Tulodiv, 600 , 50 , 300 , 600 mg, 50 mg, 300 mg, FC tablets

TULODIV is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 18 years of age, who are antiretroviral treatment-nau00efve or are infected with HIV without documented or clinically suspected resistance to any of the three antiretroviral agents in TULODIV.

TULODIV therapy should be initiated by a medical practitioner experienced in the management of HIV infection. TULODIV should not be administered to patients younger than 18 years. TULODIV is a fixed-dose tablet and should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance less than 50 ml/min. Separate preparations of dolutegravir, abacavir or lamivudine should be administered in cases where discontinuation or dose adjustment is indicated. In these cases, the medical practitioner should refer to the individual professional information for these medicinal products. Since the recommended dose of dolutegravir is 50 mg twice daily for patients with resistance to integrase inhibitors, the use of TULODIV is not recommended for patients with integrase inhibitor resistance.

Special Populations

Adults and adolescents
The recommended dose of TULODIV in adults and adolescents weighing more than 40 kg is one tablet once daily.

Elderly
There are limited data available on the use of dolutegravir, abacavir and lamivudine in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2). When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicinal products or disease.

Renal impairment
Whilst no dosage adjustment of dolutegravir or abacavir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore, TULODIV should not be used in patients with a creatinine clearance less than 50 ml/min (see section 4.3 and 5.2).

Hepatic impairment
A dose reduction of abacavir may be required for patients with mild hepatic impairment (Child-Pugh grade A). As dose reduction is not possible with TULODIV, the separate preparations of dolutegravir, abacavir or lamivudine should be used when this is judged necessary. TULODIV is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see section 4.3 and 5.2).

Method of administration: For oral use. TULODIV can be taken with or without food.

• Hypersensitivity to abacavir, dolutegravir or lamivudine, or to any of the components listed in section 6.1.
• Patients with moderate and severe hepatic impairment due to the abacavir component (see section 4.2 and 5.2).
• Patients with renal impairment with a creatinine clearance of < 50 ml/min due to the lamivudine component (see section 4.2 and 5.2).
• TULODIV is contraindicated in combination with dofetilide or pilsicainide.
• Metformin is contraindicated in patients taking TULODIV.
• TULODIV is contraindicated during first trimester of pregnancy and in mothers who are breastfeeding their infants.

Hypersensitivity to abacavir (see section 4.8)
In clinical studies conducted before the introduction of screening for the HLA-8*5701 allele, approximately 5 % of participants receiving abacavir developed a hypersensitivity reaction, which in some cases has proved fatal.

Risk factors
Studies have shown that carriage of the HLA-8*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. In the prospective study CNA 106030 (PREDICT-1), use of pre-therapy screening for the HLA-8*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-8*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-8*5701 allele. Medical Practitioners should screen for carriage of the HLA-8*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-8*5701 status who have previously tolerated abacavir (see "Special considerations following an interruption of abacavir therapy"). Use of abacavir in patients known to carry the HLA-8*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-8*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. Some of the other 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 (predominantly infiltrates, which can be localised). 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-8*5701 status, any patient developing signs or symptoms of hypersensitivity MUST contact their medical practitioner immediately for advice. If a hypersensitivity reaction is diagnosed TULODIV MUST be discontinued immediately. TULODIV, or any other medicinal product containing abacavir, MUST NEVER be restarted following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death. To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, TULODIV should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). TULODIV, or any other medicinal product containing abacavir, should not be restarted even if a recurrence of symptoms occurs following rechallenge with alternative medication(s). An Alert Card with information for the patient about this hypersensitivity reaction is included in the TULODIV pack.

Special considerations following an interruption of TULODIV therapy
Regardless of a patient's HLA-B*5701 status, if therapy with any abacavir containing product has been discontinued and restarting therapy with TULODIV 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, TULODIV 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 TULODIV in these patients, this should be done only under direct medical supervision. On 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 TULODIV, this must be done only if medical care can be accessed readily by the patient or others.

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 medical practitioner IMMEDIATELY.
• Patients who are hypersensitive to abacavir should be reminded that they must never take TULODIV or any other medicinal product containing abacavir again, regardless of their HLA-8*5701 status.
• In order to avoid restarting TULODIV, patients who have experienced a hypersensitivity reaction should be asked to return the remaining TULODIV tablets to the pharmacy.
• Patients who have stopped TULODIV for any reason and particularly due to possible adverse reactions or illness, must be advised to contact their medical practitioner before restarting.
• Each patient should be reminded to read the patient information leaflet included in the TULODIV 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.

Hypersensitivity to dolutegravir
Hypersensitivity reactions have been reported with dolutegravir and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue TULODIV 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 TULODIV after the onset of hypersensitivity may result in a life-threatening reaction.

Myocardial infarction
In a reported 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).

Lipodystrophy and metabolic abnormalities
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 and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome
Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis
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.

Opportunistic infections
Patients receiving TULODIV should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others
Patients should be advised that antiretroviral therapy, including TULODIV, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Lactic acidosis/hyperlactataemia
Use of TULODIV can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate and respond as follows:

• Lactate 2-5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5-10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism.
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality). The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering TULODIV to patients with known risk factors for liver disease. Treatment with TULODIV should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

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 HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see above), 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
Pancreatitis has been observed in some patients receiving TULODIV. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of TULODIV until diagnoses of pancreatitis is excluded.

Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of lamivudine is increased due to decreased clearance, hence a dose reduction of lamivudine is required whilst no dosage adjustment of dolutegravir or abacavir is necessary. Therefore, TULODIV should not be used in patients with a creatinine clearance less than 50 ml/min (see section 4.2, 4.3 and 5.2).

Liver disease
Use of TULODIV can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of TULODIV has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information for these medicines. 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. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Patients with HIV and hepatitis B or C virus co-infection
Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines. Patients co-infected with HIV and HBV who discontinue TULODIV should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Caution should be given to co-administering medications (prescription and non-prescription) that may change the exposure of abacavir, dolutegravir, lamivudine or medications that may have their exposure changed by TULODIV (see section 4.3 and 4.5). 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 section 4.5). 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 medicinal products (see section 4.5). TULODIV is recommended to be administered 2 hours before or 6 hours after taking supplements or multivitamins containing calcium, iron or magnesium, or alternatively, administered with food (see section 4.5). Metformin concentrations may be increased by TULODIV. Metformin is contraindicated in patients taking TULODIV (see section 4.3). TULODIV should not be administered concurrently with other medicinal products containing any of the same active components (abacavir, dolutegravir, 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 TULODIV is not recommended for patients taking these medicines (see section 4.5).

Women of childbearing potential
Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of TULODIV in women of childbearing potential to exclude inadvertent (unintentional) use of TULODIV during the first trimester of pregnancy.

Pregnancy
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. Abacavir and lamivudine may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown. Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0, 19 %) compared to non-dolutegravir regimens (0, 11 %). 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, the benefits and risks of continuing dolutegravir 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. Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known.

Breastfeeding
HIV infected women should not breastfeed their infants in order to avoid transmission of HIV. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the new born was 33 hours compared to 14 hours in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants. Abacavir is 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.

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.

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 TULODIV should be borne in mind when considering the patient's ability to drive or operate machinery.

Hypersensitivity to abacavir (see section 4.4 Boxed warning)
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 urticaria!) 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.

Skin and subcutaneous tissue disorders: rash (usually maculopapular or urticaria!)

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, hepatitis, 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, TULODIV, 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-8*5701 status, patients who develop this hypersensitivity reaction must discontinue TULODIV and must never be rechallenged with TULODIV, 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 TULODIV 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 section 4.4 Boxed Warning).

Table 2: Tabulated summary of adverse reactions associated with the combination of abacavir, dolutegravir and lamivudine

System Organ Class
Frequency
Adverse reactions

Blood and lymphatic system disorders
Less frequent: neutropenia, anaemia, thrombocytopenia, pure red cell aplasia

Immune system disorders
Frequent: hypersensitivity
Less frequent: immune reconstitution syndrome

Metabolism and nutrition disorders
Frequent: anorexia
Less frequent: hypertriglyceridaemia, hyperglycaemia, lactic acidosis

Psychiatric disorders
Frequent: insomnia, abnormal dreams, depression, anxiety, nightmare, sleep disorder
Less frequent: suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness)

Nervous system disorders
Frequent: headache, dizziness, somnolence, lethargy
Less frequent: peripheral neuropathy, paraesthesia

Respiratory, thoracic and mediastinal disorders
Frequent: cough, nasal symptoms

Gastrointestinal disorders
Frequent: nausea, diarrhoea, vomiting, flatulence, abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, gastro-oesophageal reflux disease, dyspepsia
Less frequent: pancreatitis

Hepatobiliary disorders
Frequent: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations
Less frequent: hepatitis, acute hepatic failure, increased bilirubin

Skin and subcutaneous tissue disorders
Frequent: rash, pruritus, alopecia
Less frequent: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders
Frequent: arthralgia, muscle disorders (including myalgia)
Less frequent: rhabdomyolysis

General disorders and administration site conditions
Frequent: fatigue, asthenia, fever, malaise
Investigations
Frequent: Creatinine phosphokinase (CPK) elevations
Less frequent: amylase elevations

Table 3: Tabulated summary of adverse reactions associated with the individual components of TULODIV

System Organ Class
Frequency
Adverse reactions

Abacavir
Blood and lymphatic system disorders
Less frequent: neutropenia, anaemia, thrombocytopenia

Immune system disorders
Frequent: hypersensitivity
Less frequent: hypersensitivity, immune reconstitution syndrome

Metabolism and nutrition disorders
Frequent: anorexia

Psychiatric disorders
Frequent: insomnia, abnormal dreams

Nervous system disorders
Frequent: headache

Gastrointestinal disorders
Frequent: nausea, vomiting

Hepatobiliary disorders
Less frequent: hepatitis

Skin and subcutaneous tissue disorders
Frequent: rash, pruritis

General disorders and administration site conditions
Frequent: fatigue, fever, malaise

There is currently limited experience with overdosage in dolutegravir. The patient should be treated symptomatically and supportively with appropriate monitoring as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.