indicate that abacavir binds poorly to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics at therapeutic doses and binds poorly to plasma proteins (<36%). This suggests a low likelihood of drug interactions due to displacement from plasma protein binding.

Available data indicate that abacavir and lamivudine penetrate the central nervous system (CNS) and enter cerebrospinal fluid (CSF). Studies have shown that the AUC ratio of CSF to plasma ranges from 30 to 44%. Peak concentrations in CSF exceed the IC50 of abacavir (0.08 µg/mL or 0.26 µmol) by ninefold when the drug is administered at a dose of 600 mg twice daily. The mean ratio of lamivudine concentration in CSF to serum concentration 2 and 4 hours after oral administration is approximately 12%. The actual extent of lamivudine penetration into the CNS and its correlation with any clinical effect are unknown.

Metabolism: abacavir is primarily metabolized in the liver; less than 2% of the administered dose is excreted unchanged in urine. The main metabolic pathways in humans involve alcohol dehydrogenase or glucuronidation, forming the 5’-carboxylic acid and 5’-glucuronide metabolites, into which approximately 66% of the administered dose is converted. These metabolites are excreted in urine.

Metabolism is a minor elimination pathway for lamivudine. Lamivudine is primarily excreted unchanged by the kidneys. The potential for metabolic interactions with lamivudine is low, as only a small portion (5–10%) of the administered dose is metabolized in the liver.

Elimination: the mean elimination half-life of abacavir is approximately 1.5 hours. No significant accumulation occurs after repeated oral administration of abacavir 300 mg twice daily. Abacavir is eliminated via hepatic metabolism, with subsequent excretion of metabolites primarily in urine. Approximately 83% of the administered dose of abacavir is recovered in urine as unchanged drug and metabolites. The remainder is excreted in feces.

The elimination half-life of lamivudine ranges from 5 to 7 hours. The mean total clearance of lamivudine is approximately 0.32 L/h/kg, with the majority being renal clearance (>70%), mediated by the organic cation transport system.

Carcinogenesis: data from carcinogenicity studies in mice and rats showed an increased incidence of malignant and benign tumors following oral administration of abacavir. Malignant tumors occurred in the preputial glands of males and clitoral glands of females, as well as in the liver, 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 exposures 24–32 times higher than in humans. The exception is tumor development in the preputial glands, which occurred at a dose of 110 mg/kg, approximately 6 times the systemic exposure in humans. Humans do not have a structural equivalent of these glands. Although the carcinogenic potential of the drug in humans is unknown, these data suggest that the potential clinical benefit of the drug outweighs the carcinogenic risk in humans.

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

Special patient groups

Patients with hepatic impairment. Pharmacokinetic data were obtained separately for abacavir and lamivudine. Abacavir is primarily metabolized in the liver. The pharmacokinetics of abacavir were studied in patients with mild hepatic impairment (Child–Pugh score 5–6). Results showed that abacavir AUC increased on average by 1.89-fold and the elimination half-life by 1.58-fold. Due to the high variability in abacavir exposure, dose adjustment recommendations cannot be provided for patients in this group.

Data on lamivudine use in patients with moderate to severe hepatic impairment indicate that liver dysfunction does not significantly affect lamivudine pharmacokinetics.

Patients with renal impairment. Pharmacokinetic data were obtained separately for abacavir and lamivudine. Abacavir is primarily metabolized by the liver, with approximately 2% excreted unchanged in urine. The pharmacokinetics of abacavir in patients with end-stage renal disease are similar to those in patients with normal renal function. Lamivudine studies showed increased plasma concentrations (AUC) in patients with impaired renal function due to reduced clearance. Dose reduction is recommended for patients with creatinine clearance less than 50 mL/min; therefore, a separate lamivudine pharmaceutical formulation should be used for treating this patient group.

Clinical characteristics.

Indications.

Abalam should be prescribed as part of combination antiretroviral therapy for the treatment of HIV infection in adults and children with body weight of at least 25 kg.

