Tenoxop-e
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENOHOPE-E (TENOHOPE-E)
Composition:
Active substances: 1 tablet contains tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Blue 30 K505002: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, indigo carmine (E 132).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: biconvex, film-coated, light blue, capsule-shaped tablets with the imprint «L 24» on one side and smooth on the other.
Pharmacotherapeutic group.
Antiviral agents for treatment of HIV infection, combinations.
ATC code J05A R03.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of Action and Pharmacodynamic Effects. Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleotide analogue of adenosine monophosphate. Both emtricitabine and tenofovir exhibit antiviral activity specific against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when used in combination within cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of viral DNA.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases, and there is no evidence of mitochondrial toxicity in vitro or in vivo.
Antiviral Activity In Vitro. Synergistic antiviral activity has been observed with the combination of emtricitabine and tenofovir in vitro. Additional synergistic effects have been observed in combination studies with protease inhibitors and with nucleoside and non-nucleoside reverse transcriptase inhibitors of HIV.
Resistance. Resistance has been observed in vitro and in some HIV-1-infected patients due to the development of M184V/I mutations with emtricitabine or the K65R mutation with tenofovir. No other resistance pathways to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with the M184V/I mutation are cross-resistant to lamivudine but remain sensitive to didanosine, stavudine, tenofovir, zalcitabine, and zidovudine. The K65R mutation may also be selected by abacavir or didanosine and leads to reduced susceptibility to these agents as well as to lamivudine, emtricitabine, and tenofovir. Patients with HIV-1 harboring the K65R mutation should avoid tenofovir disoproxil fumarate.
Patients with HIV-1 who have three or more thymidine analogue-associated mutations (TAMs), including the reverse transcriptase mutations M41L or L210W, exhibit reduced susceptibility to tenofovir disoproxil fumarate.
Pharmacokinetics.
Absorption. After oral administration, emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed, with tenofovir disoproxil fumarate being converted to tenofovir. Peak concentrations of emtricitabine and tenofovir in plasma are observed within 0.5 to 3 hours after dosing under fasting conditions. Administration with food delays the time to peak concentration of tenofovir by approximately three-quarters of an hour and increases the AUC and Cmax of tenofovir by approximately 35% and 15%, respectively, when taken with a high-fat or light meal compared to fasting. To optimize absorption of tenofovir, administration with food is recommended.
Distribution. After oral administration of emtricitabine or tenofovir disoproxil fumarate, emtricitabine and tenofovir are distributed throughout the body. In vitro, plasma protein binding of emtricitabine in human plasma is < 4% and is independent of concentration over the range of 0.02 to 200 mcg/mL. In vitro binding of tenofovir to plasma protein or serum protein is less than 0.7% and 7.2%, respectively, over the concentration range of tenofovir from 0.01 to 25 mcg/mL.
Biotransformation. Metabolism of emtricitabine is limited. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form 3'-sulfoxide diastereomers (approximately 9% of the dose) and glucuronide conjugation to form the 2'-O-glucuronide (approximately 4% of the dose). In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited in vitro the metabolism of drugs mediated by any of the major human CYP450 isoenzymes involved in drug biotransformation. Emtricitabine also did not inhibit uridine-5'-diphosphoglucuronosyltransferase, the enzyme responsible for glucuronidation.
Elimination. Emtricitabine is primarily eliminated by the kidneys, with approximately 86% of the administered dose recovered unchanged in urine and 14% in feces. About 13% of the emtricitabine dose was recovered in urine as three metabolites. Systemic clearance of emtricitabine averages 307 mL/min. The oral elimination half-life of emtricitabine is approximately 10 hours.
Tenofovir is primarily eliminated by the kidneys through both glomerular filtration and active tubular secretion. After intravenous administration, approximately 70–80% of the dose is excreted unchanged in urine. The apparent clearance of tenofovir is approximately 307 mL/min. Renal clearance is estimated at approximately 210 mL/min, which exceeds the glomerular filtration rate, indicating that tubular secretion plays a significant role in tenofovir elimination. The oral elimination half-life of tenofovir is approximately 12–18 hours.
Age. Pharmacokinetic studies of emtricitabine or tenofovir in elderly patients (over 65 years of age) have not been conducted.
Sex. Pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.
