Levobeta may be available in the countries listed below.
Carbidopa monohydrate (a derivative of Carbidopa) is reported as an ingredient of Levobeta in the following countries:
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Famotidine is reported as an ingredient of Ulceran in the following countries:
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Ethambutol is reported as an ingredient of Rifafour in the following countries:
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Docpara may be available in the countries listed below.
Paracetamol is reported as an ingredient of Docpara in the following countries:
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Dilacor XR is a brand name of diltiazem, approved by the FDA in the following formulation(s):
A generic version of Dilacor XR has been approved by the FDA. However, this does not mean that the product will necessarily be commercially available - possibly because of drug patents and/or drug exclusivity. The following products are equivalent to Dilacor XR and have been approved by the FDA:
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Dilacor XR. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
Patents are granted by the U.S. Patent and Trademark Office at any time during a drug's development and may include a wide range of claims.
Carbocistéine Winthrop Sans Sucre may be available in the countries listed below.
Carbocisteine is reported as an ingredient of Carbocistéine Winthrop Sans Sucre in the following countries:
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Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].
Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Baraclude is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with Baraclude is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) [see Warnings and Precautions (5.2)].
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals [see Warnings and Precautions (5.3)].
Baraclude® (entecavir) is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
The following points should be considered when initiating therapy with Baraclude:
Baraclude should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
The recommended dose of Baraclude for chronic hepatitis B virus infection in nucleoside-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.
The recommended dose of Baraclude in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance mutations rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
The recommended dose of Baraclude for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
Baraclude (entecavir) Oral Solution contains 0.05 mg of entecavir per milliliter. Therefore, 10 mL of the oral solution provides a 0.5-mg dose and 20 mL provides a 1-mg dose of entecavir.
In subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3)]. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 1. The once-daily dosing regimens are preferred.
| Creatinine Clearance (mL/min) | Usual Dose (0.5 mg) | Lamivudine-Refractory or Decompensated Liver Disease (1 mg) |
|---|---|---|
| a For doses less than 0.5 mg, Baraclude Oral Solution is recommended. b If administered on a hemodialysis day, administer Baraclude after the hemodialysis session. | ||
| ≥50 | 0.5 mg once daily | 1 mg once daily |
| 30 to <50 | 0.25 mg once dailya OR 0.5 mg every 48 hours | 0.5 mg once daily OR 1 mg every 48 hours |
| 10 to <30 | 0.15 mg once dailya OR 0.5 mg every 72 hours | 0.3 mg once dailya OR 1 mg every 72 hours |
| <10 Hemodialysisb or CAPD | 0.05 mg once dailya OR 0.5 mg every 7 days | 0.1 mg once dailya OR 1 mg every 7 days |
No dosage adjustment is necessary for patients with hepatic impairment.
The optimal duration of treatment with Baraclude for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
None.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see Adverse Reactions (6.1)]. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Baraclude has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated [see Clinical Pharmacology (12.4)]. Therefore, therapy with Baraclude is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating Baraclude therapy, HIV antibody testing should be offered to all patients. Baraclude has not been studied as a treatment for HIV infection and is not recommended for this use.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including Baraclude, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Lactic acidosis with Baraclude use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with Baraclude should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with Baraclude 0.5 mg/day (n=679), Baraclude 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for Baraclude-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for Baraclude-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of Baraclude and lamivudine were comparable in these studies.
The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for Baraclude-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of Baraclude-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.
Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which Baraclude was compared with lamivudine are presented in Table 2.
| Nucleoside-Naïveb | Lamivudine-Refractoryc | |||
|---|---|---|---|---|
| Body System/ Adverse Reaction | Baraclude 0.5 mg n=679 | Lamivudine 100 mg n=668 | Baraclude 1 mg n=183 | Lamivudine 100 mg n=190 |
| a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. | ||||
| b Studies AI463022 and AI463027. | ||||
| c Includes Study AI463026 and the Baraclude 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Baraclude (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. | ||||
| Any Grade 2–4 adverse reactiona | 15% | 18% | 22% | 23% |
| Gastrointestinal | ||||
| Diarrhea | <1% | 0 | 1% | 0 |
| Dyspepsia | <1% | <1% | 1% | 0 |
| Nausea | <1% | <1% | <1% | 2% |
| Vomiting | <1% | <1% | <1% | 0 |
| General | ||||
| Fatigue | 1% | 1% | 3% | 3% |
| Nervous System | ||||
| Headache | 2% | 2% | 4% | 1% |
| Dizziness | <1% | <1% | 0 | 1% |
| Somnolence | <1% | <1% | 0 | 0 |
| Psychiatric | ||||
| Insomnia | <1% | <1% | 0 | <1% |
Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of Baraclude compared with lamivudine are listed in Table 3.
