Revovir

Clevudine.

Each Capsule contains 30 mg of clevudine.
Clevudine is a white, odorless crystalline powder having a slightly bitter taste. It is soluble in water and in methanol, sparingly soluble in ethanol, in isopropanol, and in acetone, very slightly soluble in octanol, in ethyl ether, and practically insoluble in n-hexane. It is not hygroscopic.
Chemical name: 1-(2-Deoxy-2-fluoro-β-L-arabinofuranosyl) thymine.
Molecular formula: C₁₀H₁₃O₅FN₂.
Molecular weight: 260.22.
Melting point: 190-194°C.
Partition coefficient: log P=-0.48 (1-octanol/water).
Excipients/Inactive Ingredients: It contains microcrystalline cellulose, magnesium stearate and hard gelatin capsule.

Pharmacology: Pharmacodynamics: Mechanism of action: Antiviral Activity: The EC50 value determined for clevudine against extracellular DNA is 0.0146 ± 0.0024 µM which is similar to that obtained for lamivudine 0.0163 ± 0.0024 µM. EC50 values against intracellular replicative intermediates of HBV range from 0.018 to 0.067 µM and from 0.015 to 0.037 µM against nuclear DNA. These values are also similar to those obtained for lamivudine.
Inhibition of HBV DNA polymerase: The mechanism by which clevudine exerts its antiviral effect is believed to be mediated by the intracellular formation of its mono-, di- and triphosphate (TP) forms. Clevudine enters cells via both facilitated nucleoside transport and non-facilitated passive diffusion. It is the first thymidine analogue found to be a substrate for three intracellular enzymes cytosolic thymidine kinase, cytosolic deoxycytidine kinase and mitochondrial deoxypyrimidine kinase. Pai et al. demonstrated that 5'-triphosphate of clevudine inhibited endogenous viral polymerase activity in a dose-dependent manner. Liu et al. reported that clevudine 5'-triphosphate acts as a potent inhibitor of HBV DNA polymerase with a Ki value of 0.1 µM. Further, Seigneres et al reported that in an endogenous assay with wild type HBV, clevudine-TP inhibited DNA-dependent DNA polymerase with an EC50 value of 0.7 µM. Aguesse-Germon and Ying reported that clevudine 5'-triphosphate causes time-dependent inhibition of the elongation of the DNA primer. In primary duck hepatocytes, clevudine strongly caused inhibited viral DNA synthesis, as shown by a marked decrease in viral single-stranded DNA at a concentration of 10 µM. Clevudine had no effect on mitochondrial structure, DNA content, or function. The lack of cytotoxicity reflects the inability of human cellular DNA polymerases α, β, γ, and δ to utilize the 5'-triphosphate of clevudine as a substrate.
Decrease in ccc-DNA (ccc: covalently closed circular) levels: In woodchuck models, Zhu et al. reported that administration of clevudine (10 mg/kg/day) for 56 weeks resulted in marked reductions in serum WHV DNA, DNA replicative intermediates, and cccDNA. By week six, cccDNA levels were between 13 and 44% of pretreatment values. By week 30 of treatment, cccDNA levels had dropped to between 1.2 and 5.4% of pretreatment levels. In another study with woodchucks infected with WHV, analysis of the cccDNA levels in the 10 mg/kg cohort showed an average 10-fold decrease in the levels of cccDNA after 28 days of treatment. Summers and Mason reported that viral cccDNA declined 20-100 fold after 30 weeks of treatment with clevudine in woodchuck models of HBV.