Before initiating treatment with abacavir, screening for HLA-B*5701 allele carriage must be performed in every HIV-infected patient, regardless of their race. Abacavir must not be used in patients who are carriers of the HLA-B*5701 allele.

Contraindications.

Abalam is contraindicated in patients with hypersensitivity to abacavir, lamivudine, or any other component of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

The interaction profile of Abalam is determined by the interaction profiles of abacavir and lamivudine contained in the formulation. Clinical studies have shown no clinically significant interaction between abacavir and lamivudine.

Abacavir is metabolized by uridine diphosphate-glucuronosyltransferase enzymes and alcohol dehydrogenase; concomitant administration of inducers or inhibitors of glucuronosyltransferase enzymes with compounds eliminated via alcohol dehydrogenase may alter abacavir exposure. Lamivudine is eliminated via the kidneys. Active renal secretion of lamivudine into urine occurs via organic cation transporters (OCT); co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.

Abacavir and lamivudine are minimally metabolized by cytochrome P450 enzyme system (e.g., CYP3A4, CYP2C9, or CYP2D6) and do not exhibit inhibitory or inductive effects on the enzyme system. Therefore, the likelihood of drug interactions between Abalam and non-nucleoside antiretroviral protease inhibitors or other medicinal products metabolized by major cytochrome P450 enzymes is low.

Abalam should not be taken together with other medicinal products containing lamivudine (see section "Special warnings and precautions for use").

The list of interactions in Table 1 below should not be considered exhaustive, but is representative of the classes studied.

