Tenofovir Disoproxil Fumarate / Lamivudine / Efavirenz Tablets IP 300 mg / 300 mg / 600 mg
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only Label claim Each film coated tablet contains Tenofovir Disoproxil Fumarate IP 300 mg Lamivudine IP 300 mg Efavirenz IP 600 mg Colour:
Titanium dioxide List of Excipients: Microcrystalline cellulose, Croscarmellose sodium, Hydroxypropyl cellulose, Sodium lauryl sulfate, Sodium chloride, Magnesium stearate, Lactose monohydrate, film coat {Titanium dioxide, Polyethylene glycol, Talc, Polyvinyl alcohol} Therapeutic indications Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is a fixed dose combination of tenofovir disoproxil fumarate, lamivudine and efavirenz.
It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy. The choice of Tenofovir Disoproxil Fumarate/Lamivudine/ Efavirenz 600mg/300mg/300mg Tablets to treat antiretroviral experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or the treatment history of the patient. Consideration should be given to official treatment guidelines for HIV-1 infection (e.g. by WHO). Posology and method of administration Therapy should be prescribed by a physician experienced in the management of HIV-1 infection. Posology Adults: The recommended dose of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is one tablet taken orally once daily. Method of administration It is recommended that Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets be swallowed whole with water. It is recommended that Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets be taken on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions. In order to improve the tolerability of efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended. It is anticipated that tenofovir exposure will be approximately 35% lower following administration of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets on an empty stomach as compared to the individual component tenofovir disoproxil fumarate when taken with food. In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited. Children The safety and efficacy of Tenofovir disoproxil fumarate in patients under the age of 18 years have not been established. Tenofovir disoproxil fumarate must not be administered to children until further data become available describing the safety and efficacy of Tenofovir disoproxil fumaratein patients under the age of 18 years. So, the fixed dose combination Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is not recommended for use in children due to a lack of data on safety and efficacy. Elderly Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should be administered with caution to elderly patients. Dose adjustments Where discontinuation of therapy with one of the components of Tenofovir Disoproxil Fumarate/ Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is indicated or where dose modification is necessary, separate preparations of tenofovir disoproxil fumarate, lamivudine and efavirenz are available. Please refer to the Summary of Product Characteristics for these medicinal products. If Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is coadministered with rifampicin, an additional 200 mg/day (800 mg total) of efavirenz may be considered. Renal impairment Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require dose interval adjustment of lamivudine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet. Hepatic impairment The pharmacokinetics of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets have not been studied in patients with hepatic impairment. Patients should be monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz. If Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis. If therapy with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is discontinued, consideration should be given to the long half-life of efavirenz and long intracellular half-lives of tenofovir and lamivudine. Because of interpatient variability in these parameters and concerns regarding development of resistance, HIV treatment guidelines should be consulted, also taking into consideration the reason for discontinuation. Contraindications Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is contraindicated in patients with clinically significant hypersensitivity to tenofovir, lamivudine, efavirenz or to any of the excipients contained in the formulation. Herbal preparations containing St.John´s wort (Hypericum perforatum) must not be used while taking Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz. Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and Tenofovir Disoproxil Fumarate/Lamivudine/ Efavirenz 600mg/300mg/300mg Tablets must not be co-administered. Special warning and precautions for use General As a fixed combination, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should not be administered concomitantly with other medicinal products containing any of the same active components, efavirenz, lamivudine or tenofovir disoproxil fumarate. Efavirenz Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should not be administered concomitantly with other cytidine analogues such as emtricitabine. Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should not be administered concomitantly with adefovir dipivoxil. Transmission of HIV Treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets has not been shown to eliminate the risk of transmission of HIV infection by sexual contact or by blood transfer, although the risk may be reduced. Patients should continue to use appropriate precautions to prevent transmission of HIV. Didanosine Co-administration of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets and didanosine is not recommended since exposure to didanosine is significantly increased following co-administration with tenofovir disoproxil fumarate. Liver disease The safety and pharmacokinetics of efavirenz has not been investigated in patients with severe liver disease. Therefore Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should only be used in this group of patients if the benefits are considered to outweigh the risks, and with close safety monitoring. Liver toxicity Increased transaminase levels may occur months after starting efavirenz and may be more frequent in patients with HBV- and/or HCV co-infection. Discontinuation is recommended if hepatoxicity is symptomatic, or if the transaminase levels are > 10 times the upper limit of normal. Hepatic failure has occurred in patients with no preexisting hepatic disease or other identifiable risk factors. Liver enzyme monitoring should be considered for patients without pre-existing hepatic dysfunction or other risk factors. Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV. Lamivudine and tenofovir disoproxil fumarate are also active against HBV. Therefore, discontinuation of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Tenofovir Disoproxil Fumarate/Lamivudine/ Efavirenz 600mg/300mg/300mg Tablets. If appropriate, resumption of specific anti-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. Rash A mild-to-moderate rash very commonly develops within two weeks after starting efavirenz and does not require treatment discontinuation. The rash usually resolves within two weeks. Severe rash or erythema, including Stevens-Johnson syndrome, requires immediate discontinuation. Central nervous system and psychiatric effects Central nervous system and psychiatric side effects are very common after starting efavirenz. These symptoms typically occur within the first week of treatment and usually resolve within 4 weeks of treatment. There is a potential additive effect with alcohol and other psychoactive drugs. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation they should contact their doctor or health care provider immediately to determine whether the benefits outweigh the risks of continued therapy. Renal function Tenofovir is primarily excreted by the kidneys through a combination of glomerular filtration and active tubular secretion. Thus, clearance is decreased in patients with impaired renal function. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function (< 80 ml/min). In such patients, Tenofovir Disoproxil Fumarate/ Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with moderate to severe renal impairment, the plasma half-life of lamivudine is increased due to decreased clearance. Decreased doses are recommended for patients with creatinine clearance <50 ml/ min. The use of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is not recommended in patients with creatinine clearance < 50 ml/min, since appropriate dose reductions cannot be achieved with the combination tablet. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets. Routine monitoring of calculated creatinine clearance and serum phosphate should be performed in patients at risk for renal impairment. In patients receiving tenofovir disoproxil fumarate renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations, if serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance decreases below 50 ml/min. Consideration should also be given to interrupting treatment with Tenofovir Disoproxil Fumarate/ Lamivudine/Efavirenz 600mg/300mg/300mg Tablets in patients whose creatinine clearance falls below 50 ml/min or whose serum phosphate decreases below 1.0 mg/dl (0.32 mmol/l). Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should be avoided with concurrent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly. Bone effects In a controlled clinical study decreases in bone mineral density of spine and changes in bone biomarkers from baseline were observed in both treatment groups, but were significantly greater in the tenofovir disoproxil fumarate treatment group than in the comparator group treated with stavudine (each in combination with lamivudine and efavirenz) at 144 weeks. Decreases in bone mineral density of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks. Tenofovir was studied in HIV-1 infected paediatric subjects 12 years of age and older. Under normal circumstances, bone mineral density increases rapidly in this age group. In this study, the mean rate of bone gain was less in the tenofovir-treated group compared to the placebo group. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. Due to the possible effects of tenofovir on bone metabolism, Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should only be used in adolescents under the age of 18 if the benefits are considered to exceed the risk. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected then appropriate consultation should be obtained. Lactic acidosis Lactic acidosis is a rare but severe, potentially life-threatening complication associated with use of nucleoside reverse transcriptase inhibitors (NRTI). Several other agents of this class are known to cause lactic acidosis. Preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, considered a putative class effect of nucleoside analogues, is very low for tenofovir disoproxil fumarate and lamivudine. However, this risk cannot be excluded. Lactic acidosis may occur after a few to several months of NRTI treatment. Patients with hyperlactataemia may be asymptomatic, critically ill, or may have non-specific symptoms such as dyspnoea, fatigue, nausea, vomiting, diarrhoea and abdominal pain. Risk factors for NRTIrelated lactic acidosis include female gender and obesity. Patients at increased risk should be closely monitored clinically. Screening for hyperlactataemia in asymptomatic patients treated with NRTIs, however, is not recommended. Symptomatic patients usually have levels > 5 mmol/l and require discontinuation of all NRTIs. Lactic acid levels > 10 mmol/l usually are a medical emergency. Lipodystrophy and metabolic disorders Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. Whereas for some other antiretrovirals there is considerable evidence for this adverse reaction, the evidence for tenofovir, lamivudine and efavirenz as causative agents is weak; indeed switching from a thymidine analogue (e.g. stavudine) to tenofovir has been shown to increase limb fat in patients with lipoatrophy. A higher risk of lipodystrophy has been associated e.g. with older age of the patient, longer duration of antiretroviral therapy and related metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of fasting serum lipids and blood glucose as well as appropriate management of lipid disorders should be considered. 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 postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some lateonset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently 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. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV. Pancreatitis Treatment with Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur. Opportunistic infections Patients receiving antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians or health care providers experienced in the treatment of HIV infection. Immune Reactivation syndrome In HIV infected patients with pre-existing severe immune deficiency, typically in the first few weeks or months after initiation of combination ART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens (e.g. CMV retinitis, mycobacterial infections, Pneumocystis pneumonia) may arise and cause serious clinical conditions or aggravation of symptoms. Treatment should be instituted when necessary. Osteonecrosis Although the etiology 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. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. Elderly patients Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate (see below). Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains 1.9 mmol (43 mg) sodium per tablet. To be taken into consideration by patients on a controlled sodium diet. Interaction with other medicinal products and other forms of interaction Interactions relevant to lamivudine Co-administration with trimethoprim / sulfamethoxazole results in a 40% increase in lamivudine area under the concentration curve. No dose adjustment of Tenofovir Disoproxil Fumarate/ Lamivudine/Efavirenz 600mg/300mg/300mg Tablets is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. Interactions relevant to tenofovir Didanosine Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended. Renally eliminated medicinal products Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products. Tenofovir disoproxil fumarate should be avoided with concurrent use of a nephrotoxic medicinal product, such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2. Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate. Interactions relevant to efavirenz Efavirenz is eliminated through hepatic metabolism, mainly catalyzed by the genetically polymorphic cytochrome (CYP) 450 isoform CYP2B6, but also by CYP3A. Therefore, agents that alter the activity of CYP2B6 or CYP3A may alter the plasma concentration of efavirenz. Efavirenz is a clinically important inducer of cytochrome P450 enzymes, such as CYP3A4; therefore interactions with medicinal products metabolized by this pathway may occur. In vitro, efavirenz is also an inhibitor of UDP-glucuronosyl transferases, CYP3A4, CYP2C9 and CYP2C19. In the great majority of cases where efavirenz interacts in vivo with known CYP3A substrates, the net result after multiple doses is a decreased systemic exposure of the drug interacting with efavirenz. Though efavirenz might act in vivo as a net inhibitor of CYP3A4 after the first doses, it has not been demonstrated that this happens once CYP3A4 induction has set in. Efavirenz should not be administered concurrently with terfenadine, astemizole, cisapride pimozide, bepridil or ergot derivatives, since this may result in altered plasma concentrations of these drugs. Table of drug interactions for Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets The following list of interactions should not be considered exhaustive, but as representative of the classes of medicinal products where caution should be exercised (increased exposure is indicated as “↑”, decreased exposure as “↓”, no change as “[emoji662]”, thrice daily as t.i.d., twice daily as “b.i.d.”, and once daily as “q.d.”). Medicinal products by therapeutic areas Interaction Recommendations concerning coadministration ANTI-INFECTIVES Antiretrovirals Nucleoside analogues Zidovudine Stavudine Abacavir No interaction expected Abacavir / tenofovir Abacavir and Efavirenz /Lamivudine/ Tenofovir Disoproxil Fumarate 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets should not be co-administered, as the additive effect of abacavir is expected to be limited or absent Emtricitabine / lamivudine Emtricitabine and Efavirenz /Lamivudine/ Tenofovir Disoproxil Fumarate 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets should not be coadministerad, due to the similarity between emtricitabine and lamivudine, and consequently expected lack of additive effects. Didanosine (400 mg q.d.) / tenofovir Didanosine AUC ↑ 40-60% The risk of didanosinerelated adverse effects (e.g., pancreatitis, lactic acidosis appears to be increased, and CD4 cells may decrease significantly on co-administration. Also didanosine at 250 mg co-administered with tenofovir within several different antiretroviral combination regimens has been associated with a high rate of virological failure. Coadministration of Efavirenz /Lamivudine/ Tenofovir Disoproxil Fumarate 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets and didanosine is not recommended . N o n - n u c l e o s i d e inhibitors of reverse transcriptase Nevirapine Etravirine Concomitant use with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets is not recommended because of additive toxicity and no benefit in terms of efficacy. Protease inhibitors Fosamprenavir/ritonavir (700/100 mg b.i.d)) / efavirenz amprenavir Ctrough ↓ 17% No significant interaction with twice daily regimen at steady state. No dose adjustment necessary. Fosamprenavir/ritonavir (1400/200 mg q.d.)) / efavirenz Amprenavir Cmin: ↓ 36% at steady state Avoid concomitant use of Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets and once-daily fosamprenavir regimen. Saquinavir HCG/ritonavir (1000/100mg b.i.d) / efavirenz No clinically relevant interaction was noted. Insufficient data are available for making a dosing recommendation for saquinavir, with or without ritonavir, when coadministered with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets. Co-administration with saquinavir, with or without ritonavir, is not recommended. Indinavir (800 mg t.i.d) / efavirenz Indinavir AUC ↓ 31%, Ctrough↓ 40% Concomitant use of Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets with unboosted indinavir is not recommended. I n d i n a v i r / r i t o n a v i r (800/100 mg b.i.d.) / efavirenz Indinavir AUCss ↓ 25%, Ctrough ↓ 50% Concomitant use of Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets with boosted indinavir is only recommended when it is possible to monitor the plasma concentration of indinavir. Ritonavir (500 mg b.i.d) / efavirenz Interaction studies have shown moderate increases in the AUC for both ritonavir and efavirenz. Avoid concomitant use of Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets with full-dose ritonavir, due to low tolerability. Nelfinavir (various doses) / efavirenz Interaction studies have shown variable results, including a 20% increase in nelfinavir AUC and Cmin, as well as a 25% decrease in AUC and 45% decrease in Cmin. Concomitant use with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets is only recommended when it is possible to monitor the plasma concentration of nelfinavir. Lopinavir/ritonavir soft capsules or oral solution / efavirenz L o p i n a v i r / r i t o n a v i r tablets (400/100 mg b.i.d.) (500/125 mg b.i.d.) /efavirenz Lopinavir/ritonavir (400 mg/100 mg b.i.d.) /tenofovir Substantial decrease in lopinavir exposure. Lopinavir Cmin ↓= 40% Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz Lopinavir/ritonavir: No significant effect on lopinavir/ ritonavir PK parameters. Tenofovir: AUC: ↑ 32% Cmax: [emoji662] Cmin: ↑ 51% Insufficient data are available to make a dosing recommendation for lopinavir/ritonavir when dosed with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets. Co-administration of lopinavir/ritonavir and Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets is not recommended. Atazanavir/ritonavir/ tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) Atazanavir: AUC: ↓ 25% (↓ 42 to ↓ 3) Cmax: ↓ 28% (↓ 50 to ↑ 5) Cmin: ↓ 26% (↓ 46 to ↑ 10) Co-administration of atazanavir/ ritonavir with tenofovir resulted in increased exposure to tenofovir. Higher tenofovir concentrations could potentiate tenofovirassociated adverse events, including renal disorders. C o - a d m i n i s t r a t i o n of atazanavir/ ritonavir and Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets is not recommended. Atazanavir/ritonavir/ efavirenz (400 mg q.d./100 mg q.d./600 mg q.d., all administered with food) Atazanavir/ritonavir/ efavirenz (400 mg q.d./200 mg q.d./600 mg q.d., all administered with food) Atazanavir: AUC: [emoji662]* (↓ 9% to ↑ 10%) Cmax: ↑ 17%* (↑ 8 to ↑ 27) Cmin: ↓ 42%* (↓ 31 to ↓ 51) Atazanavir: AUC: [emoji662]*/** (↓ 10% to ↑ 26%) Cmax: [emoji662]*/** (↓ 5% to ↑ 26%) Cmin: ↑ 12%*/** (↓ 16 to ↑ 49) (CYP3A4 induction). * When compared to atazanavir 300 mg/ritonavir 100 mg q.d. in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. ** based on historical comparison. Co-administration of efavirenz with atazanavir/ritonavir is not recommended. Tipranavir/ritonavir /efavirenz Appropriate data on the interaction between the approved tipranavir regimen and efavirenz are lacking. The combination of Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets and tipranavir/ ritonavir should be avoided.. D a r u n a v i r / r i t o n a v i r (300/100 mg b.i.d) / efavirenz Darunavir/ritonavir (300 mg/100 mg b.i.d.) / tenofovir Darunavir AUC at steady state ↓ 13%, Cmin ↓ 31%. Efavirenz AUC ↑ 21%, Cmin ↑ 17% Darunavir: No significant effect on darunavir/ ritonavir PK parameters. Tenofovir: AUC: ↑ 22% Cmin: ↑ 37% The clinical significance of the changes in darunavir and efavirenz concentrations has not been established, and may vary depending on, e.g., whether there is clinically significant resistance to darunavir. Darunavir/ritonavir should be used with caution in combination with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets . CCR-5 antagonists Maraviroc (100 mg b.i.d) / efavirenz 600 mg q.d Maraviroc AUC: ↓ 45% Maraviroc Cmax: ↓ 51% When co-treating with maraviroc and efavirenz in the absence of a boosted PI, the maraviroc dose should be increased to 600 mg twice daily. For other combinations, please refer to the SmPC for the medicinal product containing maraviroc. Integrase strand transfer inhibitors Raltegravir (400 mg single dose) / efavirenz Raltegravir (400 mg b.i.d.) / tenofovir Raltegravir AUC ↓ 36% Raltegravir AUC ↑ 49% Raltegravir Cmax ↑ 64% No dosage adjustment is necessary if Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets and raltegravir are co-administered. Antifungals Ketoconazole (400 mg single dose; efavirenz 600 mg to steady state) / efavirenz Ketoconazole AUC ↓ 72% Consider alternative antifungal agent, or use therapeutic drug monitorng (TDM) if available. Itraconazole (200 mg b.i.d) / efavirenz Itraconazole AUC at steady state ↓ 39%, Cmin ↓ 44% Consider alternative antifungal agent, or use TDM if available. Posaconazole (400 mg b.i.d./400 mg q.d.) / efavirenz Posaconazole: AUC ↓ 50% Cmax ↓ 45% Concomitant use of posaconazole and efavirenz should be avoided. Fluconazole (200 mg q.d) / efavirenz No significant interaction Voriconazole (200 b.i.d) / efavirenz (600mg) No data available Efavirenz and voriconazole at standard doses must not be coadministered. Voriconazole (200 mg b.i.d.) / efavirenz 400 mg q.d) Voriconazole AUCss: ↓ 77%; efavirenz AUCss: ↑ 44% The dose reduction for efavirenz with voriconazole at standard dose leads to a significant alteration in the pharmacokinetics of both drugs and must thus not be used. Voriconazole (400 mg b.i.d) / efavirenz 300 mg q.d) Voriconazole AUCss ↓ 7%; efavirenz AUCss↑ 17%; both compared with standard doses of voriconazole and efavirenz (200 mg b.i.d and 600 mg q.d, respectively) If coadministration is considered necessary, voriconazole should be dosed 400 mg b.i.d and efavirenz dosed at 300 mg q.d. As this dose reduction of efavirenz cannot be accommodated for with Tenofovir Disoproxil Fumarate/ L a m i v u d i n e / E f a v i r e n z 6 0 0 m g / 3 0 0 m g / 3 0 0 m g Tablets, alternative formulations of efavirenz, tenofovir and lamivudine should be used. Antibacterials/Antituberculotics Clarithromycin (500 mg b.i.d, multiple doses) / efavirenz Clarithromycin AUC ↓ 39%; 14-OH-chlaritromycin AUC ↑ 34% The clinical significance, if any, of these alterations in clarithromycin exposure are not known. A high frequency of rash was seen when the drugs were co-administered in healthy volunteers. Consider azithromycin instead, if possible. Azithromycin (600 mg single dose) / efavirenz (400 mg once daily), No clinically significant pharmacokinetic interaction No dosage adjustment is necessary for either medicinal product Rifampicin (600 mg q.d, multiple doses)/ efavirenz Efavirenz AUC ↓ 26%, Cmin ↓ 32% When co-treating, a dose increase of efavirenz from 600 mg to 800 mg q.d. should be considered.