Tenofovir Disoproxil Fumarate Tablets

Pharmacological action Mechanism of action: Tenofovir disoproxil fumarate is a ring-opening nucleoside phosphinated diester structural analogue of adenosine monophosphate. Tenofovir disoproxil fumarate first needs to be converted into tenofovir by hydrolysis of the diester, and then phosphorylated by cellular enzymes to form tenofovir diphosphate, which can terminate DNA synthesis. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate 5'-deoxyadenosine triphosphate and terminating the DNA chain after integration with DNA. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerase and mitochondrial DNA polymerase. Anti-HIV activity Antiviral activity: The antiviral activity of tenofovir against laboratory and clinically isolated HIV-1 was evaluated in lymphoblastoid cell lines, primary monocytes/macrophages, and peripheral blood lymphocytes. The EC50 (50% effective concentration) values of tenofovir range from 0.04M to 8.5M. In studies of the combined use of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), tenofovir had no antagonistic effect. In cell culture, tenofovir has antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G, and O (EC50 values range from 0.5M to 2.2M), and has strain-dependent activity against HIV-2 (EC50 values range from 1.6M to 5.5M). Drug resistance: HIV-1 isolates with reduced sensitivity to tenofovir were selected in cell culture. These viruses all have the K65R mutation in their reverse transcriptase, which reduces sensitivity to tenofovir by 2–4-fold. In addition, tenofovir increases the K70E substitution in HIV-1 reverse transcriptase, resulting in reduced sensitivity to tenofovir. In Study 903 (tenofovir disoproxil fumarate lamivudine efavirenz vs stavudine lamivudine efavirenz) in treatment-naïve subjects, genomic analysis of viral isolates from subjects with virologic failure at week 144 revealed that mutations associated with resistance to efavirenz and lamivudine were most common, with no difference between the two treatment groups. Among the isolates from patients analyzed, the K65R mutation occurred in 8/47 (17%) in the tenofovir disoproxil fumarate group and in 2/49 (4%) in the stavudine group. Of the eight subjects in the tenofovir disoproxil fumarate group who had viral K65R at week 144, seven occurred within the first 48 weeks of treatment and one occurred at week 96. One subject in the tenofovir disoproxil fumarate group had a K70E mutation in the virus isolate. No other mutations that confer resistance to tenofovir disoproxil fumarate were found in this study. In Study 934 (tenofovir disoproxil fumarate emtricitabine efavirenz vs zidovudine/lamivudine efavirenz) of treatment-naive subjects, genotyping of HIV-1 isolated from all subjects who had confirmed virological response failure or premature treatment termination at week 144 with HIV-1 RNA 400 copies/mL was performed. Results showed that mutations associated with efavirenz resistance were the most common and were similar in both treatment groups. Among the isolates analyzed, the M184V mutation, which is associated with resistance to emtricitabine and lamivudine, occurred in 2/19 patients in the tenofovir disoproxil fumarate/emtricitabine group and in 10/29 patients in the zidovudine/lamivudine group. In Study 934, which lasted 144 weeks, no subjects had the K65R mutation detected in HIV-1 using standard genotyping. Cross-resistance: Cross-resistance exists between certain reverse transcriptase inhibitors. The K65R and K70E mutations selected by tenofovir have also been selected in some HIV-1-infected subjects receiving abacavir or didanosine. HIV isolates containing this mutation have reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance to these drugs may occur in patients harboring the K65R or K70E mutations. HIV-1 isolates from 20 subjects with an average of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N) showed a 3.1-fold reduction in susceptibility to tenofovir. In studies 902 and 907 in treatment-experienced subjects (tenofovir disoproxil fumarate standard background therapy (SBT) vs placebo SBT), 14 