Triploco 600 mg, 200 mg, 300 mg FC tablet.

TRIPLOCO is indicated for use alone as a complete regimen or in combination with other anti-retroviral agents for the treatment of HIV-1 infection in adults.

Adults
Take one TRIPLOCO film-coated tablet daily on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.
Paediatrics
TRIPLOCO is not recommended for use by patients under the age of 18 years.
Renal impairment
TRIPLOCO is a fixed dose combination and should not be used by patients that require dose adjustment, such as those with moderate or severe renal impairment resulting in a creatinine clearance of less than 50 ml/min.
Method of administration
For oral use.

• Hypersensitivity to efavirenz, emtricitabine, tenofovir disoproxil fumarate or to any of the components listed in section 6.1.
• A history of previous liver injury/failure with efavirenz containing antiretroviral treatment (ART).
• Pregnancy and lactation (see section 4.6).
• Patients with moderate to severe renal impairment i.e. creatinine clearance of less than 50 ml/min (see section 4.4 and 5.2).
• TRIPLOCO should not be used concurrently with the following medicinal products due to CYP3A4 competition: terfenadine, astemizole, bepridil, cisapride, ergot derivatives, midazolam, pimozide or triazolam. Failure to observe this contraindication can result in reduced metabolism of these medicines and may result in serious and/or life-threatening side effects such as cardiac dysrhythmias, prolonged sedation and/or respiratory depression (see section 4.5).
• TRIPLOCO and voriconazole should not be administered concurrently because voriconazole plasma concentrations are reduced significantly by efavirenz (see section 4.5).
• TRIPLOCO should not be co-administered with herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see sections 4.4 and 4.5).
• Administration to patients with:
• a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.
• a history of symptomatic cardiac dysrhythmia or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
• severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.
• Co-administration with medicinal products that are known to prolong the QTc interval (proarrhythmic). These medicinal products include: antiarrhythmics of classes IA and III, neuroleptics, antidepressants, certain antibiotics including some from the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungals, certain non-sedating antihistamines (terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see sections 4.4 and 4.5).

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS INCLUDING FATAL CASES HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTI-RETROVIRALS (SEE SECTION 4.4). TRIPLOCO IS NOT INDICATED FOR THE TREATMENT OF CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV). THE SAFETY AND EFFICACY OF TRIPLOCO IN PATIENTS CO-INFECTED WITH HBV AND HIV HAS NOT BEEN ESTABLISHED. PATIENTS ON TENOFOVIR AND EMTRICITABINE HAVE DISPLAYED SEVERE EXACERBATIONS OF HEPATITIS B UPON DISCONTINUATION OF TREATMENT. LIVER FUNCTION SHOULD BE MONITORED CLOSELY FOR SEVERAL MONTHS AFTER DISCONTINUATION OF TRIPLOCO IN PATIENTS WITH HIV AND HBV CO-INFECTION. CLINICAL AND LABORATORY FOLLOW-UP IS NECESSARY AND IF APPROPRIATE ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE SECTION 4.4).

Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis have been reported, including fatal cases, with the use of nucleoside analogues alone or in combination with other anti-retrovirals, with the majority being in women. Obesity and prolonged nucleoside exposure are potential risk factors. Patients with known risk factors for liver disease should only be given nucleoside analogues under cautious observation. 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 u2013 5 mmol/L with minimum symptoms: switch to agents that are less likely to cause lactic acidosis.
• Lactate 5 u2013 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop nucleoside/nucleotide reverse transcriptase inhibitors (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. Any patient that develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations) should immediately cease TRIPLOCO treatment.

Liver disease
Use of TRIPLOCO can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of TRIPLOCO 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. TRIPLOCO is not recommended in patients with moderate to severe hepatic impairment because there are insufficient data to determine whether dose adjustments are required.

Liver failure
There is some evidence that efavirenz is associated with three clinical pathological patterns of drug induced liver failure in HIV positive patients of which the sub massive necrosis histological pattern seems to be associated with high morbidity/mortality risk and may present many months after therapy has been initiated or even stopped. Risk factors include younger age, CD4+ counts u2265350 cell/u03bcl and female gender. Early detection and treatment of the liver failure and the immediate discontinuation of TRIPLOCO or efavirenz containing medicines should be stressed. Patients who discontinued treatment with TRIPLOCO should be followed up for symptoms/signs of liver failure for up to 12 months.

Liver enzymes
In patients with a known or suspected history of Hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. Caution should be exercised and the risk weighed against the benefits of therapy for patients fitting the above profile as well as those with hepatic impairment. Patients on TRIPLOCO or efavirenz containing antiretroviral treatment (ART) should be regularly monitored for jaundice (including a laboratory bilirubin and liver enzymes) and bleeding tendencies.

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 Professional Information for these medicines. Patients co-infected with HIV and HBV who discontinue TRIPLOCO 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 TRIPLOCO therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Renal impairment (see section 4.3)
Efavirenz is not predominantly excreted by the kidneys while tenofovir disoproxil fumarate and emtricitabine are excreted by the kidneys. Since TRIPLOCO is a fixed-dose combination product and the dose of the individual components cannot be altered, patients with creatinine clearance less than 50 ml/min should not receive TRIPLOCO.

