Damicava 600 mg/50 mg/300 mg Film-coated tablets

DAMICAVA 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 medicines in DAMICAVA.

DAMICAVA therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

DAMICAVA should not be administered to patients younger than 18 years. DAMICAVA is a fixed-dose tablet and should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance (CrCL) 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 such cases the medical practitioner should refer to the individual product information for these medicines. Since the recommended dose of dolutegravir is 50 mg twice daily for patients with resistance to integrase inhibitors, the use of DAMICAVA is not recommended for patients with integrase inhibitor resistance.

Rifampicin decreased the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking DAMICAVA. There is evidence that the concentration of isoniazid is increased by dolutegravir as contained in DAMICAVA.

Special populations

Adults and adolescents weighing at least 40 kg: The recommended dose is one tablet per day.

Missed dose: If the patient misses a dose of DAMICAVA, the patient should take DAMICAVA as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

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 - Special Patient Populations). When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicine 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, DAMICAVA is contraindicated in patients with a creatinine clearance less than 50 mL/min (see sections 4.3 and 5.2 - Special Patient Populations).

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 DAMICAVA, the separate preparations of dolutegravir, abacavir or lamivudine should be used when administering treatment to such patients. DAMICAVA is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see sections 5.2 u2013 Special populations and 4.3).

Method of administration

Oral. DAMICAVA can be taken with or without food.

DAMICAVA is contraindicated in:

• Patients with known hypersensitivity to dolutegravir, abacavir, lamivudine or to any other ingredient contained in DAMICAVA as listed in section 6.1.
• Combination with dofetilide or pilsicainide.
• Patients with moderate to severe hepatic insufficiency due to the abacavir component (see section 5).
• Patients with renal insufficiency with a creatinine clearance of < 50 mL/min due to the lamivudine component (see section 5).
• Patients who are also taking metformin (see section 4.5).

Safety and efficacy of the individual active ingredients in various antiretroviral regimens with similar dosages as contained in DAMICAVA have been established in clinical studies. However, safety and efficacy of the actives combined in a fixed drug combination (FDC) for the treatment of HIV, as in DAMICAVA have not been established in clinical studies.

All warnings included in this leaflet are relevant to the individual components, abacavir, lamivudine and dolutegravir. No additional warnings relevant to DAMICAVA are included.

Hypersensitivity to abacavir u2013 refer to boxed warning.

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

Lactic acidosis/hyperlactataemia and severe hepatomegaly with steatosis: Use of abacavir and lamivudine as in DAMICAVA can result in potentially fatal lactic acidosis and severe hepatomegaly with steatosis due to mitochondrial dysfunction. Clinical features indicative of lactic acidosis include nausea, vomiting, abdominal pain, dyspnoea, tachypnoea, fatigue and unexplained 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 to 5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 to 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, 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 DAMICAVA to patients with known risk factors for liver disease. Treatment with DAMICAVA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis of hepatotoxicity.

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 DAMICAVA alone or in combination.

Caution should be exercised when administering DAMICAVA particularly to those with known risk factors for liver disease. Treatment with DAMICAVA 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).

Pancreatitis: Pancreatitis has been observed in some patients receiving DAMICAVA. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of DAMICAVA until diagnosis of pancreatitis is excluded.

Renal insufficiency: In patients with moderate to severe renal impairment, the terminal half-life of DAMICAVA is increased due to decreased clearance.

Hepatic impairment: Use of DAMICAVA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of DAMICAVA has not been established in patients with significant underlying liver disorders/diseases. 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. DAMICAVA is contraindicated in patients with moderate to severe hepatic impairment (see section 5).

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.

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 (IRIS): 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 antiretroviral 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 DAMICAVA 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 health care professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

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 package inserts for these medicines. Patients co-infected with HIV and HBV who discontinue DAMICAVA 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. Discontinuation of DAMICAVA therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

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

Cardiovascular events: The risk of cardiovascular events is increased in abacavir containing medicines, including DAMICAVA. Patients with a high risk of cardiovascular events, should avoid using abacavir containing medicines, including DAMICAVA.

