Abacavir and lamivudine: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABACAVIR AND LAMIVUDINE

Composition:

Active substances: abacavir (in the form of abacavir sulfate), lamivudine;

One tablet contains abacavir (in the form of abacavir sulfate) 600 mg, lamivudine 300 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Orange YS-1-13065-A (hypromellose, titanium dioxide (E 171), macrogol, polysorbate 80, Yellow FCF (E 110)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: orange, capsule-shaped, film-coated tablets, with RF 90 debossed on one side and smooth on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antivirals. Antivirals 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 corresponding triphosphates (TP), which serve as active metabolites. Lamivudine-TP and carbovir-TP (the active triphosphate of abacavir) are substrates and competitive inhibitors of HIV reverse transcriptase (RT). Their primary antiviral activity results from incorporation of the monophosphate into the DNA chain, leading to chain termination. The triphosphates of abacavir and lamivudine exhibit minimal affinity for host cell DNA polymerases.

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

In-vivo Resistance

HIV-1 isolates resistant to abacavir have been selected in vitro. These isolates possess specific genotypic changes near the RT gene (codons M184V, K65R, L74V, and Y115F). During selection, the M184V mutation appeared first and led to approximately a 2-fold increase in IC50. Continued passage with increasing drug concentrations resulted in selection of double RT mutations 65R/184V and 74V/184V, or triple RT mutations 74V/115Y/184V. In the presence of two mutations, sensitivity to abacavir changed 7–8-fold, and with a combination of three mutations, sensitivity decreased 8-fold.

Resistance to abacavir in vitro and in vivo develops relatively slowly, requiring the emergence of multiple mutations to achieve an eightfold increase in half-maximal inhibitory concentration (IC50) compared to wild-type virus, which may have clinical significance.

HIV-1 resistance to lamivudine is caused by a mutation at codon M184V, located near the active site of the viral reverse transcriptase. This variant 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 vivo Resistance (therapy in treatment-naïve patients).

Mutations at codon M184V or M184I emerge in HIV-1-infected patients receiving antiretroviral therapy containing lamivudine.

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

Table 1

Treatment	Abacavir + fixed-dose combination of lamivudine and zidovudine	Abacavir + lamivudine + NNRTI	Abacavir + lamivudine + PI (or PI/ritonavir)	Total
Number of subjects	282	1094	909	2285
Number of virological treatment failures	43	90	158	291
Number of genotypes at treatment	40 (100%)	51 (100%)¹	141 (100%)	232 (100%)
K65R	0	1 (2%)	2 (1%)	3 (1%)
L74V	0	9 (18%)	3 (2%)	12 (5%)
Y115F	0	2 (4%)	0	2 (1%)
M184V/I	34 (85%)	22 (43%)	70 (50%)	126 (54%)
TAMs²	3 (8%)	2 (4%)	4 (3%)	9 (4%)

Notes:

Includes three non-virological failures and four unconfirmed virological failures.
Number of subjects with ≥1 thymidine analogue mutations (TAMs).

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

In vivo resistance (treatment-experienced patients).

Clinically significant reduction in susceptibility to abacavir has been demonstrated in clinical isolates from patients with uncontrolled viral replication who had previously received treatment and were resistant to other nucleoside inhibitors. In a meta-analysis of 5 clinical trials in which abacavir was added to enhance 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; L74V and 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 nucleoside reverse transcriptase inhibitor (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 to the above, the Q151M mutation complex, typically occurring in combination with A62V, V75I, F77L, and F116Y, leads to high-level resistance to abacavir.

Table 2

Baseline reverse transcriptase mutation level	Week 4
	Median change in vRNA (log10 copies/mL)	Percentage <400 copies/mL vRNA
No mutations	-0.96	40%
M184V alone	-0.74	64%
One NRTI-associated mutation	-0.72	65%
Any two NRTI-associated mutations	-0.82	32%
Any three NRTI-associated mutations	-0.30	5%
Four or more NRTI-associated mutations	-0.07	11%

Phenotypic resistance and cross-resistance.