CrCl (ml/min) = 140-age (years) x weight (kg) (x 0,85 if female)
72 x serum creatinine (mg/dL)

Renal impairment, has been reported in association with the use of tenofovir disoproxil fumarate (see section 4.8). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRIPLOCO. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment. TRIPLOCO should be avoided with concurrent or recent use of a nephrotoxic agent. In patients with moderate to severe renal impairment, the terminal half-life of TRIPLOCO is increased due to decreased clearance. The dose of TRIPLOCO should therefore be adjusted (see section 4.2).

QTc Prolongation
QTc prolongation has been observed with the use of efavirenz (see sections 4.3 and 4.5). For patients at increased risk of Torsade de Pointes or who are receiving medicinal products with a known risk for Torsade de Pointes, the administration of TRIPLOCO is contraindicated (see section 4.3).

Psychiatric symptoms
There have been reports of patients treated with efavirenz, which is a component of TRIPLOCO, experiencing serious side effects such as severe depression, suicidal ideation, suicide attempts, aggressive behaviour, paranoid reactions and manic reactions. Although efavirenz was associated with an increase in these psychiatric experiences, there are other associated factors such as a history of injection medicine use, psychiatric history and the use of psychiatric medication. Other adverse events such as death by suicide, psychosis like behaviour and delusions have been reported.

Patients with psychiatric adverse experiences should seek medical evaluation for an assessment on whether their symptoms are related to the use of efavirenz, and thus TRIPLOCO (see section 4.8).

Nervous system symptoms
Nervous system symptoms that may be reported during treatment with TRIPLOCO are related to efavirenz, which has the potential to cause: dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, euphoria, confusion, agitation, amnesia, stupor, abnormal thinking and depersonalisation. Nervous system symptoms are more likely to abate after the first 2 to 4 weeks of therapy. It is important to inform patients that they can expect an improvement with continued therapy and that dosing at bedtime may improve the tolerability of nervous system symptoms.

Co-administration of TRIPLOCO with alcohol or psychoactive medicines can result in additive central nervous system effects.

Opportunistic infections
Patients receiving TRIPLOCO 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 providers experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts need to be done.

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

Triple nucleoside therapy
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil fumarate as in TRIPLOCO, was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.

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. 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 signs and symptoms.

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

Skin rash
Rashes may occur and are usually mild to moderate maculopapular skin eruptions that occur within the first two weeks of initiating efavirenz therapy. In most cases the rash resolves after one month of continuing efavirenz therapy. If treatment is interrupted due to the rash, it may be re-initiated later. The various skin rashes may be treated with antihistamines and/or corticosteroids if indicated. This may result in faster resolution and improved tolerability of the rash. TRIPLOCO should be discontinued in patients experiencing the following skin rashes: rashes associated with blistering, desquamation, mucosal involvement, or rashes associated with fever.

Bone effects
The effects of when tenofovir disoproxil fumarate associated changes in bone mineral density and biochemical markers on long-term bone health and future fracture risk, are not known. Osteomalacia associated with the use of tenofovir has been reported associated with proximal renal tubulopathy (see section 4.8). HIV patients who have a history of pathologic bone fracture or are at risk for osteopenia should be considered for bone monitoring. Supplementation with Vitamin D and calcium may be beneficial. If bone abnormalities are suspected, then appropriate consultation must be sought.

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 TRIPLOCO. 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. TRIPLOCO 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.

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.

Convulsions
Patients with a history of convulsions must be monitored for possible convulsions when using efavirenz therapy. Please see section 4.5 for anticonvulsants such as phenytoin and phenobarbital, for the precautions and plasma level monitoring that may be required.

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.

Paediatric use
Tenofovir disoproxil fumarate has not been adequately investigated for use in paediatric patients and therefore TRIPLOCO is not recommended for use in patients under the age of 18 years.

Use in the elderly
In general, elderly patients should be treated cautiously, with heightened awareness that this population group tends to experience decreased hepatic, renal or cardiac function and that they usually have concomitant disease or other medicine therapy. There are insufficient studies on the use of efavirenz, emtricitabine and tenofovir by subjects 65 years and older to determine whether they do respond differently than younger subjects.

Co-administration with related medicines
Do not co-administer TRIPLOCO with the following related medicines:

• emtricitabine, tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate and efavirenz.
• lamivudine, which is similar to emtricitabine including lamivudine/zidovudine, abacavir sulphate/lamivudine or abacavir sulphate/lamivudine/zidovudine.

