Abacavir/ Dolutegravir/ Lamivudine

Registered South African indications:

• Human immunodeficiency virus (HIV) infection
  - In those who are antiretroviral treatment-naive or are infected with HIV without documented or clinically suspected resistance to any of the three antiretroviral medicines in abacavir/dolutegravir/lamivudine

Hypersensitivity reactions

• Hypersensitivity to abacavir
• In clinical studies conducted before the introduction of screening for the HLA-B*5701 allele, approximately 5% of subjects receiving abacavir developed a hypersensitivity reaction, which in some cases has proved fatal

Risk factors

• Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir
• In the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding abacavir in patients with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66 of 847) to 3.4% (27 of 803) (p<0.0001) and the incidence of hypersensitivity reactions confirmed by skin patch testing from 2.7% (23 of 842) to 0.0% (0 of 802) (p<0,0001). Based on this study, it is estimated that 48% to 61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701 allele
• Clinicians should screen for carriage of the HLA-B*5701 allele in any HIV infected patient without prior exposure to abacavir
• Screening is recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir
• Use of abacavir in patients known to carry the HLA-B*5701 allele is not recommended
• In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision making
• Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction

Clinical description

• The hypersensitivity reaction is characterised by the appearance of symptoms indicating multi-organ involvement
• The majority of patients have fever and/or rash as part of the syndrome
• Symptoms of hypersensitivity may include fatigue, malaise, gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and respiratory signs and symptoms such as dyspnoea, sore throat, cough and abnormal chest x-ray findings
• The symptoms of this hypersensitivity reaction can occur at any time during treatment with abacavir, but usually occur within the first six weeks of therapy
• The symptoms worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of abacavir

Clinical management

• Regardless of their HLA-B*5701 status, any patient developing signs or symptoms of hypersensitivity must contact their doctor immediately for advice
• If a hypersensitivity reaction is diagnosed abacavir/ dolutegravir/ lamivudine must be discontinued immediately
• Abacavir/ dolutegravir/ lamivudine, or any other medicinal product containing abacavir, must never be restarted following a hypersensitivity reaction
• To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, abacavir/ dolutegravir/ lamivudine should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible
• Abacavir/ dolutegravir/ lamivudine, or any other medicinal product containing abacavir, should not be restarted even if a recurrence of symptoms occurs following rechallenge with alternative medicine(s)
• An alert card with information for the patient about this hypersensitivity reaction is included in the abacavir/ dolutegravir/ lamivudine pack

Special considerations following an interruption of abacavir/ dolutegravir/ lamivudine therapy

• Regardless of a patient’s HLA-B*5701 status, if therapy with any abacavir containing product has been discontinued and restarting therapy with abacavir/ dolutegravir/ lamivudine is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction
• If a hypersensitivity reaction cannot be ruled out, abacavir/ dolutegravir/ lamivudine or any other medicinal product containing abacavir should not be restarted
• There have been infrequent reports of hypersensitivity reaction following re-introduction of abacavir, where the interruption was preceded by a single key symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms or a respiratory symptom)
• If a decision is made to restart abacavir/ dolutegravir/ lamivudine in these patients, this should be done only under direct medical supervision
• On very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction
• If a decision is made to restart abacavir/ dolutegravir/ lamivudine, this must be done only if medical care can be accessed readily by the patient or others
• Screening for carriage of the HLA-B5701 allele is recommended prior to re-initiation of abacavir in patients of unknown HLA-B5701 status who have previously tolerated abacavir
• Re-initiation of abacavir in such patients who test positive for the HLA-B*5701 allele is not recommended

