Source: Health Products Regulatory Authority (ZA) Publisher: GlaxoSmithKline South Africa (Pty) Ltd, 39 Hawkins Avenue, Epping Industria 1, 7460
TRELAVUE is contraindicated in patients with known hypersensitivity to dolutegravir, abacavir or lamivudine, or to any of the excipients.
TRELAVUE is contraindicated in combination with dofetilide or pilsicainide.
TRELAVUE is contraindicated for patients with moderate and severe hepatic impairment due to the abacavir component (see PHARMACOLOGICAL ACTION).
TRELAVUE is contraindicated during pregnancy or in mothers who are breastfeeding their infants (see PREGNANCY AND LACTATION).
TRELAVUE is contraindicated in patients with renal impairment with a creatinine clearance of <50 ml/min due to the lamivudine component (see PHARMACOLOGICAL ACTION).
Metformin is contraindicated in patients taking TRELAVUE.
Warnings relevant to dolutegravir, abacavir and lamivudine are included in this section. There are no additional warnings relevant to TRELAVUE.
Hypersensitivity to abacavir – refer to Boxed Warning.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
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 HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see below), other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.
Pancreatitis has been observed in some patients receiving TRELAVUE.
Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of TRELAVUE until diagnoses of pancreatitis is excluded.
Hypersensitivity reactions have been reported with dolutegravir and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue TRELAVUE immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRELAVUE after the onset of hypersensitivity may result in a life-threatening reaction.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of abacavir and lamivudine. A majority of these cases have been in women.
Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).
In patients with suspicious symptoms of biochemistry, measure the venous lactate level (normal <2 mmol/ℓ) and the serum bicarbonate and respond as follows:
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any patient with a raised lactate level. Blood for lactate assay should be heparinised and stored on ice. After recovery, NRTIs should be avoided. Seek expert advice on medicine selection. The above lactate values may not be applicable to paediatric patients. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of TRELAVUE alone or in combination.
Caution should be exercised when administering TRELAVUE particularly to those with known risk factors for liver disease. Treatment with TRELAVUE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients (see SIDE EFFECTS). Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose.
Lipid disorders should be managed as clinically appropriate.
In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are tuberculosis, cytomegalovirus retinitis, generalised and/or atypical focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Auto-immune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection (see Patients co-infected with hepatitis B virus (HBV) later in this section and SIDE EFFECTS).
Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting therapy with TRELAVUE in hepatitis B co-infected patients. Clinical study and marketed use of lamivudine, have shown that some patients with chronic HBV disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If TRELAVUE is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication should be considered.
Patients receiving TRELAVUE may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by medical practitioners experienced in the treatment of these associated HIV diseases.
Patients should be advised that antiretroviral therapy, including TRELAVUE, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
In a prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous six months was correlated with an increased risk of myocardial infarction. As a precaution the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir and action taken to minimise all modifiable risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).
Caution should be given to co-administering medications (prescription and non- prescription) that may change the exposure of dolutegravir, abacavir, lamivudine or medications that may have their exposure changed by TRELAVUE (see CONTRAINDICATIONS and INTERACTIONS).
The co-administration of dolutegravir with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir + ritonavir (ATV+RTV), lopinavir + ritonavir (LPV+RTV) or darunavir + ritonavir (DRV+RTV) (see INTERACTIONS).
Dolutegravir should not be co-administered with polyvalent cation-containing antacids. Dolutegravir is recommended to be administered 2 hours before or 6 hours after these agents (see INTERACTIONS).
TRELAVUE is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, administered with food (see INTERACTIONS).
Metformin concentrations may be increased by TRELAVUE. Metformin is contraindicated in patients taking TRELAVUE (see CONTRAINDICATIONS). TRELAVUE should not be administered concurrently with other medicinal products containing any of the same active components (dolutegravir, abacavir, and/or lamivudine).
Since the recommended dose of dolutegravir is 50 mg twice daily for patients taking efavirenz, nevirapine, rifampicin and tipranavir/ritonavir, the use of TRELAVUE is not recommended for patients taking these medicines (see INTERACTIONS).
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50 >50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MRP2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters.
