Approval Date: 05/18/2017
Revision date: November 29, 2017
Revision date: December 18, 2017
Revision Date: 08/02/2018
Nascent
Tenofovir disoproxil fumarate Tablets Instructions
Please read the instructions carefully and use under the direction of your physician
Warning: lactic acidosis/severe hepatomegaly with steatosis and worsening hepatitis after interruption of therapy
Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with nucleoside analogs (including tenofovir disoproxil fumarate tablets) in combination therapy with other antiretrovirals [see PRECAUTIONS].
Acute exacerbations of severe hepatitis have been reported in HBV-infected patients discontinuing antihepatitis B therapy, including tenofovir disoproxil fumarate tablets. For patients discontinuing anti-hepatitis B therapy (including tenofovir disoproxil fumarate tablets), liver function should be closely monitored during at least several months of clinical and laboratory follow-up. If necessary, patients may be rechallenged with anti-hepatitis B therapy [see PRECAUTIONS].
[Drug Name
Generic Name: tenofovir disoproxil fumarate tablets
English name:Tenofovir Disoproxil Fumarate Tablets
Hanyu Pinyin:FumasuanTinuofuwei’erbifuzhiPian
[Ingredients]This product The main ingredient is tenofovir disoproxil fumarate, the chemical name of which is 9-[(R)-2-[[bis[[(isopropoxycarbonyl) span>oxycarbonyl]methoxy]Oxophosphoryl]methoxy]-propyl]adenine fumarate(1:1).
Chemical structural formula:
Molecular Formula:C19H30N5O10P-C4H4O4
Molecular weight:635.52
[Properties]This product It is a blue oval film-coated tablet, which appears white or off-white after removing the coating.
[Indications
HIV-1Infection
Tenofovir disoproxil fumarate is indicated in combination with other antiretrovirals for the treatment of adultsHIV-1infection.
Starting treatment with tenofovir disoproxil fumarateHIV-1infection, the following should be considered:
Tenofovir disoproxil fumarate should not be used in combination with fixed-dose combination formulations containing tenofovir, including:
Efavirenz/Entriptabine/tenofovir disoproxil fumarate;
Ripivirine/Entragitabine/tenofovir disoproxil fumarate;
Eviravir/Kerbistat/emtricitabine/tenofovir disoproxil fumarate;
Entacitabine tenofovir.
Chronic hepatitis B
Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in adults and ≥12year-old pediatric patients.
After initiation of treatment with tenofovir disoproxil fumarateHBVinfection, the following points should be considered:
The establishment of this indication in adult patients is based on the results from initial The indication was based on safety and efficacy data obtained from subjects receiving nucleoside therapy for the first time and from previously treated subjects with proven lamivudine resistance. Subjects were hepatically compensatedHBeAgpositive and HBeAgnegative chronic hepatitis B adult subjects.
Tenofovir disoproxil fumarate was administered in a limited number of chronic hepatitis B subjects with decompensated liver disease have been evaluated.
The number of subjects in clinical trials with adefovir-associated at baseline The number of subjects with adefovir-related mutations at baseline in clinical trials is too small to draw conclusions about efficacy.
[Specification]0.3g
[Dosage].
Adults and12year-old and12year-old pediatric patients (35kgor more) recommended dose
for HIV-1or chronic hepatitis B: the dose is 300 mg(one tablet) once daily by mouth, on an empty stomach or with food.
For the treatment of chronic hepatitis B, the optimal course of therapy has not been defined. The safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg has not been studied.
Adjustment of dose in adults with renal impairment
Drug exposure was significantly increased when tenofovir disoproxil fumarate was given in subjects with moderate to severe renal impairment (see [Pharmacokinetics]. In patients with baseline creatinine clearance<50mL/minute, the drug should be administered according to Table1Adjust the dosing interval for tenofovir disoproxil fumarate.
The recommended dosing interval here is based on the dosing interval at different levels of renal impairment in non =”font-family:Arial”>HIV and non-HBV at different levels of renal impairment family:isoline”>infected subjects, including pharmacokinetic data modeled from a single dose in patients with end-stage renal disease requiring hemodialysis.
The safety and efficacy of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate to severe renal impairment. The clinical response to treatment and renal function should be closely monitored in these patients (see [Precautions]).
For mild renal impairment (creatinine clearance50 to 80mL/minute). minutes) in patients who do not require dose adjustment. Calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be monitored regularly in these patients (see [Precautions]).
Table 1 For patients with altered creatinine clearance Dose adjustment
Creatinine clearance(mL/ min)a
Hemodialysis patients
50
30-49
10-29
Recommended300mg Dosing interval
every24hours
every48hours
per72~
96once an hourevery7days or a total of aboutdialysis span>12hours after2
1.Use the ideal (lean) weight calculation.
2.Generally once a week (assuming weekly3times of hemodialysis, each lasting approximately4 (hours). Tenofovir disoproxil fumarate should be administered after completion of dialysis.
In creatinine clearance 10mL/minute non-hemodialysis patients, the pharmacokinetics of tenofovir have not been evaluated, so there are no dosing recommendations for these patients.
No data are available on dosing recommendations for pediatric patients with renal impairment.
[Adverse Reactions
Patients on tenofovir disoproxil fumarate have had rare renal impairment, renal failure, and proximal tubular lesions (including) =”font-family:Arial”>Fanconi syndrome) have occurred and have been reported to cause skeletal abnormalities (sometimes resulting in fractures). Renal function monitoring is recommended for those taking this product.
Tenofovir disoproxil fumarate may cause adverse reactions in close to one-third of patients when used in combination with other antiretroviral drugs. These adverse reactions are usually mild to moderate gastrointestinal events. Close to1% of adult patients taking tenofovir disoproxil fumarate discontinued therapy because of GI adverse events.
Lactic acidosis, severe fatty hepatomegaly associated with tenofovir disoproxil fumarate.
The combination of this product with dehydroinositide is not recommended because it can lead to an increased risk of adverse reactions. Rare reports of pancreatitis and lactic acidosis, sometimes fatal, have been reported.
