Aedatri 300mg Tablet

AEDATRI is indicated for the treatment of HIV-1 infection in adults aged 18 years and older.

Posology
Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.
Adults
The dose of AEDATRI is one tablet taken orally, once daily, without regard to food.
Paediatrics
AEDATRI is not recommended for use in patients younger than 18 years of age.
Dose adjustment for renal impairment
Significantly increased exposure occurred when tenofovir, as in AEDATRI, was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in AEDATRI, have not been evaluated in non-haemodialysis patients with creatinine clearance < 50 mL/min; therefore, no dosing recommendations are available for these patients. AEDATRI is not suitable for use in patients with renal impairment with creatinine clearance less than 50 mL/min. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking AEDATRI.
Method of administration
AEDATRI tablets are to be taken orally, once daily, without regard to food.

• AEDATRI is contraindicated in patients with known hypersensitivity to dolutegravir, lamivudine, tenofovir disoproxil fumarate or any of the components of AEDATRI.
• Uncontrolled renal failure (see section 4.4).
• Pregnancy and lactation (see section 4.6).
• Women of child-bearing age not using highly effective contraception.
• Concomitant use with adefovir dipivoxil.
• Co-administration with dofetilide and pilsicainide.
• Co-administration with didanosine.
• Co-administration with metformin.
• Patients younger than 18 years of age.
• Moderate and severe hepatic impairment.

Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in AEDATRI have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in AEDATRI for the treatment of HIV have not been established in clinical studies.
The complete patient information leaflets of the other medicines used in combination should be consulted before initiation of therapy.
Metabolic abnormalities
Combination antiretroviral therapy, including AEDATRI has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Lipodystrophy
Combination antiretroviral therapy, including AEDATRI, has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients.
A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also 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, atypical mycobacterial infections, cytomegalovirus retinitis, pneumocystis jirovecii, 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 Gravesu2019 disease, Guillain-Barre syndrome, polymyositis) 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), including components of AEDATRI. 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 AEDATRI may continue to develop opportunistic infections and other complications of HIV infection and therefore should remain under close clinical observation by doctors experienced in the treatment of patients with HIV associated diseases.
The risk of HIV transmission to others
Patients must be advised that treatment with AEDATRI has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in AEDATRI. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and respond as follows:
- Lactate 2 to 5 mmol/L: monitor regularly and be alert for clinical signs.
- Lactate 5 to 10 mmol/L without symptoms: monitor closely.
- Lactate 5 to 10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g., sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma).
- Lactate > 10 mmol/L: STOP all therapy (80 % mortality in case studies). 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 acidotic patient with a raised lactate level.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of AEDATRI alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering AEDATRI to patients with known risk factors for liver disease. Treatment with AEDATRI should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Caution should be exercised when administering nucleoside analogues as contained in AEDATRI to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicines and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. However, cases have also been reported in patients with no known risk factors. Patients at increased risk should be followed closely.
There are no study results demonstrating the effect of AEDATRI on clinical progression of HIV-1.
Mitochondrial dysfunction
Nucleoside and nucleotide analogues as contained in AEDATRI 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 postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipidaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsions, abnormal behaviour). Whether the neurological disorders are transient or permanent is unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms.
Pancreatitis
Pancreatitis has been observed in some patients receiving lamivudine, as in AEDATRI. It is unclear whether this is due to lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of AEDATRI until diagnosis of pancreatitis is excluded.
Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of AEDATRI is increased due to decreased clearance. The dose of AEDATRI should therefore be adjusted (see section 4.2).
Liver disease
Use of AEDATRI can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of AEDATRI has not been established in patients with significant underlying liver disorders. 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 according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Renal impairment
AEDATRI is a combination medicine and the dose of the individual components cannot be altered. Tenofovir and lamivudine are principally eliminated by the kidney. AEDATRI is not recommended for patients with creatinine clearance < 50 mL/min or patients who require haemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia) has been reported with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal function (serum creatinine and serum phosphate) is therefore recommended before taking AEDATRI.
Renal function
Since AEDATRI is primarily eliminated by the kidneys, co-administration of AEDATRI with medicines that reduce renal function or compete for active tubular secretion, may increase serum concentrations of AEDATRI and/or increase the concentrations of other renally eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.
Renal monitoring
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
Co-administration and risk of renal toxicity
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicine (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g., cidofovir, a known nephrotoxic medicine). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicines, which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicines which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.
AEDATRI should be avoided with concurrent or recent use of a nephrotoxic medicine. Patients at risk of, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic substances should be carefully monitored for changes in serum creatinine and phosphorus.
K65R mutation
AEDATRI should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.
Bone mineral density
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline are significantly greater with tenofovir disoproxil fumarate as contained in AEDATRI. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected, then appropriate consultation should be obtained. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia. AEDATRI may cause a reduction in bone mineral density. The effects of tenofovir disoproxil fumarate-associated changes in bone mineral density on long-term bone health and future fracture risk are currently unknown. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.
Patients with HIV and hepatitis B or C virus co-infection
AEDATRI is not indicated for the treatment of chronic HBV infection. The safety and efficacy of AEDATRI has not been established for the treatment of patients co-infected with HBV and HIV. 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 with chronic hepatitis B or C treated with AEDATRI are at an increased risk for severe and potentially fatal hepatic adverse reactions. Doctors should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV).
Exacerbations of hepatitis
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Flares after treatment discontinuation: Acute exacerbations of hepatitis have been reported in patients after the discontinuation of hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.
Hypersensitivity reactions
Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir and were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. Discontinue AEDATRI and other suspect medicines 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 AEDATRI or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.
Important identified risks
Depression (including suicidal ideation and behaviours, particularly in patients with pre-existing history of depression or psychiatric illness).
Use in elderly
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Excipients
AEDATRI contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium free.