Table 1

Drug Groups	Interaction, geometric mean change (%) (possible mechanism)	Recommendations for concomitant use
Antiretroviral drugs
Didanosine/abacavir	Interaction not studied	No dose adjustment required
Didanosine/lamivudine	Interaction not studied
Zidovudine/abacavir	Interaction not studied
Zidovudine/lamivudine 300 mg zidovudine single dose 150 mg lamivudine single dose	Lamivudine: AUC ↔ Zidovudine: AUC ↔
Emtricitabine/lamivudine Zalcitabine/lamivudine		Due to similarities, Abalam should not be used concomitantly with other cytidine analogues such as emtricitabine and zalcitabine
Anti-infective agents
Trimethoprim/sulfamethoxazole (co-trimoxazole)/abacavir	Interaction not studied	No dose adjustment of Abalam required. When concomitant use with co-trimoxazole is justified, clinical monitoring of patients is necessary. Concomitant use with high-dose trimethoprim/sulfamethoxazole for treatment of Pneumocystis jirovecii pneumonia and toxoplasmosis has not been studied – it should be avoided.
Trimethoprim/sulfamethoxazole (co-trimoxazole)/lamivudine (160 mg/800 mg once daily for 5 days / 300 mg single dose)	Lamivudine: AUC ↑ 40% Trimethoprim: AUC ↔ Sulfamethoxazole: AUC ↔ (OCT inhibition)
Antimycobacterial agents
Rifampicin/abacavir	Interaction not studied. Possible slight decrease in abacavir plasma concentration due to induction of uridine diphosphate glucuronosyltransferase.	Insufficient data to recommend dose adjustment
Rifampicin/lamivudine	Interaction not studied
Anticonvulsants
Phenobarbital/abacavir	Interaction not studied. Possible slight decrease in abacavir plasma concentration due to induction of uridine diphosphate glucuronosyltransferase.	Insufficient data to recommend dose adjustment
Phenobarbital/lamivudine	Interaction not studied
Phenytoin/abacavir	Interaction not studied. Possible slight decrease in abacavir plasma concentration due to induction of uridine diphosphate glucuronosyltransferase.	Insufficient data to recommend dose adjustment. Monitor phenytoin concentrations.
Phenytoin/lamivudine	Interaction not studied
Antihistamines (H2-histamine receptor antagonists)
Ranitidine/abacavir	Interaction not studied.	No dose adjustment required
Ranitidine/lamivudine	Interaction not studied. Clinically significant interaction unlikely. Only a portion of ranitidine is eliminated via renal OCT.
Cimetidine/abacavir	Interaction not studied.	No dose adjustment required
Cimetidine/lamivudine	Interaction not studied. Clinically significant interaction unlikely. Only a portion of cimetidine is eliminated via renal OCT.
Cytotoxic agents
Cladribine/lamivudine	Interaction not studied. Lamivudine in vitro promotes inhibition of intracellular phosphorylation of cladribine, creating a risk of loss of efficacy of cladribine with concomitant clinical use. Some clinical reports also confirm a possible interaction between lamivudine and cladribine.	Concomitant use of lamivudine with cladribine is not recommended
Opioid agents
Methadone/abacavir (40 to 90 mg once daily for 14 days / 600 mg single dose, then 600 mg twice daily for 14 days)	Abacavir: AUC ↔ Cmax ↓35% Methadone: CL/F ↑22%	No dose adjustment of Abalam required. Dose adjustment of methadone is not usually needed in most patients; re-titration of methadone dose may occasionally be required.
Methadone/lamivudine	Interaction not studied
Retinoids
Retinoid compounds (e.g., isotretinoin)/abacavir	Interaction not studied. Possible interaction via shared elimination pathway by alcohol dehydrogenase.	Insufficient data to recommend dose adjustment
Retinoid compounds (e.g., isotretinoin)/lamivudine	Interaction not studied
Antiviral drugs
Ribavirin/abacavir	Interaction not studied. Theoretically possible reduction in intracellular phosphorylated metabolites.	Caution is advised when using both drugs concomitantly (see section "Special precautions").
OTHER drugs
Ethanol/abacavir (0.7 g/kg single dose / 600 mg single dose)	Abacavir: AUC ↑41% Ethanol: AUC ↔ (inhibition of alcohol dehydrogenase)	No dose adjustment required
Ethanol/lamivudine	Interaction not studied
Sorbitol solution (3.2 g, 10.2 g, 13.4 g)/lamivudine	Lamivudine oral solution 300 mg single dose Lamivudine: AUC ↓ 14%; 32%; 36% Cmax ↓ 28%; 52%; 55%.	Whenever possible, avoid continuous concomitant use of Abalam with medicinal products containing sorbitol or other osmotic polyols or monosaccharide alcohols (e.g., xylitol, mannitol, lactitol, maltitol). More frequent monitoring of HIV-1 viral load is required if continuous concomitant use cannot be avoided.
Riociguat/abacavir	Riociguat ↑ In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving abacavir/dolutegravir/lamivudine (600 mg/50 mg/300 mg once daily) resulted in approximately three-fold higher AUC (0-∞) of riociguat compared to the historical AUC (0-∞) of riociguat recorded in healthy volunteers.	Dose reduction of riociguat may be necessary. For dosing recommendations, refer to riociguat prescribing information.

Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no significant changes; AUC = area under the concentration–time curve; C_max = maximum observed concentration; CL/F = oral clearance.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

This section contains special precautions applicable to both abacavir and lamivudine. There are no additional warnings specific to the use of Ablam.

Patients should be aware that treatment with modern antiretroviral drugs does not reduce the risk of HIV transmission via sexual contact or exposure to infected blood; therefore, they must use appropriate preventive measures.

Hypersensitivity (see also section "Adverse reactions")

Abacavir is associated with a 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 during abacavir treatment. Some of these reactions may be life-threatening and, rarely, if not appropriately managed, may be fatal.