Ethnic Origin. There is no clinically significant pharmacokinetic difference for emtricitabine related to ethnicity. The pharmacokinetics of tenofovir have not been specifically studied in different ethnic groups.
Pediatric Population. Overall, the pharmacokinetics of emtricitabine in infants, children, and adolescents (aged 4 months to 18 years) are similar to those observed in adults. Pharmacokinetic studies of tenofovir in children and adolescents (up to 18 years of age) have not been conducted.
Renal Impairment. Limited pharmacokinetic data are available for emtricitabine and tenofovir in patients with impaired renal function following co-administration of individual agents or in combination. Pharmacokinetic parameters were primarily assessed after single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg in HIV-negative patients with varying degrees of renal impairment. The degree of renal impairment was categorized based on baseline creatinine clearance (CrCl): normal renal function (CrCl > 80 mL/min), mild impairment (CrCl = 50–79 mL/min), moderate impairment (CrCl = 30–49 mL/min), and severe impairment (CrCl = 10–29 mL/min).
Mean (% CV) exposure to emtricitabine increased from 12 (25%) mcg•h/mL in patients with normal renal function to 20 (6%) mcg•h/mL, 25 (23%) mcg•h/mL, and 34 (6%) mcg•h/mL in patients with mild, moderate, and severe renal impairment, respectively.
Mean (% CV) exposure to tenofovir increased from 2185 (12%) mcg•h/mL in patients with normal renal function to 3064 (30%) mcg•h/mL, 6009 (42%) mcg•h/mL, and 15,985 (45%) mcg•h/mL in patients with mild, moderate, and severe renal impairment, respectively.
An increased dosing interval in patients with moderate renal impairment is expected to result in higher peak plasma concentrations and lower Cmin levels compared to patients with normal renal function. The clinical implications of this are unknown.
In patients with end-stage renal disease (ESRD) requiring hemodialysis, drug exposure is significantly increased, reaching 53 (19%) mcg•h/mL for emtricitabine over 72 hours and 42,857 (29%) ng•h/mL for tenofovir over 48 hours.
Dose interval adjustment is recommended for patients with creatinine clearance of 30–49 mL/min. The drug is not recommended for patients with CrCl < 30 mL/min or for those on hemodialysis (see section "Dosage and Administration").
Hepatic Impairment. The pharmacokinetics of the drug in patients with hepatic impairment have not been studied. However, dose adjustment is unlikely to be necessary in patients with hepatic impairment.
The pharmacokinetics of emtricitabine have not been studied in patients not infected with hepatitis B virus (HBV) with varying degrees of hepatic impairment. Overall, the pharmacokinetics of emtricitabine in HBV-infected patients are similar to those in healthy individuals and HIV-infected patients.
A single 245 mg dose of tenofovir disoproxil was administered to HIV-negative patients with varying degrees of hepatic impairment classified according to the Child-Pugh-Turcotte (CPT) scale. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic impairment, indicating no need for dose adjustment in these patients. Mean (% CV) Cmax and AUC0–∞ values for tenofovir were 223 (34.8%) ng/mL and 2050 (50.8%) ng•h/mL, respectively, in individuals without hepatic impairment, compared to 289 (46.0%) ng/mL and 2310 (43.5%) ng•h/mL in patients with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2740 (44.0%) ng•h/mL in patients with severe hepatic impairment.
Clinical characteristics.
Indications.
The medicinal product is indicated for use in combination antiretroviral therapy for the treatment of HIV-1 infected adults (aged 18 years and older).
Contraindications.
Hypersensitivity to the active substances or to any of the excipients.
Interaction with other medicinal products and other forms of interaction.
Since the medicinal product contains emtricitabine and tenofovir disoproxil fumarate, any interactions identified with these substances individually may also occur with TenoHop-E. Interaction studies have been conducted only in adults.
The steady-state pharmacokinetics of emtricitabine and tenofovir were not affected when emtricitabine and tenofovir disoproxil fumarate were administered together, compared to administration of each medicinal product separately.
In vitro and clinical pharmacokinetic interaction studies have shown that the likelihood of CYP450-mediated interactions involving emtricitabine and tenofovir disoproxil fumarate with other medicinal products is low.
Concomitant use not recommended: Due to similarity with emtricitabine, TenoHop-E should not be taken concomitantly with other cytidine analogues such as lamivudine (see section "Special precautions for use").