Phenotypic resistance to abacavir requires the M184V mutation together with at least one other abacavir-selected mutation, or M184V 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; similarly, M184V together 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 is possible considering the existing resistance profile.

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

Pharmacokinetics.

No clinically significant difference has been observed between administering abacavir and lamivudine on an empty stomach or with food, indicating that the drug can be taken independently of meals.

Absorption: Abacavir and lamivudine are rapidly and well absorbed from the gastrointestinal tract. The absolute bioavailability of abacavir and lamivudine following oral administration in adults is 83% and 80–85%, respectively. The median time to reach maximum serum concentration (t_max) is 1.5 hours and 1 hour for abacavir and lamivudine, respectively. After a single oral dose of 600 mg abacavir, the mean C_max is 4.26 µg/mL, and the mean AUC_∞ is 11.95 µg·h/mL. Following 7 days of oral administration of 300 mg lamivudine once daily, the mean steady-state C_max 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 and 1.3 L/kg for abacavir and lamivudine, respectively. In vitro studies on plasma protein binding indicate that at therapeutic concentrations, abacavir binds poorly or moderately (~49%) to human plasma proteins. Lamivudine shows linear pharmacokinetics within the therapeutic dose range and binds poorly to plasma proteins (less than 36%). This suggests a low likelihood of drug interactions via displacement from plasma protein binding.

Available data indicate that both abacavir and lamivudine penetrate the central nervous system (CNS) and enter cerebrospinal fluid (CSF). Studies have shown that the ratio of AUC in CSF to plasma ranges from 30 to 44%. Peak concentrations exceed the IC₅₀ of abacavir (0.08 µg/mL or 0.26 µmol) by 9-fold when administered at a dose of 600 mg twice daily. The mean ratio of lamivudine concentration in CSF to serum at 2 and 4 hours after oral administration is approximately 12%. The extent of CNS penetration of lamivudine and its correlation with any clinical effect is unknown.

Metabolism: Abacavir is primarily metabolized in the liver; less than 2% of the administered dose is excreted unchanged in urine. In humans, metabolism mainly occurs via alcohol dehydrogenase or glucuronidation pathways, 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 likelihood of metabolic interactions with lamivudine is low, as only a small portion (5–10%) of the administered dose is metabolized in the liver.

Elimination: The elimination half-life of abacavir is approximately 1.5 hours. No significant accumulation occurs after multiple oral doses of 300 mg abacavir 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 (over 70%), mediated by the organic cation transport system.

Carcinogenesis:

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but like other nucleoside analogs, both inhibit cellular DNA replication in in vitro mammalian assays such as the mouse lymphoma assay. In vivo micronucleus tests in rats with the combination of abacavir and lamivudine were negative.

Lamivudine showed no genotoxic activity in vivo at doses where plasma concentrations exceeded therapeutic levels by 40–50 times. Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.

The carcinogenic potential of the combination of abacavir and lamivudine has not been studied. Carcinogenicity studies in mice and rats with oral lamivudine showed no carcinogenic potential. In contrast, oral administration of abacavir in mice and rats resulted in increased incidences 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. An exception was the development of preputial gland tumors, which occurred at a dose of 110 mg/kg. The systemic exposure level at which no carcinogenic effect was observed in mice and rats was 3–7 times higher than the equivalent systemic exposure in humans. 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 degrees of myocardial degeneration were observed in rats and mice treated with abacavir for 2 years. The equivalent 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 the AUC of abacavir increased on average by a factor of 1.89 and the elimination half-life by a factor of 1.58. Due to the substantial variability in abacavir exposure, dose adjustment recommendations for patients in this group cannot be established.

Data from patients with moderate and severe hepatic impairment indicate that impaired liver function does not significantly affect the pharmacokinetics of lamivudine.