of 304 (5%) subjects who experienced virologic failure on tenofovir disoproxil fumarate through week 96 had a greater than 1.4-fold reduction in susceptibility to tenofovir (median 2.7-fold). Genotyping of isolates at baseline and failure revealed the presence of the K65R mutation in the HIV-1 reverse transcriptase gene. Virologic responses to tenofovir disoproxil fumarate were evaluated in treatment-experienced subjects enrolled in studies 902 and 907 with respect to baseline viral genotype (N=222). In these clinical trials, 94% of the baseline HIV-1 isolates evaluated expressed at least one nucleoside reverse transcriptase inhibitor (NRTI) mutation. Virologic responses in the genotype studies were similar to the overall trial results. Several exploratory analyses evaluated the impact of specific mutations and mutation patterns on virologic outcomes. Statistical testing was not performed because of the large number of comparisons. Tenofovir disoproxil fumarate exhibited varying degrees of cross-resistance to preexisting mutations associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), which was related to the number and type of specific mutations. HIV-1 subjects treated with tenofovir disoproxil fumarate who developed three or more zidovudine resistance-associated mutations (including M41L or L210W reverse transcriptase mutations) had a reduced response to tenofovir disoproxil fumarate treatment; however, these subjects still showed an improved response compared to placebo. The presence of D67N, K70R, T215Y/F, and K219Q/E/N mutations did not appear to affect the response to tenofovir disoproxil fumarate treatment. Subjects whose viruses developed the L74V substitution mutation but did not have a zidovudine resistance-associated substitution mutation (N=8) had a reduced response to tenofovir disoproxil fumarate. Data were limited for subjects whose viruses expressed the Y115F (N=3), Q151M (N=2) substitution mutation, or the T69 insertion mutation (N=4), and all subjects had a reduced response. In the protocol-specified analyses, HIV-1 subjects with the M184V mutation associated with resistance to abacavir/emtricitabine/lamivudine did not have a reduced virologic response to tenofovir disoproxil fumarate. HIV-1 RNA responses in these patients persisted through Week 48. Phenotypic Analyses of Studies 902 and 907: Baseline HIV-1 phenotyping in treatment-experienced subjects (N=100) demonstrated an association between baseline viral susceptibility to tenofovir disoproxil fumarate and patient response to tenofovir disoproxil fumarate treatment. Table 14 summarizes HIV-1 RNA responses by baseline tenofovir disoproxil fumarate susceptibility. Anti-HBV activity: Antiviral activity: The antiviral activity of tenofovir against HBV was evaluated in the HepG22.2.15 cell line, and the EC50 value of tenofovir was between 0.14 and 1.5 M, and the CC50 (50% cytotoxic concentration) value was greater than 100 M. The antiviral activity of tenofovir in combination with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine was studied in cell culture, and no antagonism was observed. Resistance: Cumulative genotypic resistance to tenofovir disoproxil fumarate was assessed annually through Week 384 using paired pre- and during-treatment isolate HBV reverse transcriptase amino acid sequence (partial or full sequence) samples for subjects who received tenofovir disoproxil fumarate monotherapy for at least 24 weeks in studies 0102, 0103, 0106, 0108, 0121, and LOC114648 but still had viremic HBV DNA greater than or equal to 400 copies/mL (69 IU/mL) at the end of each study year (or when tenofovir disoproxil fumarate monotherapy was discontinued). In the nucleoside-naive population of studies 0102 and 0103, HBeAg-positive subjects had higher baseline viral loads than HBeAg-negative subjects and a significantly higher proportion of subjects who were still viremic at the last dose of tenofovir disoproxil fumarate monotherapy (15% vs. 5%, respectively). HBV isolates from subjects who remained viremic showed mutations that emerged during treatment (Table 15); however, no specific