As a fixed-dose combination, the medicinal product should not be taken concomitantly with other medicinal products containing any of its components, emtricitabine or tenofovir disoproxil fumarate.
The medicinal product should not be taken concomitantly with adefovir dipivoxil.
Didanosine. Concomitant administration of the medicinal product and didanosine is not recommended (see section "Special precautions for use" and Table 1).
Medicinal products eliminated via the kidneys. Since emtricitabine and tenofovir are primarily eliminated via the kidneys, concomitant administration of the medicinal product with other medicinal products that are eliminated by active tubular secretion (e.g., cidofovir) may lead to increased serum concentrations of emtricitabine and/or the concomitantly administered medicinal products due to competition for this elimination pathway.
Concomitant use of nephrotoxic medicinal products, either currently or recently, should be avoided with the medicinal product, such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (see section "Special precautions for use").
Other interactions.
Interactions between components of the medicinal product, protease inhibitors, and nucleoside reverse transcriptase inhibitors are presented in Table 1 below (increase is indicated by "↑", decrease by "↓", no change by "↔", twice daily by "b.i.d.", once daily by "q.d."). Where possible, 90% confidence intervals are provided in parentheses.
Table 1
Interactions between components of TenoHop-E and other medicinal products
| Medicinal product by treatment indication |
Effects on the change in mean percentage concentration of the active substance in AUC, Cmax, Cmin with 90% confidence intervals if available (mechanism) |
Recommendation regarding concomitant use with Tenohop-E (emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) |
| ANTI-INFECTIVES |
||
| Antiretrovirals |
||
| Protease inhibitors |
||
| 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) Tenofovir: AUC: ↑ 37% Cmax: ↑ 34% Cmin: ↑ 29% |
Dose adjustment is not recommended. Increased exposure to tenofovir may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions"). |
| Atazanavir/Ritonavir / Emtricitabine |
Interaction not studied. |
|
| Darunavir/Ritonavir / Tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) |
Darunavir: AUC: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 22% Cmin: ↑ 37% |
Dose adjustment is not recommended. Increased exposure to tenofovir may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions"). |
| Darunavir/Ritonavir / Emtricitabine |
Interaction not studied. |
|
| Lopinavir/Ritonavir / Tenofovir disoproxil fumarate (400 mg q.d. / 100 mg q.d. / 300 mg q.d.) |
Lopinavir/Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 32% (↑ 25 to ↑ 38) Cmax: ↔ Cmin: ↑ 51% (↑ 37 to ↑ 66) |
Dose adjustment is not recommended. Increased exposure to tenofovir may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions"). |
| Lopinavir/Ritonavir / Emtricitabine |
Interaction not studied. |
|
| Nucleoside reverse transcriptase inhibitors (NRTIs) |
||
| Didanosine / Tenofovir disoproxil fumarate |
Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse reactions (see section "Adverse reactions"). |
Concomitant use of Tenohop-E and didanosine is not recommended (see section "Special warnings and precautions"). |
| Rare, sometimes fatal, cases of pancreatitis and lactic acidosis have been reported. Concomitant use of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg per day was associated with a significant decrease in CD4 lymphocyte count, possibly related to increased intracellular interaction of phosphorylated (i.e., active) didanosine. A reduced dose of 250 mg didanosine, when used concomitantly with tenofovir disoproxil fumarate therapy, has been associated with reports of high rates of virological inefficacy in several controlled combination trials for the treatment of HIV-1 infection. |
||
| Didanosine / Emtricitabine |
Interaction not studied. |
|
Studies conducted with other medicinal products.
Emtricitabine. In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation.
Clinically significant interactions are absent when emtricitabine is administered concomitantly with indinavir, zidovudine, stavudine, or famciclovir.
Tenofovir disoproxil fumarate. Concomitant administration of lamivudine, indinavir, efavirenz, nelfinavir, or saquinavir (boosted with ritonavir), methadone, ribavirin, rifampicin, adefovir dipivoxil, or the hormonal contraceptive norgestimate/ethinylestradiol with tenofovir disoproxil fumarate did not result in any clinically significant pharmacokinetic interactions.
Tenocho-E. Concomitant administration of tacrolimus with the medicinal product did not result in any clinically significant pharmacokinetic interactions.
Special precautions for use.