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. Studies on lamivudine have shown that plasma concentrations (AUC) are increased in patients with impaired renal function due to reduced clearance. Patients with a creatinine clearance of less than 50 mL/min should have their dose reduced; therefore, a separate lamivudine pharmaceutical formulation is used for treating this patient group.

Clinical characteristics.

Indications.

Abacavir and Lamivudine are indicated, 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 carriage of the HLA-B*5701 allele 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.

Abacavir and Lamivudine are contraindicated in patients with hypersensitivity to abacavir, lamivudine, or any other component of the medicinal product.

Abacavir and Lamivudine are contraindicated in patients with moderate or severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

The interaction profile of the medicinal product is determined by the interaction profiles of its components, abacavir and lamivudine. Clinical studies have shown no clinically significant interaction between abacavir and lamivudine.

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

Abacavir and lamivudine are minimally metabolized by cytochrome P450 enzyme systems (e.g., CYP3A4, CYP2C9, or CYP2D6) and have no inhibitory or inductive effects on the cytochrome P450 enzyme system. Therefore, the potential for interactions between this medicinal product and antiretroviral non-nucleoside reverse transcriptase inhibitors or other medicinal products metabolized by major cytochrome P450 enzymes is low.

Abacavir and Lamivudine should not be taken together with other medicinal products containing lamivudine (see section "Special precautions").

The list of interactions provided in Table 1 should not be considered exhaustive, but is representative of the classes of medicinal products that have been studied.

Table 1. Drug interactions

Drug classes		Interaction, geometric mean change (%) (possible mechanism)	Recommendations for co-administration
Antiretroviral agents
Didanosine/abacavir		Interaction not studied.	No dose adjustment necessary.
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, abacavir and lamivudine 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 abacavir and lamivudine is necessary. When co-administration with co-trimoxazole is justified, patients should be monitored clinically. Co-administration with high doses of trimethoprim/sulfamethoxazole for treatment of Pneumocystis jirovecii pneumonia and toxoplasmosis has not been studied and 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. A slight decrease in plasma concentration of abacavir is possible due to induction of uridine diphosphate glucuronosyltransferase.	Insufficient data to recommend dose adjustment.
Rifampicin/lamivudine		Interaction not studied.
Anticonvulsants
Phenobarbital/abacavir		Interaction not studied. A slight decrease in plasma concentration of abacavir is possible due to induction of uridine diphosphate glucuronosyltransferase.	Insufficient data to recommend dose adjustment.
Phenobarbital/lamivudine		Interaction not studied.
Phenytoin/abacavir		Interaction not studied. A slight decrease in plasma concentration of abacavir is possible 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 necessary.
Ranitidine/lamivudine	Interaction not studied. Clinically significant interaction unlikely. Only a fraction of ranitidine is eliminated renally via OCT.
Cimetidine/abacavir	Interaction not studied.			No dose adjustment necessary.
Cimetidine/lamivudine	Interaction not studied. Clinically significant interaction unlikely. Only a fraction of ranitidine is eliminated renally via OCT.

Cytotoxic agents
Cladribine/lamivudine	Interaction not studied. Lamivudine in vitro promotes inhibition of intracellular phosphorylation of cladribine, leading to a potential risk of loss of cladribine efficacy in case of combined clinical use. Some clinical reports also confirm a possible interaction between lamivudine and cladribine.		Concomitant use of lamivudine with cladribine is not recommended.
Opioid drugs
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 need to adjust the dose of abacavir and lamivudine. Dose adjustment of methadone is unlikely to be required for most patients; however, re-titration of methadone may occasionally be necessary.
Methadone/lamivudine	Interaction not studied.