Myocardial infarction: 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 taken during co-administration of medicines that may change the exposure of dolutegravir, abacavir, lamivudine or medications that may have their exposure be changed by use of DAMICAVA (see sections 4.3 and 4.5).

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 medicines (see section 4.5). DAMICAVA is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, administered with food (see section 4.5).

DAMICAVA may increase metformin concentrations. Therefore, metformin is contraindicated in patients that are on DAMICAVA treatment (see sections 4.3 and 4.5).

Co-administration of DAMICAVA with medicines containing any of its active components (abacavir, lamivudine and dolutegravir) is contraindicated. Since the recommended dose of dolutegravir is 50 mg twice daily for patients taking efavirenz, nevirapine, rifampicin and tipranavir/ritonavir, the use of DAMICAVA is not recommended for patients taking these medicines (see section 4.5).

Mannitol DAMICAVA contains mannitol which may have an effect on the glycaemic control of patients with diabetes mellitus. DAMICAVA may have a mild laxative effect.

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 DAMICAVA in women of childbearing potential to exclude inadvertent (unintentional) use of DAMICAVA during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.

Pregnancy: 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. Late onset neurological disorders relating to mitochondrial dysfunction have been observed in infants/children who have been exposed in utero and/or postnatally to nucleoside analogues as contained in DAMICAVA (see section 4.4).

Breastfeeding: HIV infected women should not breastfeed their infants in order to avoid transmission of HIV or follow appropriate guidelines. 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 newborn was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants. Lamivudine is excreted in human milk at similar concentrations to those found in serum.

Fertility: There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility (see section 5.3).

DAMICAVA may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or operating machines until they know how DAMICAVA affects them.

Hypersensitivity to abacavir (see also 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 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.

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 rhabdomyolysis, 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, DAMICAVA, or any other medicine 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 DAMICAVA and must never be rechallenged with DAMICAVA, or any other medicine containing abacavir. Most undesirable effects occurring frequently (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients are due to abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If DAMICAVA 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 DAMICAVA therapy in boxed warning).

The undesirable effects observed for the combination of the three components of this medicine are generally consistent with the side effect profiles for the individual components dolutegravir, abacavir and lamivudine. However, the following common treatment-emergent undesirable effects were observed with the combination but were not listed in the prescribed information for any of the individual components.

• Gastrointestinal disorders: abdominal distension, gastro-oesophageal reflux disease, dyspepsia.
• Nervous system disorders: somnolence.
• Psychiatric disorders: depression, nightmare and sleep disorders.
• Metabolism and nutrition disorders: hypertriglyceridaemia and hyperglycaemia.

In addition, fatigue and insomnia were observed at greater frequency with the combination when compared with the individual components. The frequency category for fatigue and insomnia was frequent with the combination.

Undesirable effects associated with the DAMICAVA film-coated tablets:

MedDRA system organ class Frequency Side effects

Metabolism and nutrition disorders: Less frequent: Hypertriglyceridaemia and hyperglycaemia.

Psychiatric disorders: Frequent: Depression, nightmares, sleep disorder. Less frequent: Insomnia, anxiety, suicidal ideation or suicide attempt.

Nervous system disorders: Frequent: Somnolence, lethargy.

Gastrointestinal disorders: Frequent: Abdominal distension, gastro-oesophageal reflux disease, dyspepsia.

General disorders and administrative site conditions: Frequent: Fatigue.

Investigations: Frequent: CPK elevations, ALT/AST elevations.

Table 6: Reported adverse events associated with individual components of the DAMICAVA System organ class Dolutegravir Abacavir Lamivudine Blood and lymphatic system disorder Less frequent: neutropenia, anaemia, thrombocytopenia. Immune system disorders Less frequent: hypersensitivity. (see section 4.4) Frequent: medicine Hypersensitivity. (see section 4.4).

Signs and symptoms: Data are limited with regards to dolutegravir overdosage.

Treatment: 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.