TenoHop-E should not be used concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil fumarate, or other cytidine analogues such as lamivudine (see section "Interaction with other medicinal products and other forms of interaction"). The drug should not be administered simultaneously with adefovir dipivoxil.
Concomitant use of tenofovir disoproxil fumarate and didanosine.
Not recommended. Concurrent administration of tenofovir disoproxil fumarate and didanosine results in a 40–60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events (see section "Interaction with other medicinal products and other forms of interaction"). Rare, sometimes fatal cases of pancreatitis and lactic acidosis have been reported. Concurrent administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. A reduced dosage of 250 mg didanosine administered together with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological treatment failure in several studied combinations.
Triple nucleoside therapy.
Reports have indicated a high rate of virological treatment failure and early emergence of resistance when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine administered once daily. There is close structural similarity between lamivudine and emtricitabine, as well as similarities in pharmacokinetics and pharmacodynamics of these two substances. Therefore, similar problems may occur when TenoHop-E is used with a third nucleoside analogue.
Opportunistic infections.
In patients receiving TenoHop-E or any other antiretroviral therapy, opportunistic infections and other complications of HIV infection may continue to occur; therefore, patients should remain under close clinical supervision by physicians experienced in treating HIV-related diseases.
HIV transmission.
Since it has not been proven that effective viral suppression by antiretroviral treatment significantly reduces the risk of sexual transmission of infection, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken in accordance with national recommendations.
Renal impairment.
Emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion. Reports of renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported during clinical use of tenofovir disoproxil fumarate (see section "Adverse reactions").
Calculation of creatinine clearance is recommended in all patients prior to initiating treatment with the drug, and monitoring of renal function (creatinine clearance and serum phosphate levels) every 2–4 weeks during the first 3 months of treatment, and then every 3–6 months in patients without risk factors for renal impairment. For patients at risk of renal dysfunction, including those who previously experienced renal events while receiving adefovir dipivoxil, more frequent monitoring of renal function should be considered.
Patients with renal impairment (creatinine clearance < 80 mL/min), including patients on hemodialysis.
The safety of tenofovir in the kidneys has been studied only in patients with mild renal dysfunction (creatinine clearance < 80 mL/min). Data from limited clinical studies indicate that prolonged dosing intervals are not optimal and may lead to increased toxicity and possibly inadequate response. Furthermore, in a small clinical study, a subgroup of patients with creatinine clearance between 50 and 60 mL/min receiving tenofovir disoproxil fumarate in combination with emtricitabine every 24 hours had 2–4 times higher tenofovir exposure and experienced worsening renal function (see section "Pharmacokinetics"). Therefore, careful benefit-risk assessment is required when administering the drug to patients with creatinine clearance < 60 mL/min, along with careful monitoring of renal function. Additionally, close observation of clinical response to treatment is necessary in patients receiving the drug with prolonged dosing intervals. Use of TenoHop-E is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients requiring hemodialysis, as the required dose reduction cannot be achieved with the fixed-dose combination tablet (see sections "Dosage and administration" and "Pharmacokinetics").
If serum phosphate levels fall below 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases below 50 mL/min in any patient receiving the drug, renal function should be reassessed within one week, including measurement of blood glucose, serum potassium, and urine glucose concentration (see section "Adverse reactions"). Consideration should also be given to discontinuing treatment in patients whose creatinine clearance decreases below 50 mL/min or whose serum phosphate levels fall below 1 mg/dL (0.32 mmol/L). Discontinuation of TenoHop-E treatment should also be considered in cases of progressive decline in renal function if no other cause is identified.
Concomitant or recent use of nephrotoxic medicinal products with TenoHop-E should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use of the drug and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.
Cases of acute renal failure after initiation of high doses or multiple nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported in patients with risk factors for renal dysfunction. When the drug is used concomitantly with NSAIDs, renal function should be closely monitored.
A higher risk of worsening renal function has been observed in patients receiving tenofovir disoproxil fumarate in combination with a protease inhibitor boosted with ritonavir or cobicistat. These patients require strict monitoring of renal function (see section "Interaction with other medicinal products and other forms of interaction"). For HIV-1-infected patients with renal risk factors, careful consideration is needed when combining tenofovir disoproxil fumarate with a boosted protease inhibitor.
Patients with HIV-1 mutations. The drug should be avoided in patients previously treated with antiretroviral agents who have HIV-1 strains with the K65R mutation (see section "Pharmacodynamics").