Retinoids
Retinoid compounds (e.g., isotretinoin)/abacavir	Interaction not studied. A possible interaction due to shared elimination pathway via alcohol dehydrogenase.		Insufficient data to recommend dose adjustment.
Retinoid compounds (e.g., isotretinoin)/lamivudine	Interaction not studied.
OTHER medicinal products
Ethanol/abacavir (0.7 g/kg single dose/600 mg single dose)		abacavir: AUC ↑41 % Ethanol: AUC ↔ (inhibition of alcohol dehydrogenase)		No need for dose adjustment.
Ethanol/lamivudine		Interaction not studied.
Sorbitol solution (3.2 g, 10.2 g, 13.4 g)/lamivudine (oral solution 300 mg single dose)		Lamivudine: AUC ↓ 14%; 32%; 36% Cmax ↓ 28%; 52%, 55%.		Concomitant long-term use of abacavir and lamivudine with medicinal products containing sorbitol or other osmotic polyols or monosaccharide alcohols (e.g., xylitol, mannitol, lactitol, maltitol) should be avoided. If avoidance is not possible, more careful monitoring of HIV-1 viral load is recommended.

Abbreviations: ↑ – increase; ↓ – decrease; ↔ – no significant changes; AUC – area under the concentration-time curve; Cmax – maximum recorded concentration; CL/F – clearance after oral administration.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

This section contains information on special considerations for the use of abacavir and lamivudine. There are no additional warnings regarding the use of Abacavir and Lamivudine tablets.

Patients should be aware that treatment with current antiretroviral agents does not reduce the risk of HIV transmission via sexual contact or infected blood; therefore, appropriate preventive measures must be used.

Hypersensitivity (see also section "Adverse reactions")

Abacavir use is associated with the risk of developing hypersensitivity reactions (HSR) (see section "Adverse reactions"), characterized by fever, rash, and other symptoms indicating multi-organ involvement. Some of these reactions may be life-threatening and, rarely, may be fatal if not managed appropriately.

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

Therefore, the following recommendations should be followed:

Prior to initiating therapy, HLA-B*5701 allele status must be documented in every HIV patient, regardless of race.
Abacavir and Lamivudine must never be prescribed to patients who are HLA-B*5701 positive, or to patients who are HLA-B*5701 negative but who have a suspected history of HSR to abacavir when using other abacavir-containing medicinal products (e.g., fixed-dose combinations containing lamivudine, zidovudine and abacavir, or lamivudine, abacavir and dolutegravir).
Abacavir and Lamivudine must be discontinued immediately if HSR is suspected, even in patients who are HLA-B*5701 negative. Reinitiating abacavir and lamivudine therapy after onset of HSR may lead to life-threatening conditions.
After discontinuation of Abacavir and Lamivudine due to suspected HSR, reinitiation of therapy with Abacavir and Lamivudine or any other abacavir-containing medicinal product (e.g., fixed-dose combinations containing lamivudine, zidovudine and abacavir, or lamivudine, abacavir and dolutegravir) is absolutely contraindicated.
Reinitiating abacavir therapy 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.
Patients must be informed of the necessity to remove and read the package leaflet and the special "Warning Card" and to carry the latter with them at all times.

Clinical manifestations of abacavir HSR

Abacavir HSR has been well characterized in clinical trials and post-marketing experience. Symptoms typically appear within the first six weeks of starting abacavir therapy (median onset: 11 days), although they may occur at any time during treatment.

Abacavir HSR almost always includes fever and/or rash. Other symptoms associated with abacavir HSR (see section "Adverse reactions") include respiratory and gastrointestinal symptoms. It is important to note that these symptoms may lead to misdiagnosis as lung diseases (e.g., pneumonia, bronchitis, pharyngitis) or gastroenteritis instead of HSR.

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

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

Lactic acidosis

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

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

Lactic acidosis typically occurs after several months of treatment.

Nucleoside analogues should be discontinued if symptomatic hyperlactatemia, metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur.

Nucleoside analogues should be used with caution in patients (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 who are receiving alpha-interferon and ribavirin are at particular risk.

Patients at increased risk require ongoing monitoring.

Lipodystrophy

Combination antiretroviral therapy is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients.