Clinical Studies: Two randomized, double-blind, placebo-controlled studies, L-FMAU-301 and L-FMAU-302, were conducted as phase III studies to evaluate the safety, biochemical response and antiviral activity of clevudine 30 mg QD for 24 weeks of treatment with up-to 24 weeks of follow-up following the cessation of treatment in chronic HBV-infected patients.
In both double-blinded and placebo controlled studies, patients were randomized to either the clevudine 30 mg group or the placebo group in a 3:1 ratio. In study L-FMAU-301, HBeAg positive patients with chronic hepatitis B were enrolled. In the L-FMAU-302 study, the population comprised patients with HBeAg negative (presumed precore mutant) chronic hepatitis B. These studies included 329 patients with chronic hepatitis (defined as having HBsAg in the serum for more than 6 months) ranging from 18 to 60 years in age. Chronic hepatitis B, defined had HBV DNA levels ≥6 10 copies/mL for HBeAg positive patients or ≥5 log copies/mL for HBeAg negative patients and alanine aminotransferase (ALT) levels between 1.2 and 15 times the upper limit of normal range (ULN). In addition, they had to be nucleoside therapy-naive.
HBeAg-positive: Study L-FMAU-301: The median changes in HBV DNA levels from baseline were -5.10 and -0.27 log copies/mL at the end of 24 weeks of treatment in the REVOVIR and placebo groups, respectively (p<0.0001). Twenty-four weeks after the treatment period, median changes in HBV DNA levels from baseline were -2.02 and -0.68 log copies/mL in REVOVIR and placebo groups, respectively (p<0.0001). Serum HBV DNA levels were below the lower limit of detection (300 copies/mL) in the Amplicor PCR assay in 59.0% and 0% at 24-week in REVOVIR and placebo groups, respectively. The proportion of patients with normal ALT levels was 68.2% in the REVOVIR group and 17.5% in placebo group at 24-week. The ALT normalization rates further increased in the REVOVIR group after cessation of therapy rising to 80.1% at 34-week and then decreasing slightly thereafter to 61.2% at 6 months post-treatment. HBeAg had disappeared in 10.4% and 12.3% of subjects at 24-week and in 15.3% and 12.0% at 48-week in the REVOVIR and placebo groups, respectively.
HBeAg-negative: Study L-FMAU-302: The median changes in HBV DNA levels from baseline were -4.25 and -0.48 log copies/mL at the end of the 24-week treatment period in the REVOVIR and placebo groups, respectively (p<0.0001). Post-treatment antiviral activity was sustained showing a -3.11 log reduction of median changes in HBV DNA levels from baseline at 24-week off therapy in the REVOVIR group as compared with a -0.66 log reduction in the placebo group, which was a statistically significant difference. Serum HBV DNA levels were below the lower limit of detection (300 copies/mL) in the Amplicor PCR assay in 92.1% and 0% at 24-week (end of treatment), 47.5% and 4.8% at 34-week (10-week post-treatment), and 16.4% and 0% at 48-week (6-month post-treatment) in the REVOVIR and placebo groups, respectively. Viral breakthrough was not observed during the entire dosing period. A statistically significant difference was observed in the proportion of patients with normal ALT levels in the REVOVIR group (74.6%) and that in the placebo group (33.3%) at 24-week. The ALT normalization rates further increased in the REVOVIR group after the cessation of therapy, going up to 86.7% at 34-week and then slightly decreasing thereafter to 70.5% at 48-week. (See Table 1.)