Bone effects.
In a study comparing tenofovir disoproxil fumarate versus stavudine, both in combination with lamivudine and efavirenz in antiretroviral-naïve patients, both treatment groups showed slight decreases in bone mineral density of the hip and spine. Decreases in spine bone mineral density and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate group up to 144 weeks. Hip bone mineral density reductions were significantly greater in this group up to 96 weeks. However, after 144 weeks, there was no increased risk of fractures or evidence of clinically significant bone abnormalities.
Bone abnormalities (rarely leading to fractures) may be associated with proximal renal tubulopathy (see section "Adverse reactions"). If bone abnormalities are suspected, appropriate consultations should be obtained.
Patients with HIV and concomitant hepatitis B or C virus infection.
Patients with chronic hepatitis B or C undergoing antiretroviral therapy are at increased risk of severe and potentially fatal adverse reactions affecting the liver.
Physicians should refer to current guidelines for HIV treatment regarding optimal management of HIV infection in patients with concomitant hepatitis B virus (HBV) infection.
In cases of concomitant antiviral therapy for hepatitis B or C, the appropriate product information for these medicinal products should also be consulted.
The safety and efficacy of the drug have not been established for the treatment of chronic HBV infection. In pharmacodynamic studies, emtricitabine and tenofovir, alone and in combination, demonstrated activity against HBV (see section "Pharmacodynamics"). Limited clinical experience indicates that emtricitabine and tenofovir disoproxil fumarate exhibit activity against HBV when used in antiretroviral combination therapy for control of HIV infection.
Discontinuation of treatment with the drug in patients with concomitant HIV and HBV infection may be associated with severe acute worsening of hepatitis. Patients with concomitant HIV and HBV infection who discontinue TenoHop-E should be closely monitored clinically and by laboratory testing for several months after stopping treatment. Reinitiation of hepatitis B treatment may be warranted if necessary. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as hepatitis flare after treatment may lead to hepatic decompensation.
Liver disease.
The safety and efficacy of the drug have not been established in patients with pre-existing significant liver function impairment. The pharmacokinetics of the drug in patients with hepatic impairment have not been studied. The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment, and no dose adjustment is required for these patients. Due to the minimal hepatic metabolism and renal elimination pathway of emtricitabine, it is unlikely that patients with hepatic impairment will require dose adjustment of the drug (see section "Pharmacokinetics").
Patients with prior liver function abnormalities, including chronic active hepatitis, have an increased frequency of liver function disturbances during combination antiretroviral therapy (CART), and should be monitored according to standard practice. If there is evidence of worsening liver disease, treatment interruption or discontinuation should be considered for such patients.
Lactic acidosis.
Lactic acidosis, usually associated with hepatic steatosis, has been reported with nucleoside analogue use. Early symptoms (symptomatic hyperlactatemia) include benign gastrointestinal symptoms (nausea, vomiting, and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including muscle weakness). Lactic acidosis has high mortality and may be associated with pancreatitis, liver failure, or renal failure. Generally, lactic acidosis occurs after several months of treatment.
Treatment with nucleoside analogues should be discontinued in cases of symptomatic hyperlactatemia and metabolic or lactic acidosis, progressive hepatomegaly, or rapid increases in aminotransferase levels.
Caution should be exercised when using nucleoside analogues in any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Treatment of patients with concomitant hepatitis C infection with alpha-interferon and ribavirin may pose a particular risk.
Patients at increased risk should be closely monitored.
Lipodystrophy.
In HIV-infected patients, CART has been associated with redistribution of body fat (lipodystrophy). The long-term consequences of these phenomena are currently unknown. Knowledge of the mechanisms is incomplete. Hypotheses have linked visceral lipomatosis to protease inhibitors and lipoatrophy to nucleoside reverse transcriptase inhibitors. Increased risk of lipodystrophy has been associated with individual factors such as older age, and with drug-related factors such as longer duration of antiretroviral therapy, as well as associated metabolic disturbances. Clinical evaluation should include assessment of physical signs of fat redistribution. Fasting serum lipid levels and blood glucose levels should be monitored. Metabolic disturbances should be managed as clinically indicated (see section "Adverse reactions").