| Nucleoside-Naïveb | Lamivudine-Refractoryc | |||
|---|---|---|---|---|
| Test | Baraclude 0.5 mg n=679 | Lamivudine 100 mg n=668 | Baraclude 1 mg n=183 | Lamivudine 100 mg n=190 |
| a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 X ULN and >2 X baseline. | ||||
| b Studies AI463022 and AI463027. | ||||
| c Includes Study AI463026 and the Baraclude 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of Baraclude (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. | ||||
| d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis. | ||||
| e Grade 3 = 3+, large, ≥ 500 mg/dL; Grade 4 = 4+, marked, severe. | ||||
| f Grade 3 = 3+, large; Grade 4 = ≥ 4+, marked, severe, many. | ||||
| ULN=upper limit of normal. | ||||
| Any Grade 3–4 laboratory abnormalityd | 35% | 36% | 37% | 45% |
| ALT >10 X ULN and >2 X baseline | 2% | 4% | 2% | 11% |
| ALT >5.0 X ULN | 11% | 16% | 12% | 24% |
| Albumin <2.5 g/dL | <1% | <1% | 0 | 2% |
| Total bilirubin >2.5 X ULN | 2% | 2% | 3% | 2% |
| Lipase ≥2.1 X ULN | 7% | 6% | 7% | 7% |
| Creatinine >3.0 X ULN | 0 | 0 | 0 | 0 |
| Confirmed creatinine increase ≥0.5 mg/dL | 1% | 1% | 2% | 1% |
| Hyperglycemia, fasting >250 mg/dL | 2% | 1% | 3% | 1% |
| Glycosuriae | 4% | 3% | 4% | 6% |
| Hematuriaf | 9% | 10% | 9% | 6% |
| Platelets <50,000/mm3 | <1% | <1% | <1% | <1% |
Among Baraclude-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log10/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 4 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If Baraclude is discontinued without regard to treatment response, the rate of post-treatment flares could be higher. [See also Warnings and Precautions (5.1).]
| Subjects with ALT Elevations >10 X ULN and >2 X Referencea | ||
|---|---|---|
| Baraclude | Lamivudine | |
| a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for Baraclude-treated subjects and 10 weeks for lamivudine-treated subjects. | ||
| Nucleoside-naïve | ||
| HBeAg-positive | 4/174 (2%) | 13/147 (9%) |
| HBeAg-negative | 24/302 (8%) | 30/270 (11%) |
| Lamivudine-refractory | 6/52 (12%) | 0/16 |
Study AI463048 was a randomized, open-label study of Baraclude 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1)]. Among the 102 subjects receiving Baraclude, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 2 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).
Eighteen of 102 (18%) subjects treated with Baraclude and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the Baraclude group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with Baraclude and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.
No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 X baseline and >10 X ULN) through Week 48. Eleven of 102 (11%) subjects treated with Baraclude and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.
The safety profile of Baraclude 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects [see Warnings and Precautions (5.2)].
The following adverse reactions have been reported during postmarketing use of Baraclude. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to Baraclude exposure.
Immune system disorders: Anaphylactoid reaction.
Metabolism and nutrition disorders: Lactic acidosis.
Hepatobiliary disorders: Increased transaminases.
Skin and subcutaneous tissue disorders: Alopecia, rash.
Since entecavir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)], coadministration of Baraclude with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of Baraclude with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when Baraclude is coadministered with such drugs.
Pregnancy Category C.
There are no adequate and well-controlled studies of Baraclude in pregnant women. When pregnant rats and rabbits received entecavir at 28 and 212 times the human exposure at the highest human dose, there were no signs of embryofetal toxicity. Because animal reproduction studies are not always predictive of human response, Baraclude should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to entecavir, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.
There are no studies in pregnant women and no data on the effect of Baraclude on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
It is not known whether Baraclude is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Baraclude, a decision should be made to discontinue nursing or to discontinue Baraclude taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.
Safety and effectiveness of entecavir in pediatric patients below the age of 16 years have not been established.
Clinical studies of Baraclude did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Entecavir is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.2)].
Clinical studies of Baraclude did not include sufficient numbers of subjects from some racial/ethnic minorities (Black/African American, Hispanic) to determine whether they respond differently to treatment with the drug. There are no significant racial differences in entecavir pharmacokinetics.
Dosage adjustment of Baraclude is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Liver transplant recipients: The safety and efficacy of Baraclude in liver transplant recipients are unknown. If Baraclude treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function must be carefully monitored both before and during treatment with Baraclude [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
There is limited experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Following a single 1-mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.