HBVandHIVco-infected patients who had severe hepatitis B after interruption of tenofovir disoproxil fumarate treatment () () family:Arial”>HBV) with acute worsening has been reported.
The following adverse reactions are based on the literature (including clinical trials and post-marketing reports):
Adverse reactions are listed in Table 2. The frequency of occurrence of each group is listed in descending order, and each frequency of occurrence is defined as follows: very common (≥1/10), common (≥), common (≥) = “font-family:Arial”>1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10,000, 1/1000).
Table 2 Tenofovir disoproxil fumarate adverse reactions
Organ Systems/Frequency
Variety
Metabolism and nutrition
Very common:
Low phosphatemia
Unusual:
Hypokalemia
Rare:
Lactic acidosis
Nervous system
Very common:
Dizziness
Digestion
Very common:
Diarrhea, nausea, vomiting
Common:
Bloating
Unusual:
Pancreatitis
Liver and gallbladder
Common:
Elevated transaminases
Rare:
Hepatocellular steatosis, hepatitis
skin and subcutaneous tissue
Very common:
Rash
Rare:
Angioneurotic edema
Muscle, bone and connective tissue
Unusual:
Rhabdomyolysis, muscle atrophy
Rare:
chondromalacia (manifested by bone pain and uncommon fractures), myopathy
Renal and urinary system
Unusual:
Elevated creatinine
Rare:
Acute renal failure, renal failure, acute tubular necrosis, proximal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis), nephrolithiasis, nephrogenic uremic syndrome
Systemic and administered topically
Very common:
Lackluster
The following adverse reactions were reported voluntarily during clinical use and the population size of their source is unknown, so it is not possible to reliably estimate their frequency or establish a causal relationship between them and drug exposure.
Immune system: allergic reactions, including neuroedema;
Metabolic and nutritional: hypophosphatemia, hypokalemia, lactic acidosis;
Respiratory, thoracic and mediastinal: dyspnea;
Gastrointestinal : abdominal pain, increased amylase and pancreatitis;
hepatobiliary: fatty liver, elevated liver enzymes (most commonly aspartate aminotransferase, alanine aminotransferase, alanine glutamyl transpeptidase), hepatitis;
skin and subcutaneous tissue: rash;
Musculoskeletal and connective tissues: rhabdomyolysis, osteochondrosis (manifested as bone pain, which may cause fractures), myasthenia gravis, myopathy (all associated with proximal renal tubular lesions (associated with proximal tubular lesions);
Renal and urinary system: renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubular lesions, proteinuria, elevated creatinine, acute tubular necrosis, nephrogenic uremia, polyuria and interstitial nephritis (including acute cases);
Systemic and dosing site: debilitating.
The following adverse reactions (already listed under the body system headings above) may be caused by proximal renal tubular lesions: rhabdomyolysis, osteochondrosis, hypokalemia myasthenia gravis, myopathy, and hypophosphatemia.
[Contraindicated]Tenofovir disoproxil fumarate is contraindicated in Patients with prior hypersensitivity to any of the components of this drug.
[Precautions
Lactic acidosis/severe fatty hepatomegaly
Lactic acidosis and severe fatty hepatomegaly have been reported with nucleoside analogue therapy alone or in combination with other antiretroviral drugs, including Fatal cases have occurred. Most of these cases have occurred in women. Obesity and chronic exposure to nucleosides may be risk factors. Special care should be taken when giving nucleoside analogs in patients with known risk factors for liver disease; however, cases have been reported in patients without known risk factors. Tenofovir disoproxil fumarate therapy should be withheld in any patient with clinical or laboratory findings suggestive of lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if transaminases are not significantly elevated).
Worsening of hepatitis B after treatment interruption
For infectedHBVBut patients interrupting tenofovir disoproxil fumarate therapy must be closely monitored, including clinical and laboratory follow-up for at least several more months after discontinuation of therapy. If conditions are appropriate, patients may be permitted to restart anti-hepatitis B virus therapy.
New or more severe renal impairment
Tenofovir is primarily cleared by the kidney. Renal impairment has been reported with tenofovir disoproxil fumarate, including the development of acute renal failure andFanconi syndrome (renal tubular injury with severe hypophosphatemia).
Creatinine clearance calculations are recommended for all patients prior to initiation of therapy and when clinically appropriate during treatment with tenofovir disoproxil fumarate. Calculated creatinine clearance and serum phosphorus should be monitored regularly in patients at risk for renal impairment, including those who have experienced prior renal adverse events while on adefovir therapy.
It is recommended that all patients with creatinine clearance below 50mL/minute and adjust the dosing interval of tenofovir disoproxil fumarate in patients who are closely monitored for renal function. There are no available safety or efficacy data in patients with renal impairment treated with tenofovir disoproxil fumarate as directed by dose adjustment, so the potential benefit of treatment with tenofovir disoproxil fumarate and the potential risk of nephrotoxicity should be evaluated.
If current or recent use of nephrotoxic agents (e.g., high-dose or multi-dose NSAIDs) = “font-family:Arial”>
[NSAIDs]), treatment with tenofovir disoproxil fumarate should be avoided, (see [Drug Interactions]). With risk factors for renal insufficiency and stable disease on tenofovir
HIV infected patients who have had initiation of high or multiple doses
NSAIDs and then reported cases of acute renal failure. Some patients require hospitalization or even renal replacement therapy. If needed, alternative medicines to NSAIDs may be considered in patients at risk for renal insufficiency.
Persistent or worsening bone pain, extremity pain, fractures, and/or muscle pain or weakness may be a sign of proximal tubular lesions and should be immediately evaluated for renal function in patients at risk.
In combination with other drugs
Tenofovir disoproxil fumarate should not be used in combination with fixed-dose combination formulations containing tenofovir, including: “font-family:Arial”>
Efavirenz/emtricitabine/ Tenofovir disoproxil fumarate,
Ripivirine/emtricitabine/ Tenofovir disoproxil fumarate,
Eviraprevir/cobicistat/emtricitabine Tapine/ tenofovir disoproxil fumarate, or
Entransitabine tenofovir.