Essential patient information

• Prescribers must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction
• Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death and that the risk of a hypersensitivity reaction is increased if they are HLA-B*5701 positive
• Patients must also be informed that HLA-B*5701 negative patients can also experience abacavir hypersensitivity reaction
• Therefore, any patient who develops signs or symptoms consistent with a possible hypersensitivity reaction to abacavir must contact their doctor immediatelly
• Patients who are hypersensitive to abacavir should be reminded that they must never take abacavir/ dolutegravir/ lamivudine or any other medicinal product containing abacavir again, regardless of their HLA-B*5701 status
• In order to avoid restarting abacavir/ dolutegravir/ lamivudine, patients who have experienced a hypersensitivity reaction should be asked to return the remaining abacavir/ dolutegravir/ lamivudine tablets to the pharmacy
• Patients who have stopped abacavir/ dolutegravir/ lamivudine for any reason and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting
• Each patient should be reminded to read the package leaflet included in the abacavir/ dolutegravir/ lamivudine pack
• They should be reminded of the importance of removing the alert card included in the pack and keeping it with them at all times

Contraindications

South African recommendations

• Hypersensitivity to dolutegravir, abacavir, or lamivudine or to any of the components of the fixed dose combination
• Pregnancy
• Lactation
• Renal impairment with a creatinine clearance <50ml/min
• Moderate and severe hepatic impairment (Child-Pugh grade B or C) due to the abacavir component
• Coadministration with dofetilide
• Coadministration with pilsicainide
• Coadministration with metformin

Recommendations in other jurisdictions

• Hypersensitivity to the active substances or to any of the excipients
• Coadministration with medicinal products with narrow therapeutic windows, that are substrates of organic cation transporter (OCT) 2, including but not limited to fampridine (also known as dalfampridine)

Cautions

South African recommendations

• Renal impairment  CrCl≥50ml/min
• Mild hepatic impairment (Child-Pugh grade A)
• Elderly
• Patients with evidence of lipodystrophy
• Patients with low CD4 counts, at risk of immune reconstitution inflammatory syndrome (IRIS)
• Risk of transmission of HIV to others through sexual contact or blood contamination
• Risk factors for osteonecrosis
  - Advanced HIV-disease
  - Long-term exposure to combination antiretroviral therapy (cART)
• Mitochondrial dysfunction
  - Foetal exposure in utero to nucleoside and nucleotide analogues ( including in HIV-negative infants/ children)
• HIV patients, risk of continued opportunistic infections despite treatment
• Patients with known risk factors for liver disease, caution with abacavir/dolutegravir/lamivudine use due to potential for lactic acidosis or hepatotoxicity
• Patients with modifiable risk factors for myocardial infarction (e.g., smoking, hypertension, and hyperlipidaemia) when prescribing abacavir/dolutegravir/lamivudine
• Integrase inhibitor resistance
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• HIV transmission
• Positive HLA-B*5701 status
• Previous suspected abacavir hypersensitivity reaction (HSR)
• Liver disease, including chronic active hepatitis
• Chronic hepatitis B or C co-infection
• Severe immune deficiency at the time of initiation of combination antiretroviral therapy
• Mitochondrial dysfunction
  - Foetal exposure in utero to nucleoside and nucleotide analogues ( including in HIV-negative infants/ children)
• Risk factors for myocardial infarction (e.g., smoking, hypertension, hyperlipidaemia)
• Risk factors for osteonecrosis (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, higher body mass index)
• Integrase inhibitor resistance
• Co-administration with certain drugs (rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John's wort, etravirine without boosted protease inhibitors, efavirenz, nevirapine, or tipranavir/ritonavir, polyvalent cation-containing antacids, metformin, cladribine, any other medicinal products containing dolutegravir, abacavir, lamivudine or emtricitabine)

Forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Therapy should be initiated by a medical practitioner experienced in the management of HIV infection

Human immunodeficiency virus (HIV) infection
- In those who are antiretroviral treatment-naive or are infected with HIV without documented or clinically suspected resistance to any of the three antiretroviral medicines in abacavir/dolutegravir/lamivudine

Abacavir/ Dolutegravir/ Lamivudine
600/50/300 (mg)

• ≥40kg: Oral (fct, tab): 1 tab, dly taken with or without food

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Abacavir/dolutegravir/lamivudine is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases, refer to the individual product information for these medicines

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Since the recommended dosage of dolutegravir is 50mg twice daily for patients with resistance to integrase inhibitors, the use of abacavir/dolutegravir/lamivudine is not recommended for patients with integrase inhibitor resistance