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

Therefore, the following recommendations should be followed:

• Before initiating treatment, the HLA-B*5701 allele status must be documented for every HIV patient.
• Ablam must never be prescribed to patients who are HLA-B*5701 positive, or to patients who are HLA-B*5701 negative but who previously experienced suspected HSR to abacavir when treated with other abacavir-containing medicinal products.
• Ablam must be discontinued immediately, even in patients lacking the HLA-B*5701 allele, if HSR is suspected. Continuing treatment with Ablam after onset of HSR may lead to life-threatening conditions.
• After discontinuation of Ablam due to suspected HSR, treatment with Ablam or any other abacavir-containing medicinal product must never be resumed.
• Resuming abacavir treatment after HSR results in rapid recurrence of symptoms within hours. These symptoms are typically more severe than the initial reaction and may include life-threatening hypotension and death.
• To prevent re-exposure to Ablam, patients with suspected HSR should return any remaining tablets.
• Patients must be informed of the necessity to remove and read the package leaflet and the special "Warning card," and to carry the latter at all times.

WARNING CARD

(must carry this card at all times)

ABALAM

(abacavir sulfate/lamivudine)

film-coated tablets

Since Ablam contains abacavir, patients treated with Ablam may experience hypersensitivity reactions (serious allergic reactions), which may be life-threatening if treatment with Ablam 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;
   • dyspnea, sore throat, or cough;
   • nausea, vomiting, diarrhea, or abdominal pain;
   • sudden weakness, fatigue, or malaise.

If you have stopped treatment with Ablam due to a hypersensitivity reaction, YOU MUST NEVER AGAIN USE Ablam tablets or any other medicine containing abacavir, as this may result in a life-threatening drop in blood pressure or death within hours.

Clinical manifestations of abacavir HSR

Abacavir HSR has been well characterized in clinical trials and post-marketing experience. Symptoms typically appear within the first 6 weeks of starting abacavir treatment (on average, after 11 days), although these reactions may occur at any time during treatment.

Almost all HSRs include fever and/or rash. Other symptoms observed as part of abacavir HSR are described in detail in the "Adverse reactions" section and include respiratory and gastrointestinal symptoms. It is important to note that such symptoms may lead to misdiagnosis as lung diseases (pneumonia, bronchitis, pharyngitis) or gastroenteritis rather than HSR.

Symptoms associated with hypersensitivity reactions worsen with continued therapy and may become life-threatening. These symptoms usually resolve after discontinuation of abacavir.

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

Body weight and metabolic parameters

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to disease control and lifestyle. Regarding lipids, there is evidence in some cases of a treatment effect, whereas for weight gain, there is no strong evidence linking it to any specific therapy. Monitoring of blood lipids and glucose should follow established HIV treatment guidelines. Lipid abnormalities should be managed according to clinical circumstances.

Pancreatitis

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

Risk of virological treatment failure

Triple nucleoside therapy: Reports have indicated a high rate of early virological treatment failure and emergence of resistance when abacavir and lamivudine are combined with tenofovir disoproxil fumarate in a once-daily regimen.

The risk of virological treatment failure with Ablam may be higher than with other therapeutic regimens.

Liver disease

The efficacy and safety of Ablam in patients with significant liver dysfunction have not been established. Ablam is not recommended for patients with moderate or severe hepatic impairment (see section "Dosage and administration").

In patients with pre-existing liver dysfunction, including chronic active hepatitis, increased frequency of liver function abnormalities has been observed during combination antiretroviral therapy. These patients should be monitored according to standard practice. The physician should consider discontinuing or stopping treatment if there is evidence of worsening liver disease.

Patients co-infected with hepatitis B or C virus

There is an increased risk of serious and potentially fatal hepatic adverse reactions in patients with chronic hepatitis B or C on combination antiretroviral therapy. If concomitant antiviral therapy for hepatitis B or C is administered, the physician should also refer to the relevant product information for those medicinal products.

If lamivudine is used concomitantly for treatment of both HIV and hepatitis B infection, additional information regarding lamivudine use in hepatitis B infection should be consulted (refer to the product information for lamivudine-containing medicinal products indicated for hepatitis B treatment).

If Ablam is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver function and hepatitis B virus replication markers is necessary, as clinical and laboratory signs of hepatitis flare may occur after stopping lamivudine treatment in these patients (refer to the product information for lamivudine-containing medicinal products indicated for hepatitis B treatment).