In medicine interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, bocepravir, telaprevir, and oral contraceptives containing norgelgestromin and ethinyl estradiol. In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) (IC50 = 1,93 μM), multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6,34 μM) and MATE2-K (IC50 = 24,8 μM). Given dolutegravir's in vivo exposure, it has a low potential to affect the transport of MATE2-K substrates in vivo. In vivo, dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 or MATE1 (dofetilide, pilsicainide or metformin) (see Table 3).
In vitro, dolutegravir inhibited the basolateral renal transporters: organic anion transporter (OAT) 1 (IC50 = 2,12 μM) and OAT3 (IC50 = 1,97 μM). However, dolutegravir had no notable effect on the pharmacokinetics in vivo of the OAT substrates tenofovir and para aminohippurate, and therefore has low propensity to cause medicine interactions via inhibition of OAT transporters.
Abacavir and lamivudine do not inhibit or induce CYP enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6).
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicines that induce these enzymes or transporters may theoretically decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other medicines that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration (see Table 3).
Efavirenz, nevirapine, rifampicin and tipranavir/ritonavir each reduced the plasma concentrations of dolutegravir significantly and require dolutegravir dose adjustment to 50 mg twice daily. Etravirine also reduced plasma concentrations, but the effect of etravirine was mitigated by co-administration of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir. Therefore no dolutegravir dose adjustment is necessary when co-administered with etravirine and either lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. Another inducer, fosamprenavir in combination with ritonavir decreased plasma concentrations of dolutegravir but does not require a dosage adjustment of dolutegravir. A medicine interaction study with the UGT1A1 inhibitor, atazanavir, did not result in a clinically meaningful increase in the plasma concentrations of dolutegravir. Tenofovir, ritonavir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, bocepravir, telaprevir, prednisone, rifabutin and omeprazole had no or a minimal effect on dolutegravir pharmacokinetics, therefore no dolutegravir dose adjustment is required when co-administered with these medicines.
The likelihood of metabolic interactions with abacavir and lamivudine is low. Abacavir and lamivudine are not significantly metabolised by CYP enzymes. The primary pathways of abacavir metabolism in human are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine. The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein binding, and almost complete renal clearance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is renal.
Table 3. Medicine Interactions studied with dolutegravir:
| Concomitant Medicine Class: Medicine Name | Effect on Concentration of dolutegravir or Concomitant Medicine | Clinical Comment |
|---|---|---|
| HIV-1 Antiviral Agents | ||
| Non-nucleoside Reverse Transcriptase Inhibitor: Etravirine (ETR) | Dolutegravir ↓ AUC ↓ 71 % Cmax ↓ 52 % Cτ ↓ 88 % ETR ⟷ | Etravirine decreased plasma dolutegravir concentration, which may result in loss of virologic response and possible resistance to dolutegravir. TRELAVUE should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir. |
| Non-nucleoside Reverse Transcriptase Inhibitor: Efavirenz (EFV) | Dolutegravir ↓ AUC ↓ 57 % Cmax ↓ 39 % Cτ ↓ 75 % EFV ⟷ | Efavirenz decreased dolutegravir plasma concentrations. Since the dose of dolutegravir is 50 mg twice daily when co- administered with efavirenz the co-administration of efavirenz with TRELAVUE is not recommended. |
| Non-nucleoside Reverse Transcriptase Inhibitor: Nevirapine | Dolutegravir ↓ | Co-administration with nevirapine has the potential to decrease dolutegravir plasma concentration due to enzyme induction and has not been studied. Effect of nevirapine on dolutegravir exposure is likely similar to or less than that of efavirenz. Since the dose of dolutegravir is 50 mg twice daily when co- administered with nevirapine, the co-administration of nevirapine with TRELAVUE is not recommended. |