mutations that were highly prevalent and associated with resistance to tenofovir disoproxil fumarate (genotypic and phenotypic analyses) emerged. Cross-resistance: Cross-resistance was observed between HBV nucleoside/nucleotide analog reverse transcriptase inhibitors. Based on cell-based assays, HBV strains with lamivudine- and telbivudine-resistance-associated rtV173L, rtL180M, and rtM204I/V mutations were 0.7 to 3.4 times more susceptible to tenofovir than wild-type virus. Dual mutations of rtL180M and rtM204I/V reduced susceptibility to tenofovir by 3.4-fold. The sensitivity of HBV strains with entecavir resistance-related rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations to tenofovir is 0.6 to 6.9 times that of wild-type viruses. The sensitivity of HBV strains with adefovir resistance-related rtA181V and/or rtN236T mutations to tenofovir is 2.9 to 10 times that of wild-type viruses, and the sensitivity of virus strains carrying the rtA181T mutation gene to tenofovir is 0.9 to 1.5 times that of wild-type viruses. In studies 0102, 0103, 0106, 0108, and 0121, 152 subjects had HBV mutations known to be resistant to HBV nucleoside/nucleotide analog reverse transcriptase inhibitors when they started treatment with tenofovir disoproxil fumarate: 14 subjects carried adefovir resistance-associated mutations (rtA181S/T/V and/or rtN236T), 135 subjects carried lamivudine resistance-associated mutations (rtM204I/V), and 3 subjects carried adefovir and lamivudine resistance-associated mutations. After 384 weeks of follow-up with tenofovir disoproxil fumarate, 10/14 adefovir-resistant HBV subjects, 124/135 lamivudine-resistant HBV subjects, and 2/3 adefovir and lamivudine-resistant HBV subjects achieved and maintained viral suppression (HBVDNA less than 400 copies/ml [69 IU/ml]). 3/5 subjects carrying rtA181T/V and rtN236T mutant viruses still had viremia. Toxicology studies Genotoxicity Tenofovir disoproxil fumarate can cause gene mutations in an in vitro mouse lymphocyte test and the results were negative in the Ames test. In an in vivo mouse micronucleus test, tenofovir disoproxil fumarate was administered to male mice and the results were negative. Reproductive toxicity Based on body surface area comparison, tenofovir disoproxil fumarate was administered to rats at a dose equivalent to 10 times that of humans. Male rats were given the drug for 28 consecutive days before mating, and female rats were given the drug continuously from 15 days before mating to the 7th day of pregnancy. The results showed that tenofovir disoproxil fumarate had no effect on fertility, mating behavior, and early embryonic development. However, changes in the estrous cycle occurred in female rats. Carcinogenicity* Long-term oral administration of tenofovir disoproxil fumarate carcinogenicity studies were conducted in mice and rats, with the highest exposure levels being approximately 16 times (mice) and 5 times (rats) of the human HIV-1 infection treatment dose, respectively. Female mice had an increase in liver adenomas at high doses (exposure levels 16 times higher than humans). No carcinogenicity was observed in rats at the highest exposure level of 5 times the human therapeutic dose. Other Toxicity In toxicology studies, bone toxicity was observed in rats, dogs, and monkeys when tenofovir and tenofovir disoproxil fumarate were administered at exposure levels greater than or equal to 6 times that in humans (based on AUC). In monkeys, bone toxicity was diagnosed as osteomalacia. In monkeys, osteomalacia was reversible after tenofovir dose reduction or discontinuation. In rats and dogs, bone toxicity was manifested as decreased bone mineral density. The underlying mechanism of bone toxicity is unknown. Evidence of renal toxicity was found in four species. In these animals, varying degrees of increases in serum creatinine, urea nitrogen, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed. These toxicities were observed at exposure levels 2 to 20 times higher than in humans (based on AUC). The relationship of renal abnormalities, especially phosphaturia, to bone toxicity is unknown.