The long-term consequences of these adverse reactions are currently unknown. Knowledge of their mechanisms is incomplete. A link is expected between visceral lipomatosis and protease inhibitors, and between lipoatrophy and nucleoside reverse transcriptase inhibitors. The risk of lipodystrophy is greater with individual factors such as older age, and with drug-related factors such as duration of antiretroviral therapy and associated metabolic disturbances. Physical signs of fat redistribution should be assessed during clinical examination. Monitoring of serum lipid and glucose levels is recommended. Management of lipid disorders should follow appropriate clinical guidelines (see section "Adverse reactions").

Pancreatitis

Cases of pancreatitis have been reported; however, a causal relationship with lamivudine and abacavir use has not been established.

Virological failure risk

Triple nucleoside therapy: Reports have indicated a high rate of early virological failure and emergence of resistance with the combination of abacavir and lamivudine with tenofovir disoproxil fumarate administered once daily.

The risk of virological failure with abacavir and lamivudine may be higher than with other therapeutic regimens.

Liver disease

The efficacy and safety of Abacavir and Lamivudine in patients with significant hepatic impairment have not been established. Abacavir and Lamivudine is contraindicated in patients with moderate to severe hepatic impairment (see section "Contraindications").

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

Patients co-infected with hepatitis B or C

There is an increased risk of serious and potentially fatal hepatic adverse reactions in patients with chronic hepatitis B or C receiving 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 the treatment of both HIV and hepatitis B, additional information on the use of lamivudine in hepatitis B therapy should be sought (refer to the product information for lamivudine-containing medicinal products indicated for hepatitis B treatment).

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

Since abacavir and ribavirin share similar phosphorylation pathways, an intracellular interaction between these agents is considered possible, potentially leading to reduced intracellular phosphorylated metabolites of ribavirin and, as a potential consequence, reduced likelihood of achieving sustained virological response in patients infected with hepatitis C virus when treated with pegylated interferon plus ribavirin. Some data suggest that HIV/hepatitis C virus co-infected patients receiving antiretroviral therapy containing abacavir may have a reduced response to pegylated interferon/ribavirin treatment. Caution should be exercised when these two agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Mitochondrial dysfunction

In vitro and in vivo studies have shown that nucleoside and nucleotide analogues may cause mitochondrial dysfunction to varying degrees. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during the intrauterine and/or postnatal period. The main adverse reactions reported include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Delayed neurological disorders (hypertonia, seizures, behavioral abnormalities) have also been reported. It is currently unknown whether such neurological disorders are transient or permanent. Any child exposed to nucleoside or nucleotide analogues in utero, even if HIV-negative, requires ongoing clinical and laboratory monitoring and evaluation for possible mitochondrial dysfunction if symptoms occur. These data do not affect current national recommendations for the use of antiretroviral agents in pregnant women to prevent vertical HIV transmission.

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, leading to severe clinical conditions or symptom exacerbation. Such reactions typically occur within the first weeks or months of initiating combination antiretroviral therapy. Examples include cytomegalovirus retinitis, disseminated or focal mycobacterial infections, or Pneumocystis jirovecii (P. carinii) pneumonia. Any inflammatory conditions should be promptly investigated and, if necessary, treated. Autoimmune disorders (such as Graves' disease) have also been reported during the immune reconstitution period, although their onset is more variable and may occur several months after starting therapy.

Osteonecrosis

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

Opportunistic infections

Despite treatment with Abacavir and Lamivudine or any other antiretroviral therapy, HIV infection does not resolve, and opportunistic infections and other HIV-related complications may still develop. Therefore, such patients should remain under the regular clinical supervision of experienced physicians.

Myocardial infarction

Observational epidemiological studies have suggested a possible association between myocardial infarction and abacavir use in HIV patients. These studies were primarily conducted in patients with prior antiretroviral experience. Clinical trials have reported a limited number of myocardial infarction cases, and a small increase in risk could not be excluded. Overall, available data from observational studies and randomized trials are insufficient to confirm or rule out a causal relationship between abacavir use and myocardial infarction risk. Currently, no established biological mechanism explains a potential increased risk. When prescribing Abacavir and Lamivudine, preventive measures should be taken to minimize modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia).

