Vemlidy Drug Information

is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients 6 years of age and older and weighing at least 25 kg with compensated liver disease . VEMLIDY is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 6 years of age and older and weighing at least 25 kg with compensated liver disease.

Testing

Prior to Initiation of VEMLIDY Prior to initiation of VEMLIDY, patients should be tested for HIV-1 infection. VEMLIDY alone should not be used in patients with HIV-1 infection . Prior to or when initiating VEMLIDY, and during treatment with VEMLIDY on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended Dosage in Adults and Pediatric Patients 6 Years of Age and

Older and Weighing at Least 25 kg The recommended dosage of VEMLIDY in adults and pediatric patients 6 years of age and older and weighing at least 25 kg is one 25 mg tablet taken orally once daily with food.

Dosage in Patients with Renal Impairment No dosage adjustment of

VEMLIDY is required in patients with estimated creatinine clearance greater than or equal to 15 mL per minute, or in patients with end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are receiving chronic hemodialysis. On days of hemodialysis, administer VEMLIDY after completion of hemodialysis treatment. VEMLIDY is not recommended in patients with ESRD who are not receiving chronic hemodialysis . No data are available to make dose recommendations in pediatric patients with renal impairment.

Dosage in Patients with Hepatic Impairment No dosage adjustment of

VEMLIDY is required in patients with mild hepatic impairment (Child-Pugh A). VEMLIDY is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

Clinical Trials Experience

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. Adverse Reactions in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease The safety assessment of VEMLIDY was based on pooled data through the Week 96 data analysis from 1298 subjects in two randomized, double-blind, active-controlled trials, Trial 108 and Trial 110, in adult subjects with chronic hepatitis B and compensated liver disease. A total of 866 subjects received VEMLIDY 25 mg once daily . Further safety assessment was based on pooled data from Trials 108 and 110 from subjects who continued to receive their original blinded treatment through Week 120 and additionally from subjects who received open-label VEMLIDY from Week 96 through Week 120 (n = 361 remained on VEMLIDY; n = 180 switched from TDF to VEMLIDY at Week 96). Based on the Week 96 analysis, the most common adverse reaction (all Grades) reported in at least 10% of subjects in the VEMLIDY group was headache.

The proportion of subjects who discontinued treatment with VEMLIDY or TDF due to adverse reactions of any severity was 1.5% and 0.9%, respectively. Table 1 displays the frequency of the adverse reactions (all Grades) greater than or equal to 5% in the VEMLIDY group. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (All Grades) Reported in ≥5% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis Double-blind phase. ) VEMLIDY (N=866) TDF (N=432) Headache 12% 10% Abdominal pain Grouped term including abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness. 9% 6% Cough 8% 8% Back pain 6% 6% Fatigue 6% 5% Nausea 6% 6% Arthralgia 5% 6% Diarrhea 5% 5% Dyspepsia 5% 5% Additional adverse reactions occurring in less than 5% of subjects in Trials 108 and 110 included vomiting, rash, and flatulence.

The safety profile of VEMLIDY in subjects who continued to receive blinded treatment through Week 120 was similar to that at Week 96. The safety profile of VEMLIDY in subjects who remained on VEMLIDY in the open-label phase through Week 120 was similar to that in subjects who switched from TDF to VEMLIDY at Week 96. Renal Laboratory Tests In a pooled analysis of Trials 108 and 110 in adult subjects with chronic hepatitis B and a median baseline estimated creatinine clearance between 106 and 105 mL per minute (for the VEMLIDY and TDF groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/dL in both treatment groups at Week 96. Median change from baseline to Week 96 in estimated creatinine clearance was -1.2 mL per minute in the VEMLIDY group and -4.8 mL per minute in those receiving TDF. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, change from baseline in renal laboratory parameter values in each group at Week 120 were similar to those at Week 96. In the open-label phase, median change in estimated creatinine clearance by Cockcroft-Gault method from Week 96 to Week 120 was -0.6 mL per minute in subjects who remained on VEMLIDY and +1.8 mL per minute in those who switched from TDF to VEMLIDY at Week 96. Mean serum creatinine and median serum phosphorus values at Week 120 were similar to those at Week 96 in subjects who remained on VEMLIDY and in subjects who switched from TDF to VEMLIDY. The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known. Bone Mineral Density Effects In a pooled analysis of Trials 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 96 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.7% with VEMLIDY compared to -2.6% with TDF at the lumbar spine and -0.3% compared to -2.5% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 11% of VEMLIDY subjects and 25% of TDF subjects at Week 96. BMD declines of 7% or greater at the femoral neck were experienced by 5% of VEMLIDY subjects and 13% of TDF subjects at Week 96. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, mean percentage change in BMD in each group at Week 120 was similar to that at Week 96. In the open-label phase, mean percentage change in BMD from Week 96 to Week 120 in subjects who remained on VEMLIDY was 0.6% at the lumbar spine and 0% at the total hip, compared to 1.7% at the lumbar spine and 0.6% at the total hip in those who switched from TDF to VEMLIDY. The long-term clinical significance of these BMD changes is not known.

Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving VEMLIDY in Trials 108 and 110 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis Double-blind phase. ) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. VEMLIDY (N=866) TDF (N=432) ULN=Upper Limit of Normal ALT (>5 × ULN) 8% 10% LDL-cholesterol (fasted) (>190 mg/dL) 6% 1% Glycosuria (≥3+) 5% 2% AST (>5 × ULN) 3% 5% Creatine Kinase (≥10 × ULN) 3% 3% Serum Amylase (>2.0 × ULN) 3% 3% The overall incidence of blinded treatment ALT flares (defined as confirmed serum ALT greater than 2 × baseline and greater than 10 × ULN at 2 consecutive postbaseline visits, with or without associated symptoms) was similar between VEMLIDY (0.6%) and TDF (0.9%) through Week 96. ALT flares generally were not associated with coincident elevations in bilirubin, occurred within the first 12 weeks of treatment, and resolved without recurrence. Based on the Week 120 analysis, the frequencies of lab abnormalities in subjects who remained on VEMLIDY in the open-label phase were similar to those in subjects who switched from TDF to VEMLIDY at Week 96. Amylase and Lipase Elevations and Pancreatitis At Week 96, in Trials 108 and 110, eight subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain; abdominal tenderness, pain, and distension; and biliary pancreatitis and pancreatitis.

Of these eight, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with TDF had associated symptoms or discontinued treatment. From Week 96 to Week 120, one additional subject who continued open-label VEMLIDY and none of the subjects who switched from TDF to VEMLIDY had elevated amylase levels and associated symptoms.

Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with VEMLIDY and TDF in Trials 108 and 110 are presented in Table 3. Table 3 Lipid Abnormalities: Mean Change from Baseline in Lipid Parameters in Patients with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis) VEMLIDY (N=866) TDF (N=432) Baseline Week 96 Baseline Week 96 mg/dL Change The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 96 values. mg/dL Change Total Cholesterol (fasted) 188 -1 193 -25 HDL-Cholesterol (fasted) 60 -5 61 -12 LDL-Cholesterol (fasted) 116 +7 120 -10 Triglycerides (fasted) 102 +13 102 -7 Total Cholesterol to HDL ratio 3 0 3 0 In the open-label phase, lipid parameters at Week 120 in subjects who remained on VEMLIDY were similar to those at Week 96. In subjects who switched from TDF to VEMLIDY, mean change from Week 96 to Week 120 in total cholesterol was 23 mg/dL, HDL-cholesterol was 5 mg/dL, LDL-cholesterol was 16 mg/dL, triglycerides was 30 mg/dL, and total cholesterol to HDL ratio was 0 mg/dL. Adverse Reactions in Virologically Suppressed Adult Subjects with Chronic Hepatitis B The safety of VEMLIDY in virologically suppressed adults is based on Week 48 data from a randomized, double-blind, active-controlled trial (Trial 4018) in which subjects taking TDF at baseline were randomized to switch to VEMLIDY (N=243) or to continue their TDF treatment (N=245). Adverse reactions observed with VEMLIDY in Trial 4018 were similar to those in Trials 108 and 110. Renal Laboratory Tests, Bone Mineral Density Effects, and Serum Lipids In virologically suppressed adults in Trial 4018, changes from baseline in renal function, BMD, and lipid parameters in the VEMLIDY and TDF groups at Week 48 were similar to those observed in Trials 108 and 110 at Week 96. Adverse Reactions in Adult Subjects with Chronic Hepatitis B and Renal Impairment In an open-label trial (Trial 4035) in virologically suppressed adult subjects with chronic hepatitis B switching to VEMLIDY 25 mg, the safety of VEMLIDY was assessed in 78 subjects with moderate to severe renal impairment (estimated creatinine clearance between 15 and 59 mL per minute by Cockcroft-Gault method; Part A, Cohort 1) and 15 subjects with ESRD (estimated creatinine clearance below 15 mL per minute) receiving chronic hemodialysis (Part A, Cohort 2). The safety of VEMLIDY, including changes from baseline in renal function, BMD, and lipid parameters, was similar to that observed in clinical trials of VEMLIDY in subjects with compensated liver disease but without renal impairment. Adverse Reactions in Pediatric Subjects with Chronic Hepatitis B The safety of VEMLIDY was evaluated in HBV-infected treatment-naïve and treatment-experienced pediatric subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (Cohort 1; N=70) and 6 to less than 12 years and weighing at least 25 kg (Cohort 2, Group 1: N=18) through Week 24 in a randomized, double-blind, placebo-controlled clinical trial (Trial 1092). Subjects were then eligible to roll over to receive open-label VEMLIDY. Safety data are available through Week 96. The safety profile of VEMLIDY was similar to that in adults. Bone Mineral Density Effects Among the Cohort 1 and Cohort 2, Group 1 subjects treated with VEMLIDY and placebo, the mean percent change in BMD from baseline to Week 24 was 1.6% (N=48) and 1.9% (N=23) for lumbar spine, and 1.9% (N=50) and 2.0% (N=23) for whole body, respectively.