The main ingredient of this product is tenofovir disoproxil fumarate, and its chemical name is: 9-((R)-2-((bis(((isopropoxycarbonyl)oxy(methoxy)phosphinyl)-propyl)adenine fumarate (1:1). Chemical structure: Molecular formula: C19H30N5O10.C4H4O4 Molecular weight: 635.52

This product is a film-coated tablet, which appears white or off-white after removing the coating.

HIV-1 infection Tenofovir disoproxil fumarate is indicated for use in combination with other antiretroviral drugs to treat HIV-1 infection in adults. When initiating treatment of HIV-1 infection with tenofovir disoproxil fumarate, the following points should be considered: Tenofovir disoproxil fumarate should not be used in combination with fixed-dose combinations containing tenofovir, including: Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate Emtricitabine/Tenofovir Alafenamide Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Emtricitabine/Rilpivirine/Tenofovir Alafenamide Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Emtricitabine Tenofovir Alafenamide Tenofovir Chronic Hepatitis B Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in adults and pediatric patients ≥ 12 years of age. The following points should be considered when initiating tenofovir disoproxil fumarate for the treatment of HBV infection: This indication in adult patients was established based on safety and efficacy data obtained from nucleoside-naive subjects and previously treated subjects with demonstrated lamivudine resistance. Subjects were adult HBeAg-positive and HBeAg-negative subjects with chronic hepatitis B with compensated liver function. Tenofovir disoproxil fumarate has been evaluated in a limited number of subjects with chronic hepatitis B with decompensated liver disease. The number of subjects with adefovir-associated mutations at baseline in clinical trials was too small to draw conclusions about efficacy.

Recommended dose for adult patients with HIV-1 For the treatment of adult HIV-1: the dose is 300 mg (one tablet) once a day, orally, and is not affected by diet. Recommended dose for the treatment of chronic hepatitis B in adults and children aged ≥12 years For the treatment of chronic hepatitis B: the dose is 300 mg (one tablet) once a day, orally, and is not affected by diet. For the treatment of chronic hepatitis B, the optimal course of treatment has not been determined. The safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been studied. Dose adjustment for adults with renal impairment When tenofovir disoproxil fumarate is administered to subjects with moderate to severe renal impairment, drug exposure is significantly increased (see [Pharmacokinetics]). Baseline creatinine clearance

