Atripla^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gilead Sciences International, Ltd. (United Kingdom)

Manufactured By

Gilead Sciences Ireland, UC (Ireland)

Or

Patheon Inc. (Canada)

Or

Takeda GmbH (Germany)

Labeled By

GILEAD SCIENCES IRELAND, UC (Ireland)

ATC Code

J05AR06 (Emtricitabine, Tenofovir disoproxil, and Efavirenz)

Active Substances

Efavirenz (Rec.INN registered by WHO)

Emtricitabine (Rec.INN registered by WHO)

Tenofovir (Rec.INN registered by WHO)

Dosage Form

Atripla®

Film-coated tablets, 245 mg+200 mg+600 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink, capsule-shaped, engraved with “123” on one side.

Excipients: croscarmellose sodium – 108 mg, hypromellose – 38.4 mg, magnesium stearate – 23.5 mg, microcrystalline cellulose – 268.1 mg, sodium lauryl sulfate – 12 mg.

Film coating composition: opadry II pink – 46.5 mg: iron oxide black – 0.05%, iron oxide red – 0.92%, macrogol 3350 – 20.2%, polyvinyl alcohol – 40%, talc – 14.8%, titanium dioxide – 24.03%.

30 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

A combination product with fixed doses of efavirenz, emtricitabine, and tenofovir.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus-1 (HIV-1). Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not have significant inhibitory activity against human immunodeficiency virus-2 (HIV-2) RT or human DNA polymerases (α, β, γ, and δ).

Emtricitabine is a nucleoside analogue of cytidine and belongs to the nucleoside reverse transcriptase inhibitors (NRTIs).

Tenofovir is an NRTI, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate.

Emtricitabine and tenofovir are phosphorylated by intracellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when present simultaneously in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of viral DNA synthesis. Emtricitabine triphosphate, like tenofovir diphosphate, is a weak inhibitor of mammalian DNA polymerases, and no evidence of mitochondrial toxicity was observed in vitro or in vivo.

In vitro antiviral activity

Efavirenz exhibits antiviral efficacy against most laboratory isolates of non-B subtypes (A, AE, AG, C, D, F, G, J, and N), but reduced antiviral activity has been established against group O viruses. Emtricitabine exhibits antiviral activity against HIV-1 subtypes A, B, C, D, E, F, and G. Tenofovir exhibits antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G, and O. Both emtricitabine and tenofovir exhibit specific activity against HIV-2 strains and antiviral activity against hepatitis B virus. In vitro studies of combinations of efavirenz and emtricitabine, efavirenz and tenofovir, and emtricitabine and tenofovir showed additive or synergistic antiviral effects.

Resistance

Resistance to efavirenz can be detected in vitro and results in single or multiple amino acid substitutions in the HIV-1 RT gene, including L100I, V108I, V179D, and Y181C. K103N is the most frequently observed substitution in the RT gene in viral isolates from patients with resumption of active HIV replication in clinical studies of efavirenz. Substitutions in the RT gene at positions 98, 100, 101, 108, 138, 188, 190, or 225 have been observed, but less frequently, and often only in combination with K103N. In vitro studies of cross-resistance between efavirenz, nevirapine, and delavirdine have shown that the K103N substitution leads to loss of susceptibility to all three NNRTIs. The emergence of cross-resistance between efavirenz and NRTI drugs is unlikely because they have different binding sites and mechanisms of action. The likelihood of cross-resistance between efavirenz and protease inhibitors (PIs) is also low due to the involvement of different enzymes as targets. Resistance to emtricitabine or tenofovir has been observed in vitro and in some HIV-1-infected patients due to the emergence of M184V or M184I substitutions in the RT gene during emtricitabine use or K65R substitution in the RT gene during tenofovir use. No other possible mechanisms of resistance development to emtricitabine or tenofovir have been established. Viral isolates resistant to emtricitabine with M184V/I mutations were also resistant to lamivudine but remained susceptible to didanosine, stavudine, tenofovir, and zidovudine. The K65R mutation can also be observed with the use of abacavir or didanosine and, in turn, can also lead to reduced efficacy when these agents are used in combination with lamivudine, emtricitabine, and tenofovir. The use of tenofovir disoproxil fumarate should be avoided in patients with HIV-1 strains carrying the K65R mutation. In the presence of K65R and M184V/I mutations, susceptibility to efavirenz is fully preserved. In HIV-1-infected patients expressing three or more thymidine analogue-associated mutations, including the M41L or L210W substitution in the RT gene, reduced susceptibility to tenofovir disoproxil fumarate was noted.

In vivo resistance (in treatment-naive patients, ART)

Currently, data on the development of treatment resistance in patients receiving the drug are limited. However, in previously ART-naive patients and in cases where efavirenz, emtricitabine, and tenofovir disoproxil fumarate were used as separate drugs (or efavirenz and the combination product containing emtricitabine and tenofovir disoproxil fumarate), in all patients with confirmed HIV RNA greater than 400 copies/ml and in patients who discontinued therapy, upon genotyping of HIV-1 isolates, it was found that M184V/I mutations were detected in 10.5% of cases when studying isolates from patients receiving therapy including efavirenz, emtricitabine, and tenofovir disoproxil fumarate, and in 34.5% of cases when studying isolates from patients receiving efavirenz and the combination of lamivudine and zidovudine (p<0.05); it was also shown that the K65R mutation was not detected in the analyzed samples; and that genotypic resistance to efavirenz, manifested by the K103N mutation, was found in samples from 68% of patients receiving therapy including efavirenz, emtricitabine, and tenofovir disoproxil fumarate, and in 72% of patients receiving efavirenz and the combination of lamivudine and zidovudine.

