Galexos

Galexos® is indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection :

• in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis
• in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.

Limitations Of Use

• Efficacy of Galexos in combination with Peg-IFN-alfa and RBV is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism.
• Galexos is not recommended in patients who have previously failed therapy with a treatment regimen that included Galexos or other HCV protease inhibitors.

Testing Prior To The Initiation Of Therapy

Testing For HBV infection

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with Galexos.

Q80K Testing In HCV Genotype 1a-Infected Patients

Galexos in Combination with Sofosbuvir

In HCV genotype 1a-infected patients with compensated cirrhosis, screening for the presence of virus with the NS3 Q80K polymorphism may be considered prior to initiation of treatment with Galexos with sofosbuvir.

Galexos in Combination with Peg-IFN-alfa and RBV

Prior to initiation of treatment with Galexos in combination with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.

Hepatic Laboratory Testing

Monitor liver chemistry tests before and during Galexos combination therapy.

Galexos Combination Treatment

Administer Galexos in combination with other antiviral drugs for the treatment of chronic HCV infection. Galexos monotherapy is not recommended. The recommended dosage of Galexos is one 150 mg capsule taken orally once daily with food. The capsule should be swallowed as a whole. For specific dosing recommendations for the antiviral drugs used in combination with Galexos, refer to their respective prescribing information.

Galexos can be taken in combination with sofosbuvir or in combination with Peg-IFN-alfa and RBV.

Galexos In Combination With Sofosbuvir

Table 1 displays the recommended treatment regimen and duration of Galexos in combination with sofosbuvir in patients with chronic HCV genotype 1 infection.

Table 1: Recommended Treatment Regimen and Duration for Galexos and Sofosbuvir Combination Therapy in Patients with Chronic HCV Genotype 1 Infection

Galexos In Combination With Peg-IFN-alfa And RBV

Table 2 displays the recommended treatment regimen and duration of Galexos in combination with Peg-IFN-alfa and RBV in mono-infected and HCV/HIV-1 co-infected patients with HCV genotype 1 or 4 infection. Refer to Table 3 for treatment stopping rules for Galexos combination therapy with Peg-IFN-alfa and RBV.

Table 2: Recommended Treatment Regimen and Duration for Galexos, Peg-IFN-alfa, and RBV Combination Therapy in Patients with Chronic HCV Genotype 1 or 4 Infection

Discontinuation Of Dosing

Galexos In Combination With Sofosbuvir

No treatment stopping rules apply to the combination of Galexos with sofosbuvir.

Galexos In Combination With Peg-IFN-alfa And RBV

During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA greater or equal to 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virologic response at Weeks 4, 12, and 24.

Table 3: Treatment Stopping Rules in Patients Receiving Galexos in Combination with Peg-IFN-alfa and RBV with Inadequate On-Treatment Virologic Response

Dosage Adjustment Or Interruption

To prevent treatment failure, avoid reducing the dosage of Galexos or interrupting treatment. If treatment with Galexos is discontinued because of adverse reactions or inadequate on-treatment virologic response, Galexos treatment must not be reinitiated.

If adverse reactions potentially related to the antiviral drug(s) used in combination with Galexos occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption.

If any of the other antiviral drug(s) used in combination with Galexos for the treatment of chronic HCV infection are permanently discontinued for any reason, Galexos should also be discontinued.

Not Recommended In Patients With Moderate Or Severe Hepatic Impairment

Galexos is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C).

Because Galexos is used only in combination with other antiviral drugs (including Peg-IFN-alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. Refer to the respective prescribing information for a list of contraindications.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Hepatitis B Virus Reactivation In Patients Coinfected With HCV And HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Galexos. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Galexos and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Serious Symptomatic Bradycardia When Co-administered With Sofosbuvir And Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was co-administered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with Coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with Galexos in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co-administered Galexos and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia.
• Cardiac monitoring in an in-patient setting for the first 48 hours of Coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with Galexos who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with Galexos should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.

Hepatic Decompensation And Hepatic Failure

Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with Galexos in combination with Peg-IFN-alfa and RBV or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made; and a causal relationship between treatment with Galexos and these events has not been established.

Galexos is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C).

In clinical trials of Galexos, modest increases in bilirubin levels were observed without impacting hepatic function. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during Galexos combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:

• Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Discontinue Galexos if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.

Risk Of Serious Adverse Reactions Associated With Combination Treatment

Because Galexos is used in combination with other antiviral drugs for the treatment of chronic HCV infection, consult the prescribing information for these drugs before starting therapy with Galexos. Warnings and Precautions related to these drugs also apply to their use in Galexos combination treatment.