Drug interactions

Abacavir and Lamivudine should not be taken together 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").

Abacavir and Lamivudine contains the azo dye tartrazine (FD&C Yellow No. 5), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Fertility. Animal studies have shown no evidence of effects of abacavir and lamivudine on fertility.

Pregnancy. When deciding on the use of antiretroviral agents for treating HIV infection in pregnant women and for reducing the risk of vertical HIV transmission 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 Abacavir and Lamivudine may inhibit cellular DNA replication, and abacavir has shown carcinogenic properties in animal models. The clinical significance of these findings is unknown. Transplacental passage of abacavir and lamivudine in humans has been established. The use of this medicinal product during pregnancy is justified only if the expected benefit to the mother outweighs the potential risk to the fetus. Although animal study results are not fully predictive for humans, data from rabbit studies suggest a possible risk of early embryonic death.

In pregnant women who received abacavir during the first trimester (over 800 cases) and during the second and third trimesters (over 1000 cases), data indicate no congenital malformations or neonatal disorders. In pregnant women who received lamivudine during the first trimester (over 1000 cases) and during the second and third trimesters (over 1000 cases), data also indicate no congenital malformations or neonatal disorders. There are no data specifically on the use of Abacavir and Lamivudine during pregnancy; however, based on the above data, the risk of congenital malformations in humans is unlikely.

Pregnant patients co-infected with hepatitis who have been treated with lamivudine-containing products such as Abacavir and Lamivudine require careful monitoring, as hepatitis symptoms may recur after discontinuation of lamivudine therapy.

Mitochondrial dysfunction

Nucleotide and nucleoside analogues cause varying degrees of mitochondrial damage in vitro and in vivo. Cases of mitochondrial dysfunction have been reported in HIV-negative newborns and infants exposed to nucleoside analogues during the fetal or intranatal period (see section "Special precautions for use").

Breastfeeding. Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human breast milk. Based on studies of over 200 mother-infant pairs, abacavir concentrations in infant serum during breastfeeding are very low (< 4% of maternal serum levels) and progressively decrease to undetectable levels by the time the infant reaches 24 weeks of age. There are no data on the safety of abacavir and lamivudine in children under 3 months of age. Therefore, women should not breastfeed while receiving abacavir and lamivudine. Additionally, HIV-infected women are advised to avoid breastfeeding under any circumstances to prevent transmission of HIV to their infants.

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, the patient's clinical status and the adverse effect profile of Abacavir and Lamivudine should be taken into account.

Dosage and Administration

Treatment with Abacavir and Lamivudine should be initiated by a physician experienced in managing HIV infection.

Due to the inability to adjust the dose when using fixed-dose combination tablets containing abacavir and lamivudine, Abacavir and Lamivudine should not be prescribed to adults or children weighing less than 25 kg.

Abacavir and Lamivudine 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 Abacavir and Lamivudine must be discontinued or dose adjustment is required, abacavir or lamivudine should be prescribed as individual agents. In such cases, physicians should refer to the prescribing information for these medicinal products.

Adults and children (body weight ≥25 kg)

The recommended dose of Abacavir and Lamivudine for adults and children is 1 tablet once daily.

Older patients

Pharmacokinetics of abacavir and lamivudine in patients aged 65 years and older has not been studied to date. Increased caution is advised in these patients due to age-related changes such as reduced renal function, hematological abnormalities, higher incidence of hepatic, renal, or cardiac dysfunction, other comorbidities, and concomitant use of other medicinal products.

Patients with renal impairment

While dose adjustment of abacavir is not required in patients with renal impairment, the dose of lamivudine should be reduced due to decreased creatinine clearance. Therefore, Abacavir and Lamivudine are not recommended for use when creatinine clearance is less than 50 mL/min.

