Item nanme:Tenofovir disoproxil fumarate tablets Item character:This product is a white almond shaped film coated tablet, with "Gilead" engraved on one side and "4331" engraved on the bottom, showing white after removing the coating
Indication: HIV-1 infection
Tenofovir dipivoxil fumarate is suitable for combination with other antiretroviral drugs in the treatment of adult HIV-1 infection.
The following points should be considered when starting the treatment of HIV-1 infection with tenofovir dipivoxil fumarate:
Dinoflurane fumarate should not be used in combination with fixed dose compound preparations containing tenofovir
·Efevren / emtratabine / tenofovir fumarate
·Ribavirin / entecitabine / tenofovir fumarate
·Iveracivir / combist / emtricitabine / tenofovir dipivoxil fumarate
·Entecitabine and tenofovir
Chronic hepatitis B
Tenofovir dipivoxil fumarate is suitable for the treatment of chronic hepatitis B in adults and children over 12 years old.
The following points should be taken into account when starting to use tenofovir and dipyridyl fumarate in the treatment of HBV infection
·The establishment of this indication in adult patients is based on safety and efficacy data obtained from subjects initially treated with nucleoside and previously treated subjects with proven lamivudine resistance. The subjects were HBeAg positive and HBeAg negative adults with liver function compensation.
·Tenofovir dipivoxil fumarate has been evaluated in a limited number of chronic hepatitis B subjects with decompensated liver disease.
·The number of subjects with adefovir related mutations at baseline in clinical trials is too small to conclude the efficacy.
Item specifications:300mg*30tab/box
Usage and dosage:Recommended dose for adults and children 12 years old and over (35kg or above)
Treatment of HIV-1 or chronic hepatitis B: dose: 300mg (one tablet) a time, once a day, orally, empty or taken simultaneously with food.
For the treatment of chronic hepatitis B, the best treatment has not been clear. The safety and efficacy of chronic hepatitis B children with weight less than 35kg have not been studied.
The adjustment of the dosage of adult renal function impaired patients
The drug exposure was significantly increased in subjects with moderate to severe renal impairment when tenofovir fumarate was given (see pharmacokinetic). For patients with a baseline creatinine clearance rate of less than 50ml/ minute, the interval of administration of tenofovir fumarate dipyrfurate should be adjusted according to table 1.
The recommended interval is based on a pharmacokinetic data model of single administration in non HIV and non HBV infected subjects at different levels of renal impairment, including patients with advanced renal disease requiring hemodialysis.
Among patients with moderate to severe renal dysfunction, the safety and efficacy of these interval adjustment recommendations have not been evaluated clinically, so the clinical response and renal function of treatment should be closely monitored in these patients (see "precautions").
For patients with mild renal function damage (creatinine clearance rate of 50-80ml/ min), no dose adjustment is needed. The calculated creatinine clearance rate and serum phosphorus should be monitored regularly in these patients. (see "precautions").
In the non hemodialysis patients with creatinine clearance rate less than 10ml/ min, the pharmacokinetics of tenofovir has not been evaluated, so there is no suggestion for these patients.
There is no recommended data for administration in children with renal dysfunction.
Adverse reactions The following adverse reactions are also discussed in other sections of the manual:
·Acidosis / severe hepatomegaly with fatty degeneration. (see [precautions])
·Hepatitis B worsened after discontinuation of treatment. (see [precautions])
·A new attack or worsening of renal damage. (see [precautions])
·The density of bone mineral decreased. (see [precautions])
·Immune reconstruction syndrome. (see [precautions])
Clinical trial of adult HIV-1 infection patients
Clinical trials: in the 28-215 week clinical trial and registered drug delivery program, more than 12000 subjects received independent treatment with tenofovir fumarate or combined with other antiretroviral drugs. In clinical trials, 1544 subjects received a daily dose of 300mg of tenofovir fumarate and more than 11000 subjects in the registered drug delivery program.
The most common adverse reactions (incidence greater than or equal to 10%, grade 2-4) were found in these three controlled clinical trials, including rash, diarrhea, headache, pain, depression, weakness and nausea.