Photosensitivity

Photosensitivity reactions have been observed with Galexos combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with Galexos in combination with Peg-IFN-alfa and RBV. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.

Use sun protective measures and limit sun exposure during treatment with Galexos. Avoid use of tanning devices during treatment with Galexos. Discontinuation of Galexos should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue Galexos in the setting of a photosensitivity reaction, expert consultation is advised.

Rash

Rash has been observed with Galexos combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of Galexos have been reported in subjects receiving Galexos in combination with Peg-IFN-alfa and RBV. Most of the rash events in Galexos-treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, Galexos should be discontinued. Patients should be monitored until the rash has resolved.

Sulfa Allergy

Galexos contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of Galexos.

Risk Of Adverse Reactions Or Reduced Therapeutic Effect Due To Drug Interactions

Coadministration of Galexos with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions.

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION).

Risk Of Hepatitis B Virus Reactivation In Patients Coinfected With HCV And HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection.

Symptomatic Bradycardia When Used In Combination With Sofosbuvir And Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.

Pregnancy

Advise patients taking Galexos of the potential risk to the fetus. In addition, when Galexos is taken with RBV, advise patients to avoid pregnancy during treatment and within 6 months of stopping RBV and to notify their healthcare provider immediately in the event of a pregnancy.

Hepatic Decompensation And Failure

Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to contact their healthcare provider immediately if such symptoms occur.

Photosensitivity

Advise patients of the risk of photosensitivity reactions related to Galexos combination treatment and that these reactions may be severe. Instruct patients to use effective sun protection measures to limit exposure to natural sunlight and to avoid artificial sunlight (tanning beds or phototherapy) during treatment with Galexos.

Advise patients to contact their healthcare provider immediately if they develop a photosensitivity reaction. Inform patients not to stop Galexos due to photosensitivity reactions unless instructed by their healthcare provider.

Rash

Advise patients of the risk of rash related to Galexos combination treatment and that rash may become severe. Advise patients to contact their healthcare provider immediately if they develop a rash. Inform patients not to stop Galexos due to rash unless instructed by their healthcare provider.

Administration

Advise patients to use Galexos only in combination with other antiviral drugs for the treatment of chronic HCV infection. Advise patients to discontinue Galexos if any of the other antiviral drugs used in combination with Galexos are permanently discontinued for any reason. Advise patients that the dose of Galexos must not be reduced or interrupted, as it may increase the possibility of treatment failure.

Advise patients to take Galexos every day at the regularly scheduled time with food. Inform patients that it is important not to miss or skip doses and to take Galexos for the duration that is recommended by the healthcare provider. Inform patients not to take more or less than the prescribed dose of Galexos at any one time.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis And Mutagenesis

Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted.

If Galexos is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis.

Impairment Of Fertility

In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at exposures less than the exposure in humans at the recommended clinical dose.

If Galexos is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility.

Use In Specific Populations

Pregnancy

Risk Summary

If Galexos is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to prescribing information for RBV and for other drugs used in combination with Galexos for information on use in pregnancy.

No adequate human data are available to establish whether or not Galexos poses a risk to pregnancy outcomes. In animal reproduction studies with simeprevir, embryofetal developmental toxicity (including fetal loss) was observed in mice at simeprevir exposures greater than or equal to 1.9 times higher than exposure in humans at the recommended clinical dose while no adverse embryofetal developmental outcomes were observed in mice and rats at exposures similar to the exposure in humans at the recommended clinical dose. Given these findings, pregnant women should be advised of potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In embryofetal development studies in rats and mice, pregnant animals were administered simeprevir at doses up to 500 mg/kg/day (rats) and at 150, 500 and 1000 mg/kg/day (mice) on gestation days 6 to 17 (rats) and gestation days 6 to 15 (mice), resulting in late in utero fetal losses in mice at an exposure greater than or equal to 1.9 times higher than the exposure in humans at the recommended clinical dose. In addition, decreased fetal weights and an increase in fetal skeletal variations were observed in mice at exposures greater than or equal to 1.2 times higher than the exposure in humans at the recommended clinical dose. No adverse embryofetal developmental effects were observed in mice (at the lowest dose tested) or in rats (at up to the highest dose tested) at exposures similar to the exposure in humans at the recommended clinical dose.

In a rat pre-and post-natal development study, maternal animals were exposed to simeprevir from gestation day 6 to lactation/post-partum day 20 at doses up to 1000 mg/kg/day. At maternally toxic doses, the developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at maternal exposures similar to the exposure in humans at the recommended clinical dose. Subsequent survival, behavior and reproductive capacity of the offspring were not affected.