| Protease Inhibitor: Atazanavir (ATV) | Dolutegravir ↑ AUC ↑ 91 % Cmax ↑ 49 % Cτ ↑ 180 % ATV ⟷ | Atazanavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Protease Inhibitor: Atazanavir/ritonavir (ATV + RTV) | Dolutegravir ↑ AUC ↑ 62 % Cmax ↑ 33 % Cτ ↑ 121 % ATV ⟷ RTV ⟷ | Atazanavir/ritonavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Protease Inhibitor: Tipranavir/ritonavir (TPV + RTV) | Dolutegravir ↓ AUC ↓ 59 % Cmax ↓ 47 % C ↓ 76 % TPV ⟷ RTV ⟷ | Tipranavir/ritonavir decreases dolutegravir concentrations. Since the dose of dolutegravir is 50 mg twice daily when co- administered with tipranavir/ritonavir, the co-administration of tipranavir/ritonavir with TRELAVUE is not recommended. |
| Protease Inhibitor: Fosamprenavir/ ritonavir (FPV + RTV) | Dolutegravir ↓ AUC ↓ 35 % Cmax ↓ 24 % C ↓ 49 % FPV ⟷ RTV ⟷ | Fosamprenavir/ritonavir decreases dolutegravir concentrations, but based on limited data, did not result in decreased efficacy in Phase III studies. No dose adjustment is necessary in INI-naïve patients. |
| Protease Inhibitor: Nelfinavir | Dolutegravir ⟷ | This interaction has not been studied. Although an inhibitor of CYP3A4, based on data from other inhibitors, an increase is not expected. No dose adjustment is necessary. |
| Protease Inhibitor: Lopinavir/ritonavir (LPV + RTV) | DTG ⟷ AUC ⟷ Cmax ⟷ Cτ ⟷ LPV ⟷ RTV ⟷ | Lopinavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Darunavir/ritonavir (DRV/RTV) | Dolutegravir ↓ AUC ↓ 32 % Cmax ↓ 11 % Cτ ↓ 38 % DRV ⟷ RTV ⟷ | Darunavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Nucleoside Reverse Transcriptase Inhibitor: Tenofovir (TDV) | Dolutegravir ⟷ TDV ⟷ | Tenofovir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Lopinavir/ritonavir + Etravirine (LPV/RTV + ETR) | Dolutegravir ⟷ AUC ↑ 10 % Cmax ↑ 7 % Cτ ↑ 28 % LPV ⟷ RTV ⟷ ETR ⟷ | Lopinavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Darunavir/ritonavir + Etravirine (DRV/RTV + ETR) | Dolutegravir ↓ AUC ↓ 25 % Cmax ↓ 12 % Cτ ↓ 36 % DRV ⟷ RTV ⟷ | Darunavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Other Agents | ||
| Dofetilide Pilsicainide | Dofetilide ↑ Pilsicainide ↑ | Co-administration of dolutegravir has the potential to increase dofetilide or pilsicainide plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Dofetilide or pilsicainide co-administration with dolutegravir is contraindicated due to the potential life-threatening toxicity caused by high dofetilide or pilsicainide concentration (see CONTRAINDICATIONS). |
| Oxcarbazepine Phenytoin Phenobarbital Carbamazepine St. John's wort | Dolutegravir ↓ | Co-administration may decrease dolutegravir plasma concentration and has not been studied. Co-administration with these metabolic inducers should be avoided. |
| Antacids containing polyvalent cations (e.g., Mg, Al or Ca) | Dolutegravir ↓ AUC ↓ 74 % Cmax ↓ 72 % C24 ↓ 74 % | Co-administration of antacids containing polyvalent cations decreased dolutegravir plasma concentration. TRELAVUE is recommended to be administered 2 hours before or 6 hours after taking antacid products containing polyvalent cations. |
| Calcium supplements | Dolutegravir ↓ AUC ↓ 39 % Cmax ↓ 37 % C24 ↓ 39 % | TRELAVUE is recommended to be administered 2 hours before or 6 hours after taking products containing calcium, or alternatively, administer with food. |
| Iron supplements | Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 57 % C24 ↓ 56 % | TRELAVUE is recommended to be administered 2 hours before or 6 hours after taking products containing iron, or alternatively, administer with food. |
| Metformin | Metformin ↑ | Co-administration of dolutegravir increased metformin plasma concentration. Metformin is contraindicated in patients taking TRELAVUE (see CONTRAINDICATIONS). |
| Rifampicin | Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 43 % Cτ ↓ 72 % | Rifampicin decreased dolutegravir plasma concentration. Since the dose of dolutegravir is 50 mg twice daily when co- administered with rifampicin, the co-administration of rifampicin with TRELAVUE is not recommended. |
| Oral contraceptives (Ethinyl estradiol (EE) and Norgestromin (NGMN)) | Effect of dolutegravir: EE ⟷ AUC ↑ 3 % Cmax ↓ 1 % Cτ ↑ 2 % Effect of dolutegravir: NGMN ⟷ AUC ↓ 2 % Cmax ↓ 11 % Cτ ↓ 7 % | Dolutegravir did not change ethinyl estradiol and norgestromin plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is necessary when co- administered with dolutegravir. |
| Methadone | Effect of dolutegravir: Methadone ⟷ AUC ↓ 2 % Cmax ⟷ 0 % Cτ ↓ 1 % | Dolutegravir did not change methadone plasma concentrations to a clinically relevant extent. No dose adjustment of methadone is necessary when co-administered with dolutegravir. |
Abbreviations: ↑ = increase; ↓ = decrease; ⟷ = no significant change; AUC = area under the concentration versus time curve; Cmax = maximum observed concentration, Cτ = concentration at the end of dosing interval.