Baraclude® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2 - amino - 1,9 - dihydro - 9 - [(1S,3R,4S) - 4 - hydroxy - 3 - (hydroxymethyl) - 2 - methylenecyclopentyl] - 6H - purin - 6 - one, monohydrate. Its molecular formula is C12H15N5O3∙H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:
Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° ± 0.5° C.
Baraclude film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. Baraclude 0.5-mg and 1-mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only). Baraclude Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. Baraclude Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.
Entecavir is an antiviral drug [see Clinical Pharmacology (12.4)].
The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.
Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1.0 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5-mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1-mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.
In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.
Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44%–46%, and a decrease in AUC of 18%–20% [see Dosage and Administration (2)].
Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
Binding of entecavir to human serum proteins in vitro was approximately 13%.
Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system [see Drug Interactions, below].
After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128–149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see Drug Interactions (7)].
Gender: There are no significant gender differences in entecavir pharmacokinetics.
Race: There are no significant racial differences in entecavir pharmacokinetics.
Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1-mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of Baraclude should be based on the renal function of the patient, rather than age [see Dosage and Administration (2.2)].
Pediatrics: Pharmacokinetic studies have not been conducted in children.
Renal impairment: The pharmacokinetics of entecavir following a single 1-mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 5 [see Dosage and Administration (2.2)].
| Renal Function Group | ||||||
|---|---|---|---|---|---|---|
| Baseline Creatinine Clearance (mL/min) | ||||||
| Unimpaired >80 n=6 | Mild >50–≤80 n=6 | Moderate 30–50 n=6 | Severe <30 n=6 | Severe Managed with Hemodialysisa n=6 | Severe Managed with CAPD n=4 | |
| a Dosed immediately following hemodialysis. CLR = renal clearance; CLT/F = apparent oral clearance. | ||||||
| Cmax (ng/mL) (CV%) | 8.1 (30.7) | 10.4 (37.2) | 10.5 (22.7) | 15.3 (33.8) | 15.4 (56.4) | 16.6 (29.7) |
| AUC(0–T) (ng•h/mL) (CV) | 27.9 (25.6) | 51.5 (22.8) | 69.5 (22.7) | 145.7 (31.5) | 233.9 (28.4) | 221.8 (11.6) |
| CLR (mL/min) (SD) | 383.2 (101.8) | 197.9 (78.1) | 135.6 (31.6) | 40.3 (10.1) | NA | NA |
| CLT/F (mL/min) (SD) | 588.1 (153.7) | 309.2 (62.6) | 226.3 (60.1) | 100.6 (29.1) | 50.6 (16.5) | 35.7 (19.6) |
Following a single 1-mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days [see Dosage and Administration (2.2)].
Hepatic impairment: The pharmacokinetics of entecavir following a single 1-mg dose were studied in subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of Baraclude is recommended for patients with hepatic impairment.
Post-liver transplant: The safety and efficacy of Baraclude in liver transplant recipients are unknown. However, in a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated [see Use in Specific Populations (8.7)].
The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.
The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate [see Drug Interactions (7)].
Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 μM.
Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir against lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010–0.059 μM).
The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with Baraclude is unlikely to reduce the antiviral efficacy of Baraclude against HBV or of any of these agents against HIV. In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the Cmax of entecavir using the 1-mg dose.
A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (HIV-1) isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to >10 μM; the lower EC50 values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.
In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions (>70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase.
Nucleoside-naïve subjects: Genotypic evaluations were performed on evaluable samples (>300 copies/mL serum HBV DNA) from 562 subjects who were treated with Baraclude for up to 96 weeks in nucleoside-naïve studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562=<1%), and 1 of them experienced virologic rebound (≥1 log10 increase above nadir). In addition, emerging amino acid substitutions at rtM204I/V and rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562=<1%) who experienced virologic rebound. For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA <300 copies/mL at end of dosing (up to 96 weeks).
HBeAg-positive (n=243) and -negative (n=39) treatment-naïve subjects who failed to achieve the study-defined complete response by 96 weeks were offered continued entecavir treatment in a rollover study. Complete response for HBeAg-positive was <0.7 MEq/mL (approximately 7 x 105 copies/mL) serum HBV DNA and HBeAg loss and, for HBeAg-negative was <0.7 MEq/mL HBV DNA and ALT normalization. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these 282 subjects, 141 HBeAg-positive and 8 HBeAg-negative subjects entered the long-term follow-up rollover study and were evaluated for entecavir resistance. Of the 149 subjects entering the rollover study, 88% (131/149), 92% (137/149), and 92% (137/149) attained serum HBV DNA <300 copies/mL by Weeks 144, 192, and 240 (including end of dosing
Clopidogrel Sandoz may be available in the countries listed below.
Clopidogrel besilate (a derivative of Clopidogrel) is reported as an ingredient of Clopidogrel Sandoz in the following countries:
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