The likelihood of interactions is low due to the limited metabolism and plasma protein binding and almost complete renal clearance. Zidovudine plasma levels are not significantly altered when co-administered with lamivudine. Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine. Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in lamivudine plasma levels. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of co-trimoxazole. The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal. No medicine interaction studies have been conducted using AEDATRI. As AEDATRI contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with AEDATRI. Important medicine interaction information for AEDATRI is summarised in Table 1, 2 and 3. The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines or are potential medicine interactions. While the tables include potentially significant interactions, they are not all inclusive. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicines is low.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed.
Tenofovir
Renally eliminated medicines
Tenofovir, as in AEDATRI, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of AEDATRI with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered medicines due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir, as in AEDATRI. Tenofovir has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, oral contraceptives and ribavirin. Tables 1 and 2 summarise pharmacokinetic effects of co-administered medicine on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics of co-administered medicine.
When administered with multiple doses of tenofovir, the C max and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with tenofovir, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

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 AEDATRI in women of childbearing potential to exclude inadvertent (unintentional) use of AEDATRI during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.
Pregnancy
AEDATRI is contraindicated in pregnancy (see section 4.3). 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). 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. Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine (see section 4.4). AEDATRI should not be prescribed in women who plan to become pregnant. Women of child-bearing age should not use AEDATRI unless they are reliably using highly effective contraception. Treatment with AEDATRI should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with AEDATRI; and especially in the event that pregnancy is suspected.
Breastfeeding
AEDATRI is contraindicated in lactation (see section 4.3). HIV infected mothers should not breastfeed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Mothers breastfeeding their infants should not use AEDATRI. Lamivudine is excreted in human milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infant due to slow elimination; the half-life of dolutegravir in the newborn was 33 hr compared to 14 hr in adults. There is insufficient information on the effects of dolutegravir in neonates/infants.
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.

AEDATRI causes dizziness, impaired concentration and/or drowsiness and may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or using machines until they know how AEDATRI affects them.

a. Summary of the safety profile
Studies revealed the most severe adverse reactions linked to dolutegravir treatment are hypersensitivity reactions that include rash and severe liver effects. The most common adverse reactions of dolutegravir are nausea (13 %), diarrhoea (18 %) and headache (13 %). Renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported rarely in patients receiving tenofovir disoproxil. Monitoring of renal function is recommended for patients receiving AEDATRI (see section 4.4).
b. Tabulated list of adverse reactions
Table 5 Adverse effects for AEDATRI
MedDRA system organ class Frequency Side effects Blood and lymphatic system disorders Less frequent Neutropenia, anaemia, thrombocytopenia, pure red cell aplasia. Immune system disorders Less frequent Hypersensitivity, immune reactivation syndrome. Metabolism and nutrition disorders Frequent Hypophosphatemia. Less frequent Lactic acidosis. Frequency unknown Hypokalaemia. Psychiatric disorders Frequent Insomnia, abnormal dreams, depression, anxiety. Less frequent Suicidal ideation or suicide attempt. Nervous system disorders Frequent Headache, dizziness. Less frequent Peripheral neuropathy, paraesthesia. Respiratory, thoracic and mediastinal disorders Frequent Cough, nasal symptoms. Less frequent Dyspnoea. Gastrointestinal disorders Frequent Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort. Less frequent Pancreatitis, elevated serum amylases. Hepato-biliary disorders Less frequent Hepatitis. Frequency unknown Hepatic steatosis. Skin and subcutaneous tissue disorders Frequent Rash, pruritus, hair loss. Musculoskeletal, connective tissue and bone disorders Less frequent Arthralgia, myalgia. Frequency unknown Rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, osteonecrosis. Renal and urinary disorders Less frequent Rare acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased serum creatinine, acute tubular necrosis. Frequency unknown Nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus. General disorders and administrative site conditions Frequent Fatigue, malaise, fever. Less frequent Asthenia. Frequency unknown Immune reconstitution syndrome. Investigations Frequent Raised alanine aminotransferase (ALT) and aspartate aminotransferase (AST), raised creatinine kinase.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Dolutegravir
Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of AEDATRI. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As AEDATRI is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
Lamivudine
Limited data are available on the consequences of ingestion of acute overdose in humans. If overdosage occurs the patient should be monitored, and palliative supportive treatment applied as required.
Tenofovir disoproxil fumarate
If overdose occurs the patient must be monitored for evidence of toxicity and palliative supportive treatment be applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 mL/min. The elimination of tenofovir by peritoneal dialysis has not been studied.