Tenofovir is structurally a nucleoside analogue; therefore, the risk of lipodystrophy cannot be excluded. However, results from 144-week clinical trials in antiretroviral-naïve HIV-infected patients indicate that the risk of lipodystrophy with tenofovir disoproxil fumarate is lower than with stavudine when used in combination with lamivudine and efavirenz.
Mitochondrial function impairment.
In vitro and in vivo studies have shown that nucleoside and nucleotide analogues may cause varying degrees of mitochondrial injury. Reports of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally. The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Reports of some later-onset neurological disorders (hypertonia, convulsions, abnormal behavior) have also occurred. It is currently unknown whether these neurological disorders are temporary or permanent. Any child exposed to nucleoside and nucleotide analogues in utero, including HIV-negative children, should undergo further clinical and laboratory evaluation for possible mitochondrial dysfunction if appropriate signs or symptoms occur. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune reconstitution syndrome.
In HIV-infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, potentially causing severe clinical conditions or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after starting CART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and appropriate treatment initiated if necessary.
Autoimmune disorders (such as Graves' disease) have also been reported during immune reconstitution; however, the time to onset has varied widely, and these events may occur many months after starting treatment.
In HIV-infected patients with concomitant hepatitis B virus infection, hepatitis flare associated with immune reconstitution syndrome may occur after initiation of antiretroviral therapy.
Osteonecrosis.
Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been most frequently observed in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical attention if they experience joint pain, joint stiffness, or difficulty moving.
Elderly patients.
The effect of the drug in patients over 65 years of age has not been studied. Elderly patients more commonly have decreased renal function; therefore, caution should be exercised when treating elderly patients with the drug.
TenoHop-E contains lactose monohydrate. Therefore, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.
Use during pregnancy and breastfeeding.
Pregnancy.
Limited data from pregnant women (300–1000 pregnancy outcomes) suggest no malformations or embryo/fetal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Therefore, use of the drug during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding.
Emtricitabine and tenofovir have been detected in human breast milk. There is insufficient information on the effects of emtricitabine and tenofovir on newborns/infants; therefore, the drug should not be used during breastfeeding.
Generally, HIV-infected women should not breastfeed their infants under any circumstances to avoid transmission of HIV to the child.
Ability to influence reaction speed when driving or operating machinery.
No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, patients should be informed that dizziness has been reported during treatment with both emtricitabine and tenofovir disoproxil fumarate.
Method of Administration and Dosage
Treatment should be initiated by a physician experienced in the management of HIV infection.
Dosing
The recommended dose of the medicinal product is 1 tablet orally once daily. To optimize tenofovir absorption, it is recommended to take the medicinal product with food. Even a light meal improves the absorption of tenofovir from the combination tablet (see section "Pharmacokinetics").
Elderly patients. There are no available data on which to base dosing recommendations for patients over 65 years of age. However, there is no need to adjust the recommended daily dose for adults unless there is evidence of renal impairment.
Renal impairment. Emtricitabine and tenofovir are eliminated in urine, and exposure to emtricitabine and tenofovir increases in patients with impaired renal function. Data on safety and efficacy in patients with moderate and severe renal impairment (creatinine clearance < 50 mL/min) are limited, and safety data in patients with mild renal impairment (creatinine clearance 50–80 mL/min) have not yet been evaluated. Therefore, the medicinal product may be used in patients with renal impairment only if the potential benefit of treatment is considered to outweigh the potential risks. Patients with renal impairment may require careful monitoring of renal function (see section "Special precautions"). For patients with creatinine clearance of 30 to 49 mL/min, adjustment of the dosing interval is recommended. This dosage adjustment has not been clinically confirmed; therefore, these patients should be carefully monitored for clinical response (see sections "Pharmacokinetics", "Special precautions").
Mild renal impairment (creatinine clearance 50–80 mL/min). Take 1 tablet once daily (see section "Special precautions").
Moderate renal impairment (creatinine clearance 30–49 mL/min). It is recommended to take the medicinal product every 48 hours (see section "Special precautions").
Severe renal impairment (creatinine clearance < 30 mL/min) and patients on hemodialysis. The medicinal product is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or for patients requiring hemodialysis, as it is not possible to achieve the necessary dose reduction with the combination tablet.
Hepatic impairment. Dose adjustment is not required. If treatment is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), careful monitoring of these patients should be conducted to detect signs of hepatitis flare (see section "Special precautions").