Efavirenz
Efavirenz is contraindicated for use with medicines that are eliminated predominantly by CYP3A4 hepatic enzymes and that rely on this isoenzyme for clearance (see section 4.3). Altered plasma concentrations may result after co-administration of efavirenz with medicines that are metabolised by isoenzymes 2C9, 2C19, and 3A4 (which are reportedly inhibited by efavirenz) and CYP3A4 (which is reportedly induced by efavirenz). Appropriate dose adjustments may be necessary. Inducers of the CYP3A4 isoenzyme can be expected to increase elimination of efavirenz resulting in lowered plasma concentrations. Medicines regarded as inducers of CYP3A4 include phenobarbital, rifampicin and rifabutin.

Emtricitabine and tenofovir disoproxil fumarate
Medicines such as acyclovir, adefovir, dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir may cause an increase in serum concentrations of emtricitabine and tenofovir. Emtricitabine and tenofovir are primarily eliminated by the kidneys, and therefore have the potential to interact with medicines that reduce renal function or compete for active tubular secretion. Caution should be exercised when TRIPLOCO is given with medicines with potential for this interaction since the serum concentrations of each medicine may increase.

Tenofovir increases the plasma concentrations of didanosine. Suppression of CD4 cell counts have been observed in patients on a combination regimen of tenofovir disoproxil fumarate with didanosine at a daily dose of 400 mg. Patients receiving tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse events. This combination should be undertaken with caution. Didanosine should be discontinued in patients who develop didanosine-associated adverse events (Table 2 in section 4.5 can be consulted for didanosine dosing adjustment recommendations).

Although the mechanism of interaction is not clearly understood, atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The impact of raised tenofovir serum concentrations may involve a higher incidence of tenofovir-related adverse events including renal disorders. TRIPLOCO should be discontinued immediately in patients that experience tenofovir-related side effects. Table 2 in section 4.5 can be consulted for atazanavir dosing adjustment recommendations.

Important medicine interactions for TRIPLOCO are summarised in this leaflet and further tabulated in Table 1, based upon investigations of interaction profiles for the individual active ingredients efavirenz, emtricitabine and tenofovir disoproxil fumarate. Please also see section 4.3. Interaction studies for TRIPLOCO have not been conducted and therefore the information herein is not all inclusive but highlights potentially significant interactions.

Table 1: Contraindicated medicines or medicines not recommended for use with TRIPLOCO

Women of childbearing potential
Women of childbearing age who are using TRIPLOCO should avoid falling pregnant and should ensure this by using a barrier method of contraception in combination with other methods of contraception. Pregnancy testing should also be conducted prior to initiating TRIPLOCO treatment.

Contraception in males and females
Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives, see section 4.5) while on therapy with TRIPLOCO. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of TRIPLOCO is recommended.

Pregnancy
TRIPLOCO should not be used during pregnancy. Administration of efavirenz in the first trimester has the potential to cause harm to the unborn foetus and should the woman become pregnant, she should be educated on the potential harm to the foetus. Efavirenz has been associated with teratogenicity in animals. Retrospective studies of pregnancies with first-trimester exposure to efavirenz as part of a combination regimen have noted a few cases of neural tube defects, including meningomyelocele.

Breastfeeding
TRIPLOCO should not be taken by breast-feeding women. Mothers should be instructed that they may not breastfeed their infants if they are on TRIPLOCO in order to avoid transmission of HIV to the infant. Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants. A risk to the infants cannot be excluded.

Fertility
No human data on the effect of TRIPLOCO are available. Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil on fertility.

Co-administration of TRIPLOCO with alcohol or psychoactive medicines can result in additive central nervous system effects. Patients experiencing central nervous system symptoms such as dizziness, impaired concentration and/or drowsiness should avoid tasks related to operation of machinery and other potentially hazardous tasks.

The Professional Information for efavirenz, emtricitabine and tenofovir disoproxil fumarate in combination with other anti-retroviral medicines, can be referred to for additional information TRIPLOCO side effects are summarised in the tables below.

Table 3: Side effects associated with the use of TRIPLOCO active ingredients

Table 4: Side effects reported from post-marketing surveillance of TRIPLOCO

Standard supportive treatment should be applied for patients who have overdosed on TRIPLOCO. Treatment is based on evidence of toxicity and monitoring of vital signs as well as observation of the patientu2019s clinical status.

Efavirenz
Accidental intake of > 600 mg of efavirenz has resulted in nervous system symptoms such as involuntary muscle contractions. Unabsorbed efavirenz may be removed by activated charcoal. Efavirenz is not effectively removed by haemodialysis.

Emtricitabine and tenofovir disoproxil fumarate
There is no data of severe side effects for emtricitabine and tenofovir disoproxil fumarate. The available studies are at the prescribed doses and therefore data is limited. Emtricitabine and tenofovir may be removed by haemodialysis. A 3-hour haemodialysis period starting 1,5 hours post-dosing (blood flow rate of 400 ml/min and a dialysate flow rate of 600 ml/min) may be able to remove around 30 % of the emtricitabine dose. It is not known whether emtricitabine can be removed by peritoneal dialysis. The extraction coefficient of 54 % for tenofovir results in efficient removal. A 4-hour haemodialysis session following a 300 mg single-dosing of tenofovir disoproxil fumarate may be able to remove approximately 10 % of the administered dose.