Virkel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIREKIL (VIRKIL)

Composition:

Active substance: tenofovir disoproxil;

One film-coated tablet contains 300 mg of tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil;

Excipients: pregelatinized starch, sodium croscarmellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, Opadry White (Y-1-7000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, white in color, with "TDF" debossed on one side and smooth on the other.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors.

ATC code J05AF07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action and Pharmacodynamic Effects

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted into the active substance tenofovir, a nucleoside monophosphate (nucleotide) analogue. Tenofovir is subsequently converted into the active metabolite tenofovir diphosphate by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and HBV polymerase by competing with the natural deoxyribonucleotide substrate for direct binding and by causing DNA chain termination after incorporation into the DNA. Tenofovir diph游戏副本

Clinical characteristics.

Indications.

HIV-1 infection

The medicinal product is indicated for the treatment of HIV-1 infected patients in combination with other antiretroviral medicinal products.

The medicinal product is indicated for the treatment of HIV-1 infected adolescents aged 12 to < 18 years with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or toxicity precluding the use of first-line medicinal products.

Selection of the medicinal product for treatment of HIV-1 infected patients previously treated with antiretroviral medicinal products should be based on individual data from viral resistance testing and/or patient treatment history.

Hepatitis B

The medicinal product is indicated for the treatment of chronic hepatitis B in adults with:

• compensated liver disease, with evidence of active viral replication, persistent elevation of serum alanine aminotransferase (ALT) levels, and histological evidence of active inflammation and/or fibrosis (see section "Pharmacodynamics");
• documented lamivudine-resistant hepatitis B (see sections "Pharmacodynamics" and "Adverse reactions");
• decompensated liver disease (see sections "Pharmacodynamics", "Special precautions" and "Adverse reactions").

The medicinal product is indicated for the treatment of chronic hepatitis B in adolescents aged 12 to < 18 years with:

• compensated liver disease, with evidence of active immune disease, i.e. active viral replication, persistent elevation of serum ALT levels, and histological evidence of active inflammation and/or fibrosis (see sections "Pharmacodynamics", "Special precautions" and "Adverse reactions").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Children under 12 years of age.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Based on in vitro data and the known elimination pathway of tenofovir, the likelihood of CYP450-mediated interactions between tenofovir and other medicinal products is low.

Not recommended for concomitant use. The medicinal product should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

The medicinal product should not be used concomitantly with adefovir dipivoxil.

Didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended (see section "Special precautions" and Table 1).

Medicinal products eliminated by the kidneys. Since tenofovir is primarily eliminated by the kidneys, concomitant use of tenofovir disoproxil fumarate with medicinal products that reduce renal filtration or compete for active tubular secretion via hOAT1, hOAT3, or MRP4 transport proteins (e.g., cidofovir) may increase serum concentrations of tenofovir and/or concomitantly administered medicinal products.

Use of tenofovir disoproxil fumarate should be avoided with concomitant or recent use of nephrotoxic medicinal products. These include, for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2 (see section "Special precautions").

Given that tacrolimus may affect renal function, special monitoring is recommended if it is used concomitantly with tenofovir disoproxil fumarate.

Other interactions. Interactions between tenofovir disoproxil fumarate and other medicinal products are presented below in Table 1 (increase is denoted by "↑", decrease by "↓", no change by "↔", twice daily by "b.i.d.", and once daily by "q.d.").

Table 1. Interactions between tenofovir disoproxil fumarate and other medicinal products

1 Data obtained with concomitant use with ledipasvir/sofosbuvir. Sequential administration (12 hours apart) yielded similar results.

2 Predominant circulating metabolite of sofosbuvir.

3 The study was conducted with an additional dose of voxilaprevir 100 mg to achieve voxilaprevir exposures expected in patients infected with hepatitis C virus.

Studies conducted with other medicinal products. No clinically significant pharmacokinetic interactions were observed when tenofovir disoproxil fumarate was administered concomitantly with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir-boosted), methadone, ribavirin, rifampicin, tacrolimus, and the hormonal contraceptive norgestimate/ethinylestradiol.

