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1、HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VIREAD safely and effectively. See full prescribing informationfor VIREAD.VIREAD® (tenofovir disoproxil fumarate tabletsInitial U.S. Approval: 2001WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY
2、 WITH STEATOSIS and POST TREATMENT EXACERBATION OFHEPATITISSee full prescribing information for complete boxed warning. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use ofnucleoside analogs, including VIREAD. (5.1 Severe acute exacerbatio
3、ns of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic functionshould be monitored closely in these patients. Ifappropriate, resumption of anti-hepatitis B therapy may bewarranted. (5.2-RECENT MAJOR CHANGES- Indications a
4、nd Usage (1.2 10/2010 Dosage and Administration (2.1, 2.2, 2.3 10/2010 Warnings and PrecautionsNew Onset or Worsening Renal Impairment (5.3 10/2009Decreases in Bone Mineral Density (5.6 03/2010-INDICATIONS AND USAGE- VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reve
5、rse transcriptase inhibitor.VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1VIREAD is indicated for the treatment of chronic hepatitis B in adults. (1-DOSAGE AND ADMINISTRATION- Rec
6、ommended dose for the treatment of HIV-1 or chronic hepatitis B in adults: 300 mg once daily taken orally withoutregard to food. (2.1 Recommended dose for the treatment of HIV-1 in pediatric patients (12 years of age and 35 kg: 300 mg once daily taken orally without regard to food. (2.2 Dose recomme
7、nded in renal impairment in adults:Creatinine clearance 30-49 mL/min: 300 mg every 48 hours.(2.3Creatinine clearance 10-29 mL/min: 300 mg every 72 to 96 hours.(2.3Hemodialysis: 300 mg every 7 days or after approximately 12hours of dialysis. (2.3-DOSAGE FORMS AND STRENGTHS- Tablets: 300 mg. (3-CONTRA
8、INDICATIONS- None. (4-WARNINGS AND PRECAUTIONS- New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl before initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in patients at risk. Avoid administeringVIREAD w
9、ith concurrent or recent use of nephrotoxic drugs. (5.3 Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA and TRUVADA. Do not administer in combination with HEPSERA. (5.4 HIV testing: HIV antibody testing should be offered to all HBV-infected pa
10、tients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviralcombination regimen in HIV-infected patients with or without HBV coinfection. (5.5 Decreases in bone mineral density (BMD: Observed in HIV-infected patients. Consider assessment of BMD in
11、 patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6 Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.7 Immune reconstitution syndrome: Observed in HIV-infected patients. M
12、ay necessitate further evaluation and treatment. (5.8 Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and considertreatment modification. (5.9-ADVERSE REACTIONS-In HIV-infected subjects: Most common adverse reactions (incidence 1
13、0%, Grades 2 - 4 are rash, diarrhea, headache, pain, depression, asthenia, and nausea. (6In HBV-infected subjects with compensated liver disease: most common adverse reaction (all grades was nausea (9%. (6In HBV-infected subjects with decompensated liver disease: most common adverse reactions (incid
14、ence 10%, all grades were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch-DRUG INTERACTIONS- Didanosine:Coadministration increases d
15、idanosineconcentrations. Use with caution and monitor for evidence ofdidanosine toxicity (e.g., pancreatitis, neuropathy. Considerdose reductions or discontinuations of didanosine if warranted.(7.1 Atazanavir:Coadministration decreases atazanavirconcentrations and increases tenofovir concentrations.
16、 Useatazanavir with VIREAD only with additional ritonavir; monitor for evidence of tenofovir toxicity. (7.2 Lopinavir/ritonavir:Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.3-USE IN SPECIFIC POPULATIONS- Pregnancy: There is a registry available.
17、 Enroll patients by calling 1-800-258-4263. Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3 Safety and efficacy not established in patients less than 12 years of age. (8.4See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient LabelingRevised: Octobe
18、r 2010 FULL PRESCRIBING INFORMATION: CONTENTS*WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS1 INDICATIONS AND USAGE1.1 HIV-1 Infection1.2 Chronic Hepatitis B2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in Adults2.2 Recommended Dose in Ped
19、iatric Patients (12 Years ofAge and 35 kg2.3 Dose Adjustment for Renal Impairment in Adults3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis5.2 Exacerbation of Hepatitis after Discontinuation ofTreatment5.3 New Onset or Wo
20、rsening Renal Impairment5.4 Coadministration with Other Products5.5 Patients Coinfected with HIV-1 and HBV5.6 Decreases in Bone Mineral Density5.7 Fat Redistribution5.8 Immune Reconstitution Syndrome5.9 Early Virologic Failure6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials Experience6.