Mitochondrial function disorders

Nucleoside and nucleotide analogues may affect mitochondrial function to varying degrees, most notably 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 associated with regimens containing zidovudine. Major reported adverse effects include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These effects are often transient. Rarely, delayed neurological disorders (hypertension, seizures, behavioral disturbances) have been reported. It is currently unknown whether such neurological disorders are transient or permanent. Any infant exposed to nucleoside or nucleotide analogues in utero, even if HIV-negative, requires ongoing clinical and laboratory monitoring for possible mitochondrial dysfunction if symptoms arise. These data do not affect current national recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Immune reconstitution syndrome

In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy may result in an inflammatory response to asymptomatic or residual opportunistic infections, leading to 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, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms 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 these may manifest several months after starting treatment.

Osteonecrosis

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

Opportunistic infections

Despite treatment with Ablam or any other antiretroviral therapy, HIV infection is not eradicated, and patients may still develop opportunistic infections and other HIV-related complications. Therefore, such patients should remain under continuous clinical supervision by experienced physicians.

Cardiovascular events

Although clinical and observational studies on abacavir have yielded conflicting results, some studies suggest an increased risk of cardiovascular events (particularly myocardial infarction) in patients receiving abacavir. Therefore, when prescribing Ablam, measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia). Additionally, in patients with high cardiovascular risk, alternative treatment regimens not containing abacavir should be considered.

Drug interactions

Ablam must not be taken concomitantly with other medicinal products containing lamivudine or emtricitabine.

Concomitant use of lamivudine with cladribine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Excipients.

Ablam contains the azo dye Yellow West FCF, which may cause allergic reactions.

The product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. When deciding on the use of antiretroviral agents for treating HIV infection in pregnant women and for reducing the risk of vertical transmission of HIV to the newborn, data from animal studies and clinical experience in pregnant women should be considered.

Data from animal studies on lamivudine and abacavir in pregnant animals are available. Abacavir animal studies indicate embryotoxicity in rats but not in rabbits. Lamivudine studies showed increased early embryonic mortality in rabbits but not in rats. The active components of Ablam may inhibit cellular DNA replication, and abacavir has been shown to have carcinogenic properties in animal models. The clinical significance of these findings is unknown. Transplacental passage of abacavir and lamivudine in humans has been demonstrated. Use of the drug during pregnancy is justified only if the expected benefit to the mother outweighs the potential risk to the fetus. Although animal studies are not fully predictive for humans, data from animal experiments suggest a possible risk of early embryonic death.

Data from pregnant women receiving abacavir during the first trimester (over 800 cases) and during the second and third trimesters (over 1000 cases) indicate no congenital malformations or fetotoxic/neonatal effects. Data from pregnant women receiving lamivudine during the first trimester (over 1000 cases) and during the second and third trimesters (over 1000 cases) also indicate no congenital malformations or fetotoxic/neonatal effects. There are no data on the use of Ablam during pregnancy, but based on the above, the risk of congenital malformations in humans is unlikely.

Special attention should be given to patients co-infected with hepatitis who were treated with lamivudine-containing products such as Ablam and subsequently become pregnant, as hepatitis symptoms may recur after discontinuation of lamivudine treatment.

Mitochondrial dysfunction

Nucleotide and nucleoside analogues cause varying degrees of mitochondrial damage in vitro and in vivo. Reports of mitochondrial dysfunction have occurred in HIV-negative newborns and infants exposed to nucleoside analogues during pregnancy or delivery (see section "Special precautions for use").