HIV-1andHBVco-infected patients
due to the presence ofHIV-1 resistance risk, tenofovir disoproxil fumarate may only be used as part of an antiretroviral combination regimen forHBVandHIV-1 co-infected patients.
AllHBVinfected patients should have HIV-1antibody testing before starting tenofovir disoproxil fumarate therapy. Testing. Screening for chronic hepatitis B is also recommended for allHIV-1infected patients prior to initiation of tenofovir disoproxil fumarate therapy.
Drug Interactions
Maximal serum concentration of desoxifovir dipivoxil fumarate when co-administered with desoxifovir extended-release tablets or enteric-coated formulations(Cmax)and area under the plasma concentration time curve( AUC) were significantly higher (see Table 5). The mechanism of this interaction has not been clarified. Higher dehydrocreatinine concentrations have the potential to cause adverse events associated with dehydrocreatinine, including pancreatitis and peripheral neuropathy.
After receiving tenofovir and dehydrocreatinine daily 400 mgwas observed in patients withCD4+cell counts were decreased.
at a weight >60kg in patients with 60 kg, the dose of dehydrocreatinine should be reduced to 250 mgwhen combined with tenofovir disoproxil fumarate family:equine”>. There are no data on the recommended dose adjustment of desoxycreatin in adult or pediatric patients weighing 60 kg. When co-administered, tenofovir disoproxil fumarate and desoxycreatin enteric solvent can be administered in the fasted state or with light food (400 Kcal,20%fat) administered simultaneously. Desoxycarbophil extended-release tablets and tenofovir disoproxil fumarate should be coadministered in the fasted state.
Tenofovir disoproxil fumarate should be administered with caution when co-administered with desoxycarbital, and patients receiving the co-administration should be closely monitored for adverse events associated with desoxycarbital . In patients who develop adverse reactions associated with desoxycarb, desoxycarb should be discontinued.
Because tenofovir is primarily cleared by the kidney, tenofovir disoproxil fumarate in combination with drugs that can cause decreased renal function or compete with active renal tubular clearance Combination with drugs that can increase serum concentrations of tenofovir and/or increase concentrations of other drugs that are cleared by the kidneys. Such drugs include, but are not limited to, adefovir, cidofovir, acyclovir, vaniclovir, ganciclovir, and valganciclovir.
Higher concentrations of tenofovir have the potential to cause adverse events associated with tenofovir disoproxil fumarate, including renal disease.
Atazanavir and lopinavir/Ritonavir can increase tenofovir concentrations. The mechanism of this interaction has not been clarified. Adverse reactions associated with tenofovir disoproxil fumarate should be monitored in patients receiving lopinavir/ritonavir and tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate should be discontinued in patients experiencing adverse events associated with tenofovir disoproxil fumarate.
Tenofovir disoproxil fumarate reduces atazanavir’sAUCandCminwhen combined with tenofovir disoproxil fumarate, atazanavir300 mgis recommended with ritonavir100mg administered concurrently. Atazanavir should not be coadministered with tenofovir disoproxil fumarate if ritonavir is not available.
Bone effect
In clinical studies, it was found that patients treated with tenofovir disoproxil fumarateHIVinfected adult patients, bone mineral density at the lumbar spine and hip (BMD) decreased relative to baseline. Most of the decrease in bone mineral density occurred in the first24 to48weeks until week 144, the decline remained stable. and clinically relevant fractures (except in fingers and toes) were reported by patients. In addition, biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum calcitonin, serum carboxy-terminal peptide, and urinary amino-terminal peptide) were significantly elevated in the tenofovir disoproxil fumarate group, suggesting increased bone transformation. Serum parathyroid hormone levels and 1 in the tenofovir disoproxil fumarate group,25vitaminD levels were also higher. The impact of tenofovir disoproxil fumarate-associated changes in bone mineral density and biochemical markers on long-term bone health and future fracture risk remains unclear.
Cases of osteochondrosis (associated with proximal renal tubular lesions) have been reported in association with the use of tenofovir disoproxil fumarate. (See [Adverse Reactions])
In cases with pathological fractures or with osteosclerosis or at risk of bone lossBone monitoring should be considered in patients with HIVinfection. Although the role of calcium and vitamin D supplementation has not been studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, an appropriate consultation should be performed.
Fat redistribution
Receiving combination anti-retroviral therapy for Redistribution of body fat has been previously observed in HIVinfected patients/ Accumulation includes centripetal obesity, increased dorsal collar fat (buffalo back), peripheral wasting, facial wasting, chest enlargement, and Cushing’s-like facies. The mechanisms by which these phenomena occur and the long-term consequences are not yet clear. Cause and effect have not been established.
Immune reconstitution inflammatory syndrome
Antiretroviral combination therapy including tenofovir disoproxil fumarate inHIVinfected patients with previously reported immune reconstitution inflammatory syndrome. During the initial phase of combination anti-retroviral therapy, the patient’s immune response system is likely to produce an inflammatory response to recalcitrant or residual opportunistic infections (e.g., Mycobacterium avium tuberculosis infection, cytomegalovirus, Yersinia pneumonia (PCP), or tuberculosis), for which more further evaluation and treatment is necessary.
In addition, there have been cases of autoimmune dysregulation during immune reconstitution therapy (e.g. Graves’ disease, polymyositis, and Grimm-Barre syndrome) have been reported, however, the timing of onset is more diverse and may also occur within a few months after initiation of therapy.
Early virologic failure
Clinical Trials in HIVInfected Subjects demonstrated that compared to triple drug regimens containing two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor or one HIVprotease inhibitor, certain drug regimens containing only Some drug regimens containing only three nucleoside reverse transcriptase inhibitors (NRTI) are less effective overall. In particular, early virologic failure and high resistance substitution have been reported and should be taken into account. Thus, triple nucleoside regimens should be used with caution. Patients treated with triple nucleoside regimens should be carefully monitored and improved therapies should be considered.
[For pregnant and lactating women
U.S. Pregnancy ClassificationBClass:
Reproduction studies were conducted in rats and rabbits, and the highest doses compared on the basis of body surface area were human14 and 19fold, the results showed no evidence of impaired fertility or harm to the embryo because of tenofovir. However, no adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, tenofovir disoproxil fumarate should not be used during pregnancy unless highly indicated.