Pharmacokinetics

The bioequivalence of one film-coated tablet of the drug and the combination of one 600 mg efavirenz film-coated tablet, one 200 mg emtricitabine hard capsule, and one 245 mg tenofovir disoproxil film-coated tablet (equivalent to 300 mg tenofovir disoproxil fumarate), when taken simultaneously, has been confirmed in a single-dose, fasting study in healthy volunteers.

In HIV-infected patients, the C_max of efavirenz in plasma is observed at 5 hours, and steady-state plasma concentrations are achieved within 6-7 days. With once-daily administration of 600 mg efavirenz, C_max is 12.9±3.7 mmol (%CV 29%) (steady-state C_min is 5.6±3.2 mmol (57%), AUC – 184±73 mmol×h (40%).

Emtricitabine is rapidly absorbed, with its C_max in blood reached within 1-2 hours after administration. With multiple administrations of emtricitabine, steady-state C_max is 1.8±0.7 µg/ml (39%), C_min is 0.09±0.07 µg/ml (80%) and AUC is 10.0±3.1 µg×h/ml (31%) over a 24-hour dosing interval.

After oral administration of 300 mg tenofovir disoproxil fumarate on an empty stomach to HIV-1-infected patients, C_max in blood is reached within 1 hour and is 296±90 ng/ml (30%), AUC – 2287±685 ng×h/ml (30%), respectively. The bioavailability of tenofovir in patients after oral administration of tenofovir disoproxil fumarate on an empty stomach is about 25%.

The drug is recommended to be taken on an empty stomach, as food intake may increase the concentration of efavirenz in the blood and increase the frequency of adverse drug reactions.

The degree of binding of efavirenz to plasma proteins is high (>99%), primarily to albumin. In vitro studies have shown that the binding of emtricitabine to human plasma proteins is less than 4% and is independent of dose over the range of 0.02 to 200 µg/ml. After oral administration, emtricitabine is freely distributed in the body. The average ratio of plasma concentration to whole blood concentration is about 1.0, and the ratio of seminal fluid concentration to plasma concentration is about 4.0. When tenofovir is used in the dose range of 0.01 to 25 µg/ml, its concentration in blood and binding to plasma or serum proteins in vitro is higher and is less than 0.7% and 7.2%, respectively. After oral administration, tenofovir is freely distributed in the body.

Studies of metabolism in humans and in vitro studies on human liver microsomes have shown that efavirenz is metabolized by cytochrome (CYP) system isoenzymes to form hydroxylated metabolites with subsequent glucuronidation of the formed metabolites. The metabolites are pharmacologically inactive against HIV-1. In vitro studies suggest that CYP3A4 and CYP2B6 isoenzymes are the primary isoenzymes responsible for the metabolism of efavirenz, and that efavirenz inhibits CYP isoenzymes such as 2C9, 2C19, and 3A4. In vitro, efavirenz did not inhibit CYP2E1, and inhibited CYP2D6 and CYP1A2 only at concentrations significantly higher than those used in treatment. The plasma concentration of efavirenz may be increased in patients homozygous for the G516T polymorphism of the CYP2B6 isoenzyme gene.

Efavirenz has been found to induce CYP3A4 and CYP2B6 isoenzymes, leading to an increase in its own metabolism. Efavirenz has also been shown to induce uridine diphosphate-glucuronosyltransferase (UGT1A1). When co-administered with efavirenz, the blood concentration of raltegravir (a substrate of UGT1A1) decreases.

Data on the metabolism of emtricitabine are limited. It is known that emtricitabine undergoes oxidation of the thiol moiety to form 3′-sulfoxide diastereomers (about 9% of the dose) and glucuronic acid conjugates in the form of 2′-O-glucuronide (about 4% of the dose). In vitro studies have established that neither tenofovir disoproxil fumarate nor tenofovir are substrates of cytochrome system enzymes. In turn, neither emtricitabine nor tenofovir inhibit the metabolism of drugs mediated by the major CYP isoenzymes. Emtricitabine did not inhibit uridine-5′-diphosphoglucuronosyltransferase (UDP), the enzyme responsible for conjugation with glucuronic acid.

Efavirenz has a relatively long T_1/2 of at least 52 hours after a single dose and from 40 to 55 hours after multiple doses of the drug. About 14-34% of the radiolabeled efavirenz dose is found in the urine and less than 1% is excreted unchanged in the urine.

After oral administration, the T_1/2 of emtricitabine is about 10 hours. Emtricitabine is primarily excreted by the kidneys, with the entire administered dose found in the urine (almost 86%) and feces (about 14%). Thirteen percent of the administered emtricitabine dose is found in the urine as three metabolites. The total clearance of emtricitabine is 307 ml/min.

After oral administration, the T_1/2 of tenofovir is approximately 12-18 hours. Elimination of tenofovir occurs mainly through the kidneys via filtration and active tubular transport. The expected total clearance of tenofovir averages 307 ml/min. Renal clearance is approximately 210 ml/min, with an increased glomerular filtration rate. This indicates that active tubular secretion plays a significant role in the elimination of tenofovir.