21、2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Didanosine7.2 Atazanavir7.3 Lopinavir/Ritonavir7.4 Drugs Affecting Renal Function8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Patients with Impaired Renal Function10 OVERDOSAGE11 DESCRIPTION12 CLIN
22、ICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Clinical Efficacy in Patients with HIV-1 Infection14.2 Clinical Efficacy
23、in Patients with Chronic Hepatitis B16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION AND FDAAPPROVED PATIENT LABELING* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEG
24、ALY WITHSTEATOSIS and POST TREATMENT EXACERBATION OF HEPATITISLactic acidosis and severe hepatomegaly with steatosis, including fatalcases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals See Warnings and Precautions (5.1.Severe acut
25、e exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical andlaboratory follow-up for at least several months in patients who discontinueanti-hepatitis B t
26、herapy, including VIREAD. If appropriate, resumption ofanti-hepatitis B therapy may be warranted See Warnings and Precautions(5.2.1 INDICATIONS AND USAGEInfection1.1 HIV-1VIREAD® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pedi
27、atric patients 12 years of age and older.The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection: VIREAD should not be used in combination with TRUVADA® or ATRIPLA® See Warnings and Precautions (5.4.1.2 Chronic Hepatitis BVIREAD is
28、 indicated for the treatment of chronic hepatitis B in adults.The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller
29、 number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease See Clinical Studies (14.2. VIREAD was evaluated in a limited number of subjects with chronic hepatiti
30、s B and decompensated liver disease. See Adverse Reactions (6.1, Clinical Studies(14.2 The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions ofefficacy See Microbiology (12.4, Clinical Studies (14.2.2
31、DOSAGE AND ADMINISTRATION2.1 Recommended Dose in AdultsFor the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.2.2 Recommended Dose in
32、 Pediatric Patients (12 Years of Age and 35 kg For the treatment of HIV-1 in pediatric patients 12 years of age and older with body weight 35 kg (77 lb: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.2.3 Dose Adjustment for Renal Impairment in AdultsSignificantl
33、y increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment See Clinical Pharmacology (12.3. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in
34、 Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval
35、 adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients See Warnings and Precautions (5.3.No dose adjustment is necessary for patient
36、s with mild renal impairment (creatinine clearance 5080 mL/min. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment See Warnings and Precautions (5.3.Table 1 Dosage Adjustment for Patients with Altered Creatinine Clear
37、anceCreatinine Clearance(mL/minaHemodialysis Patients50 3049 1029Recommended 300 mg Dosing Interval Every 24hoursEvery 48hoursEvery 72 to96 hoursEvery 7 days or after a total ofapproximately 12 hours ofdialysis ba. Calculated using ideal (lean body weight.b. Generally once weekly assuming three hemo
38、dialysis sessions a week of approximately 4 hours duration.VIREAD should be administered following completion of dialysis.The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available f
39、or these patients.No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.3 DOSAGE FORMS AND STRENGTHSVIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofo
40、vir disoproxil. The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly w
41、ith steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercise
42、d when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic
43、acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacer
44、bations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.5.3 New Onset or Worsening Ren
45、al ImpairmentTenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia, has been reported with the use of VIREAD See Adverse Reactions (6.2.It is recommended that creatinine clea
46、rance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously ex
47、perienced renal events while receiving HEPSERA®.Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min See Dosage and Administration (2.3. No safety or efficacy data are available in patients with renal
48、 impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.5.4 Coadministration with Other ProductsVIREAD shoul
49、d not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil See Drug Interactions (7.4.Coinfected with HIV-1 and HBV5.5
50、PatientsDue to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is
51、also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.5.6 Decreases in Bone Mineral DensityAssessment of bone mineral density (BMD should be considered for adults and pediatric patients 12 years of age and older who ha
52、ve a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation
53、should be obtained.In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the
54、lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9 compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4
55、.5 in the stavudine group. In both groups, the majority of the reduction in BMD occurred in the first 2448 weeks of the study and this reduction was sustained through Week 144. Twenty-eightpercent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spi
56、ne or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphata
57、se, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatas
58、e, these changes resulted in values that remained within the normal range.In a clinical study of HIV-1 infected pediatric subjects 12 years of age and older (Study 321, bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the
59、 mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4% lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar sp
60、ine and -0.458 for total body. Skeletal growth (height appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.The effects of VIREAD-associated changes in BMD an
61、d biochemical markers on long-term bone health and future fracture risk are unknown.Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures have been reported in association with the use of VIREAD See Adverse Reactions (6.2.The bone effects of VIREAD h
62、ave not been studied in patients with chronic HBV infection.Redistribution5.7 FatIn HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appea
63、rance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual oppo