Untreated patients
Study of the adverse effects of 903-treatment: a double-blind control trial was conducted in 600 untreated subjects, who received 144 weeks of tenofovir dipyrfurate fumarate (n=299) or stavudine (n=301) combined with lamivudine and iffeviren (study 903), the most common adverse reactions were mild to moderate gastrointestinal events and dizziness.
Mild adverse reactions (Level 1) are common, with similar incidence in both groups, including dizziness, diarrhea and nausea. The summary of the medium to severe adverse reactions during the selected treatment is shown in Table 2.
Laboratory abnormalities: in addition to the increase of cholesterol and triglyceride (40% and 9%) in the stavudine group, respectively, were more common than that of tinofivir fumarate group (19% and 1%, respectively), the other laboratory abnormalities observed in the study were similar in the tenofovir dipyrfurate fumarate and stavidin treatment groups. Level 3 and level 4 reality
See Table 3 for summary of laboratory abnormality.
Study of adverse reactions during 934-treatment: in study 934, 511 subjects who had not received antiretroviral treatment received tenofovir fumarate dipyrfurate + entetazidine combined with iffenoren (n = 257) or zidovdine / lamivudine combined with iffeviren (n = 254). The adverse reactions observed in the trial were generally consistent with those observed in previous studies of subjects who had received or not been treated (Table 4).
Laboratory abnormality: laboratory anomalies observed in this test are generally consistent with those observed in previous studies (Table 5).
Patients who have been treated
Adverse reactions during treatment: adverse reactions in treated subjects are 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 terminated clinical trials due to gastrointestinal adverse reactions was less than 1% (study 907).
The summary of adverse reactions caused by moderate to severe treatment within 48 weeks of study 907 is shown in Table 6.
Laboratory abnormality: laboratory abnormalities observed in this trial were similar to those observed in the tinofivir fumarate dipyrfurate and placebo treatment groups. The summary of level 3 and level 4 laboratory abnormalities is shown in Table 7.
Clinical trial of adult chronic hepatitis B and compensatory liver disease subjects
Adverse reactions during treatment: the control clinical trials (Studies 0102 and 0103) of 641 chronic hepatitis B subjects showed that the patients in the 48 week double blind group with tinofivir fumarate showed more nausea: 9% in the tinofivir fumarate group and 2% in the adefovir group. Adverse reactions reported during other treatment periods reported by more than 5% of the subjects in the tinofivir fumarate treatment group included abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharytis, back pain and rash.
In the study, less than 1% of subjects (5/585) had a confirmed increase of 0.5mg/dl in serum creatinine relative to baseline during the treatment of tinofivir dipyrfurate fumarate in 0102 and 0103 (week 48-240). No significant changes in tolerance were observed during 240 weeks of continuous treatment.
Laboratory abnormal results: as of week 48, the summary of laboratory abnormalities at Level 3 and level 4 is shown in Table 8. The results of grade 3 / 4 laboratory abnormalities in subjects treated with tenofovir dipyrfurate fumarate for 240 weeks were similar in the above study.
The total incidence of ALT rebound (i.e. serum ALT is greater than 2 × baseline, and greater than 10 × ULN, with or without related symptoms) during treatment, and tenofovir fumarate group (2.6%) is similar to adefovir group (2%). ALT rebound usually occurs in the first 4-8 weeks of treatment, and the HBV DNA concentration decreases. No subjects showed evidence of the loss of compensation. Without the adjustment of the study drug treatment, the typical ALT rebound was relieved in 4 to 8 weeks.
The adverse reactions of lamivudine resistant chronic hepatitis B subjects treated with tenofovir fumarate were consistent with those in other adult HBV clinical trials.