Pharmacokinetics in special patient groups

No significant differences in the pharmacokinetics of emtricitabine and tenofovir between men and women have been found. Limited data suggest that plasma concentrations of efavirenz may be higher in women, but cases of resistance to efavirenz were observed no less frequently in women than in men.

Pharmacokinetic parameters were determined after a single administration of 200 mg emtricitabine or 245 mg tenofovir disoproxil to patients with varying degrees of renal impairment, without HIV infection. The severity of renal impairment was determined by creatinine clearance (CrCl) (renal function not impaired if CrCl>80 ml/min, mild impairment if CrCl is 50-79 ml/min, moderate impairment if CrCl is 30-49 ml/min, and severe impairment if CrCl is 10-29 ml/min). Mean (%CV) emtricitabine exposure increased from 12 µg×h/ml (25%) in patients without renal impairment to 20 µg×h/ml (6%), 25 µg×h/ml (23%), and 34 µg×h/ml (6%) in patients with mild, moderate, and severe renal impairment, respectively.

Mean (%CV) tenofovir exposure increased from 2185 ng×h/ml (12%) in patients without renal impairment to 3064 ng×h/ml (30%), 6009 ng×h/ml (42%), and 15,985 ng×h/ml (45%) in patients with mild, moderate, and severe renal impairment, respectively. In patients with end-stage renal disease between hemodialysis procedures, the blood concentration of emtricitabine gradually increased over a period of more than 72 hours to 53 µg×h/ml (19%), and the concentration of tenofovir increased over a period of more than 48 hours to 42,857 ng×h/ml (29%).

The drug should be used with caution in patients with mild hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment and is not recommended for use in patients with moderate hepatic impairment. After a single administration of efavirenz to a single patient with severe hepatic insufficiency (Child-Pugh class C), a twofold increase in T_1/2 was noted, indicating a possible greater degree of accumulation. With multiple doses of the drug, no significant effect of liver damage on the pharmacokinetics of efavirenz was detected in patients with mild hepatic insufficiency (Child-Pugh class A) compared to patients in the control group. There are currently insufficient data to conclude whether moderate and severe hepatic insufficiency (Child-Pugh class B and C) affect the pharmacokinetics of efavirenz. In general, the pharmacokinetics of emtricitabine in patients with viral hepatitis B did not differ from the corresponding pharmacokinetic parameters in healthy volunteers and HIV-infected patients.

A single 300 mg dose of tenofovir disoproxil fumarate was evaluated according to the Child-Pugh classification in patients with varying degrees of hepatic impairment without HIV infection. In patients with hepatic impairment, no significant changes in the pharmacokinetics of tenofovir were observed, suggesting that no dose adjustment of tenofovir disoproxil fumarate is required in such patients.

Indications

Treatment of HIV-1 infection in adult patients who have received combined antiretroviral therapy for more than 3 months and have a plasma HIV-1 RNA level of less than 50 copies/ml on it.

ICD codes

Dosage Regimen

The drug is taken orally.

The recommended dose of the drug is 1 tablet/day.

It is recommended to take the drug on an empty stomach, as food intake may increase the exposure of efavirenz and lead to an increased frequency of adverse drug reactions. To improve the tolerability of efavirenz due to possible nervous system adverse reactions, it is recommended to take the drug at bedtime.

If dose adjustment or discontinuation of one of the components of the drug is necessary, the patient should be switched to taking efavirenz, emtricitabine, or tenofovir as monotherapy drugs. When discontinuing therapy with the drug, features such as the long T_1/2 of efavirenz and the prolonged T_1/2 of emtricitabine and tenofovir from the intracellular space must be taken into account. Due to individual variability in drug elimination in patients and the possible development of resistance, clinical guidelines approved for the treatment of HIV infection should be followed, and the reasons for therapy discontinuation should be considered.

If simultaneous use of the drug with rifampicin is necessary in patients weighing 50 kg and above, additional administration of efavirenz at a dose of 200 mg/day (up to 800 mg) may be required.

Dose adjustment of the drug in elderly patients (over 65 years) is not required, but the use of the drug is recommended with caution, as renal and hepatic insufficiency is highly likely in this patient group.

In patients with moderate and severe renal impairment, an increase in the interval between emtricitabine and tenofovir administration may be required, which cannot be achieved with treatment with the combination drug. In patients with mild renal impairment, no dose adjustment of the drug is required.

In patients with mild hepatic impairment (Child-Pugh class A), treatment with the drug can be carried out without adjustment of the recommended dose.

The efficacy and safety of the drug in children and adolescents under 18 years of age have not been established.

Adverse Reactions

The safety profile of the combined use of efavirenz, emtricitabine, and tenofovir was studied in 460 patients, taken in the form of a combined drug or as single-component drugs. The adverse effect of combination therapy generally did not differ from the corresponding results of therapy with individual drugs.

The most frequently occurring adverse drug reactions, probably and possibly related to the drug intake, belong to mental disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

There are reports of severe skin reactions, including Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric reactions (severe depression, completed suicide, psychotic behavior, seizures); impaired liver function; pancreatitis and lactic acidosis (in some cases with fatal outcome).

Impaired renal function, renal failure, and tubulointerstitial nephropathy (including Fanconi syndrome) have also been reported, in some cases leading to impaired bone structure (increased risk of bone fractures). Patients taking the drug are recommended to regularly monitor renal function.