Method of administration
If patients have difficulty swallowing, the tablet may be crushed in approximately 100 mL of water, orange juice, or grape juice and taken immediately.
If a patient misses a dose of the medicinal product and less than 12 hours have passed since the scheduled time, the patient should take the dose as soon as possible with food and continue with the usual dosing schedule. If a patient misses a dose and more than 12 hours have passed since the scheduled time—i.e., the time for the next dose is approaching—the patient should not take the missed dose but should continue taking the medicinal product according to the regular schedule.
If vomiting occurs within 1 hour after taking the medicinal product, the patient should take another tablet. If vomiting occurs more than 1 hour after taking the medicinal product, another tablet is not required.
Children.
TenoHop-E is not recommended for patients under 18 years of age, as the safety and efficacy of the medicinal product have not been established in this age group.
Overdose.
In case of overdose, the patient should be observed for signs of toxicity (see section "Adverse reactions"); standard supportive treatment should be administered if necessary.
Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose may be removed by hemodialysis. It is unknown whether emtricitabine or tenofovir is removed by peritoneal dialysis.
Adverse Reactions
Safety Profile
The most commonly reported adverse reactions probably related to emtricitabine and/or tenofovir disoproxil fumarate were nausea (12%) and diarrhea (7%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in this study was consistent with previous experience with these agents when each was used separately in combination with other antiretroviral drugs.
In patients receiving tenofovir disoproxil fumarate, rare cases of renal failure, renal impairment, and proximal renal tubulopathy (including Fanconi syndrome) have been observed, which sometimes led to bone abnormalities (infrequently contributing to fractures). Patients receiving the drug should undergo monitoring of renal function (see section "Special Warnings and Precautions for Use").
Lipoatrophy has been associated with tenofovir disoproxil fumarate and emtricitabine (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").
Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it may increase the risk of adverse reactions (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Rare cases of pancreatitis and lactic acidosis, sometimes resulting in fatal outcomes, have been reported (see section "Special Warnings and Precautions for Use").
Discontinuation of the drug in patients with concurrent HIV and HBV infection may be associated with severe exacerbations of hepatitis (see section "Special Warnings and Precautions for Use").
Summary Table of Adverse Reactions
Adverse reactions that possibly were related to the components of the drug and observed in clinical trials and post-marketing surveillance are listed in Table 2 below by system organ class and frequency. Within each frequency group, adverse events are listed in order of decreasing severity. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), or rare (≥ 1/10,000 to < 1/1,000).
Table 2
Adverse Reactions Associated with Individual Components of Tenochope-E
| Frequency |
Emtricitabine |
Tenofovir disoproxil fumarate |
| Blood and lymphatic system disorders |
||
| Common: |
neutropenia |
|
| Uncommon: |
anemia2 |
|
| Immune system disorders |
||
| Common: |
allergic reactions |
|
| Metabolism and nutrition disorders |
||
| Very common: |
hypophosphatemia1 |
|
| Common: |
hyperglycemia, hypertriglyceridemia |
|
| Uncommon: |
hypokalemia1 |
|
| Rare: |
lactic acidosis |
|
| Psychiatric disorders |
||
| Common: |
insomnia, abnormal dreams |
|
| Nervous system disorders |
||
| Very common: |
headache |
dizziness |
| Common: |
dizziness |
headache |
| Gastrointestinal disorders |
||
| Very common: |
diarrhea, nausea |
|
| Common: |
increased amylase levels, including increased pancreatic amylase, increased serum lipase levels, vomiting, abdominal pain, dyspepsia |
abdominal pain, abdominal distension, flatulence |
| Uncommon: |
pancreatitis |
|
| Hepatobiliary disorders |
||
| Common: |
increased serum aspartate aminotransferase (AST) and/or increased serum alanine aminotransferase (ALT), hyperbilirubinemia |
increased transaminases |
| Rare: |
fatty liver degeneration, hepatitis |
|
| Skin and subcutaneous tissue disorders |
||
| Very common: |
rash |
|
| Common: |
vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discoloration (increased pigmentation)2 |
|
| Uncommon: |
angioneurotic edema3 |
|
| Rare: |
angioneurotic edema |
|
| Musculoskeletal and connective tissue disorders |
||
| Very common: |
increased creatine kinase levels |
|
| Uncommon: |
acute skeletal muscle necrosis1,3, muscle weakness1 |
|
| Rare: |
osteomalacia (manifested as bone pain and infrequently leading to fractures)1,3, myopathy1 |
|
| Renal and urinary disorders |
||
| Uncommon: |
increased creatinine levels, proteinuria |
|
| Rare: |
renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy including Fanconi syndrome, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus |
|
| General disorders and administration site conditions: |
||
| Very common: |
asthenia |
|
| Common: |
pain, asthenia |
|
1 A side effect may occur as a result of proximal renal tubulopathy. It is not considered to be causally related to tenofovir disoproxil fumarate in the absence of this condition.