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Pharmacokinetics: The pharmacokinetics of clevudine following single dose administration to healthy volunteers over the dose range of 150 to 1,200 mg are summarized in Table 2. (See Table 2.)

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The mean Cmax values ranged from 0.6 μg/mL to 4.7 μg/mL over the dose range of 150 mg to 1,200 mg, while the mean AUC_{0 → ∞} values ranged from 2.3 hr•μg/mL to 34.3 hr•μg/mL over the same dose range. The half-life of clevudine appeared to be independent of dose (also see Table 2). The overall clevudine renal clearance was 195 mL/min which indicated the drug was excreted by both glomerular filtration and active excretion. (See Table 3.)

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Table 3 summarizes the pharmacokinetics of clevudine at the steady state, as measured at week 12.
Based on an analysis of clevudine pharmacokinetics at the steady state, the mean half-life of clevudine appears to be approximately 70 hours, supporting a once daily dosing regimen.
Toxicology: Mutagenecity, Immune Toxicity and Carcinogenicity: Mutagenesis: The genetic toxicology studies performed consisted of a bacterial reverse mutation assay (Ames assay) conducted at a clevudine concentration of 5,000 μg/plate in the presence and absence of metabolic activation, an in vitro assay for chromosomal aberrations in CHO cells, and a rat in vivo micronucleus assay conducted with an oral dose of 2,000 mg/kg. All three studies were negative for mutagenic activity attributable to clevudine.
Immune toxicity: In a 28-day oral humoral and cell-mediated immune toxicity study in male mice conducted at clevudine concentrations of 85, 250, 750 mg/kg/day, no immune toxicity was noted in B or T cell proliferation assays.
Carcinogenesis: In the long-term oral carcinogenicity studies in mice and rats, carcinogenesis was not observed at 88 times the exposure of human recommended dose, 30 mg/day.

CLEVUDINE (REVOVIR) is indicated for the inhibition of virus replication in chronic hepatitis B patients (HBeAg positive or HBeAg negative) with evidence of active viral replication and elevations in serum aminotransferases (ALT or AST).

The usual adult dose for oral use is 1 capsule (30 mg of clevudine) once daily or as prescribed by the physician.

Acute toxicity studies showed that the approximate LD50 for clevudine was greater than 5,000 mg/kg in mice and greater than 3,000 mg/kg in rats. There is no experience of CLEVUDINE overdosage reported in patients. In healthy volunteers administered 1,200 mg/day of clevudine, the adverse events that occurred were mild and resolved without treatment.

CLEVUDINE (REVOVIR) is contraindicated in the following patients: Patients with previously demonstrated hypersensitivity to clevudine or any of its ingredients.
Patients under 18 years of age.
Patients with renal impairment: Since clevudine is primarily eliminated by the kidneys, the elimination half-life of clevudine may be prolonged in patients with renal impairment.
However, clinical studies for dosage adjustment in patients with renal impairment have not been performed yet. This drug is contraindicated in patients with creatinine clearance <60 mL/min.

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.
Typically severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy. 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.