Discontinuation of the drug in patients with co-existing HIV infection and viral hepatitis B may be accompanied by a serious exacerbation of chronic hepatitis.

The frequency was determined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), or rare (from ≥1/10,000 to <1/1000).

Adverse drug reactions requiring urgent treatment, associated solely with the intake of the combined drug and not observed with the use of single-component drugs, include

Common – anorexia.

Uncommon – dry mouth, incoherent speech, increased appetite, decreased libido, myalgia.

Adverse drug reactions associated with the drug intake and related to single-component drugs

Efavirenz

Immune system disorders uncommon – hypersensitivity.

Metabolism and nutrition disorders common – hypertriglyceridemia³; uncommon – hypercholesterolemia³.

Psychiatric disorders common – depression (severe in 1.6% of cases)³, anxiety³, abnormal dreams³, insomnia³; uncommon – suicidal behavior³, suicide attempt³, psychosis³, mania³, paranoia³, hallucinations³, euphoria³, affect lability³, confusion³, aggression³; rare – completed suicide^3,4, delusions^3,4, neurosis^3,4.

Nervous system disorders common – cerebellar coordination and balance disturbances³, somnolence (2%)³, headache (5.7%)³, impaired concentration (3.6%)³, dizziness (8.5%)³; uncommon – seizures³, amnesia³, thinking abnormal³, ataxia³, impaired coordination³, agitation³, tremor.

Eye disorders uncommon – blurred vision.

Ear and labyrinth disorders uncommon – tinnitus, vertigo.

Cardiac disorders uncommon – flushing.

Gastrointestinal disorders common – diarrhea, vomiting, abdominal pain, nausea, increased activity of hepatic transaminases (AST, ALT, and GGT); uncommon – pancreatitis, acute hepatitis; rare – hepatic failure^3,4.

Skin and subcutaneous tissue disorders very common – skin rash (pronounced and moderate – 11.6%, all grades – 18%); common – pruritus; uncommon – Stevens-Johnson syndrome, erythema multiforme³, severe skin rash (<1%); rare - photoallergic dermatitis.

Reproductive system and breast disorders uncommon – gynecomastia.

General disorders common – fatigue.

Emtricitabine

Blood and lymphatic system disorders: common – neutropenia; uncommon – anemia.

Immune system disorders common – allergic reactions (including urticaria); uncommon – angioedema⁴.

Metabolism and nutrition disorders common – hyperglycemia, hypertriglyceridemia.

Psychiatric disorders common – abnormal dreams, insomnia.

Nervous system disorders very common – headache; common – dizziness.

Gastrointestinal disorders very common – diarrhea, nausea; common – general increase in amylase activity, including pancreatic-related, increased lipase activity, vomiting, abdominal pain, dyspepsia, increased AST and ALT activity, hyperbilirubinemia.

Skin and subcutaneous tissue disorders common – vesiculobullous, pustular, maculopapular rash, pruritus, skin discoloration (hyperpigmentation).

Musculoskeletal and connective tissue disorders very common – increased CPK activity.

General disorders common – pain, asthenia.

Tenofovir

Metabolism and nutrition disorders very common – hypophosphatemia²; uncommon – hypokalemia²; rare – lactic acidosis³.

Nervous system disorders very common – dizziness; common – headache.

Gastrointestinal disorders very common – diarrhea, vomiting, nausea; common – abdominal pain, abdominal distension, flatulence, increased activity of hepatic transaminases; uncommon – pancreatitis³; rare – hepatic steatosis³, hepatitis.

Renal and urinary disorders uncommon – increased creatinine concentration, proteinuria; rare – renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy including Fanconi syndrome (including acute interstitial nephritis)⁴, nephrogenic diabetes insipidus.

Skin and subcutaneous tissue disorders very common – skin rash.

Musculoskeletal and connective tissue disorders uncommon – rhabdomyolysis², muscular weakness²; rare – osteomalacia (manifesting as bone pain and fractures in some cases)^2,4, myopathy².

Immune system disorders rare – angioedema.

General disorders very common – asthenia.

¹ In children, anemia is common, and skin discoloration with emtricitabine use (areas of hyperpigmentation) is very common.

² This adverse reaction may occur as a consequence of proximal renal tubulopathy. In the absence of this condition, the occurrence of this adverse drug reaction is not considered causally related to tenofovir use.

³ A detailed description of selected adverse drug reactions is provided below.

⁴ These adverse drug reactions were identified in patients receiving Efavirenz, Emtricitabine, or tenofovir during routine clinical practice monitoring. The frequency of occurrence was determined based on statistical calculations considering the total number of patients treated with efavirenz, emtricitabine, or tenofovir in clinical studies.

Description of selected adverse reactions

Skin rash

In clinical studies of efavirenz, skin rash manifested as mild to moderate maculopapular skin eruptions occurring within the first 2 weeks of starting efavirenz. In most patients, the skin rash resolves with continued therapy within one month. The drug can be re-administered to patients who discontinued it due to the appearance of a skin rash. Upon re-administration of the drug, patients should be advised to use antihistamines and corticosteroids.

Psychiatric

Patients with a history of mental illness may have an increased risk of developing serious psychiatric reactions listed in the corresponding section of adverse drug reactions related to efavirenz.