Patients with hepatic impairment

There are no data on the use of Abacavir and Lamivudine in patients with moderate hepatic impairment; therefore, administration is not recommended except in cases of special necessity. Close monitoring is required for patients with mild to moderate hepatic impairment. If possible, therapeutic drug monitoring of plasma abacavir levels should be considered. Abacavir and Lamivudine are contraindicated in patients with severe and moderate hepatic impairment.

Children.

Abacavir and Lamivudine are not recommended for use in children weighing less than 25 kg due to the inability to adjust the dose. For treatment selection, physicians should consult the prescribing information for lamivudine and abacavir.

Overdose.

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

Treatment. In case of overdose, patients should be monitored for signs of drug toxicity (see section "Adverse Reactions"), and standard supportive therapy should be administered as needed. Because lamivudine is dialyzable, hemodialysis may be used to manage overdose, although this treatment approach has not been well studied. It is unknown whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Adverse reactions

The adverse reactions are consistent with the known safety profiles of abacavir and lamivudine when administered as individual medicinal products. For many of the adverse reactions, it is unclear whether they are related to the active substances abacavir and lamivudine, to the broad range of other medicinal products used in the treatment of HIV infection, or whether they represent symptoms of the underlying disease.

Many of the adverse reactions listed in Table 2 (nausea, vomiting, diarrhoea, fever, malaise, rash) commonly occurred 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, medications containing abacavir must be permanently discontinued.

Adverse reactions associated with the use of abacavir or lamivudine are listed in Table 2 by system organ class and frequency. Frequency categories are defined as follows: 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.

Table 2. Adverse reactions associated with the use of abacavir and lamivudine

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. Uncommon: lactic acidosis.	Uncommon: lactic acidosis.
Nervous system disorders	Common: headache.	Common: headache, insomnia. Very rare: peripheral neuropathy (or paraesthesia).
Respiratory, thoracic and mediastinal disorders		Common: cough, nasal symptoms.
Gastrointestinal disorders	Common: nausea, vomiting, diarrhoea. Uncommon: pancreatitis, although a causal relationship with abacavir has not been established.	Common: nausea, vomiting, abdominal pain or cramps, diarrhoea. Uncommon: 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. Uncommon: angioedema.
Musculoskeletal and connective tissue disorders		Common: arthralgia, myalgia. Uncommon: rhabdomyolysis.
General disorders and administration site conditions	Common: malaise, lethargy, feeling weak.	Common: increased fatigue, malaise, fever.

Use in children.

According to the results of a clinical study in which HIV-infected children aged 12 months to 17 years received abacavir and lamivudine once or twice daily, no additional safety requirements were identified when the medicinal product was administered once or twice daily in children compared to the same dosing regimen in adults.

Description of individual adverse reactions.

Hypersensitivity (see also section "Special warnings and precautions for use")

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 typically 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, liver failure.

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

Renal system: elevated creatinine, renal failure.

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

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

Lactic acidosis

Cases of lactic acidosis, sometimes fatal, have been reported with the use of nucleoside analogues, usually associated with hepatomegaly and hepatic steatosis (see section "Special warnings and precautions for use").

Lipodystrophy

In some patients receiving combination antiretroviral therapy, redistribution and/or accumulation of body fat has been observed, including central obesity, dorsocervical fat accumulation ("buffalo hump"), increased intra-abdominal and visceral fat, loss of peripheral and facial subcutaneous fat, and breast enlargement.

Metabolic disturbances

Combination antiretroviral therapy is associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia (see "Special warnings and precautions for use").

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy, inflammatory reactions to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstitution; however, 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 recognized risk factors, advanced stages of HIV disease, or prolonged use of combination antiretroviral therapy. The frequency of this phenomenon is unknown (see section "Special warnings and precautions for use").

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

30 or 90 tablets in a high-density polyethylene bottle closed with a child-resistant polypropylene cap, with an instruction leaflet for medical use and a warning card.

30 or 90 tablets in a high-density polyethylene bottle closed with a child-resistant polypropylene cap, 1 bottle in a cardboard box, with an instruction leaflet for medical use and a warning card.

Prescription category. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.