Kavideza 600 mg. 50 mg. 300 mg Film-coated tablets

KAVIDEZA 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 KAVIDEZA.

Posology
KAVIDEZA therapy should be initiated by a medical practitioner experienced in the management of HIV infection.
Adults and adolescents
The recommended dose of KAVIDEZA in adults and adolescents weighing more than 40 kg is one tablet once daily. KAVIDEZA should not be administered to patients younger than 18 years. KAVIDEZA 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 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 KAVIDEZA is not recommended for patients with integrase inhibitor resistance.
Special Populations:
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 medicines 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, KAVIDEZA should not be used in patients with a creatinine clearance less than 50 mL/min (see sections 5.2 and 4.3).
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 KAVIDEZA, the separate preparations of dolutegravir, abacavir or lamivudine should be used when this is deemed necessary. KAVIDEZA is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see sections 5.2 and 4.3).
Paediatric population
KAVIDEZA should not be used in children under the age of 18 years.
Method of administration
Oral use. KAVIDEZA can be taken with or without food (see section 5.2).

• KAVIDEZA is contraindicated in patients with known hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients of KAVIDEZA.
• KAVIDEZA is contraindicated in combination with dofetilide and pilsicainide.
• KAVIDEZA is contraindicated in moderate and severe hepatic impairment due to the abacavir component (see section 5.1).
• KAVIDEZA is contraindicated during pregnancy or in mothers who are breastfeeding their infants (see section 4.6).
• KAVIDEZA is contraindicated in patients with renal impairment with a creatinine clearance of <50 mL/min due to the lamivudine component (see section 5.1).
• Metformin is contraindicated in patients taking KAVIDEZA.

Warnings relevant to dolutegravir, abacavir and lamivudine are included in this section. There are no additional warnings relevant to KAVIDEZA.
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. Discontinue KAVIDEZA immediately if signs or symptoms of hypersensitivity reaction 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 KAVIDEZA after the onset of hypersensitivity may result in a life-threatening reaction.
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 (see section 4.8). 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. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.
Liver disease
Use of KAVIDEZA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of KAVIDEZA has not been established in patients with significant underlying liver disorders/diseases. KAVIDEZA is contraindicated in patients with moderate to severe hepatic impairment (see sections 4.3 and 5.2). In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information leaflets 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 package inserts for these medicines. Patients co-infected with HIV and HBV who discontinue KAVIDEZA 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 KAVIDEZA therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.
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.
Lactic acidosis / hyperlactataemia
Use of KAVIDEZA can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific and include nausea, vomiting, abdominal pain, generalised weakness, anorexia and sudden unexplained weight loss, 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:
u2022 Lactate 2-5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
u2022 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.
u2022 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 KAVIDEZA to patients with known risk factors for liver disease. Treatment with KAVIDEZA 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-natal 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). Whether the neurological disorders are transient or permanent is currently unknown. Any foetus exposed in utero to nucleoside and nucleotide analogues, such as lamivudine and abacavir in KAVIDEZA, 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 signs or symptoms.
Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of KAVIDEZA is increased due to decreased clearance. The dose of KAVIDEZA should therefore be adjusted.
Cardiovascular events
Although the available data from clinical and observational studies with abacavir show inconsistent results, several studies suggest an increased risk of cardiovascular events (notably myocardial infarction) in patients treated with abacavir. Therefore, when prescribing KAVIDEZA, action should be taken to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). In addition, alternative treatment options to the abacavir containing regimen should be considered when treating patients with a high cardiovascular risk.
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 KAVIDEZA 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 KAVIDEZA, 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.
Pancreatitis
Pancreatitis has been observed in some patients receiving KAVIDEZA. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of KAVIDEZA until diagnosis of pancreatitis is excluded.
Medicine interactions
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 KAVIDEZA (see sections 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. KAVIDEZA is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5). KAVIDEZA 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). Dolutegravir increase metformin concentrations. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45u201359 mL/min). Metformin is contraindicated in patients taking KAVIDEZA (see section 4.3).