Table 4. Medicine Interactions studied with abacavir:
| Concomitant Medicine Class: Medicine Name | Effect on Concentration of abacavir or Concomitant Medicine | Clinical Comment |
|---|---|---|
| Methadone (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 % | The changes in abacavir pharmacokinetics are not considered clinically relevant. The changes in methadone pharmacokinetics are not considered clinically relevant for the majority of patients, however occasionally methadone dose re-titration may be required. |
| Ethanol | Abacavir AUC ↑ 41 % Ethanol AUC ⟷ | Given the safety profile of abacavir, these findings are not considered clinically significant. |
Abbreviations: ↑ = Increase; ↓ = decrease; ⟷ = no significant change; AUC = area under the concentration versus time curve; Cmax = maximum observed concentration, CL/F = apparent clearance
Table 5. Medicine Interactions studied with lamivudine:
| Concomitant Medicine Class: Medicine Name | Effect on Concentration of lamivudine or Concomitant Medicine | Clinical Comment |
|---|---|---|
| Trimethoprim/sulfa- methoxazole (Co- trimoxazole) (160 mg/800 mg once daily for 5 days/300 mg single dose) | Lamivudine: AUC ↑ 40 % Trimethoprim: AUC ⟷ Sulfamethoxazole: AUC ⟷ | Unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see DOSAGE AND DIRECTIONS FOR USE). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis jiroveci (P. carinii) pneumonia and toxoplasmosis has not been studied. TRELAVUE should not be used for subjects with CLcr of <50 ml/min (see CONTRAINDICATIONS). |
| Emtricitabine | Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these medicines in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations. | |
| Zalcitabine | Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. TRELAVUE is therefore not recommended to be used in combination with zalcitabine. |
TRELAVUE should not be used during pregnancy and lactation as teratogenicity has been observed in animal studies.
The safe use of TRELAVUE in human pregnancy 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, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs) such as abacavir and lamivudine. The clinical relevance of transient elevations in serum lactate is unknown. There have also been reports of developmental delay, seizures and other neurological disease.
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. Therefore, mothers breastfeeding their infants should not use TRELAVUE.
There have been no studies to investigate the effect of TRELAVUE on driving performance or the ability to operate machinery. The clinical status of the patient and the adverse event profile of TRELAVUE should be borne in mind when considering the patient's ability to drive or operate machinery.
TRELAVUE contains dolutegravir, abacavir and lamivudine, therefore the adverse events associated with these may be expected.
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. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. 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. Symptoms can occur at any time while being treated with abacavir, but usually appear within the first six weeks of initiation of treatment (median time to onset 11 days).
The signs and symptoms of this hypersensitivity reaction are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.
Skin and subcutaneous tissue disorders: rash (usually maculopapular or urticarial)
Gastrointestinal disorders: nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration
Respiratory, thoracic and mediastinal disorders: dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
General disorders and administrative site conditions: fever, fatigue, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis
Nervous system disorders: headache, paraesthesia
Blood and the lymphatic system disorders: lymphopenia
Hepato-biliary disorders: elevated liver function tests, hepatic failure
Musculoskeletal connective tissue and bone disorders: myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase
Renal and urinary disorders: elevated creatinine, renal failure.
Some patients with hypersensitivity were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or re-introduced, leading to a more severe hypersensitivity reaction or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases. If hypersensitivity reaction cannot be ruled out, TRELAVUE, or any other medicinal product containing abacavir should not be restarted.