Tenofovir disoproxil fumarate should be taken with food, as food increases the bioavailability of tenofovir (see section "Pharmacokinetics").

Special precautions for use.

General

Before initiating therapy with tenofovir disoproxil fumarate, an HIV antibody test should be offered to all HBV-infected patients (see sections below "HIV-1 and hepatitis B co-infection").

HIV‑1. Since it has not been proven that effective viral suppression by antiretroviral drugs significantly reduces the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken in accordance with national recommendations.

Chronic hepatitis B. Patients should be informed that there is no evidence that tenofovir disoproxil fumarate prevents the risk of transmission of HBV to others via sexual contact or blood exposure. Appropriate preventive measures should continue to be used.

Concomitant use with other medicinal products

• Do not use with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
• Do not use concomitantly with adefovir dipivoxil.
• Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, increasing the risk of didanosine-related adverse events. 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 daily has been associated with significant decreases in CD4 cell counts, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. Reduced dosing (250 mg) of didanosine administered with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure in several studied combination regimens for the treatment of HIV-1 infection.

Nucleoside/nucleotide triple therapy

Reports have been received of high rates of early virological failure and emergence of resistance in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine administered once daily.

Effects on kidneys and bones in adults

Effect on renal function

Tenofovir is primarily eliminated by the kidneys. Reports of renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the clinical use of tenofovir disoproxil fumarate (see section "Adverse reactions").

Monitoring of renal function

Calculation of creatinine clearance is recommended for all patients before starting tenofovir disoproxil fumarate therapy, and renal function (creatinine clearance and serum phosphate level) should be checked at 2–4 weeks after starting treatment, at 3 months, and then every 3–6 months in patients without risk factors for renal impairment. Patients at increased risk of renal impairment require more frequent monitoring of renal function.

Treatment of kidney disorders

If serum phosphate level is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within 1 week, including measurement of blood glucose, blood potassium, and urine glucose concentration (see section "Adverse reactions", proximal tubulopathy). Consideration should also be given to discontinuing tenofovir disoproxil fumarate in patients whose creatinine clearance decreases to < 50 mL/min or whose serum phosphate level decreases to < 1.0 mg/dL (0.32 mmol/L). Interruption of treatment should also be considered in cases of progressive decline in renal function if no other cause is identified.

Concomitant use and risk of nephrotoxicity

Concomitant use of tenofovir disoproxil fumarate with nephrotoxic medicinal products (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2) should be avoided. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.

Cases of acute renal failure following initiation of high-dose nonsteroidal anti-inflammatory drugs (NSAIDs) or multiple NSAIDs have been reported in patients receiving tenofovir disoproxil fumarate, particularly in those with risk factors for renal impairment. When the drug is used concomitantly with NSAIDs, renal function should be appropriately monitored.

An increased risk of renal failure has been observed in patients receiving tenofovir disoproxil fumarate in combination with ritonavir-boosted or cobicistat-boosted protease inhibitors. Careful monitoring of renal function is required in these patients (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated in patients with risk factors for renal impairment.

Clinical evaluations of tenofovir disoproxil fumarate have not been conducted in patients receiving medicinal products eliminated by the same renal pathway, including human organic anion transporters (hOAT) 1 and 3 or MRP 4 (e.g., cidofovir – a known nephrotoxic medicinal product). These renal transport proteins may be involved in tubular secretion and partially in renal elimination of both tenofovir and cidofovir. Therefore, the pharmacokinetics of medicinal products eliminated via the same renal pathway, including hOAT 1 and 3 or MRP 4, may be altered when administered concomitantly. Unless clearly necessary, concomitant use of medicinal products eliminated via the same renal pathway is not recommended. If such concomitant use cannot be avoided, renal function should be monitored weekly (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

Renal safety of tenofovir disoproxil fumarate has been very limitedly studied in adult patients with renal impairment (CrCl < 80 mL/min).