KAVIDEZA contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to KAVIDEZA. No clinically significant medicine interactions are expected between dolutegravir, abacavir and lamivudine.
Effect of other medicines on the pharmacokinetics of dolutegravir, abacavir and lamivudine
Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of KAVIDEZA and other medicines that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may therefore increase dolutegravir plasma concentration. Medicines that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). The absorption of dolutegravir is reduced by certain anti-acid medicines (see Table 1). Abacavir is metabolised by UGT (UGT2B7) and alcohol dehydrogenase; co-administration of inducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co-administration of dolutegravir based on a cross-study analysis, indicating that dolutegravir has no effect on lamivudine exposure in vivo. Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, interactions due to inhibition of OCT1 are unlikely to be of clinical significance. Although abacavir and lamivudine are substrates of BCRP and P-gp in vitro, given the high absolute bioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on abacavir or lamivudine concentrations.
Effect of dolutegravir, abacavir and lamivudine on the pharmacokinetics of other medicines
In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicines that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2). In vitro, dolutegravir inhibited the renal transporters OCT2 and MATE1. In vivo, a 10 u2013 14 % decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 or MATE-1 (e.g. metformin) (see Table 1). In vitro, dolutegravir inhibited the renal uptake organic anion transporters (OAT)1 and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OAT3. In vitro, abacavir was an inhibitor of MATE1; the clinical consequences are not known. In vitro, lamivudine was an inhibitor of OCT1 and OCT2; the clinical consequences are not known. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicines are listed in Table 1.

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 KAVIDEZA in women of childbearing potential to exclude inadvertent (unintentional) use of KAVIDEZA 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:
KAVIDEZA should not be used during pregnancy and lactation as teratogenicity has been observed in animal studies. The safe use of KAVIDEZA in human pregnancy has not been established. Dolutegravir, lamivudine and abacavir were shown to cross the placenta in reproductive toxicity studies in animals. 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. For patients co-infected with hepatitis B who are being treated with a lamivudine containing medicine such as KAVIDEZA and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine. Elevations in serum lactate levels: 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 (see section 4.4). The clinical relevance of transient elevations in serum lactate is unknown. There have also been reports of developmental delay, seizures and other neurological disease.
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 < 4 % of maternal serum concentrations. Therefore, mothers breastfeeding their infants should not take KAVIDEZA.
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 (see section 5.3).

Adverse effects such as fatigue and insomnia have been observed during treatment with KAVIDEZA and should be borne in mind when considering the patientu2019s ability to drive or operate machinery.

KAVIDEZA contains dolutegravir, abacavir and lamivudine, therefore the adverse events associated with these may be expected. The side effects listed below have been identified during post-approval use of abacavir, lamivudine and dolutegravir.
Side effects based on post-marketing experience:

a. Summary of the safety profile
The most frequently reported adverse reactions considered possibly or probably related to dolutegravir and abacavir/lamivudine were nausea, insomnia, dizziness and headache. Adverse reactions listed in the table below occur frequently (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 (see section 4.4). Less frequent cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicines containing abacavir should be permanently discontinued. The most severe adverse event related to the treatment with dolutegravir and abacavir/lamivudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects (see section Boxed warning, section 4.4 and Description of selected adverse reactions in this section).

b. Tabulated list of adverse reactions
The adverse reactions considered related to treatment with the components of KAVIDEZA and post-marketing experience are listed in Table 2 by body system, organ class and frequency.

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

c. Description of selected adverse reactions
Hypersensitivity reactions. Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), which were observed more commonly with abacavir. Hypersensitivity reaction observed for each of these medicines (described below) share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Time to onset was typically 10 - 14 days for both abacavir and dolutegravir-associated reactions, although reactions to abacavir may occur at any time during therapy. Treatment with KAVIDEZA must be stopped without delay if HSR cannot be ruled out on clinical grounds, and therapy with KAVIDEZA or other abacavir or dolutegravir containing medicines must never be re-initiated. Please refer to BOXED WARNING and section 4.4 for further details on patient management in the event of a suspected HSR to KAVIDEZA.
Dolutegravir hypersensitivity
Symptoms have included rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.
Abacavir hypersensitivity
The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post-marketing surveillance. Those reported in at least 10 % of patients with a hypersensitivity reaction are in bold text. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.
Skin 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 lymphatic system disorders: Lymphopenia.
Hepatobiliary disorders: Elevated liver function tests, hepatic failure.
Musculoskeletal connective tissue and bone disorders: Myalgia, rarely myolysis, arthralgia, elevated creatinine phosphokinase.
Renal and urinary disorders: Elevated creatinine, renal failure.
Symptoms related to this HSR worsen with continued therapy and can be life-threatening and in rare instance, have been fatal. Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation and may include life-threatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).

Symptoms and signs
In overdose, side effects can be precipitated and/or be of increased severity.
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. There is currently limited experience with overdosage in dolutegravir. However, as dolutegravir is highly bound by plasma proteins, it is unlikely that it will be significantly removed by dialysis.