Nervous system

Nervous system symptoms when taking the drug are identical to the adverse reactions occurring with efavirenz intake. Symptoms of moderate and severe intensity were noted in 19% of patients (severe in 2%), and in 2% of patients the occurrence of such symptoms led to discontinuation of therapy. Typically, symptoms occur within the first 2 days of taking efavirenz and mostly resolve within 2 to 4 weeks. Nervous system symptoms occur more frequently when the drug is taken with food, which may be associated with an increase in the blood concentration of efavirenz. The tolerability of such symptoms improves if the drug is taken at bedtime.

Hepatic failure with efavirenz use

Liver damage, including in patients without a history of liver disease or risk factors, according to post-marketing use data, in some cases took a fulminant course, leading to the need for liver transplantation or a fatal outcome.

Renal failure

Since impaired renal function is possible while taking the drug, renal function should be regularly monitored during treatment.

Interaction with didanosine

Concomitant use of the drug and didanosine is not recommended, as the exposure to didanosine may increase by 40-60%, which, in turn, may lead to an increased frequency of didanosine side effects. There are reports of rare cases of pancreatitis and lactic acidosis, sometimes with fatal outcome.

Lactic acidosis and severe hepatomegaly with steatosis

During treatment with nucleoside analogues, there have been reports of the development of lactic acidosis associated with hepatic steatosis. If patients show symptoms of hyperlactatemia, metabolic and/or lactic acidosis, progressive hepatomegaly, or rapid increase in hepatic transaminase activity, treatment with nucleoside analogues should be discontinued immediately.

Lipids, lipodystrophy, and metabolic disorders

The use of combination ART is associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, or hyperlactatemia.

Combination ART has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of subcutaneous fat from the face and limbs, increased abdominal and visceral fat, breast enlargement, and dorsocervical fat accumulation (“buffalo hump”).

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the initiation of combination ART, an exacerbation of asymptomatic or residual opportunistic infections may occur. There are also reports of autoimmune disorders (Graves’ disease); however, the time of onset of such disorders varies, they can occur many months after starting treatment.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with known risk factors, in advanced stages of HIV disease, or in patients receiving combination ART for a long time. The frequency of osteonecrosis is unknown.

Patients with renal impairment

Since tenofovir has nephrotoxic potential, renal function should be carefully monitored in all patients with moderate renal impairment during treatment with the drug.

Patients co-infected with HIV and hepatitis B or C virus

The safety profile of efavirenz, emtricitabine, and tenofovir in patients co-infected with HIV and hepatitis B virus, or HIV and hepatitis C virus, was comparable to the safety profile in patients infected with HIV only. However, increased AST and ALT activity is observed more frequently in patients with co-infection compared to patients infected with HIV only.

Hepatitis progression after treatment discontinuation

In patients co-infected with HIV and hepatitis B virus, symptoms of hepatitis progression, confirmed by laboratory data, may be observed upon discontinuation of treatment.

Contraindications

Severe hepatic impairment (Child-Pugh class C); concomitant use of terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, methylergonovine); concomitant use of voriconazole; concomitant use with herbal preparations containing St. John’s wort (Hypericum perforatum); hypersensitivity to tenofovir, emtricitabine, efavirenz, or any other component of the drug.

With caution diabetes mellitus; renal failure; history of mental illness; history of seizures; history of liver disease, including chronic active hepatitis B or C; elderly patients (over 65 years of age); concomitant use of other drugs with nephrotoxic potential (aminoglycosides, amphotericin B, foscarnet sodium, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2); concomitant use of other drugs requiring dose adjustment of the combined drug or other drugs (medicinal products containing didanosine for the treatment of HIV infection; other drugs for the treatment of HIV infection, including protease inhibitors (darunavir, indinavir, lopinavir/ritonavir, ritonavir, or the combination of ritonavir and atazanavir or saquinavir), and maraviroc; medicinal products for the treatment of viral hepatitis C (boceprevir, telaprevir); lipid-lowering agents (atorvastatin, pravastatin, simvastatin); anticonvulsant drugs (carbamazepine, phenytoin, phenobarbital); agents for the treatment of bacterial infections, including tuberculosis and AIDS-associated Mycobacterium avium complex (clarithromycin, rifabutin, rifampicin); antifungal drugs (itraconazole or posaconazole); agents for the treatment of malaria (atovaquone/proguanil or artemether/lumefantrine); hormonal contraceptives (oral, parenteral forms and implants); methadone for the treatment of opiate dependence; sertraline for the treatment of depression; bupropion for smoking cessation and treatment of depression; slow calcium channel blockers (diltiazem); immunosuppressants for the prevention of transplant rejection, such as cyclosporine, sirolimus, or tacrolimus; warfarin or acenocoumarol for reducing the risk of thrombosis; extracts of Ginkgo biloba (herbal medicinal products).

Use in Pregnancy and Lactation

Pregnancy

According to reports from seven retrospective studies, neural tube defects, meningomyelocele, were observed in fetuses, all cases noted in mothers who took Efavirenz in various doses during the first trimester of pregnancy (except for combined drugs containing a fixed dose of efavirenz). Additionally, there is information on two cases (including prospective and retrospective observation) of neural tube defect detection in the case of treatment with a drug containing Efavirenz, Emtricitabine, and tenofovir as a fixed drug combination. A causal relationship of these phenomena with efavirenz intake has not been established, and the causative factor has not been identified. Since neural tube defects in fetuses occur within the first 4 weeks of embryonic development (during neural tube formation), the risk of such disorders may exist when taking efavirenz during the first trimester of pregnancy. In preclinical studies, fetal development defects were observed in female animals administered Efavirenz.