Adult patients with CrCl < 50 mL/min, including patients on haemodialysis

Data on the safety of tenofovir disoproxil fumarate in patients with renal impairment are limited. Therefore, tenofovir disoproxil fumarate should be prescribed only when the expected benefit outweighs the potential risks. Tenofovir disoproxil fumarate is not recommended for patients with acute renal failure (CrCl < 30 mL/min) or those requiring haemodialysis. If no alternative treatment is available, the dosing interval should be adjusted and renal function carefully monitored (see sections "Pharmacokinetics" and "Dosage and administration").

Effect on bones

In HIV-infected patients during a 144-week controlled clinical trial comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, both treatment groups showed a small decrease in bone mineral density (BMD) of the hip and spine. Over 144 weeks, the decrease in spine BMD and changes in bone biomarkers were significantly greater in the group receiving tenofovir disoproxil fumarate. Decreases in hip BMD were significantly greater in this group up to week 96. However, after 144 weeks of study, no increased risk of fractures or evidence of clinically significant bone abnormalities was observed.

In other studies (prospective and crossover), the most pronounced decrease in BMD was observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis who are at high risk of fractures.

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.

Effects on kidneys and bones in the paediatric population

There are uncertainties regarding the long-term effects of bone and renal toxicity. Additionally, the reversibility of renal toxicity cannot be fully established. Therefore, a multidisciplinary approach is recommended to adequately assess the individual benefit-risk ratio of treatment, make decisions regarding appropriate monitoring during treatment (including decisions on treatment discontinuation), and consider the need for dietary supplements.

Effect on kidneys

During clinical trials in HIV-infected children aged 2 to < 12 years, renal adverse reactions associated with proximal renal tubulopathy were reported (see sections "Special precautions for use" and "Pharmacodynamics").

Monitoring of renal function

Monitoring of renal function

Renal function (serum creatinine and phosphate) should be assessed before starting treatment and monitored during treatment as in adults (see above).

Treatment of renal impairment

If serum phosphate level is confirmed to be < 3.0 mg/dL (0.96 mmol/L) in any paediatric patient receiving tenofovir disoproxil fumarate, renal function should be evaluated within one week, including measurement of blood glucose, blood potassium, and urine glucose concentration (see section "Adverse reactions", proximal tubulopathy). If renal abnormalities are suspected or detected, consultation with a nephrologist is required to consider the possibility of interrupting treatment with tenofovir disoproxil fumarate. Interruption of tenofovir disoproxil fumarate treatment should also be considered in cases of progressive decline in renal function if no other cause is identified.

Concomitant use and risk of nephrotoxicity

See above recommendations for adults.

Renal failure

Use of tenofovir disoproxil fumarate is not recommended in children with renal failure (see section "Dosage and administration"), and therefore treatment with tenofovir disoproxil fumarate should not be prescribed to such paediatric patients. Treatment should be discontinued in children who develop renal failure during therapy with tenofovir disoproxil fumarate.

Effect on bones

The medicinal product may cause a decrease in BMD. The impact of BMD changes associated with tenofovir disoproxil fumarate on long-term bone health and future fracture risk is currently unknown (see section "Pharmacodynamics").

If bone abnormalities are detected or suspected in children, consultation with an endocrinologist and/or nephrologist should be sought.

Liver disorders

Data on the safety and efficacy of the medicinal product in patients with liver transplantation are very limited.

Safety and efficacy data for tenofovir disoproxil fumarate in patients infected with hepatitis B with decompensated liver disease and Child-Pugh-Turcotte score > 9 are limited. These patients have a higher risk of serious adverse reactions affecting the liver and kidneys. Therefore, hepatic and renal parameters should be monitored more closely in this patient population.