Lactating women: The Centers for Disease Control and Prevention recommends thatHIVinfected women should not breastfeed their infants to avoid postnatalHIVthe risk of transmission. Studies conducted in rats demonstrated that tenofovir was secreted into breast milk. In humans, lotion samples taken from five HIV-1infected women within one week of delivery showed that a small amount of tenofovir was secreted into human milk. The effect of this exposure on nursing infants is not known. BecauseHIV transmission and serious adverse effects are possible in nursing infants, mothers who are receiving tenofovir disoproxil fumarate should be asked to them not to breastfeed.
[Pediatric Dosage
Data from foreign clinical studies are available to support the use of tenofovir disoproxil fumarate for the treatment of2to18yearsHIV-1patients for safety. And data from studies have shown that tenofovir disoproxil fumarate is safe in the recommended dose range of 2 to 18year-old patients have in vivo pharmacokinetic profiles similar to those established in clinical trials for safe and effective doses in adults.
for2The safety and efficacy in children under the age of 2 years have not been established.
[Medication for Elderly].
The clinical study of tenofovir disoproxil fumarate did not enroll a sufficient number of patients aged65 years of age or older, and it was not possible to determine whether their response was different from that of younger subjects. In general, older patients have decreased cardiac, hepatic, and renal function, increased chances of concurrent disease or ongoing use of other medications, and dose selection should be cautious.
[Drug Interactions
At significantly higher (~300fold) the concentrations observed in vivo, tenofovir had no in vitro effect on any of the following humanCYP450Isomer-mediated inhibition of drug metabolism in vitro. CYP3A4, CYP2D6, CYP2C9 or CYP2E1. However, a small magnitude (was observed in the metabolism of CYP1Asubstrates (6%) but statistically significant decrease. Based on the results of in vitro experiments and known tenofovir clearance pathways, it is highly unlikely that there are interactions between tenofovir and other drugs mediated by CYP450. (See [pharmacokinetics]).
Tenofovir is primarily cleared by glomerular filtration and active tubular clearance binding. Co-administration of tenofovir disoproxil fumarate with drugs that cause reduced renal function or compete with active renal tubular clearance can increase serum concentrations of tenofovir and/or Increase the concentration of other drugs that are cleared by the kidneys. Drugs that reduce renal function also have the potential to increase serum concentrations of tenofovir.
In healthy volunteers, by comparison with atazanavir, dehydrocreatinine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/Ritonavir and tacrolimus combination was evaluated for tenofovir disoproxil fumarate. Table3and Table4summarize the effect of co-administered drugs on tenofovir pharmacokinetics and the effect of tenofovir disoproxil fumarate on the pharmacokinetics of co-administered drugs.
Table5summarizes the drug interactions between tenofovir disoproxil fumarate and desoxycarbital. Caution should be exercised when tenofovir disoproxil fumarate is co-administered with desoxycreatin. When co-administered with tenofovir disoproxil fumarate in multiple doses, dehydrocreatinine400 mg of family:Arial”>CmaxandAUCwere significantly higher. The mechanism of this interaction has not been clarified. The systemic exposure levels to desoxycreatin250 mg of enteric capsules in combination with tenofovir disoproxil fumarate were similar to those in the fasted state 400 mg enteric-coated capsules were similar to those when used alone.
Table 3 Drug interactions: tenofovir pharmacokinetic parameters in the presence of co-administered drugs 1 Change
Co-medication
combined drug dose (mg)
N1
Tenofovir pharmacokinetic parameters2Percentage of change in
(90%confidence interval)Cmax
AUC
Cmin
Abacavir
300once
8
NC
Adefovir
10once
22
NC
Azanavir3
400per day1times14days
33
14( 8to20)
24(21to 28))
22(15to 30))
Dehydrocreatinine(Enteric Capsules)
400once
25
Dehydrocreatinine(extended-release tablets)
250or400perday1 times7day
14
Efavirenz
600per day1times14days
29
Entragitabine
200per day1times7days
17
Indinavir
800per day3times7days
13
14() 3to33)
Lamivudine
150per day2times7days
15
Lopinavir/Ritonavir
400/100per day2times14days
24
32( 25to “font-family:Symbol”/>38)
51(37to) span style=”font-family:Symbol”/>66))
Nelfinavir
1250per day2times14days
29
Saquinavir/Ritonavir
1000/100per day2times14day
35
23( 16to 30)
1.Patients receiving tenofovir disoproxil fumarate300 mg once daily.
2.Elevated=↑;lower=↓;No effect= ;NC=Not calculated.
3.REYATAZ®prescribing information.
Receiving long-term methadone maintenance or oral contraceptives or a single dose of ribavirinHIVnegative subjects given tenofovir disoproxil fumarate multiple times, the pharmacokinetics of tenofovir at steady state were similar to those observed in previous studies, indicating that there was no clinically meaningful drug interactions.
Table 4 Drug interactions: changes in pharmacokinetic parameters of the combined drugs in the presence of tenofovir disoproxil fumarate
Co-medication
combined drug dose (mg)
N
Percentage of change in pharmacokinetic parameters of co-administered drugs( 90%confidence interval)1
Cmax
AUC
C min
Abacavir
300once
8
12() 1to26)
NA
Adefovir
10once
22
NA
Atazanavir2
400per day1times14days
34
21(27to14)
25(30to19)
40(48to32)
Azanavir2
Atazanavir/Ritonavir300/100daily1times42days
10
28(50to5)
253(42 to3)
233(46to10)
Efavirenz
600per day1times14days
30
Entragitabine
200per day1times7days
17
20( 12to 1229)
Indinavir
800per day3times7day
12
11(30to12)
Lamivudine
150per day2times7days
15
24(34to12)
Lopinavir
RitonavirLopinavir RituxanNavir400/100per “font-family:isoline”>day2times14days
24
Methadone4
40-1101time per day14day5
13
Nelfinavir
M8 Metabolites1250per day2times14days
29
oral contraceptives6
Estradiol/Norgestrel(Ortho-Tricyclen =”font-family:Times New Roman”>®) span style=”font-family:equals”>once a day7day
20
Ribavirin
600once
22
NA
Saquinavir
RitonavirLopinavir/Ritonavir1000/100perday2times14days
32
22
(6to41)
297
(12to48)
477
(23to76)
23
(3to46)Tacrolimus
0.05mg/kgper day2times7day
21
13( 1to 27)
1.Elevated=↑;lower span>=↓;;no effect=;NA=Not applicable
2. REYATAZPrescribing Information
3.InHIVinfected patients, will tenofovirDFadded to atazanavir300 mg + ritonavir100mg, the results showed that theAUC of atazanavirandCminvalues of atazanavir were higher than those of atazanavir400 mg higher than those observed for atazanaviralone2.3fold and 4fold.