Clinical effect of chronic hepatitis B in Chinese adults
In a randomized, double-blind, positive control trial (study loc114648), the safety comparison between tenofovir fumarate dipyrfurate and adefovir showed that the adverse reactions of the Chinese patients treated with tenofovir fumarate dipyrfurate group for 48 weeks were similar to other HBV clinical trials. The most common adverse events were upper respiratory tract infection, 8.2% in tinofivir fumarate and 6.7% in adefovir group. The incidence of adverse events related to the study drug was similar in the treatment group (3.9%) and adefovir group (4.8%). None of the two groups had drug-related adverse reactions reported by more than 1% of the patients. 16% of the subjects in the tinofivir fumarate group and 10% of the adefovir group reported laboratory abnormalities of level 3 or 4 during the treatment. The proportion of subjects who reported ALT abnormality of level 3 / 4 was higher than that of adefovir group (7%). There was no serum creatinine abnormality in grade 3 / 4 in this study.
Clinical trial of adult chronic hepatitis B and decompensated liver disease subjects
In a small randomized, double-blind, positive control trial (study 0108), subjects with CHB and decompensated liver disease received tinofivir fumarate dipyrfurate or other antiviral drugs for 48 weeks (see "clinical study"). Of the 45 subjects in the tinofivir fumarate group, the most common adverse reactions (any grade) were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and fever (11%). As of the 48th week of the trial, 2 / 45 (4%) of the subjects died of liver disease. 3 / 45 (7%) of the subjects were terminated due to adverse events. 4 / 45 (9%) patients showed a confirmed increase in serum creatinine (0.5mg/dl) (as of week 48, 1 patient also showed a confirmed serum phosphorus concentration less than 2mg/dl). 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) had renal failure. Because tenofovir fumarate and decompensated liver disease may affect renal function, it is difficult to determine the effect of tenofovir fumarate on renal damage in this population.
During the 48 week trial, one of 45 subjects had hepatitis attack during treatment.
Clinical trial of subjects with chronic hepatitis B in children aged 12 and over
The adverse reactions assessment was based on a randomized study of 106 children with chronic hepatitis B infection (under the age of 12 to 18) who received tenofovir fumarate dipyrfurate (n=52) or placebo (n=54) for 72 weeks (study 115). The adverse reactions of the children in the treatment group were consistent with the observation in the clinical trial of tenofovir fumarate.
The average increase in bone mineral density in the tenofovir fumarate group was lower than in the placebo group (see "note, bone effects").
Post IPO experience:
The following adverse reactions were found during the use of tenofovir fumarate dipyrfurate after approval. Since the post market response is spontaneous report, the population size of its source is unknown, so it is impossible to estimate the frequency of occurrence or establish causal relationship between the response and drug exposure.
Immune system diseases: allergic reactions, including neuroedema
Metabolic and nutritional diseases: hypophosphatemia, hypokalemia, acidosis lactate
Respiratory, chest and mediastinal diseases: dyspnea
Gastrointestinal diseases: abdominal pain, increased amylase and pancreatitis
Hepatobiliary diseases: fatty liver, liver enzyme rise (the most common glutaraletranse, glutamic transaminase, γ - glutamyltranspeptidase), hepatitis
Skin and subcutaneous tissue diseases: rash
Musculoskeletal and connective tissue diseases: rhabdomyolysis, osteomalacia (osteomalacia (osteomalacia, which may cause fractures), myasthenia, myopathy
Kidney and urinary diseases: renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, creatinine rise, acute tubular necrosis, renal avalanche, polyuria and interstitial nephritis (including acute cases)
Systemic diseases and drug site status: powerlessness
The following adverse reactions (already listed under the title of the above-mentioned body system) may be caused by proximal renal tubules: rhabdomyolysis, osteomalacia, hypokalemia, myasthenia, myopathy, hypophosphatemia.
Taboo: Tenofovir dipivoxil fumarate should not be used in patients who were previously allergic to any of the components of the drug
Matters needing attention: Acidosis of lactate / hepatomegaly with steatosis
When nucleoside analogues were used alone or combined with other antiretroviral drugs, there were reports of lactate acidosis and severe hepatomegaly with fatty degeneration, including fatal cases. Most of these cases occur in women. Obesity and long-term exposure to nucleoside may be risk factors. Special attention should be paid to nucleoside analogues given to patients with known risk factors for liver disease; however, there have been case reports in patients without known risk factors. If clinical or laboratory results of any patient indicate lactate acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if transaminase does not increase significantly), the treatment of tenofovir fumarate should be suspended.