Hepatitis flare

Flare during treatment. Spontaneous flares of chronic hepatitis B are relatively common and are characterized by a transient increase in serum ALT levels. After initiation of antiviral therapy, serum ALT levels may increase in some patients (see section "Adverse reactions"). In patients with compensated liver disease, these increases in serum ALT levels generally do not coincide with increased serum bilirubin levels or hepatic decompensation. Patients with liver cirrhosis have an increased risk of hepatic decompensation following hepatitis flare and should therefore be closely monitored during treatment.

Flare after discontinuation of treatment. Acute hepatitis flare has also been reported in patients who discontinued hepatitis B treatment. Post-treatment flares are usually associated with increased HBV DNA levels, and most are self-limiting. However, severe flares, including fatal cases, have been reported. Liver function should be monitored monthly by clinical and laboratory parameters for 6 months after discontinuation of hepatitis B treatment. Reinitiation of hepatitis B treatment may be possible if necessary. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation.

In patients with decompensated liver disease, hepatitis flare is particularly serious and sometimes fatal.

Co-infection with hepatitis C or D. Data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus are lacking.

Co-infection with HIV-1 and hepatitis B. Due to the risk of developing HIV resistance, tenofovir disoproxil fumarate should be used in patients co-infected with HIV/HBV only as part of an appropriate antiretroviral combination regimen. Patients with prior liver function abnormalities, including chronic active hepatitis, have a higher frequency of liver function abnormalities during combination antiretroviral therapy (cART), and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, consideration should be given to interrupting or discontinuing treatment. However, it should be noted that increased ALT levels may be part of viral clearance in patients with hepatitis B virus infection during tenofovir treatment (see above "Hepatitis flare").

Use with specific antiviral agents for hepatitis C virus

Increased plasma concentrations of tenofovir are observed when tenofovir disoproxil fumarate is used with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir, particularly when used in combination with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of using tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic booster has not been established. Potential risks and benefits associated with concomitant use of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil fumarate prescribed in combination with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir) should be considered, especially in patients at increased risk of renal impairment. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir together with tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.

Body mass and metabolism parameters

During antiretroviral therapy, weight gain and increases in blood lipid and glucose levels may be observed in patients. These changes may be partly related to both therapy and lifestyle. Regarding lipids, there is evidence of treatment impact in some cases, whereas for weight gain, there is no substantial evidence linking it to any specific treatment. Monitoring of blood lipids and glucose should be performed according to established HIV treatment guidelines. Lipid disorders should be clinically managed.

Post-exposure mitochondrial dysfunctionin utero

Nucleoside and nucleotide analogues cause varying degrees of mitochondrial damage, particularly with stavudine, didanosine, and zidovudine. Reports of mitochondrial dysfunction have been received in HIV-negative young children exposed to nucleoside analogues in utero and/or postnatally. This primarily concerns treatment regimens containing zidovudine. The main adverse reactions reported were haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events were often transient. Rare reports of later-onset neurological disorders (hypertension, seizures, abnormal behaviour) have been received. It is currently unknown whether such neurological disorders are transient or permanent. These outcomes should be considered for any child exposed to nucleoside and nucleotide analogues associated with serious clinical disorders of unknown aetiology, particularly neurological disorders, in utero. These outcomes do not affect current national recommendations for the use of 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 reaction to asymptomatic or residual opportunistic pathogens may occur, which may cause serious clinical conditions or exacerbation of symptoms. Typically, such reactions are observed within the first few weeks or months after starting cART. Appropriate examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment initiated if necessary.

Autoimmune disorders (such as Graves' disease or autoimmune hepatitis) have also been reported to develop in the setting of immune reconstitution; however, the time to onset of disease varied widely, and these events may occur many months after starting treatment.

Osteonecrosis

Although the aetiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed, particularly in patients with advanced HIV disease and/or long-term exposure to cART. Patients should seek medical advice if they experience joint pain, joint stiffness, or difficulty in movement.

Elderly patients

The use of tenofovir disoproxil has not been studied in patients aged 65 years and older. Elderly patients often have reduced renal function; therefore, caution should be exercised when prescribing tenofovir disoproxil fumarate to these patients.