Available data on pregnancy outcomes in women (300-1000 pregnancy outcomes) indicate that there are no congenital organ malformations in the fetus, nor neonatal or fetoplacental toxicity of emtricitabine and tenofovir. Preclinical data on two components of the drug indicate the absence of reproductive toxicity.

The drug should not be used during pregnancy, except in cases where, due to the patient’s clinical condition, treatment with the combined drug containing Efavirenz, Emtricitabine, and tenofovir is required, considering that the expected benefit for the patient outweighs the potential risk to the fetus.

Before starting treatment with the drug, women of childbearing potential should undergo a pregnancy test.

Lactation

Efavirenz, Emtricitabine, and tenofovir are excreted in human milk. Data on the effects of efavirenz, emtricitabine, and tenofovir on newborns/infants are insufficient. The risk to newborns and children under 1 year of age cannot be ruled out. Therefore, the drug should not be used during breastfeeding.

To prevent transmission of HIV to the newborn, it is recommended that HIV-infected women completely avoid breastfeeding.

Fertility

In preclinical studies, no adverse effects on fertility were identified for efavirenz, emtricitabine, and tenofovir.

Contraception in women and men

During the use of the drug, reliable methods of barrier contraception in combination with other methods (e.g., hormonal contraceptives) must be used. Since Efavirenz has a long half-life, reliable methods of contraception must also be used for 12 weeks after discontinuation of treatment with the drug.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

The drug should be prescribed with caution in patients with a history of liver disease, including chronic active hepatitis B or C.

Use in Renal Impairment

The drug should be prescribed with caution in renal failure.

Pediatric Use

The efficacy and safety of the drug in children and adolescents under 18 years of age have not been established.

Geriatric Use

The use of the drug in elderly patients (over 65 years of age) is recommended with caution, as the likelihood of renal and hepatic impairment is high in this patient group.

Special Precautions

In patients adhering to ART regimens using protease inhibitors, switching to the combined drug may lead to a decrease in the intensity of the treatment response. Such patients should be monitored for possible increases in viral load and increased side effects, since the safety profile of efavirenz differs from that of protease inhibitor class drugs.

Patients receiving the drug may have clinical manifestations of opportunistic infections or complications of HIV infection, and therefore require regular monitoring.

Although stable ART leading to sustained viral suppression significantly reduces the risk of sexual transmission of the virus, patients should be aware that the risk of HIV transmission through sexual contact or contact with blood persists even during ART. Therefore, appropriate measures to prevent virus transmission must be applied.

The drug is contraindicated in patients with severe hepatic impairment and is not recommended for patients with moderate hepatic impairment. Since Efavirenz is metabolized primarily by CYP isoenzymes, the drug should be used with caution in patients with mild hepatic impairment. Close monitoring of patients with mild hepatic insufficiency is necessary to monitor side effects associated with efavirenz intake, especially those related to the nervous system. Regular laboratory monitoring of liver function is required.

In patients with previously diagnosed liver disease, including chronic active hepatitis, hepatic impairment may be observed more frequently during combination ART; the condition of such patients should be monitored according to standard practice. If worsening of liver disease or an increase in hepatic transaminase activity of more than 5 times the ULN is observed, an assessment of the risk of toxic effects and the expected benefit of the drug should be performed. In such patients, a treatment interruption or discontinuation may be required.

In patients taking other hepatotoxic drugs, monitoring of liver enzyme activity is recommended.

During the post-registration period, reports have been received of the development of hepatic failure in patients with no history of liver disease and no other identifiable risk factors. Monitoring of hepatic transaminase activity should be performed in all patients, regardless of the presence of risk factors and/or baseline liver function status.

Patients with chronic viral hepatitis B or C receiving combination ART are at high risk of severe and potentially fatal liver complications. Physicians should follow HIV infection treatment guidelines and select optimal treatment for patients co-infected with HIV and hepatitis B virus. In case of concomitant antiviral therapy for hepatitis B or C, the respective prescribing information for those medicinal products should be consulted.

Pharmacodynamic studies have established the antiviral activity of emtricitabine and tenofovir against the hepatitis B virus when used both as monotherapy and in combination therapy. Limited clinical data indicate that Emtricitabine and tenofovir have antiviral activity against the hepatitis B virus when used as part of combination ART for the treatment of HIV infection. Discontinuation of the drug in patients co-infected with HIV and hepatitis B virus may cause severe exacerbation of hepatitis. Patients co-infected with HIV and hepatitis B virus should be closely monitored, both clinically and in the laboratory, for at least 4 months after discontinuation of therapy with the drug. In some cases, resumption of hepatitis B therapy may be required. In patients with severe liver disease or cirrhosis, treatment discontinuation is not recommended, as post-treatment exacerbation of hepatitis can lead to hepatic decompensation.

Psychiatric adverse events have been reported in patients receiving Efavirenz. Patients with a history of psychiatric disorders are at greater risk of developing serious psychiatric adverse reactions. In particular, severe depression was noted more frequently in patients with a history of depression. During the post-registration period of the drug’s use, severe depression, suicide, delirium, and psychosis-like behavior have been reported. Patients should be informed that if they experience symptoms such as depression, psychosis, or suicidal thoughts, they should immediately consult a physician to assess a possible connection between these symptoms and efavirenz intake; if such a connection is established, it should be determined whether the benefit of using the drug outweighs the potential risk.