Hepatitis B deterioration after discontinuation of treatment
Patients infected with HBV but interrupted treatment with tenofovir fumarate must be monitored closely, including clinical and laboratory follow-up for at least a few months after the treatment has been stopped. If the conditions are appropriate, patients can be allowed to restart anti hepatitis B treatment.
New or more severe renal dysfunction
Tenofovir is mainly removed by the kidney. When tenofovir fumarate was used, there were reports of renal dysfunction, including acute renal failure and Fanconi syndrome (tubular injury with severe hypophosphatemia) (see "adverse reactions - post market experience").
It is suggested that creatinine clearance rates be calculated before treatment and when clinically appropriate during the treatment with tenofovir fumarate. The calculated creatinine clearance rate and serum phosphorus should be monitored regularly for patients at risk of renal impairment, including those who had previously experienced adverse renal events at adefovir treatment.
It is recommended that the interval of administration of tenofovir fumarate should be adjusted for all patients with creatinine clearance rate less than 50ml/ minute and their renal function should be monitored closely (see "usage dosage"). There is no available safety or efficacy data in patients with renal function impairment treated with tenofovir fumarate under dose adjustment guidance. Therefore, potential benefits and potential risks of renal toxicity should be evaluated.
If a nephrotoxic preparation has been used at present or recently, the treatment of tenofovir fumarate should be avoided.
Use with other drugs
Dinoflurane fumarate should not be used in combination with fixed dose compound preparations containing tenofovir
·Efevren / emtratabine / tenofovir fumarate
·Ribavirin / entecitabine / tenofovir fumarate
·Iveracivir / combist / emtricitabine / tenofovir dipivoxil fumarate
·Entecitabine and tenofovir
Tenofovir fumarate dipyrfurate should not be administered in combination with adefovir (see "drug interaction").
Patients with HIV-1 and HBV infection
Due to the risk of HIV-1 resistance, tenofovir fumarate dipyrfurate can only be used as part of the antiretroviral combination therapy program for patients with HBV and HIV-1 infection.
All patients with HBV infection should be tested for HIV-1 antibody before treatment with tenofovir fumarate. It is also recommended that all HIV-1 infected patients should be examined for chronic hepatitis B before the treatment of tenofovir fumarate.
Decrease of bone mineral density
Bone monitoring should be considered in adults with pathological fractures, osteosclerosis or bone loss risks and children over 12 or 12 years old. Although no studies have been conducted on the role of calcium and vitamin D supplementation, such supplementation may be beneficial to all patients. If bone abnormality is suspected, proper consultation should be conducted.
Adult patients
During the 144 week period of study 903, both treatment groups found that in adults with HIV infection who had received tenofovir fumarate dipyrfurate treatment, BMD of the lumbar spine and hip decreased relative to baseline. At week 144, the mean percentage of the decrease in BMD of lumbar spine was significantly higher than that of subjects receiving stavudine + lamivudine + iffenfene (-1.0% ± 4.6), and the mean percentage of BMD of lumbar spine was significantly higher than that of subjects treated with tenofovir fumarate + lamivudine + iffeverine compared with those receiving stavudine + lamivudine + effeverin. The changes of hip bone density were similar in the two groups (the ratio of tenofovir dipyrfurate fumarate was -2.8% ± 3.5 and that of stavudine group was -2.4% ± 4.5). In the two treatment groups, the decrease of BMD occurred mostly in the first 24-48 weeks of the trial, and remained stable until the 144 week. 28% of the subjects who received tenofovir fumarate, 21% of the subjects treated with stavudine had at least 5% of the lumbar BMD or at least 7% of the hip. Four subjects in the tinofivir fumarate group and 6 of the stavidin group reported clinically related fractures (except fingers and toes). In addition, compared with the stavudine group, the biochemical markers of bone metabolism (serum bone specific alkaline phosphatase, serum calcitonin, serum carboxy terminal peptide and urinary aminoterminal peptide) of tenofovir dipyrfurate fumarate group were significantly increased, suggesting that bone transformation increased. The serum parathyroid hormone level and 1,25 vitamin D level in the tinofivir fumarate group were also higher. These changes were maintained in normal range except for bone specific alkaline phosphatase.