At Week 24, mean changes from baseline BMD Z-scores were 0.01 and -0.07 for lumbar spine, and -0.04 and -0.04 for whole body, for the VEMLIDY and placebo groups, respectively. At Week 24, BMD declines of 4% or greater at lumbar spine and whole body were experienced by 6% and 2% of VEMLIDY subjects, respectively. In the open-label phase, mean percentage change in lumbar spine and whole body BMD and BMD Z-scores from baseline to Week 96 was similar in subjects who remained on VEMLIDY compared to those who switched from placebo to VEMLIDY.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of VEMLIDY or other products containing tenofovir alafenamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Angioedema, urticaria Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

Potential for Other Drugs to Affect

VEMLIDY VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see Table 4 ). Drugs that induce P-gp activity are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect of VEMLIDY. Coadministration of VEMLIDY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

Drugs Affecting Renal Function

Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs .

Established and Other Potentially Significant Interactions Table 4 provides a listing of

established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir alafenamide or are predicted drug interactions that may occur with VEMLIDY . Information regarding potential drug-drug interactions with HIV antiretrovirals is not provided (see the prescribing information for emtricitabine/tenofovir alafenamide for interactions with HIV antiretrovirals). The table includes potentially significant interactions but is not all inclusive. Table 4 Established and Other Potentially Significant Drug Interactions This table is not all inclusive.

Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease. Clinical Comment Anticonvulsants: ↓ tenofovir alafenamide When coadministered with carbamazepine, the tenofovir alafenamide dose should be increased to two tablets once daily. Coadministration of VEMLIDY with oxcarbazepine, phenobarbital, or phenytoin is not recommended.

Carbamazepine Indicates that a drug interaction study was conducted. P-gp inducer Oxcarbazepine Phenobarbital Phenytoin Antimycobacterials: ↓ tenofovir alafenamide Coadministration of VEMLIDY with rifabutin, rifampin or rifapentine is not recommended. Rifabutin Rifampin Rifapentine Herbal Products: ↓ tenofovir alafenamide Coadministration of VEMLIDY with St.

John's wort is not recommended. St. John's wort (Hypericum perforatum)

Drugs without Clinically Significant Interactions with

VEMLIDY Based on drug interaction studies conducted with VEMLIDY, no clinically significant drug interactions have been observed with: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VEMLIDY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no statistically significant difference in the overall risk of birth defects for tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal studies, no adverse developmental effects were observed when tenofovir alafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofovir alafenamide exposure at the recommended daily dose of VEMLIDY (see Data ). No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 12 times the exposure at the recommended daily dosage of VEMLIDY. Data Human Data Based on prospective reports to the APR of over 1330 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 1080 exposed in the first trimester and over 240 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.8% to 5.2%) and 4.8% (95% CI: 2.5% to 8.3%) following first and second/third trimester exposure, respectively, to TAF-containing regimens. Methodologic limitations of the APR include the use of MACDP as the external comparator group.

The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Animal Data Embryonic fetal development studies performed in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus. The embryo-fetal NOAELs (no observed adverse effect level) in rats and rabbits occurred at tenofovir alafenamide exposures similar to and 51 times higher than, respectively, the exposure in humans at the recommended daily dose.

Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Tenofovir alafenamide was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at tenofovir alafenamide exposures approximately similar to (rats) and 51 (rabbits) times higher than the exposure in humans at the recommended daily dose of VEMLIDY. Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposures in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Since tenofovir alafenamide is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after tenofovir alafenamide administration compared to TDF, another prodrug for tenofovir administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 at tenofovir exposures of approximately 12 times higher than the exposures in humans at the recommended daily dose of VEMLIDY.

Pediatric Use The pharmacokinetics, safety, and effectiveness of VEMLIDY for the treatment of chronic HBV infection have been established in pediatric patients between the ages of 6 to less than 18 years and weighing at least 25 kg (N=59) in Trial 1092 up to 96 weeks. No clinically meaningful differences in pharmacokinetics or safety were observed in comparison to those observed in adults. Safety and effectiveness of VEMLIDY has not been established in pediatric patients with chronic HBV infection who are less than 6 years of age or weigh less than 25 kg.

If overdose occurs, monitor patient for evidence of toxicity. Treatment of overdosage with VEMLIDY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.