The medicinal product contains lactose monohydrate; therefore, patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

A large amount of data from use in pregnant women (over 1000 completed pregnancies) indicates no malformations or embryo/fetal or neonatal toxicity associated with tenofovir disoproxil fumarate. Animal studies have not shown any toxic effects on reproductive function. Tenofovir disoproxil fumarate may be used during pregnancy if necessary.

Breastfeeding period

Tenofovir has been found to pass into human breast milk. There is insufficient information on the effects of tenofovir on neonates/infants. Therefore, the medicinal product should not be used during breastfeeding.

Generally, HIV- and HBV-infected women are not recommended to breastfeed in order to avoid transmission of HIV or HBV infection to the child.

Fertility

The amount of clinical data on the effect of tenofovir disoproxil fumarate on fertility is limited. Animal studies have not shown any adverse effects of tenofovir disoproxil fumarate on fertility.

Ability to drive and use machines.

No studies on the effect on the ability to drive and use machines have been conducted. Patients should be informed that dizziness may occur during treatment with tenofovir disoproxil fumarate.

Administration and Dosage

Treatment should be initiated by a physician experienced in the management of HIV infection and/or chronic hepatitis B.

Dosage

Adults

The recommended dose for the treatment of HIV or chronic hepatitis B is 1 tablet once daily, taken orally with food.

Chronic Hepatitis B

The optimal duration of treatment is unknown. Criteria for discontinuation of treatment may include:

• For HBeAg-positive patients without cirrhosis, treatment should continue for at least 6–12 months after confirmed HBe seroconversion (loss of hepatitis B e antigen and hepatitis B virus DNA with detection of anti-HBe) or until HBs seroconversion or treatment failure occurs (see section "Special Warnings and Precautions for Use"). After discontinuation of treatment, ALT levels and hepatitis B virus DNA in serum should be monitored regularly to detect any late virological relapses;
• For HBeAg-negative patients without cirrhosis, treatment should continue until HBs seroconversion or signs of treatment failure appear. For prolonged treatment exceeding 2 years, periodic re-evaluation is recommended to confirm that the chosen therapy remains effective for the patient.

Children

HIV-1. For adolescents aged 12 to < 18 years weighing ≥ 35 kg, the recommended dose is 1 tablet once daily, taken orally with food (see sections "Pharmacodynamics" and "Adverse Reactions").

Chronic Hepatitis B. For adolescents aged 12 to < 18 years weighing ≥ 35 kg, the recommended dose is 1 tablet once daily, taken orally with food (see sections "Pharmacodynamics" and "Adverse Reactions"). The optimal duration of treatment is currently unknown.

Missed Dose

If a patient misses a dose and less than 12 hours have passed since the scheduled time, the patient should take the missed dose as soon as possible with food, then resume the regular dosing schedule. If a patient misses a dose and more than 12 hours have passed since the scheduled time (i.e., the next dose is nearly due), the patient should not take the missed dose and should continue treatment according to the regular schedule.

If vomiting occurs within 1 hour after administration, the patient should take another tablet. If vomiting occurs more than 1 hour after administration, an additional tablet is not required.

Special Patient Populations

Elderly Patients. Currently, there are no data upon which dosage recommendations can be made for patients aged 65 years and older (see section "Special Warnings and Precautions for Use").

Renal Impairment. Tenofovir is eliminated via the kidneys; therefore, patients with renal dysfunction are at increased exposure to tenofovir.

Adults. Data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (CrCl < 50 mL/min) are limited. Long-term safety data in patients with mild renal impairment (CrCl 50–80 mL/min) are lacking. Therefore, tenofovir disoproxil fumarate should be used in patients with renal impairment only if the potential benefits are considered to outweigh the risks. Dose interval adjustment is recommended for patients with CrCl < 50 mL/min, including those undergoing hemodialysis.

Mild Renal Impairment (CrCl 50–80 mL/min). Limited clinical trial data in patients with mild renal impairment support once-daily dosing of tenofovir disoproxil fumarate.