Important precautions: Patients with the need for co-administration of CLEVUDINE with other drugs.
Since clevudine is primarily eliminated by the kidneys, co-administration of CLEVUDINE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either clevudine or the co-administered drug. The effects of co-administration of CLEVUDINE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, so patients should be monitored closely for adverse events when CLEVUDINE is co-administered with such drugs.
As a result of an in vitro study about whether Clevudine is an inhibitor of the cytochrome P450 (CYP450) enzyme system, the representative metabolic enzyme of drugs, or not, it is confirmed that Clevudine is not an inhibitor of the CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, but, it has not been evaluated whether Clevudine is a substrate and inducer of the cytochrome P450 (CYP450) enzyme system or not and patients should be monitored closely for adverse events when CLEVUDINE is co-administered with drugs affected by these enzymes.
Assessment of the safety and efficacy of CLEVUDINE is based on the placebo-controlled, therapeutic confirmatory clinical trials in which patients received CLEVUDINE 30 mg once daily or placebo for 24 weeks and there are no clinical trials with the active control groups.
In the therapeutic confirmatory clinical trials, there were statistically significant differences between CLEVUDINE-treated patients and placebo-treated patients in serum HBV DNA change from baseline, the percentage of patients with HBV DNA lower than the limit of detection and the percentage of patients with normal ALT. However, seroconversion rate in HBeAg positive patients does not show statistically significant difference between CLEVUDINE and placebo groups. The histologic changes in patients on liver biopsy were not evaluated.
The optimal duration of treatment with CLEVUDINE for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown and the disease progression in patients with progressive cirrhosis should be monitored carefully.
Patients should be advised that treatment with CLEVUDINE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Activity of clevudine against nucleoside-resistant mutant virus: In vitro: Clevudine remained active against HBV harboring single mutations at M550V, V519L, M5531, and A546V but not against HBV with a mutation at M550I. Mixed results have been obtained regarding the activity of clevudine against a virus harboring the single L526M mutation. Clevudine was not active against HBV harboring the multiple mutations L526/M550I and L526M/M550V.
Clinical studies: In the clinical study to evaluate antiviral activity of clevudine in a small number of patients (n=7) with experience of lamivudine treatment and with evidence of M550I/V mutation in the HBV DNA polymerase, an obvious suppression in HBV DNA with respect to baseline was not shown.
In the results of clevudine clinical studies, the lamivudine-resistant mutant L526M and M550I/V were not found in clevudine group, but there were a few changes in conserved site of polymerase sequencing in HBV DNA separated from the serum of patients. These changes were not consistent and not related with rebound in HBV DNA values. But limited data are available from studies on the CLEVUDINE-resistant genotype.
The clinical effects of CLEVUDINE on hepatitis C and hepatitis D are unknown.
There is no clinical experience in patients with decompensated liver disease, liver transplant recipients, or patients with HCV, HDV, or HIV/HBV co-infection.
There is no clinical experience in patients receiving immunosuppressive agents in cancer chemotherapy and other therapy.
The effect of CLEVUDINE on driving vehicles, or operating machinery has not been studied, and cannot be predicted from the pharmacological actions of CLEVUDINE.
Nevertheless, both the clinical status of the patient and adverse events due to CLEVUDINE should be considered in case that patient drives a vehicle or operates machinery.
Cases of myopathy have been reported in post marketing surveillance. Myopathy has also been reported with some drugs. Uncomplicated myalgias has been reported in clevudine-treated patients. Myopathy should be considered in patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness. Myopathy is defined as persistent unexplained muscle aches and/or muscle weakness without many relationship with increase in creatine kinase (CK) values. Among patients with clevudine-associated myopathy, there has not been a uniform pattern with regard to the degree or timing of CK elevations. In addition, the predisposing factors for the development of myopathy among clevudine-treated patients are unknown. Patients should be advised to report promptly unexplained muscle pains, tenderness or weakness. Clevudine therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is diagnosed. It is not known whether the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy. Physicians considering concomitant treatment with other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness.
At the end of 3-month or 6-month follow-up after administration with clevudine for 6 months or 1 year or 1.5 years, the patients with HBV DNA below 4,700 copies/mL and normal ALT, in addition, two consecutive HBeAg seroconversion for HBeAg-positive patients at baseline, were followed up for additional 2 years. A total of 63 patients (26 HBeAg-positive patients and 37 HBeAg-negative patients) who met the above criteria were evaluated in this clinical trial. HBV DNA below 4,700 copies/mL was sustained in 35% of patients (46% in HBeAg-positive patients and 27% in HBeAg-negative patients) and the proportion of patients with HBV DNA below 141,500 copies/mL was 73% (77% in HBeAg-positive patients and 70% in HBeAg-negative patients). Normal ALT was sustained in 75% of patients (88% in HBeAg-positive patients and 65% in HBeAg-negative patients) and HBeAG seroconversion was sustained in 81% of patients.
Use in Children: The safety and effectiveness of clevudine in pediatric patients of less than 18 years in age have not been established.
Use in the Elderly: Clinical studies on clevudine did not include any subject aged 65 years or over. So it has not been determined whether they respond differently from younger subjects. Since CLEVUDINE is substantially excreted by the kidney and elderly patients are likely to have decreased renal function, care should be taken in dose determination, and it may be useful to monitor renal function during treatment period.