The following adverse reactions are also discussed in other sections of the label: severe acute hepatitis B exacerbation (see [Precautions]), new onset or worsening renal impairment (see [Precautions]), lactic acidosis/severe hepatomegaly with fatty dysmorphism (see [Precautions]). Bone effects (see [Precautions]) Immune reconstitution inflammatory syndrome (see [Precautions]) Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the actual incidence observed. Clinical trials in adult HIV-1 infected patients Clinical trials: In clinical trials and named drug programs lasting 28 days to 215 weeks, more than 12,000 subjects received tenofovir disoproxil fumarate alone or in combination with other antiretroviral drugs; In clinical trials trials; A total of 1,544 subjects were treated with tenofovir disoproxil fumarate 300 mg per day: More than 11,000 subjects were treated with tenofovir disoproxil fumarate in named drug programs. The most common adverse reactions (incidence greater than or equal to 10%, Grade 2-4) found in the three major pair-of-care clinical trials included rash, diarrhea, headache, pain, depression, fatigue, and nausea in treatment-naive patients Study 903 - Treatment-emergent adverse reactions: A double-blind controlled trial was conducted in 600 treatment-naive subjects who received 144 weeks of fomarate disoproxil fumarate (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz (Study 903). The most common adverse reactions were mild to moderate intestinal events and dizziness. Mild adverse reactions (Grade 1) were common, with a similar incidence in both groups, and included dizziness, diarrhea, and nausea. A summary of moderate to severe adverse reactions that occurred during the screening treatment period is shown in (Table 2) 1. The incidence of adverse reactions is based on all adverse events that occurred during the treatment period, regardless of whether they were related to the study drug. 2. Lipodystrophy represents a variety of adverse events described by the investigator and is not a syndrome defined by the trial protocol. 3. Peripheral neuropathy includes peripheral neuritis and neuropathy. 4. Rash events include rash, pruritus, maculopapular rash, urticaria, vesicular rash, and pustular rash. Laboratory abnormalities: Except for increased fasting cholesterol and somersault triglycerides (40% and 9%, respectively), which were more common in the stavudine group than in the tenofovir disoproxil fumarate group (19% and 1%, respectively), other laboratory abnormalities observed in this study occurred at similar frequencies in the tenofovir disoproxil fumarate and stavudine treatment groups. Grade 3 and 4 laboratory abnormalities are summarized in (Table 3) Study 934 - Treatment-Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received tenofovir disoproxil fumarate plus entecavir in combination with efavirenz (N=257) or zidovudine/lamivudine in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those observed in previous studies of treatment-experienced and treatment-naïve subjects (Table 4) Changes in Bone Mineral Density: In Study 903, HIV-1-infected adult subjects were enrolled. The mean percent decrease from baseline in lumbar spine BMD at Week 144 was significantly greater in subjects treated with tenofovir disoproxil fumarate plus entecavir (-2.2%±3.9) compared with subjects treated with stavudine plus lamivudine plus efavirenz (-1.0%±4.6). The changes in BMD of the two treatment groups were similar (-2.8%6±3.5 in the tenofovir disoproxil fumarate group and -2.4%±4.5 in the stavudine group). Most of the BMD decline in both groups occurred during weeks 24-48 of the trial and continued to week 144. Twenty-eight percent of the subjects in the tenofovir disoproxil fumarate group had a decrease in spine BMD of at least 5% or a decrease in eye bone BMD of 7% compared with 21%6 of the subjects in the stavudine group. Four subjects in the tenofovir disoproxil fumarate group and six subjects in the stavudine group reported clinically significant fractures (excluding finger and toe fractures). In addition, compared with the stavudine group, the bone metabolism biomarkers (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-terminal peptide and urinary N-terminal peptide) in the tenofovir disoproxil fumarate group were significantly increased, and the levels of serum parathyroid hormone and 1,25 vitamin D were increased; but with the exception of bone-specific alkaline phosphatase, the values of these indicators after the changes were still within the normal range (see [Precautions]) 1. The frequency of adverse reactions is based on all adverse events occurring during the treatment period, regardless of whether they are related to the therapeutic drug. 2. During the 96th to 144th week of the experiment, the subjects received emtricitabine tenofovir efavirenz, replacing tenofovir disoproxil fumarate-emtricitabine efavirenz. 