4.When administered alone or in combination with tenofovir disoproxil fumarate When administered alone or in combination with tenofovir disoproxil fumarate,Risomer (active),Sisomer and overall methadone exposure levels were comparable.
5.Each subject maintained their stable methadone dose. No pharmacokinetic changes (opiate toxicity or discontinuation signs or symptoms) were reported.
6.Dosing alone or in combination with tenofovir disoproxil fumarate Dipivoxil fumarate, with comparable levels of ethinylestradiol and 17-deacetylnorgestrel (pharmacologically active metabolite) exposure.
7.Because no clinically relevant AUCandCmin increase, so no dose adjustment is necessary when tenofovir disoproxil fumarate and saquinavir augmented with ritonavir are coadministered.
Table 5 Drug Interactions: Pharmacokinetic Parameters of Desoxymethylparaben in the Presence of Tenofovir Dipivoxil Fumarate
dehydrocreatinine1dose (mg)/dosing method2
Dosing of tenofovir disoproxil fumarate2
N
versus fasting state dehydrocreatinine400 mg administered alone Percentage (90%confidence interval)3
Cmax
AUC
Extended Release Tablets
400times per day1time47days
1hourafter hydroxycreatin administration in the fasting state
14
28( 11to 48)
44(31to59)
Entertainment Capsules
400once, on an empty stomach
de-hydrocreatinine administered2hours with food
26
48( 25to 76)
48(31to67)
400once, span style=”font-family:equinox”>with food
Taken concurrently with desoxycreatin
26
64( 41to 89)
60(44to79)
250once, on an empty stomach
de-hydrocreatinine administered2hours with food
28
10(22to3)
250once, on an empty stomach
Taken concurrently with desoxycreatin
28
14(00 /span>to 31)
250once, span style=”font-family:equinox”>with food
Taken concurrently with desoxycreatin
28
29(39to18)
11(23to2)
1.See “Precautions” for the use of desoxynivalenol with tenofovir disoproxil fumarate for the use of tenofovir disoproxil fumarate.
2.Concurrent administration with light food (~373kcal,, 20%fat).
3.Elevated=↑;lower=↓;No effect=
4.Including span style=”font-family:Arial”>4 names weighing 60kgsubjects receivingddI 250mg.
[Drug Overdose
At doses higher than tenofovir disoproxil fumarate300mgThere is limited clinical experience at therapeutic doses. In clinical studies, there have been 8 patients who received continuous 28 days of oral tenofovir disoproxil fumarate600 mg treatment . No serious adverse reactions have been reported. The possible effects of higher doses are not known.
If an overdose occurs, the patient must be monitored for evidence of toxicity and, if necessary, standard supportive therapy regimens should be used.
Tenofovir can be effectively cleared by hemodialysis with an extraction factor of approximately54%. Tenofovir disoproxil fumarate300 mg after a single dose4hours of hemodialysis clears approximately 10%of the administered dose of tenofovir family:equine”>.
[Pharmacology and Toxicology
Pharmacological effects
Mechanism: Tenofovir disoproxil fumarate is an open-loop nucleoside phosphorylated diester structural analogue of adenosine monophosphate. Tenofovir disoproxil fumarate first requires hydrolysis of the diester to tenofovir, which is then phosphorylated by cellular enzymes to form tenofovir diphosphate, also known as a chain end terminator. Tenofovir diphosphate is formed by the phosphorylation of the natural substrate 5′-deoxyadenosine triphosphate competes and terminates after integration with DNA span>DNAstrand, thereby inhibitingHIV-1 reverse transcriptase and HBVreverse transcriptase activity. Tenofovir diphosphate on mammalianDNApolymerase , and mitochondrialDNApolymeraseis a weak inhibitor.
Anti-HIVActivity:
Antiviral activity: in lymphoblastoid cell lines, primary monocytes/macrophages and peripheral blood lymphocytes were evaluated for tenofovir anti-laboratory and clinical isolationHIV-1antiviral activity. Tenofovir’sEC50 (50%effective concentration) value at 0.04μMto8.5μMbetween. In studies of tenofovir in combination with nucleoside reverse transcriptase inhibitors (abacavir, dehydroinositide, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), tenofovir had no antagonistic effects. In cell culture tenofovir has no antagonistic effect on HIV-1 of subtypes A, B, , , “font-family:Arial”>C,D, E, F,G,Ohave antiviral activity (EC50) family:isoline”>values range from:0.5μMto2.2μM), for HIV-2had activity that varied by viral strain (EC50values ranging from:1.6μMto5.5μM).
Resistance: cell cultures were selected for reduced sensitivity to tenofovirHIV-1isolated strains of viruses with reduced susceptibility to tenofovir were selected in cell culture. These viruses all have K65Rmutations in their reverse transcriptase and have reduced sensitivity to tenofovir2to4fold.
in clinical studies in untreated subjects (tenofovir disoproxil fumarate+lamivudine+Efavirenz with Stavudine+Lamivudine+ Efavirenz) in virologically failed subjects over 144 weeks The isolated viral strains were genetically analyzed and showed that mutations associated with efavirenz and lamivudine resistance were the most common, with no differences between the two treatment groups. Among the isolated viral strains from the patients analyzed, the incidence of K65R mutations in the tenofovir disoproxil fumarate group was8/47(17%) in the stavudine group and 2/49 () in the stavudine group 4%). Tenofovir disoproxil fumarate group 144 weeks of viral emergenceK65Rin 8subjects 7 occurred in the first48week and the other1one occurred in the firstweek of treatment. family:Arial”>96week. No other mutations causing resistance to tenofovir disoproxil fumarate were identified in this study.