Moderate Renal Impairment (CrCl 30–49 mL/min). Dosing every 48 hours may be considered based on pharmacokinetic modeling of single-dose data in HIV-negative and hepatitis B virus-negative patients with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. However, this dosing regimen has not been confirmed in clinical trials. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Severe Renal Impairment (CrCl < 30 mL/min) and Patients on Hemodialysis. Appropriate dose adjustment cannot be applied due to the lack of tablets with alternative active ingredient content; therefore, use of the medicinal product in these patient groups is not recommended. If no alternative treatment is available, extended dosing intervals may be considered as follows:

• In patients with severe renal impairment: 1 tablet every 72–96 hours (2 times per week);
• In patients on hemodialysis: 1 tablet every 7 days after completion of a hemodialysis session*.

* Generally, once weekly dosing is assumed, based on 3 hemodialysis sessions per week, each lasting approximately 4 hours, or after 12 hours of cumulative hemodialysis.

These dose interval adjustments have not been confirmed in clinical trials. Modeling suggests that prolonged dosing intervals with film-coated tablets may not be optimal and could lead to increased toxicity and possibly suboptimal response. Therefore, clinical response to treatment and renal function should be monitored (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

No dosage recommendations can be given for patients not undergoing hemodialysis with CrCl < 10 mL/min.

Children. The use of tenofovir disoproxil fumarate is not recommended in children with renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic Impairment. No dose adjustment is required for patients with hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Careful monitoring is required in patients with chronic hepatitis B, with or without concomitant HIV infection, upon discontinuation of the medicinal product to detect signs of hepatitis flare (see section "Special Warnings and Precautions for Use").

Administration

Tablets should be taken once daily, orally, with food.

If patients have difficulty swallowing, the tablets may be crushed and dissolved in approximately 100 mL of water, orange juice, or grape juice, and consumed immediately.

Children.

The safety and efficacy of tenofovir disoproxil fumarate in children under 12 years of age and weighing < 35 kg have not been established. Data are lacking.

Overdose.

Symptoms

In the event of overdose, patients should be monitored for signs of toxicity (see section "Adverse Reactions"), and standard supportive treatment should be administered if necessary.

Treatment

Tenofovir can be removed by hemodialysis, with a median clearance of 134 mL/min. Removal of tenofovir by peritoneal dialysis has not been studied.

Adverse Reactions

Safety Profile Summary

HIV-1 and Hepatitis B. Renal dysfunction, renal failure, and infrequent cases of proximal renal tubulopathy (including Fanconi syndrome), sometimes leading to bone abnormalities (rarely fractures), have been reported rarely in patients receiving tenofovir disoproxil fumarate. Monitoring of renal function is recommended for patients taking this medicinal product (see section "Special Warnings and Precautions for Use").

HIV-1. Adverse reactions during treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents may be expected in approximately one-third of patients. These are usually mild to moderate gastrointestinal events. Approximately 1% of patients receiving tenofovir disoproxil fumarate discontinued treatment due to gastrointestinal adverse reactions.

Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it increases the risk of adverse reactions (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely (see section "Special Warnings and Precautions for Use").

Hepatitis B. Adverse reactions during treatment with tenofovir disoproxil fumarate (mostly mild) may be expected in approximately 25% of patients. In clinical trials involving patients infected with hepatitis B virus, the most common adverse reaction associated with tenofovir disoproxil fumarate was nausea (5.4%).

Severe exacerbations of hepatitis have been reported in patients receiving therapy as well as in patients who discontinued treatment for hepatitis B (see section "Special Warnings and Precautions for Use").

Summary Table of Adverse Reactions

The assessment of adverse reactions to tenofovir disoproxil fumarate is based on safety data obtained from clinical trials and post-marketing surveillance. All adverse reactions are listed in Table 2.