Pregnancy: In reproductive toxicology studies in rats and rabbits, there were no evidence of teratogenicity and no effect on the fertility of males or females, or on the fetus. In reproductive toxicology studies using doses of up to 1,000 mg/kg/day in rats and 500 mg/kg/day in rabbits, there were no external fetal malformations or developmental variations due to CLEVUDINE since reproductive studies have been conducted in animals but not in humans. Clevudine should be used during pregnany only if clearly needed and after careful consideration of the risks and benefits. There are no data on the effect of CLEVUDINE on the transmission of HBV from mother to infant, so, appropriate measures should be taken to prevent neonatal acquisition of HBV.
Lactation: Since it is not known whether clevudine is excreted in human milk, mothers should be instructed not to breast-feed if they are taking CLEVUDINE.

Assessment of adverse reactions is based on two therapeutic confirmatory clinical trials in which 330 patients with chronic hepatitis B infection received double-blind treatment with CLEVUDINE 30 mg/day (n=246) or placebo (n=84) for 24 weeks.
No CLEVUDINE-treated patients in these studies compared with 2.4% of placebo-treated patients discontinued for adverse events or abnormal laboratory test results.
Clinical adverse events: Adverse events that occurred in 5% or more of patients during treatment with CLEVUDINE 30 mg once daily for 24 weeks are listed in Table 4. Selected clinical adverse events of moderate-severe intensity and considered related to treatment were common cold and upper respiratory infection, rash, drowsiness, and headache, and their incidences were <1% in CLEVUDINE-treated patients (Table 5). (See Table 4 and Table 5.)

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Clinical laboratory abnormalities: Frequencies of treatment-emergent laboratory abnormalities during therapy in two clinical trials in which CLEVUDINE was compared with placebo are presented in Table 6. Among the CLEVUDINE-treated patients, ALT or AST elevations occurring in the early stage of treatment were generally resolved with continued treatment. Periodic monitoring of hepatic function is recommended during treatment. (See Table 6.)

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Exacerbations of Hepatitis: An exacerbation of hepatitis was defined as ALT or AST>20xULN or >10xULN and >10x the lowest on-study value in clevudine therapeutic confirmatory trials. Percentages of patients who experienced exacerbation of hepatitis during treatment or off-treatment follow-up are shown in Table 7. (See Table 7.)