The symptoms related to this hypersensitivity reaction worsen with continued therapy and usually resolve upon discontinuation of abacavir. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation and may include life-threatening hypotension and death. Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue TRELAVUE and must never be rechallenged with TRELAVUE, or any other medicinal product containing abacavir.
There have been reports of hypersensitivity reactions following re-introduction of abacavir, where the interruption was preceded by a single key symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or a respiratory symptom). Hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction.
Many of the side effects listed 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 reaction. If TRELAVUE has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart abacavir, this must be done only under direct medical supervision (see Special considerations following an interruption of TRELAVUE therapy in Boxed Warning).
Side effects for dolutegravir, abacavir or lamivudine are listed in the tables below by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100), rare (≥1/10 000, <1/1 000) and very rare (<1/10 000), including isolated reports.
Clinical safety data with TRELAVUE are limited. The side effects observed for the combination of the three components of this medicine in analysis of pooled data from clinical trials were generally consistent with the side effect profiles for the individual components dolutegravir, abacavir and lamivudine. However, the following common treatment-emergent side effects were observed with the combination but were not listed in the prescriber information for any of the individual components:
In addition, fatigue and insomnia were observed at a greater frequency with the combination when compared with the individual components. The frequency category for fatigue and insomnia was 'very common' with the combination (previously 'common' with each individual component or with dolutegravir, respectively). There was no difference between the combination and the individual components in severity for any observed side effects.
Table 6. Adverse reactions associated with the individual components of TRELAVUE based on clinical study experience:
| System organ class | Dolutegravir | Abacavir | Lamivudine |
|---|---|---|---|
| Blood and lymphatic systems disorders | Uncommon: neutropenia, anaemia, thrombocytopenia | ||
| Immune system disorders | Uncommon: hypersensitivity (see WARNINGS AND SPECIAL PRECAUTIONS), immune reconstitution syndrome (see WARNINGS AND SPECIAL PRECAUTIONS) | Common: medicine hypersensitivity (see WARNINGS AND SPECIAL PRECAUTIONS) | |
| Metabolism and nutrition disorders | Common: anorexia | ||
| Psychiatric disorders | Common: insomnia, abnormal dreams | ||
| Nervous system disorders | Very common: headache Common: dizziness | Common: headache | Common: headache |
| Gastrointestinal disorders | Very common: nausea, diarrhoea Common: vomiting, flatulence, abdominal pain, upper abdominal pain, abdominal discomfort | Common: nausea, vomiting, diarrhoea | Common: nausea, vomiting, upper abdominal pain, diarrhoea |
| Hepatobiliary disorders | Uncommon: hepatitis | Uncommon: transient rises in liver enzymes (AST, ALT) | |
| Skin and subcutaneous tissue disorders | Common: rash, pruritus | Common: rash | |
| General disorders and administration site conditions | Common: fatigue | Common: fever, lethargy, fatigue | Common: fatigue, malaise, fever |
Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 96 weeks. 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 (see Pharmacodynamic properties - Effects on Renal Function). Small increases in total bilirubin (without clinical jaundice) were observed on dolutegravir. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see Pharmacokinetic properties - Metabolism). Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.
In addition to the side effects included from clinical trial data, the side effects listed in Table 7 below have been identified during post-approval use of abacavir and lamivudine. No dolutegravir or TRELAVUE post-marketing data are available.
Table 7. Side effects based on post-marketing experience:
| System organ class | Abacavir | Lamivudine |
|---|---|---|
| Blood and lymphatic systems disorders | pure red cell aplasia | |
| Metabolism and nutrition disorders | hyperlactataemia 1lactic acidosis | hyperlactataemia 1lactic acidosis |
| Nervous system disorders | paraesthesiae, peripheral neuropathy has been reported although a causal relationship to treatment is uncertain | |
| Gastrointestinal disorders | pancreatitis, but a causal relationship to abacavir is uncertain | rises in serum amylase, pancreatitis, although a causal relationship to lamivudine is uncertain |
| Skin and subcutaneous tissue disorders | rash (without systemic symptoms) erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis | alopecia |
| Musculoskeletal and connective tissue disorders | arthralgia, muscle disorders rhabdomyolysis |
1 Lactic acidosis (see WARNINGS AND SPECIAL PRECAUTIONS)
Redistribution/accumulation of body fat has been observed in some patients receiving combination antiretroviral therapy (see WARNINGS AND SPECIAL PRECAUTIONS).
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