Symptoms including dizziness, insomnia, drowsiness, impaired concentration, and abnormal dreams were frequently observed in clinical studies in patients receiving Efavirenz at a dose of 600 mg daily. Dizziness was also observed in clinical studies of emtricitabine and tenofovir. Headache occurred in clinical studies of emtricitabine. Neurological symptoms associated with efavirenz usually begin within the first 2 days of treatment and resolve within the first 2-4 weeks. Patients should be informed that the frequently occurring neurological symptoms are transient, resolve with continued treatment, and do not predict the development of rarer psychiatric disorders during further treatment.

Seizures have been observed in patients taking Efavirenz, generally those with a history of seizures. Patients receiving concomitant anticonvulsants metabolized in the liver, such as phenytoin, carbamazepine, and phenobarbital, should have plasma concentrations of these drugs monitored periodically. Caution should be exercised when prescribing the drug to all patients with a history of seizures.

The use of the drug is not recommended in patients with moderate and severe renal impairment (CrCl less than 50 ml/min). Patients with moderate and severe renal failure require dose adjustment of emtricitabine and tenofovir, which cannot be achieved with the use of the combination tablet. Use of the drug should be avoided with concurrent or recent use of nephrotoxic drugs. In cases where concurrent use of the drug and nephrotoxic drugs cannot be avoided, weekly monitoring of renal function is necessary.

Cases of acute renal failure after initiation of high-dose NSAIDs or use of multiple NSAIDs have been reported in patients with risk factors for renal impairment who were receiving tenofovir. When used concomitantly with NSAIDs, monitoring of renal function is required.

It is recommended to calculate CrCl in all patients before starting treatment with the drug, monitor renal function (CrCl and serum phosphate level) 2-4 weeks after starting treatment, at 3 months, and thereafter every 3-6 months in patients without risk factors for renal disease. In patients with a history of renal impairment or at risk of its development, more frequent monitoring of renal function is necessary. If the serum phosphate concentration is less than 1.5 mg/dl (0.48 mmol/l) or CrCl is below 50 ml/min, reassessment of renal function should be performed within one week, including determination of blood glucose and potassium levels, and urine glucose. Since it is not possible to take the individual components of the combination drug at different time intervals, treatment with the combination drug should be suspended in patients with CrCl below 50 ml/min or serum phosphate concentration below 1.0 mg/dl (0.32 mmol/l). The need for an interruption in treatment with the drug should be considered in case of progressive decline in renal function without an obvious cause. If discontinuation of one of the components included in the drug is required, or dose adjustment of one of the components is required, Efavirenz, Emtricitabine, and tenofovir should be used as monocomponent preparations.

In a clinical study of tenofovir with stavudine in combination with lamivudine compared with efavirenz in treatment-naive patients, a slight decrease in bone mineral density of the hip and spine was noted in both groups. However, no increased risk of fractures or other clinically significant bone abnormalities was observed. Bone abnormalities (in some cases leading to fractures) may be associated with proximal tubulopathy. If bone pathology is suspected, examination and consultation with an appropriate specialist are necessary.

There are reports of mild to moderate skin rash occurring with the individual components of the drug. Rash due to efavirenz usually resolved with continued therapy. Antihistamines and/or corticosteroids may improve therapy tolerance and accelerate rash resolution. Cases of severe rash accompanied by blistering, desquamation, or ulceration were reported in less than 1% of patients receiving Efavirenz. Erythema multiforme or Stevens-Johnson syndrome were reported in approximately 0.1% of cases. If blisters, desquamation, fever, or mucosal involvement occur, the drug should be discontinued. Experience with efavirenz in patients who discontinued NNRTI-class antiretroviral drugs is limited. The drug is not recommended for those patients who previously developed life-threatening skin reactions (e.g., Stevens-Johnson syndrome) while taking other NNRTIs.

An association has been noted between combination ART and the redistribution of subcutaneous adipose tissue (lipodystrophy) in HIV-infected patients. The long-term consequences of these effects are not established. The mechanism of development is currently not fully understood. A relationship is assumed between visceral lipomatosis and the use of protease inhibitor class drugs, as well as between lipoatrophy and the intake of NRTIs. An increased risk of lipodystrophy may be associated with individual factors, such as older age, association with drug intake, including longer duration of ART and associated metabolic disorders. Clinical assessment includes identifying signs of adipose tissue redistribution. During treatment, fasting blood lipid and glucose concentrations should be monitored. Lipid metabolism disorders should be corrected as clinically indicated.

Nucleoside and nucleotide analogues have demonstrated the ability to cause in vitro and in vivo mitochondrial dysfunction of varying degrees. The development of mitochondrial dysfunction has been reported in HIV-negative newborns exposed in utero and/or postnatally to nucleoside analogues. The main reported adverse reactions include hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes are often transient. Some long-term neurological disorders (hypertension, seizures, behavioral disorders) have been reported. It is currently unknown whether the neurological disorders are transient or permanent. All children exposed in utero to nucleoside or nucleotide analogues, even HIV-negative newborns, should be under close clinical and laboratory observation and, if relevant signs or symptoms appear, undergo a thorough examination for possible mitochondrial changes. The available data do not affect current national recommendations, according to which HIV-positive pregnant women should receive ART to prevent vertical transmission of HIV.