Not established for use in children under 18 years

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy

South African recommendations

• Contraindicated
• Evidence suggests teratogenicity has been observed in animal studies, thus posing potential risks when used during pregnancy
• The safety of abacavir/dolutegravir/lamivudine during pregnancy in humans has not been established
• Dolutegravir, lamivudine, and abacavir were shown to cross the placenta in reproductive toxicity studies in animals
• There have been reports of elevations in serum lactate levels in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs) such as abacavir and lamivudine
• Reported potential risks to infants include developmental delay, seizures, and other neurological diseases
• Women of childbearing potential should be counseled about the potential risk of neural tube defects with dolutegravir, a component of the combination therapy abacavir/dolutegravir/lamivudine; and the need for effective contraceptive measures due to the potential risks associated with abacavir/dolutegravir/lamivudine
• If a woman plans pregnancy, a discussion should be held about the benefits and risks of continuing treatment with abacavir/dolutegravir/lamivudine

Recommendations in other jurisdictions

• Caution; positive evidence of risk in studies
• Human studies show a small increase in neural tube defects with dolutegravir-containing regimens
• Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, a component of the combination therapy abacavir/dolutegravir/lamivudine
• The need for effective contraceptive measures due to the potential risks associated with abacavir/dolutegravir/lamivudine
• If a woman plans pregnancy, a discussion should be held about the benefits and risks of continuing treatment with abacavir/dolutegravir/lamivudine
• There are reports of a small increase in neural tube defects in mothers taking dolutegravir-containing regimens at the time of conception
• In the first trimester of a confirmed pregnancy, the benefits and risks of continuing abacavir/dolutegravir/lamivudine versus switching to another antiretroviral regimen should be discussed, taking into account gestational age and the critical time period of neural tube defect development
• Data from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects with dolutegravir during pregnancy, but are insufficient to fully address the risk of neural tube defects
• Dolutegravir was shown to cross the placenta in animals
• More than 1000 outcomes from exposure to dolutegravir during the second and third trimester of pregnancy indicate no evidence of increased risk of foetal/neonatal toxicity. Abacavir/dolutegravir/lamivudine may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus
• Concerning lamivudine and abacavir, available data indicates no malformative toxicity. However, both drugs may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models
• There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues

Breastfeeding

South African recommendations

• Contraindicated
• Use during lactation is contraindicated due to potential risks identified in animal studies and potential for HIV transmission
• The safety of abacavir/dolutegravir/lamivudine during lactation in humans has not been established
• Teratogenicity has been observed in animals
• HIV infected women should not breastfeed their infants in order to avoid transmission of HIV
• It is expected that abacavir and dolutegravir will be secreted into human milk
• Lamivudine is excreted in human milk at similar concentrations to those found in serum

Recommendations in other jurisdictions

• Caution; not recommended
• HIV infected women should not breastfeed their infants in any circumstance to avoid transmission of HIV
• Dolutegravir is excreted in human milk in small amounts, but there is insufficient information on the effects of dolutegravir in neonates/infants
• Abacavir and its metabolites are excreted into the milk of lactating rats and humans
• Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants 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

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

Renal Impairment

South African recommendations

• CrCl≥50ml/min: Caution; no dose adjustment recommended
  Pharmacokinetic data have been obtained for dolutegravir, abacavir and lamivudine alone. Abacavir/dolutegravir/lamivudine should not be used in patients with creatinine clearance of less than 50ml/min because, whilst no dosage adjustment of dolutegravir or abacavir is necessary in patients with renal impairment, dose reduction is required for the lamivudine component. Therefore, the separate preparation of lamivudine should be used to treat these patients
• CrCl<50ml/min: Contraindicated

Recommendations in other jurisdictions

• CrCl≥50ml/min: Caution; no dose adjustment recommended
  No dose adjustment is required in patients with mild or moderate renal impairment. However, the lamivudine exposure is significantly increased in patients with a creatinine clearance <50ml/min
• CrCl>30-49ml/min: Caution; no dose adjustment recommended
  Monitor for lamivudine-related adverse events, notably hematologic toxicities
• CrCl<30ml/min: Caution; not recommended

