Lamivudine, Abacavir and Dolutegravir

Patients with a creatinine clearance between 30 and 49 mL/min receiving dolutegravir/abacavir/lamivudine may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomised, controlled trials comparing dolutegravir/abacavir/lamivudine fixed-dose combination to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive dolutegravir/abacavir/lamivudine should be monitored for lamivudine-related adverse events, notably hematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with dolutegravir/abacavir/lamivudine combination. The fixed-dose combination should be discontinued and the individual components should be used to construct the treatment regimen.

The safety and efficacy of dolutegravir/abacavir/lamivudine has not been established in patients with significant underlying liver disorders. Dolutegravir/abacavir/lamivudine combination is not recommended in patients with moderate to severe hepatic impairment.

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 standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravir-containing regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If a pregnancy is confirmed in the first trimester while on dolutegravir/abacavir/lamivudine, the benefits and risks of continuing dolutegravir/abacavir/lamivudine versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account.

Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified.

More than 1000 outcomes from exposure to dolutegravir during second and third trimester pregnancy indicate no evidence of increased risk of foetal/neonatal toxicity. Dolutegravir/abacavir/lamivudine may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration.

There is insufficient information on the effects of dolutegravir on neonates.

Concerning lamivudine, a large amount of data (more than 5200 outcomes from first trimester) indicates no malformative toxicity. A moderate amount of data (more than 1200 outcomes from first trimester) indicates no malformative toxicity for abacavir.

Abacavir and lamivudine may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models. The clinical relevance of these findings is unknown.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIVnegative infants exposed in utero and/or post-natally to nucleoside analogues.

Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficient information on the effects of dolutegravir in neonates/infants.

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of abacavir and lamivudine when administered to babies less than three months old.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

Women of childbearing potential

Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, including consideration of effective contraceptive measures.

If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir/abacavir/lamivudine should be discussed with the patient.

Fertility

There are no data on the effects of dolutegravir, abacavir or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir, abacavir or lamivudine on male or female fertility.

Dolutegravir/abacavir/lamivudine combination has no or negligible influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of dolutegravir/abacavir/lamivudine should be borne in mind when considering the patient’s ability to drive or operate machinery.

Summary of the safety profile

The most frequently reported adverse reactions related to dolutegravir and abacavir/lamivudine were nausea (12%), insomnia (7%), dizziness (6%) and headache (6%).

Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity. Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

The most severe adverse reaction related to the treatment with dolutegravir and abacavir/lamivudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects.

Tabulated list of adverse reactions

The adverse reactions with the components of dolutegravir/abacavir/lamivudine from clinical study and post-marketing experience are listed in Table 2 by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000).

Table 2. Tabulated list of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical studies or postmarketing experience; and adverse reactions to treatment with dolutegravir, abacavir and lamivudine from clinical studies and post-marketing experience when used with other antiretrovirals:

¹ This adverse reaction was identified from clinical studies or post-marketing experience for dolutegravir, abacavir or lamivudine when used with other antiretrovirals or postmarketing experience with dolutegravir/abacavir/lamivudine.
² In combination with increased transaminases.

Description of selected adverse reactions

Hypersensitivity reactions

Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), which were observed more commonly with abacavir. Hypersensitivity reaction observed for each of these medicinal products (described below) share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Time to onset was typically 10-14 days for both abacavir and dolutegravir-associated reactions, although reactions to abacavir may occur at any time during therapy. Treatment with dolutegravir/abacavir/lamivudine must be stopped without delay if HSR cannot be ruled out on clinical grounds, and therapy with dolutegravir/abacavir/lamivudine or other abacavir or dolutegravir containing products must never be re-initiated. Please refer to section 4.4 for further details on patient management in the event of a suspected HSR to dolutegravir/abacavir/lamivudine.

Dolutegravir hypersensitivity

Symptoms have included rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.

Abacavir hypersensitivity

The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.

Skin: Rash (usually maculopapular or urticarial)

Gastrointestinal tract: Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration

Respiratory tract: Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure

Miscellaneous: Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis

Neurological/Psychiatry: Headache, paraesthesia

Haematological: Lymphopenia

Liver/pancreas: Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal: Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase

Urology: Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life-threatening and in rare instance, have been fatal.

Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include lifethreatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Changes in laboratory chemistries

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 96 weeks. In the SINGLE study a mean change from baseline of 12.6 µmol/L was observed after 96 weeks of treatment. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.

Co-infection with Hepatitis B or C

In dolutegravir Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups.

Paediatric population

There are no clinical study data on the effects of dolutegravir/abacavir/lamivudine in the paediatric population. Individual components have been investigated in infants, children and adolescents.

Based on available data with dolutegravir used in combination with other antiretroviral agents to treat infants, children and adolescents, there were no additional safety issues identified beyond those observed in the adult population.

The individual preparations of abacavir and lamivudine have been investigated separately, and as a dual nucleoside backbone, in combination antiretroviral therapy to treat ART-naive and ART-experienced HIV-infected paediatric patients (data available on the use of abacavir and lamivudine in infants less than three months are limited). No additional types of adverse reactions have been observed beyond those characterised for the adult population.