In clinical studies in untreated subjects (tenofovir disoproxil fumarate+emtricitabine+ efavirenz with zidovudine/lamivudine+Efavirenz) for all patients at week144HIV-1 RNA>400copies/mL isolated from subjects with confirmed virological response failure or early termination of treatmentHIV-1Genotypic analysis was performed. Results showed the emergence of efavirenz resistance-associated mutations was most common and similar in both treatment groups. Among the isolated virus strains analyzed in the subjects, the M184V mutation associated with emtricitabine and lamivudine resistance was found in tenofovir disoproxil fumarate+emtricitabine group occurs at a frequency of 2/19and in the zidovudine/lamivudine group it was10/29. In a study that lasted144weeks934in subjects with HIV-1who were not detected using standard genotype analysis K65R mutation was detected.
Cross-resistance: Cross-resistance exists between some specific reverse transcriptase inhibitors. The K65R mutation screened by tenofovir was found in some mutations treated with abacavir, dehydroinositide, or zalcitabineHIV-1infected subjects were also screened. The HIVisolate strains containing this mutation had reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance to these drugs may occur in patients carrying K65Rmutations. From 20 patients with an average of 3mutations of zidovudine-related reverse transcriptase (M41L, D67N,K70R, ,L210W,T215Y/F, K219Q/E/N) isolated from subjects with HIV-1viruses showed decreased susceptibility to tenofovir3.1fold.
in clinical studies in treated subjects (tenofovir disoproxil fumarate+standard background treatment (SBT) versus placebo+standard background treatment), the first96weeks during which virologic failure occurred in subjects treated with tenofovir disoproxil fumarate14/304(5%) with a decrease in susceptibility to tenofovir of more than1.4fold (median value of 2.7 times). Results of genotypic analysis of virus strains isolated at baseline and at failure showed that HIV-1reverse transcriptase gene was present in the K65Rmutation.
In subjects who have been treated in clinical studies, the baseline viral genotype (N=222) was evaluated in terms of patient virologic response to tenofovir disoproxil fumarate.
In these clinical trials,94%baselineHIV-1isolated viral strains from participants evaluated expressed at least one nucleoside reverse transcriptase inhibitor (NRTI) mutation. In the genetic subtype study, the virological response of subjects was similar to the overall trial results.
Several exploratory analyses evaluated the impact of specific mutations and mutation patterns on virologic outcomes. No statistical tests were performed because of the large number of comparative modalities present. The effect of tenofovir disoproxil fumarate on pre-existing mutations associated with zidovudine resistance (M41L, D67N, K70R, ,L210W,, T215Y/F, orK219Q/E/N) showed varying degrees of cross-resistance, the extent of which correlates with the number and type of specific mutations. Treatment with tenofovir disoproxil fumarate with 3 or more zidovudine resistance-associated mutations (containing M41LorL210Wreverse transcriptase mutation)HIV-1 subjects had a reduced response to tenofovir disoproxil fumarate treatment; however, compared to placebo These subjects still showed improved response. D67N, K70R,T215Y/F,K219Q/E/Nmutations do not appear to affect the response to tenofovir disoproxil fumarate treatment. Subjects with viral emergence of L74Vsubstitution mutations but without zidovudine resistance-associated substitution mutations (N=8) had a decreased response to tenofovir disoproxil fumarate. Viral expression of Y115F((N=3),Q151M(N=2) substitution gene mutation orT69insertion mutation (N=4) had limited data associated with subjects with decreased response in all subjects.
In the analysis specified in the trial protocol, there was an association with abacavir/emtricitabine/lamivudine resistance associated with M184VmutatedHIV-1subjects did not have a reduced virologic response to tenofovir disoproxil fumarate. In these patientsHIV-1RNAresponse in the first48 week period persisted.
Study902and907Phenotypic analysis: treated subjects (N=100) at baselineHIV-1Phenotypic analysis showed a correlation between baseline viral susceptibility to tenofovir disoproxil fumarate and patient response to tenofovir disoproxil fumarate treatment. Table 6 summarizes the sensitivity of tenofovir disoproxil fumarate by baselineresponse to HIV-1RNA.
Table 6 HIV-1 RNA response at week 24, grouped according to baseline tenofovir disoproxil fumarate susceptibility ( Intention-to-treat)1
Sensitivity of baseline tenofovir disoproxil fumarate2
Variation of HIV-1RNA3(N)
＜1
-0.74(35)
>1and ≤3
-0.56(49)
>3and ≤4
-0.3(7)
>4
-0.12(9)
1.Use of recombinant phenotypesAntivirogram™ test (Virco) to determine the sensitivity of tenofovir.
2. Relative to the sensitivity of wild-type resistant strains Altered multiplicity.
3.In the first24week periodHIV-1RNAmean change relative to baseline values (DAVG24) in log10copycopy/ mL.
Anti-HBVActivity
Antiviral activity: inHepG2 2.2 .15cell line for tenofovir antiHBVantiviral activity was evaluated and tenofovir’sEC50 value was between0.14to1.5μMbetweenCC50(50%cytotoxic concentration) values greater than100μM. To study tenofovir in cell culture with the nucleoside classHBVreverse transcriptase inhibitors entecavir, lamivudine and telbivudine, and with the nucleoside classHIV-1reverse transcriptase inhibitor emtricitabine in combination, no antagonistic effects were observed.
Resistance: for study0102,0103,, “font-family:Arial”>0106, 0108,0121and LOC114648 in receiving tenofovir disoproxil fumarate monotherapy for at least24 family:equivocal”>weeks but at the end of each study year (or at termination of tenofovir disoproxil fumarate monotherapy) viremiaHBV DNAis still greater than or equal to 400copies/ style=”font-family:equals”>ml subjects with their pre-treatment and paired during treatment isolatedHBV reverse transcriptase amino acid sequence (partial or full sequence) samples were evaluated for cumulative genotypic resistance to tenofovir disoproxil fumarate once a year up to 240weeks. Studies0102 and 0103nucleoside primary treatment population,HBeAgpositive subjects had higher baseline viral load than span>HBeAgnegative subjects and a significantly higher rate of subjects who still presented with viremia at the time point of the last dose of tenofovir disoproxil fumarate monotherapy (). span>15%and4%).