Breastfeeding. Abacavir and its metabolites are excreted in rat milk. Abacavir is also excreted in human breast milk. Data from studies of over 200 mother-infant pairs show that abacavir concentrations in infant plasma from mothers treated for HIV infection are very low (< 4% of maternal plasma concentrations) and progressively decrease to undetectable levels by 24 weeks of age. There are no data on the safety of abacavir and lamivudine in children under 3 months of age. Therefore, mothers should not breastfeed while receiving abacavir and lamivudine. HIV-infected women are advised to avoid breastfeeding their infants under any circumstances to prevent transmission of HIV infection.

Fertility. Animal studies did not reveal any effects of abacavir or lamivudine on fertility.

Ability to drive and use machines.

No specific studies have been conducted on the effects of lamivudine or abacavir on the ability to drive or operate machinery. When assessing a patient's ability to drive or operate machinery, their clinical condition and the adverse effect profile of Ablam should be considered.

Method of Administration and Dosage

Treatment with Abalam should be prescribed by a specialist experienced in the management of HIV infection.

Due to the inability to adjust the dose when using fixed-dose combination tablets, Abalam should not be prescribed to adults and adolescents weighing less than 25 kg.

Abalam may be taken regardless of food intake.

Fixed-dose combination products should not be used when there may be a need to discontinue or adjust the dose of one of the active components. If treatment with Abalam must be discontinued or dose adjustment is required, abacavir or lamivudine should be administered as individual monotherapy agents. In such cases, the physician should consult the prescribing information for these medicinal products.

Adults and children (with body weight ≥25 kg)

The recommended dose of Abalam for adults and adolescents is 1 tablet once daily.

Elderly patients

The pharmacokinetics of abacavir and lamivudine in patients aged 65 years and older have not been studied. Increased caution is advised in these patients due to age-related changes such as reduced renal function, hematological parameters, hepatic or renal impairment, cardiac conditions, other comorbidities, and concomitant medication use.

Patients with renal impairment

While abacavir dosage adjustment is not required in patients with renal impairment, lamivudine dosage should be reduced due to decreased creatinine clearance. Therefore, Abalam is not recommended for patients with creatinine clearance below 50 mL/min.

Patients with hepatic impairment

Abacavir is primarily metabolized in the liver. There are no clinical data available in patients with moderate or severe hepatic impairment; therefore, Abalam is not recommended except in cases of critical necessity. Close monitoring is required in patients with mild hepatic impairment (Child-Pugh class 5–6), including monitoring of plasma abacavir levels if possible (see section "Special Warnings and Precautions for Use").

Children

Abalam is not recommended for the treatment of children weighing less than 25 kg due to the inability to adjust the dose. Physicians should refer to the prescribing information for lamivudine and abacavir when selecting appropriate therapy.

Overdose

Symptoms. No specific symptoms characteristic of abacavir or lamivudine overdose have been identified, other than those listed in the section "Adverse Reactions".

Management. In case of overdose, the patient should be closely observed for signs of drug toxicity, and supportive therapy should be administered as needed. Because lamivudine is dialyzable, hemodialysis may be used to manage overdose, although this approach has not been well studied. It is unknown whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Adverse reactions reported with the use of abacavir/lamivudine tablets as a fixed-dose combination are consistent with the known safety profiles of abacavir and lamivudine when administered as individual medicinal products. In many cases, it is unclear whether these adverse reactions are related to the active substances abacavir/lamivudine, to the concomitant use of other medicinal products used in the treatment of HIV infection, or are symptoms of the underlying disease.

Many of the adverse reactions listed in Table 2 (nausea, vomiting, diarrhoea, fever, malaise, rash) commonly occur in patients with hypersensitivity to abacavir. Therefore, patients presenting with any of these symptoms should be carefully evaluated for the presence of such hypersensitivity (see section "Special warnings and precautions for use"). Very rare cases of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been reported when abacavir hypersensitivity could not be excluded. In such cases, the use of medicinal products containing abacavir must be permanently discontinued.

Adverse reactions associated with abacavir or lamivudine are listed in Table 2 by system organ class and frequency. Frequency is defined as: very common ≥ 1/10; common ≥ 1/100, < 1/10; uncommon ≥ 1/1000, < 1/100; rare ≥ 1/10,000, < 1/1000; very rare < 1/10,000.