2 Anaemia was common, skin colour change (increased pigmentation) was very common when emtricitabine was used in paediatric patients.
3 This adverse reaction was identified during post-marketing surveillance, but was not observed in randomized controlled clinical trials in adults or in clinical trials of emtricitabine treatment of HIV in children, or in randomized controlled clinical trials or the expanded access program of tenofovir disoproxil fumarate. The frequency category was determined based on statistical calculations using the total number of patients who received emtricitabine in randomized controlled clinical trials and the expanded access program (n = 1563) or tenofovir disoproxil fumarate in randomized controlled clinical trials and the expanded access program (n = 7319).
Description of selected adverse reactions
Renal impairment. Since the medicine TenoHop-E may lead to kidney dysfunction, monitoring of kidney function is recommended (see section "Special warnings and precautions for use"). Proximal renal tubulopathy was generally resolved or improved after discontinuation of tenofovir disoproxil fumarate. However, in some HIV-infected patients, reduced creatinine clearance did not fully resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of kidney function impairment (e.g., patients with baseline risk factors for kidney disorders, patients with progressive HIV disease, or patients receiving concomitant therapy with nephrotoxic agents) have an increased risk of incomplete recovery of kidney function despite discontinuation of tenofovir disoproxil fumarate (see section "Special warnings and precautions for use").
Interaction with didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in the exposure of didanosine, which may increase the risk of didanosine-related adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). Cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely.
Lipids, lipodystrophy and metabolic disturbances: CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (see section "Special warnings and precautions for use").
CART has been associated with redistribution of body fat in HIV-infected patients (lipodystrophy), including loss of peripheral and facial subcutaneous fat, increased visceral and intra-abdominal fat, breast enlargement, and fat accumulation in the dorsocervical area (buffalo hump) (see section "Special warnings and precautions for use").
Immune Reconstitution Syndrome. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset of disease varied widely, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions for use").
Osteonecrosis. Cases of osteonecrosis have been observed in patients with risk factors, advanced HIV disease, or those receiving long-term combination antiretroviral therapy (CART). The frequency of this event is unknown (see section "Special warnings and precautions for use").
Other special patient populations
Elderly patients. The use of TenoHop-E in patients aged 65 years and older has not been studied. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised when administering TenoHop-E to elderly patients (see section "Special warnings and precautions for use").
Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, careful monitoring of renal function is recommended in all adults with renal impairment who are taking TenoHop-E (see sections "Pharmacokinetics", "Special warnings and precautions for use", "Posology and method of administration"). TenoHop-E is not recommended for paediatric patients with renal impairment (see sections "Special warnings and precautions for use", "Posology and method of administration").
Patients with concomitant HIV/hepatitis B virus or HIV/hepatitis C virus infections. In study GS-01-934, only a limited number of patients were co-infected with hepatitis B virus (n=13) or hepatitis C virus (n=26). The adverse reaction profile of emtricitabine and tenofovir disoproxil fumarate in patients co-infected with HIV/hepatitis B virus or HIV/hepatitis C virus was similar to that observed in HIV-infected patients without concomitant infection. However, as expected in this patient population, elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed more frequently than in the general HIV-infected population.
Hepatitis flare after discontinuation of therapy. Clinical and laboratory signs of hepatitis flare occurred in patients infected with hepatitis B virus after discontinuation of therapy (see section "Special warnings and precautions for use").
Shelf life.
2 years.
Storage conditions.
Store at temperatures not exceeding 30°C in the original packaging.
Keep out of reach of children.
Packaging.
30 tablets in a bottle, 1 bottle in a cardboard pack.
Prescription status. Prescription only.
Manufacturer.
MACLEODS PHARMACEUTICALS LIMITED.
Manufacturer's address and location of its business operations.
Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.