Still presenting viremic subjects with HBVisolates showed mutations that occurred during treatment (Table 7); however, the there were no specific mutations with high incidence and associated with tenofovir disoproxil fumarate resistance (genotypic and phenotypic analysis).
Table 7 Amino acid mutations in subjects with viremia in each HBV treatment trial of tenofovir disoproxil fumarate
Reparative liver disease
decompensated liver disease (N=39)4
Nucleoside primers (N= 659)1
Adefovir Transcatheters (N=247)2
Lamivudine Resistant
(N=136)3Virulence present at the end time point of tenofovir disoproxil fumarate treatment
60/659
(9%)34/247
(14%)9/136
(7%)7/39
(18%)Treatment-induced amino acid mutations5
20/446
(45%)107/27
(37%)68/8
(75%)3/5
(60%)
1.Research0102(N=246), 0103(N=171) received tenofovir disoproxil fumarate for up to 240 weeks in nucleoside primary Subjects. StudyLOC114648(N=242) treatment48 weeks of data.
2.Study0102/0103(N=195) and 0106(N=52) in adefovir treated, treated with tenofovir disoproxil fumarate after switching from adefovir to tenofovir disoproxil fumarate up to192 weeks in subjects. Study0106 is a completed study of 168week subjects. week randomized, double-blind2period trial.
3.Study. span style=”font-family:Arial”>0121(N=136)in lamivudine-resistant subjects who received tenofovir disoproxil fumarate after switching from lamivudine to tenofovir disoproxil fumarate up to. span style=”font-family:Arial”>96 weeks.
4.Research0108in patients with decompensated liver disease treated with tenofovir disoproxil fumarate up to48week subjects (N=39).
5.Denominator includes tenofovir disoproxil fumarate Pivoxil monotherapy end time point subjects with viremia and with evaluable paired genotype data.
6.19 subjects in the study. span>0102and0103in which amino acid mutations occurred during treatment in 5subjects with conserved site changes, span>14subjects showed only polymorphic locus changes,8subjects had a transient mutation whose mutation was not detected at the end-treatment time point. Only1 of the study was a one-off mutation in study LOC114648. span>subjects with tenofovir disoproxil fumarate treatmentduring 48weeks mutations.
7.10 Adefovir-treated subjects showed amino acid mutations during treatment,2 subjects showed conserved site changes, of which8 subjects showed only polymorphic locus changes.
8.6 lamivudine-resistant subjects in the study0121 amino acid mutations during treatment, of which3 subjects showed polymorphic site changes only,3 subjects showed conserved locus changes.
Cross-resistance: in HBVnucleoside/cross-resistance was observed between nucleotide analog reverse transcriptase inhibitors.
Cell-based assays of lamivudine and telbivudine resistance associatedrtV173L, rtL180M andrtM204I/VmutatedHBVstrain of HBV to tenofovir is 0.7to of the wild-type virus. /span>3.4 times. rtL180M and rtM204I/Vdouble mutations showed reduced sensitivity to tenofovir3.4fold.
Entecavir resistance-relatedrtL180M , rtT184G, rtS202G/I,rtM204VandrtM250VmutatedHBVstrain has a sensitivity to tenofovir of 0.60.6of the wild-type virus =”font-family:equivocal”> to 6.9 times that of wild-type virus.
Adefovir resistance-relatedrtA181V and/orrtN236TmutatedHBVstrain of HBV to tenofovir is 2.9to of the wild-type virus -family:Arial”>10 times, carrying rtA181T family:equivocal”>mutant gene to tenofovir was 0.9to of the wild-type virus “font-family:Arial”>1.5 times.
Study0102,0103,,0106,0108and0121there are152subjects were known to be carriers of HBV at the time of initiation of tenofovir disoproxil fumarate treatment. ForHBVnucleoside/Nucleoside analogue reverse transcriptase inhibitor resistance mutant genes:14 mutant genes carrying adefovir resistance-associated mutations (rtA181S/T/Vand/orrtN236T),135 patients carrying lamivudine-resistance-associated mutations (rtM204I/V) and 3 carried adefovir and lamivudine resistance-associated mutation genes. After treatment with tenofovir disoproxil fumarate for up to 240weeks,11/14 adefovir-resistantHBV subjects, 124/135 lamivudine-resistant HBV subjects and 2/3 adefovir- and lamivudine-resistant HBV subjects all achieved and maintained viral suppression ( HBV DNAless than400copy number/mL). 3/5name carryrtA181T/VandrtN236Tmutant viruses in subjects who still had viremia.
Toxicological studies
Genotoxicity
Tenofovir disoproxil fumarate causes genetic mutations in an in vitro mouse lymphatic assay inAmes test resulted in negative results. In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate administration to male mice was negative.
Reproductive toxicity
Comparison based on body surface area in rats at a level equivalent to human10times the dose of tenofovir disoproxil fumarate given to male rats before mating for a continuous28days, female rats were given the drug before mating until the first 7days of gestation for consecutive15days of drug administration showed no effect of tenofovir disoproxil fumarate on fertility, mating behavior, or early embryonic development. However, alterations in the estrous cycle were seen in female rats.
Carcinogenicity
Long-term oral administration of tenofovir disoproxil fumarate was studied for carcinogenicity in mice and rats, with exposure levels up to approximately human16 of the therapeutic dose for HIV-1infection in mice and rats. span style=”font-family:isoline”>fold (mice) and 5fold (rats). Female mice had increased hepatic adenomas at high doses (exposure levels 16fold higher than in humans). No carcinogenicity was seen in rats at the highest exposure level of 5fold of the human therapeutic dose.