Table 2

Body system	Abacavir	Lamivudine
Blood and lymphatic system disorders		Uncommon: neutropenia (sometimes severe), anemia (sometimes severe), thrombocytopenia. Very rare: pure red cell aplasia.
Immune system disorders	Common: hypersensitivity.
Metabolism and nutrition disorders	Common: anorexia. Very rare: lactic acidosis.	Very rare: lactic acidosis.
Nervous system disorders	Common: headache.	Common: headache, insomnia. Very rare: peripheral neuropathy (or paresthesia).
Respiratory, thoracic and mediastinal disorders		Common: cough, nasal symptoms.
Gastrointestinal disorders	Common: nausea, vomiting, diarrhea. Rare: pancreatitis, although a causal relationship with abacavir has not been established.	Common: nausea, vomiting, abdominal pain or cramps, diarrhea. Rare: increased serum amylase levels, pancreatitis.
Hepatobiliary disorders		Uncommon: transient elevations in liver enzymes (AST, ALT). Rare: hepatitis.
Skin and subcutaneous tissue disorders	Common: rash (without systemic symptoms). Very rare: erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.	Common: rash, alopecia. Rare: angioedema.
Musculoskeletal and connective tissue disorders		Common: arthralgia, muscle disorders. Rare: rhabdomyolysis.
General disorders and administration site conditions	Common: malaise, lethargy, feeling of weakness.	Common: increased fatigue, malaise, malaise.

Use in children.

In a study of 669 HIV-infected children aged 12 months to 17 years, abacavir and lamivudine were administered once or twice daily. Among them, 104 HIV-1-infected children with body weight of at least 25 kg received abacavir and lamivudine as a fixed-dose combination once daily. No additional safety requirements have been identified for administration of the medicinal product once or twice daily in children compared to the same dosing regimen in adults.

Description of individual adverse reactions.

Hypersensitivity (see also section "Special precautions")

Symptoms of hypersensitivity reactions are listed below. These reactions were observed during clinical trials or post-marketing use.

Reactions occurring at a frequency greater than 10% are indicated in bold.

Although hypersensitivity reactions usually involve fever and/or rash (maculopapular or urticarial) as part of the syndrome in nearly all patients, such reactions have also occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory, or systemic symptoms such as lethargy and malaise.

Skin: rash (typically maculopapular or urticarial).

Gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, oral ulcers.

Respiratory system: dyspnea, cough, sore throat, adult respiratory distress syndrome, respiratory failure.

Other manifestations: fever, lethargy, malaise, swelling, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis.

Nervous system: headache, paraesthesia.

Haematological reactions: lymphopenia.

Hepatobiliary system: elevated liver function tests, hepatitis, hepatic failure.

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

Urinary system: elevated creatinine, renal failure.

Symptoms associated with HSR may intensify if treatment is continued and can be life-threatening.

Resuming abacavir treatment after a hypersensitivity reaction leads to rapid return of symptoms within hours. These symptoms are typically more severe than the initial reaction and may include life-threatening hypotension and death. Similar reactions have also been observed, although rarely, in patients who restarted abacavir after experiencing only one of the main symptoms of hypersensitivity (see above) prior to discontinuation, and very rarely in patients who restarted treatment without prior HSR symptoms (e.g., in patients previously considered tolerant to abacavir).

Metabolic disturbances

During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur (see section "Special precautions").

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have been reported during immune reconstitution; these may occur many months after initiation of therapy (see section "Special precautions").

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with recognized risk factors, advanced stages of HIV disease, or long-term use of combination antiretroviral therapy. The frequency of this phenomenon is unknown (see section "Special precautions").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 30 tablets in a container; 1 container with a "Warning card" in a cardboard box.

Prescription category. Prescription only.

Manufacturer. HETERO LABS LIMITED.

Manufacturer's address and location of operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.