3. Rash events included rash, exfoliative rash, systemic rash, macules, maculopapular rash, itching, and vesicular rash. Laboratory abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those observed in previous studies (Table 5) 1. During Weeks 96 to 144 of the trial, subjects received encitabine, tenofovir efavirenz, replacing tenofovir disoproxil fumarate encitabine efavirenz. Treatment-emergent adverse reactions in patients who had received treatment: Adverse reactions in treated subjects were generally consistent with those observed in untreated subjects, including mild to moderate gastrointestinal events such as nausea, diarrhea, vomiting, and flatulence. The proportion of subjects who discontinued the clinical trial due to gastrointestinal adverse reactions was less than 1% (Study 907). A summary of moderate to severe treatment-emergent adverse reactions occurring within the first 48 weeks of Study 907 is shown in (Table 6) 1. The incidence of adverse reactions is based on the time of all adverse reactions occurring during treatment, regardless of whether they are related to the study drug 2. Peripheral neuropathy includes peripheral neuritis and neuropathy 3. Rash events include rash, pruritus, maculopapular rash, urticaria, water gown papular rash Laboratory abnormalities: The laboratory abnormalities observed in this study were similar in frequency to those observed in the tenofovir disoproxil fumarate and placebo treatment groups. A summary of grade 3 and 4 laboratory abnormalities is shown in (Table 7). Adverse reactions during treatment in adult subjects with chronic hepatitis B and compensated liver disease: A controlled clinical trial of 641 subjects with chronic hepatitis B (Studies 0102 and 0103) showed that subjects who experienced nausea during the 48-week double-blind treatment period in the tenofovir disoproxil fumarate treatment group Other adverse reactions reported during treatment included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and rash. During open-label tenofovir disoproxil fumarate treatment in studies 0102 and 0103 (weeks 48-384), 2% of subjects (13/585) experienced confirmed serum and liver elevations of 0.5 mg/dL relative to baseline. No significant changes in drug resistance characteristics were observed during 384 weeks of continuous treatment. Laboratory abnormalities: As of week 48, grade 3 and 4 laboratory abnormalities are summarized in (Table 8). Grade 3/4 laboratory abnormalities that occurred in subjects who continued to treat tenofovir disoproxil fumarate for 384 weeks in the above studies were similar. M: male, F: female The overall incidence of ALT rebound during treatment (i.e., serum ALT greater than 2X baseline value and greater than 10*ULN, with or without related symptoms) was similar for tenofovir disoproxil fumarate (2.6%) and adefovir dipivoxil (2%). ALT rebound often occurred within the first 4-8 weeks of treatment, accompanied by a decrease in HBV DNA concentration, and no subject showed evidence of decompensation. Without adjustment of study drug treatment, typical ALT rebound was basically relieved within 4 to 8 weeks. The adverse reactions experienced by lamivudine-resistant chronic hepatitis B subjects treated with tenofovir disoproxil fumarate were consistent with those in other adult HBV clinical trials. Clinical trials in Chinese adult chronic hepatitis B patients In a randomized, double-blind, active-controlled trial (Study L0C114648), a comparative safety evaluation of tenofovir disoproxil fumarate and adefovir dipivoxil showed that the adverse reactions of Chinese patients treated with tenofovir disoproxil fumarate for 48 weeks were similar to those in other HBV clinical trials. The most commonly reported adverse events were upper respiratory tract infections, which occurred in the tenofovir disoproxil fumarate group (8.2%) and the adefovir dipivoxil group (6.7%). The incidence of adverse events judged by the investigator to be related to the study drug was similar in the tenofovir disoproxil fumarate group (3.9%) and the adefovir dipivoxil group (4.8%). No drug-related adverse reactions were reported by any patient (1%) in either group. Grade 3 or 4 laboratory abnormalities during treatment were reported in the tenofovir disoproxil fumarate group (16%) and the adefovir dipivoxil group (10%). Grade 3/4 ALT abnormalities were reported in the tenofovir disoproxil fumarate group (9%). The proportion of subjects was higher than that in the adefovir dipivoxil group (7%). There were no grade 3/4 serum creatinine abnormalities in this study. Clinical trials in adult subjects with chronic hepatitis B and decompensated liver disease In a small randomized, double-blind, active-controlled trial (Study 0108), subjects with CHB and decompensated liver disease were treated with tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks (see [Clinical Studies]). Among the 45 subjects in the tenofovir disoproxil fumarate treatment group, the most common adverse reactions (of any grade) during treatment were abdominal pain (22%6), nausea (20%), insomnia (18%), itching (16%), vomiting (13%), dizziness (14%), and nausea (20%). (13%) and fever (11%). As of week 48 of the trial, 2/45 (496) subjects died due to liver disease progression. 3/45 (7%) subjects discontinued treatment due to adverse events. 4/45 (9%) subjects had confirmed increases in serum creatinine (0.5 mg/dL) (1 subject also had a confirmed serum phosphorus concentration less than 2 mg/dL as of week 48). Among them, 3 subjects (whose Child-Pugh score was greater than or equal to 10 and MELD score was greater than or equal to 14 at enrollment) developed renal failure. Because both tenofovir disoproxil fumarate and decompensated liver disease may affect renal function, it is difficult to To determine the effect of tenofovir disoproxil fumarate on renal impairment in this population. During the 48-week trial, one of the 45 subjects experienced a flare of hepatitis during treatment. Clinical trial adverse reactions in pediatric subjects aged 12 years and older with chronic hepatitis B were based on a randomized study of 106 pediatric subjects with chronic hepatitis B infection (12 to less than 18 years old) who received tenofovir disoproxil fumarate (N=52) or placebo (N-54) for 72 weeks (Study GS-US-174-0115). Adverse reactions in pediatric subjects treated with tenofovir disoproxil fumarate were consistent with those observed in the clinical trial of tenofovir disoproxil fumarate in adults.