Children 12 or over
A clinical trial (study 115) conducted in subjects aged 12 to 18 years old with chronic hepatitis B showed that the average lumbar BMD of the tinofivir fumarate and placebo group increased overall in 72 weeks, as expected in the adolescent population. The BMD of lumbar spine and body BMD (respectively +5% and +3%) in the treatment group of tenofovir fumarate treatment group were lower than those in placebo group (respectively +8% and +5%). Three subjects in the tinofivir fumarate group and two placebo groups showed significant (more than 4%) lumbar BMD loss at 72 weeks. At baseline, the mean BMD Z score of subjects randomly enrolled in the group with tenofovir fumarate showed that the lumbar spine was -0.43 and the whole body was -0.20. The mean BMD Z score of the randomized placebo group showed that the lumbar spine was -0.28 and the whole body was -0.26. The mean BMD Z score of 72 weeks of treatment with tenofovir fumarate showed that the lumbar spine-0.05, the whole body-0.15, placebo group were +0.07 and +0.06, respectively. Bone growth (height) was not affected as was the result of the HIV infected children's study.
The effect of changes in bone density and biochemical markers associated with tenofovir fumarate on long-term bone health and future fracture risk is still unknown.
Osteomalacia (related to proximal renal tubule lesions and possible fracture) associated with the use of tenofovir fumarate has been reported. (see "adverse reactions, post market experience")
Redistribution of fat
In HIV patients treated with antiretroviral therapy, redistribution / accumulation of body fat has been observed including centripetal obesity, increased collar fat (Buffalo back), peripheral weight loss, facial wasting, chest enlargement and Kirschner's face. The mechanism and long-term consequences of these phenomena are not clear. Causal relationship has not been established.
Immune reconstruction syndrome
In HIV patients who received antiretroviral treatment, including tenofovir dipyrfurate fumarate, the immune reconstruction syndrome has been reported. In the early stage of antiretroviral treatment, patients with immune system response may have inflammatory response to stubborn or residual opportunistic infections (such as Mycobacterium tuberculosis, cytomegalovirus, pneumoconidia pneumonia (PCP), or tuberculosis. Therefore, further evaluation and treatment are necessary.
In addition, there have been reports of autoimmune disorders (such as graves disease, polymyositis and green Barre syndrome) during immunoreconstruction, however, the onset time is more diversified and may occur within months of the start of treatment.
Early virology failure
Clinical trials in HIV infected subjects showed that some drug treatment schemes containing only three nucleoside reverse transcriptase inhibitors (NRTI) were generally less effective than those with two nucleoside retroviral inhibitors and one non nucleoside retroenzyme inhibitor or one HIV protease inhibitor. In particular, early reports of viral failure and high resistance should be taken into account. Therefore, we should use the triple nucleoside treatment plan carefully. Patients treated with triple nucleosides should be carefully monitored and considered for improvement.
Medication for pregnant and lactating women: American pregnancy classification B:
Reproductive studies were carried out in rats and rabbits, and the highest doses were 14 and 19 times higher than those in humans according to body surface area, respectively. The results showed that there was no evidence that tenofovir caused fertility damage or damage to the fetus. However, no adequate and well controlled study has been conducted in pregnant women. Because animal reproductive studies do not always predict human responses, tenofovir dipivoxil fumarate should not be used during pregnancy unless it is necessary.
Breastfeeding women: the Centers for Disease Control and prevention advises HIV infected mothers not to breastfeed their babies to avoid the risk of HIV transmission after birth. Studies in rats have shown that tenofovir is secreted in milk. It is not clear whether tenofovir is secreted in human milk. Because HIV transmission and serious adverse reactions may occur in breast-feeding infants, mothers who are receiving tenofovir dipivoxil fumarate should be asked not to breastfeed.
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