At the start of combination ART, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to asymptomatic or residual opportunistic infections and cause serious clinical pathology or aggravation of symptoms. Such reactions are usually observed within the first weeks or months after starting combination ART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any symptoms of inflammation should be monitored and, if necessary, treatment should be promptly initiated.

There are reports of cases of autoimmune diseases, such as Graves’ disease. The time to development of such diseases from the start of treatment varied greatly; there are data on the development of autoimmune diseases many months after the start of treatment.

Although the etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, severe immunosuppression, high BMI), cases of osteonecrosis have been reported particularly frequently in patients with advanced HIV infection and/or on long-term combination ART. Patients should be advised to seek medical consultation if they experience joint aches or pain, joint stiffness, or difficulty moving.

The use of the drug is not recommended in patients with virological failure on any prior ART.

The use of the drug is not recommended in patients with HIV-1 harboring K65R, M184V/I, or K103N mutations, as the presence of such mutations is associated with resistance to each of the three active substances of the drug.

Effect on the Ability to Drive and Operate Machinery

Dizziness may occur while taking efavirenz, emtricitabine, and tenofovir. Efavirenz may also cause impaired concentration and drowsiness. Patients should be informed that if these symptoms occur, they should refrain from engaging in potentially hazardous activities such as driving vehicles and operating machinery.

Drug Interactions

The drug contains Efavirenz, Emtricitabine, and tenofovir, therefore any interaction observed with the corresponding monocomponent drugs may also occur with the use of the combination drug. Drug interaction studies for these substances have been conducted only in adults.

The drug should not be taken simultaneously with other drugs containing Emtricitabine or tenofovir, or containing Efavirenz, except in cases where dose adjustment is required, for example, when taken concomitantly with rifampicin.

Since Emtricitabine is a cytidine analogue, the combination drug should not be taken simultaneously with other cytidine analogues, such as lamivudine. The drug should not be taken simultaneously with adefovir dipivoxil.

Efavirenz is an inducer of cytochrome P450 isoenzymes CYP3A4, CYP2B6, and UGT1A1 in vivo. When used concomitantly, Efavirenz reduces the plasma concentration of substances that are substrates of these isoenzymes. Efavirenz may be an inducer of CYP2C19 and CYP2C9 isoenzymes; however, inhibition was observed in in vitro studies, the effect of concomitant use with substrates of these enzymes is unclear.

Exposure to efavirenz may increase when used concomitantly with some medicinal products (e.g., ritonavir) or products (e.g., grapefruit juice), which inhibit the activity of CYP3A4 and CYP2B6 isoenzymes. Concomitant use with herbal preparations and substances that are inducers of these enzymes (e.g., extracts of Ginkgo Biloba and St. John’s wort, Hypericum perforatum), may lead to an increase in the initially reduced plasma concentration of efavirenz.

In vitro studies and clinical pharmacokinetic interaction studies have shown that the likelihood of CYP-mediated interaction when emtricitabine and tenofovir are used concomitantly with other drugs is low.

Efavirenz does not bind to cannabinoid receptors. There are reports of false-positive results in urine screening tests for cannabinoids in uninfected volunteers and HIV-infected patients receiving Efavirenz. To confirm positive results of cannabinoid screening tests, the use of more specific analytical methods – gas chromatography or mass spectrometry – is recommended.

The drug should not be used concomitantly with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine), because inhibition of the metabolism of these agents may lead to serious, life-threatening reactions.

Concomitant use of efavirenz at standard doses and voriconazole is contraindicated. Because the drug contains fixed-dose components, the dose of efavirenz cannot be changed; therefore, voriconazole and the combination drug should not be used simultaneously.

Concomitant use of the drug and St. John’s wort or preparations based on St. John’s wort is contraindicated. The plasma concentration of efavirenz may decrease when used concomitantly with St. John’s wort as a result of induction of the activity of drug-metabolizing enzymes and/or transport proteins by St. John’s wort. If the patient is already taking preparations based on St. John’s wort, the intake of such preparations should be discontinued, viral load should be determined and, if possible, the concentration of efavirenz. The concentration of efavirenz may increase after discontinuation of St. John’s wort preparations. The enzyme-inducing effect may persist for at least 2 weeks after discontinuation of St. John’s wort.

Concomitant use of the drug with atazanavir/ritonavir combination is not recommended.

Concomitant use of the drug and didanosine is not recommended.

Since Emtricitabine and tenofovir are eliminated primarily by the kidneys, concomitant use of the drug with drugs that reduce renal function or compete for active tubular secretion (e.g., cidofovir), may increase the concentrations of emtricitabine, tenofovir, and/or concomitantly used drugs. The drug should not be prescribed simultaneously with or soon after the use of nephrotoxic drugs (including aminoglycosides, amphotericin B, ganciclovir, sodium foscarnet, pentamidine, vancomycin, cidofovir, or interleukin-2).

No clinically significant pharmacokinetic interaction between efavirenz and azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, nelfinavir, zidovudine, antacids containing aluminum/magnesium hydroxide, famotidine, or fluconazole was found.

No clinically significant pharmacokinetic interaction between emtricitabine and stavudine, zidovudine, or famciclovir was found.

No clinically significant pharmacokinetic interaction between tenofovir and emtricitabine, nelfinavir, or ribavirin was found either.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.