Tenofovir disoproxil fumarate is contraindicated in patients with a prior hypersensitivity to any of the ingredients in this drug.

Pediatric precautions: In Study 115, 106 HBeAg-positive (9%) and HBeAg-positive (91%) subjects aged 12 to 18 years with chronic HBV infection were randomized to receive double-blind treatment with tenofovir disoproxil fumarate 300 mg (N=52) or placebo (N=54) for 72 weeks. At study entry, the mean HBV DNA value was 8.1 log. copies/mL, the mean ALT value was 101 U/L, and among the 52 subjects in the tenofovir disoproxil fumarate group, 20 were nucleoside/nucleotide-naive subjects and 32 were nucleoside/nucleotide-experienced subjects. 31 of the 32 nucleoside/nucleotide-experienced subjects had received lamivudine treatment. At 72 weeks, 8896 (46/52) subjects in the tenofovir disoproxil fumarate group and 0% (0/54] subjects in the placebo group reached HBV DNA-400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of the tenofovir disoproxil fumarate group had normalized ALT at week 72, compared with 31% (13/42) of the placebo group. One subject in the tenofovir disoproxil fumarate group had sustained HBsAg negativity and anti-HBs seroconversion during the first 72 weeks of the study. The safety and efficacy of tenofovir disoproxil fumarate in pediatric patients with chronic hepatitis B who are less than 12 years old or weigh less than 35 kg have not been established. Pregnancy and lactation precautions: US pregnancy category B: Reproduction studies have been conducted in rats and rabbits, and the highest dose based on body surface area comparison is The results showed no evidence of impaired fertility or embryo damage due to tenofovir. However, no adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies do not always predict human responses, they should be used in pregnant patients only when clearly needed. Breastfeeding women: The Centers for Disease Control and Prevention recommends that HIV-1-infected women should not breastfeed their infants to avoid the risk of postnatal HIV-1 transmission. Milk samples taken from five HIV-1-infected women within one week after delivery showed that tenofovir is secreted into human milk. The effects of this exposure on breastfeeding infants are not known. Because HIV-1 transmission and serious adverse reactions can occur in breastfed infants, mothers should be advised not to breastfeed if they are being treated with tenofovir disoproxil fumarate.

Didanosine: Caution should be exercised when co-administering tenofovir disoproxil fumarate and didanosine, and patients receiving the co-administration should be closely monitored for didanosine-related adverse events. Didanosine should be discontinued in patients who experience adverse reactions related to didanosine. The maximum serum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of didanosine were significantly increased when co-administered with tenofovir disoproxil fumarate (see [Pharmacokinetics]). The mechanism of this interaction is not clear. Higher didanosine concentrations may lead to didanosine-related adverse reactions, including pancreatitis and neuropathy. Decreased CD4 cell counts were observed in patients receiving tenofovir disoproxil fumarate and didanosine 400 mg per day. In patients weighing 60 kg, the dose of didanosine enteric-coated should be reduced to 250 mg per day when co-administered with tenofovir disoproxil fumarate. In patients weighing 60 kg, the dose of didanosine enteric-coated should be reduced to 250 mg per day when co-administered with tenofovir disoproxil fumarate.

Seal and store in a dry place below 30℃

300mg*10 tablets*3 plates

24 months

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