HIV-1 Clinical Trials. The evaluation of adverse reactions in HIV-1 clinical trials is based on results from two studies in which 653 treatment-experienced patients received tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral agents for 24 weeks, and on data from a double-blind, controlled comparative trial in which 600 treatment-naive patients received either 245 mg tenofovir disoproxil (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B Clinical Trials. The evaluation of adverse reactions in hepatitis B clinical trials is primarily based on results from two double-blind, controlled comparative studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received either 245 mg tenofovir disoproxil (as fumarate) once daily (n = 426) or adefovir dipivoxil 10 mg once daily (n = 215) for 48 weeks. Adverse reactions observed during 384 weeks of continuous treatment were consistent with the safety profile of tenofovir disoproxil fumarate. After an initial decline of approximately 4.9 mL/min (by Cockcroft-Gault equation) or 3.9 mL/min/1.73 m² (by Modification of Diet in Renal Disease [MDRD] equation) within the first 4 weeks of treatment, the annual rate of decline in renal function from baseline observed in patients receiving tenofovir disoproxil fumarate was 1.41 mL/min/year (Cockcroft-Gault) and 0.74 mL/min/1.73 m²/year (MDRD).

Patients with Decompensated Liver Disease. The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was evaluated in a double-blind, active-controlled trial (GS-US-174-0108), in which adult patients received tenofovir disoproxil fumarate (n = 45), emtricitabine and tenofovir disoproxil fumarate (n = 45), or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil fumarate group, 7% of patients discontinued treatment due to adverse reactions, and 9% of patients had confirmed increases in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphate levels < 2 mg/dL by week 48. There was no statistically significant difference between the tenofovir combination group and the entecavir group. At week 168, 16% (7 of 45) of patients in the tenofovir disoproxil fumarate group, 4% (2 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 14% (3 of 22) in the entecavir group experienced intolerance. Confirmed increases in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphate < 2 mg/dL occurred in 13% (6 of 45) of patients in the tenofovir disoproxil fumarate group, 13% (6 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 9% (2 of 22) in the entecavir group.

At week 168 in this population of patients with decompensated liver disease, the mortality rate was 13% (6 of 45) in the tenofovir disoproxil fumarate group, 11% (5 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 14% (3 of 22) in the entecavir group. The incidence of hepatocellular carcinoma was 18% (8 of 45) in the tenofovir disoproxil fumarate group, 7% (3 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 9% (2 of 22) in the entecavir group.

Patients with a high baseline score according to the Child-Pugh-Turcotte classification have been reported to have a higher risk of developing serious adverse reactions (see section "Special Warnings and Precautions for Use").

Patients with Chronic Hepatitis B Resistant to Lamivudine. No new adverse reactions to tenofovir disoproxil fumarate were identified in a randomized, double-blind trial (GS-US-174-0121), in which 280 lamivudine-resistant patients received tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 240 weeks.

Adverse reactions with a potential (at least possible) relationship to treatment are listed below by system organ class and frequency. Within each frequency group, adverse events are listed in order of decreasing severity. Adverse reactions by frequency are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

Table 2. Summary table of adverse reactions associated with tenofovir disoproxil fumarate based on clinical trial and post-marketing data

1. The adverse reaction may occur as a result of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition.

2. The adverse reaction was identified during post-marketing surveillance but was not observed in randomized controlled trials or the expanded access program for tenofovir disoproxil fumarate. The frequency category was determined by statistical calculations based on the total number of patients who received tenofovir disoproxil fumarate in randomized controlled trials and the expanded access program (n = 7319).

Description of selected adverse reactions

HIV-1 and Hepatitis B

Renal failure. Since the medicinal product may cause renal dysfunction, monitoring of renal function is recommended (see sections "Special warnings and precautions for use" and "Summary of safety profile"). Proximal renal tubulopathy was generally reversible or showed improvement after discontinuation of tenofovir disoproxil fumarate. However, in some patients, the decline in creatinine clearance did not completely resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk for renal dysfunction (e.g., patients with baseline risk factors for renal impairment, patients with advanced HIV disease, or patients receiving concomitant nephrotoxic medications) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil fumarate (see section "Special warnings and precautions for use").