Other toxicity
In toxicological studies, with greater than or equal to6 fold human exposure levels (in AUC) to rats, dogs, monkeys Osteotoxicity occurred with the administration of tenofovir and tenofovir disoproxil fumarate. In monkeys, the osteo-toxicity was diagnosed as osteochondrosis. In monkeys, osteochondrosis showed reversibility after tenofovir dose reduction or discontinuation. In rats and dogs, osteo-toxicity was manifested as a decrease in bone mineral density. The potential mechanism of osteo-toxicity is unknown.
In4species of animals in which evidence of nephrotoxicity was found. In these animals, varying degrees of increased serum creatinine, uric acid nitrogen, glycosuria, proteinuria, phosphaturia, and/ or calciuria and decreased blood phosphorus were observed. These toxicities are at higher than human2 to20fold exposure levels (in AUC) were observed. The relationship between renal abnormalities, especially phosphaturia, and osteoporosis is unknown.
[Pharmacokinetics
In healthy volunteers andHIV-1infected individuals were evaluated for the pharmacokinetics of tenofovir disoproxil fumarate. The pharmacokinetics of tenofovir in these populations were similar.
Absorption: Tenofovir disoproxil fumarate is the water-soluble diester precursor drug to the active ingredient tenofovir. In patients taking tenofovir disoproxil fumarate on an empty stomach, the oral bioavailability of tenofovir was approximately 25%. In fasted state,HIV-1infected patients taking a single oral dose of tenofovir disoproxil fumarate300 mg at1.0±0.4hours to reach maximum serum concentration (C max). CmaxandAUC values are296±90ng/mLand2287±685ng-hr/mL.
In tenofovir disoproxil fumarate doses of 75to600 mg, the pharmacokinetics of tenofovir at doses between
Effect of food on oral absorption: After a high-fat meal (700to1000kcal, containing 40%to50%of fat) followed by oral tenofovir disoproxil fumarate300 mg, oral bioavailability increased , tenofovirAUC0∞ increased by approximately40%, Cmaxincrease of about14%. However tenofovir disoproxil fumarate had no significant effect on the pharmacokinetics of tenofovir when administered with light food compared with fasted administration. Food delayed the arrival of tenofovir atCmaxby approximately1hour. In the fed state, without controlling for food composition, tenofovir disoproxil fumarate300 mg once daily, after multiple doses of tenofovirCmaxandAUCare0.33±0.12μg/mLand3.32± 1.37μg-hr/mL.
Distribution: in the tenofovir concentration range 0.01to25μg/mL, its in vitro binding to human plasma or serum proteins in vivo was less than 0.7% and 7.2%, respectively. Tenofovir was administered at 1.0 mg/kg and 3.0 mg /kgwere administered intravenously, the steady-state volume of distribution was1.3±0.6L/kgand 1.2±0.4L/kg.
Metabolism and clearance: In vitro studies have shown that neither tenofovir disoproxil nor tenofovir is family:Arial”>substrates for the CYP450enzyme.
Tenofovir after intravenous administration72hours, approximately 70% of the administered dose was recovered in urine as a prototype tenofovir drug family:isoline”>-80%. The terminal half-life of tenofovir disoproxil fumarate after a single oral dose is approximately 17 hours. Tenofovir disoproxil fumarate300 mg once daily after multiple oral administrations (in the fed state)24hours of the administered dose can be recovered in urine32±10%.
Tenofovir is cleared by a combination of glomerular filtration and active renal tubular clearance. Competition in clearance may arise with other drugs that are cleared through the kidney.
Special Populations
Race: There are insufficient racial and ethnic data to adequately determine possible pharmacokinetic differences between these populations, with the exception of Caucasians.
Gender: The pharmacokinetics of tenofovir were similar in male and female patients.
Children:52CasesHBVinfected pediatric subjects (12to<18years) after oral tenofovir disoproxil fumarate300 mgtablets once daily, tenofovir exposure was the same asHIV-1exposure in HIV-infected adults and children was similar.
Elderly: In older adults (>65 years) no pharmacokinetic studies were performed.
Hepatic impairment: in moderate to severe hepatic impairment in nonHIVinfected patients, tenofovir disoproxil fumarate300 mgpharmacokinetics of tenofovir were studied after a single dose. The pharmacokinetics of tenofovir was not substantially altered in patients with hepatic impairment compared with those without. No change in the dose of tenofovir disoproxil fumarate administration was required in patients with hepatic impairment.
Renal impairment: The pharmacokinetics of tenofovir are altered in patients with renal impairment. In patients with creatinine clearance below 50mL/minute or in end-stage renal disease (ESRD) in patients requiring dialysis, tenofovir’sCmaxandAUC0∞ increases (Table8). It is recommended that the dosing interval of tenofovir disoproxil fumarate be changed in patients with creatinine clearance<50mL/min or in patients with end-stage renal disease requiring dialysis ( See [Dosage]).
Table 8 Pharmacokinetic parameters of tenofovir* in patients with different grades of renal function (mean ± standard deviation)
baseline creatinine clearance(mL/min)
>80(N=3)
50-80(N=10))
30-49(N=8))
12-29(N=11))
Cmax(ng/mLng/mL = “font-family:equals”>)
335.431.8
330.461.0
372.1156.1
601.6185.3
AUC0-(ng-hr/mL)
2184.5257.4
3063.8927.0
6008.52504.7
15984.77223.0
CL/F(mL/min)
1043.7115.4
807.7279.2
444.4209.8
177.097.1
Renal clearance (mL/min)
243.533.3
168.627.5
100.627.5
43.031.2
*Tenofovir disoproxil fumarate300mg, single dose
Tenofovir is effectively cleared by hemodialysis with an extraction factor of approximately54%. Tenofovir disoproxil fumarate300 mg after a single dose4hours of hemodialysis clears approximately 10%of the administered dose of tenofovir family:equine”>.
[Storage]Seal and store in a dry place.
[Package]High density polyethylene bottle for oral solid medication Package with silica gel desiccant in solid paper bag for medicine. 30tablets/bottle.
[Expiration date]36. span style=”font-family:equinox”>months
[Executive Standard] YBH02462017
[Approval code]State Drug CertificateH20173185
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