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Post-marketing Survey in Korea: Adverse events were reported in 10.31%(665/6453, 1057 events) regardless of causality, from the post-marketing surveillance study which was conducted on 6,453 patients over 6 years for re-examination of the drug in Korea. The main adverse reactions were abdominal pain in 1.01% (65/6,453, 76 events), dyspepsia in 0.73% (47/6,453, 47 events), CPK increased in 0.65% (42/6,453, 44 events) and nausea in 0.51%(33/6,453, 34 events). Among them, adverse drug events that can't be eliminated the causality with this drug were reported in 3.35% (216/6,453 patients, 288 events). They were CPK increased in 0.54% (35/6,453, 37 events), myopathy in 0.42%(27/6,453, 27 events), muscle weakness in 0.40%(26/6,453, 26 events), myalgia in 0.28% (18/6,453, 19 events), abdominal pain in 0.20% (13/6,453, 15 events), asthenia legs in 0.22% (14/6,453, 14 events), dyspepsia, fatigue, each in 0.20% (13/6,453, 13 events), nausea in 0.14% (9/6,453, 9 events), and common cold in 0.12% (8/6,453, 8 events), headache in 0.11% (7/6,453, 7 events). Serious adverse events were reported in 0.93% (60/6,453, 79 events) regardless of the causality. They were hepatoma in 0.26% (17/6,453, 17 events), abdominal pain in 0.06% (4/6,453, 5 events), anorexia & weakness generalized in 0.06% (4/6,453, 4 events), esophageal varices in 0.05% (3/6,453, 3 events), hepatic failure, colitis, diarrhea, dizziness, nausea, laceration, pneumonia each in 0.03% (2/6,453, 2 events), hepatic cirrhosis, hepatic neoplasm, hepatic coma, hepatic enzymes increased, hypertension, fracture pelvis, myalgia, ovarian cyst, cerebral haemorrhage, headache, cystitis, snake bite, haemoperitoneum, ascites, cerebellar infarction, indigestion, pyelonephritis, fever, urinary tract infection, uterine haemorrhage, weight decrease, duodenal ulcer haemorrhagic, appendicitis, nephritis, fracture upper limb, septic shock, pulmonary tuberculosis, haematuria breathing difficulty, rhabdomyolysis, pleural effusion, melaena in each 0.02% (1/6,453, 1 event), respectively. Unexpected adverse events were reported in 6.85% (442/6,453, 634 events) regardless of the causality. Fatigue in 0.51% (33/6,453, 35 events) and nausea in 0.51% (33/6,453, 34 events) were the most common, followed by dizziness in 0.40% (26/6,453, 27 events), diarrhea in 0.40% (26/6,453, 26 events), pruritus in 0.28% (18/6,453, 18 events), hepatoma, hypoaesthesia, anorexia each in 0.26% (17/6,453, 17 events), generalized weakness in 0.23% (15/6,453, 15 events), insomnia and gastritis in 0.22% (14/6,453, 14 events), chest pain and weight decrease in 0.19% (12/6,453, 12 events), constipation and fever in 0.17% (11/6,453, 11 events), a weight increase in 0.12% (8/6,453, 8 events), gastrointestinal neoplasia in 0.11% (7/6,453 patients, 8 events), pain neck/shoulder in 0.11% (7/6,453, 7 events). Among them, unexpected adverse drug events that can't be eliminated the causality with this drug were 1.13% (73/6,453, 102 events). They were fatigue in 0.20% (13/6,453, 13 events), nausea in 0.14% (9/6,453, 9 events), pruritus and hypoesthesia in 0.08% (5/6,453, 5 events), chest pain, anorexia, generalized weakness, each in 0.05% (3/6,453, 3 events), nausea, myositis, eye pain, polyarthritis, constipation, insomnia, diarrhea, dizziness, flank pain, fatty liver, weight decrease, skin disorder, haematuria, each in 0.03% (2/6,453, 2 events), chest discomfort, hyperlipaemia, joint pain, acute glomerulonephritis, acute gastritis, leg pain, faecal incontinence, palpitations, increased sweating, portal hypertension, ankle oedema, aggravated rash, dermatophytosis, Bell's palsy, aggravated oedema, anxiety, oedema NOS, hand's shaking, face oedema, polymyositis, dermatitis extrinsic allergic, depressed mood, gastritis, gastroenteritis, middle ear effusion, spinal stenosis, weight increase, hemorrhoids, lichen, upper limb oemena, balance difficulty, pneumonia, dermatitis herpetiformis, back discomfort, throat irritation each in 0.02% (1/6,453, 1 event).

Interactions with foods: The oral administration of 600 mg of clevudine with a standard high-fat meal or in the fasting state resulted in reducing the rate of absorption (a decrease in Cmax and an increase in Tmax with food), but bioavailability was not affected with respect to AUC, CL/F, or coefficient of variation for Cmax.
Interactions with drugs: Since clevudine is primarily eliminated by the kidneys, co-administration of clevudine with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either clevudine or the co-administered drug. The effects of co-administration of CLEVUDINE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, so patients should be monitored closely for adverse events when CLEVUDINE is co-administered with such drugs.
As a result of an in vitro study about whether CLEVUDINE is an inhibitor of the cytochrome P450 (CYP450) enzyme system, the representative metabolic enzyme of drugs or not, it is confirmed that CLEVUDINE is not an inhibitor of the CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4. But, it has not been evaluated whether CLEVUDINE is a substrate and inducer of the cytochrome P450 (CYP450) enzyme system or not and patients should be monitored closely for adverse events when CLEVUDINE is co-administered with drugs metabolized by these hepatic enzymes.

Store at temperature not exceeding 30°C.

Antivirals

J05AF12 - clevudine ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

Rx

Cap 30 mg (white, opaque, containing a white, odorless powd) x 30's.