HIV-1

Interaction with didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, thereby increasing 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 rarely reported.

Metabolic disturbances. Body weight and levels of lipids and blood glucose may increase during antiretroviral therapy (see section "Special warnings and precautions for use").

Immune Reconstitution Syndrome. In HIV-infected patients with severe immune deficiency at the initiation of combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves’ disease or autoimmune hepatitis) have also been reported; however, the reported onset time 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 reported in patients with broadly defined risk factors, advanced HIV disease, or long-term exposure to CART. The frequency of this event is unknown (see section "Special warnings and precautions for use").

Hepatitis B

Hepatitis flare during treatment. In clinical trials involving treatment-naïve patients, ALT elevations during treatment exceeding 10 times the upper limit of normal and twice the baseline value were observed in 2.6% of patients receiving tenofovir disoproxil fumarate. The median time to ALT elevation was 8 weeks and resolved with continued treatment. In most cases, these ALT elevations were associated with a ≥ 2 log10 copies/mL reduction in viral load that preceded or coincided with the ALT increase. Liver function monitoring is recommended during treatment (see section "Special warnings and precautions for use").

Hepatitis flare after discontinuation of treatment. After stopping hepatitis B therapy in patients infected with hepatitis B virus, clinical and laboratory signs of hepatitis flare have occurred (see section "Special warnings and precautions for use").

Use in adolescents

HIV-1

Adverse reactions were evaluated in one randomized trial (Study GS-US-104-0321) involving 87 HIV-1-infected adolescent patients (aged 12 to < 18 years) who received tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with other antiretroviral agents for 48 weeks (see section "Pharmacodynamics"). Adverse reactions observed in adolescent patients receiving tenofovir disoproxil fumarate were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see sections "Pharmacodynamics" and "Summary table of adverse reactions").

In HIV-1-infected adolescents, Z-scores for BMD observed during tenofovir disoproxil fumarate treatment were lower than those observed with placebo.

In Study GS-US-104-0352, 8 of 89 pediatric patients (9.0%) receiving tenofovir disoproxil fumarate (mean duration 331 weeks) discontinued the investigational drug due to renal adverse effects. Five patients (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, four of whom discontinued tenofovir disoproxil fumarate therapy. Estimated glomerular filtration rate (eGFR) values in seven patients ranged from 70 to 90 mL/min/1.73 m². Three of these patients experienced clinically significant decreases in eGFR, which improved after discontinuation of the medicinal product.

Chronic Hepatitis B

Adverse reactions were evaluated in one randomized trial (Study GS-US-174-0115) involving 106 adolescent patients (aged 12 to < 18 years) with chronic hepatitis B who received tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks. Adverse reactions observed in adolescent patients receiving tenofovir disoproxil fumarate were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see sections "Pharmacodynamics" and "Summary table of adverse reactions").

Decreases in BMD were observed in HBV-infected adolescents. The Z-score for BMD observed in patients receiving tenofovir disoproxil fumarate was comparable to that in patients receiving placebo (see sections "Pharmacodynamics" and "Special warnings and precautions for use").

Other special patient groups

Elderly patients. Clinical studies of tenofovir disoproxil fumarate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised in the administration of tenofovir disoproxil fumarate in this population (see section "Special warnings and precautions for use").

Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, renal function should be monitored in patients with renal impairment who are receiving the medicinal product (see sections "Pharmacokinetics", "Special warnings and precautions for use", and "Dosage and administration"). The use of tenofovir disoproxil fumarate is not recommended in children with impaired renal function (see sections "Special warnings and precautions for use" and "Dosage and administration").

If adverse reactions occur, consult a physician.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 30 film-coated tablets in a bottle with a silica gel desiccant. One bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Strides Pharma Sciences Limited.

Manufacturer's address and location of its business operations.

No. 36/7, Suragadajakkana Halli, Indlavadi Cross, Anekal Taluk, Bangalore, Karnataka 562106, India.