Hepatic Impairment

South African recommendations

• Mild (Child-Pugh grade A): Caution; dose adjustment recommended
  A dose reduction of abacavir may be required for patients with mild hepatic impairment. . As dose reduction is not possible with the fixed dose combination, the separate preparations of dolutegravir, abacavir or lamivudine should be used when this is judged necessary
• Moderate to severe (Child-Pugh grade B or C): Contraindicated

Recommendations in other jurisdictions

• Mild: Caution; no dosage adjustment recommended
  Close monitoring is required, including monitoring of abacavir plasma levels if feasible
• Moderate to severe: Caution; not recommended
  No clinical data are available in patients with moderate or severe hepatic impairment, therefore the use of abacavir/dolutegravir/lamivudine is not recommended unless judged necessary

Elderly

• Caution; no information available

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings 

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Abacavir
Central Nervous System Disorders

• Headache
• Lethargy 
• Fatigue

Gastrointestinal Disorders

• Nausea and vomiting 
• Diarrhoea
• Pancreatitis

Endocrine and Metabolic Disorders

• Anorexia 
• Lactic acidosis
• Weight changes
• Changes in blood lipid levels
• Changes in blood glucose levels

Skin and Subcutaneous Tissue Disorders

• Rash  
• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Abacavir hypersensitivity reactions
• Fever

Lamivudine
Central Nervous System Disorders

• Headache
• Insomnia
• Peripheral neuropathy
• Fatigue
• Malaise

Respiratory Disorders

• Cough
• Nasal symptoms

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain 
• Diarrhoea
• Pancreatitis
• Elevations in serum amylase

Hepatobiliary Disorders

• Transient elevations in liver enzymes
• Hepatitis

Endocrine and Metabolic Disorders

• Lactic acidosis

Musculoskeletal Disorders

• Arthralgia
• Muscle disorders
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Anaemia 
• Thrombocytopenia
• Pure red cell aplasia
• Fever

Dolutegravir
Central Nervous System Disorders

• Headache
• Dizziness
• Insomnia
• Abnormal dreams
• Depression
• Suicidal ideation
• Suicide attempt
• Fatigue

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Flatulence
• Upper abdominal pain
• Abdominal pain
• Abdominal discomfort

Hepatobiliary Disorders

• Hepatitis
• Elevated alanine aminotransferase 
• Elevated aspartate aminotransferase 

Endocrine and Metabolic Disorders

• Elevated creatine phosphokinase

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity 
• Immune Reconstitution Syndrome 

• Dofetilide
• Pilsicainide
• Organic cation transporter (OCT) 2
• Fampridine (also known as dalfampridine)
• Alcohol
• Phenobarbital
• Phenytoin
• Methadone
• Trimethoprim/sulfamethoxazole
• Cladribine
• Cytidine analogues
• Zalcitabine
• CYP3A4 inhibitors
• CYP3A4 inducers
• Non-nucleoside reverse transcriptase inhibitors
• Protease inhibitors
• Antiviral agents
• Antiarrhythmics
• Anticonvulsants
• St. John's wort
• Antacids
• Calcium supplements
• Iron supplements
• Multivitamin
• Metformin
• Rifampicin

• HLA-B*5701 genotype status prior to initiation of therapy and prior to reinitiation of therapy in patients of unknown HLA-B*5701 status
• Full blood count
• Hepatic function  
• Blood glucose
• Lipid profile

Abacavir
Abacavir is a nucleotide reverse transcriptase inhibitor. It is a potent selective inhibitor of HIV-1 and HIV-2. It is metabolised intracellularly to the active moiety, carbovir triphosphate which interferes with HIV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.

Lamivudine
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication and is also active against zidovudine-resistant clinical isolates of HIV.

Dolutegravir
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration which is essential for the HIV replication cycle.

COMBINATION PREPARATIONS

Abacavir/ Dolutegravir/ Lamivudine

Tablet 600mg/300mg/50mg

• Cagol (Emcure Pharmaceuticals SA)
• Damicava (Cipla Medpro)
• Kavideza (Mylan)
• Trelavue (GSK) originator