Lactation

Risk Summary

It is not known whether Galexos and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, simeprevir was detected in plasma of nursing pups, likely due to the presence of simeprevir in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Galexos and any potential adverse effects on the breastfed child from Galexos or from the underlying maternal condition.

If Galexos is administered with RBV, the nursing mother's information for RBV also applies to this combination regimen. Refer to prescribing information for RBV and for other drugs used in combination with Galexos for more information on use during lactation.

Data

Animal Data

Although not measured directly, simeprevir was likely present in the milk of lactating rats in the pre-and post-natal development study, because systemic exposures (AUC) of simeprevir were observed in nursing pups on lactation/post-partum day 6 at concentrations approximately 10% of maternal simeprevir exposures.

Females And Males Of Reproductive Potential

If Galexos is administered with RBV, follow the recommendations for pregnancy testing and contraception within RBV's prescribing information. Refer to prescribing information for other drugs used in combination with Galexos for additional information on use in females and males of reproductive potential.

Infertility

There are no data on the effect of simeprevir on human fertility. Limited effects on male fertility were observed in animal studies. If Galexos is administered with RBV, the information for RBV with regard to infertility also applies to this combination regimen. In addition, refer to prescribing information for other drugs used in combination with Galexos for information on effects on fertility.

Pediatric Use

The safety and efficacy of Galexos in pediatric patients have not been established.

Geriatric Use

Clinical studies of Galexos did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dosage adjustment of Galexos is required in geriatric patients.

Race

Patients of East Asian ancestry exhibit higher simeprevir plasma exposures, but no dosage adjustment is required based on race.

Renal Impairment

No dosage adjustment of Galexos is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of Galexos have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.

Refer to the prescribing information for the other antiviral drug(s) used in combination with Galexos regarding their use in patients with renal impairment.

Hepatic Impairment

No dosage adjustment of Galexos is required in patients with mild hepatic impairment (Child-Pugh A).

Galexos is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C). In clinical trials of Galexos in combination with Peg-IFN-alfa and RBV, higher simeprevir exposures were associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving Galexos combination therapy.

The safety and efficacy of Galexos have not been established in liver transplant patients. See the Peg-IFN-alfa prescribing information regarding its contraindication in patients with hepatic decompensation.

Because Galexos is administered in combination with other antiviral drugs, refer to the prescribing information of the antiviral drugs used in combination with Galexos for a description of adverse reactions associated with their use.

The following serious and otherwise important adverse reactions are described below and in other sections of the labeling:

• Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone
• Hepatic Decompensation and Hepatic Failure
• Photosensitivity
• Rash

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 clinical practice.

Galexos In Combination With Sofosbuvir

The safety profile of Galexos in combination with sofosbuvir in patients with HCV genotype 1 infection with compensated cirrhosis (Child-Pugh A) or without cirrhosis is based on pooled data from the Phase 2 COSMOS trial and the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials which included 317 subjects who received Galexos with sofosbuvir (without RBV) for 12 or 24 weeks.

Table 4 lists adverse events (all grades) that occurred with at least 10% frequency among subjects receiving 12 or 24 weeks of treatment with Galexos 150 mg once daily in combination with sofosbuvir 400 mg once daily without RBV. The overall safety profile appeared similar among cirrhotic and non-cirrhotic subjects.

The majority of the adverse events reported were Grade 1 or 2 in severity. Grade 3 or 4 adverse events were reported in 4% and 13% of subjects receiving 12 or 24 weeks of Galexos with sofosbuvir, respectively. Serious adverse events were reported in 2% and 3% of subjects receiving 12 or 24 weeks of Galexos with sofosbuvir, respectively. One percent and 6% of subjects receiving 12 or 24 weeks of Galexos with sofosbuvir, respectively, discontinued treatment due to adverse events.

Table 4: Adverse Events (all Grades) that Occurred ≥ 10% Frequency Among Subjects Receiving 12 or 24 Weeks of Galexos in Combination with Sofosbuvir±

Rash and Photosensitivity

In trials of Galexos in combination with sofosbuvir, rash (including photosensitivity reactions) was observed in 12% of Galexos-treated subjects receiving 12 weeks of treatment compared to 16% of Galexos-treated subjects receiving 24 weeks of treatment.

Most of the rash events in Galexos-treated subjects were of mild or moderate severity (Grade 1 or 2). Among 317 subjects, Grade 3 rash was reported in one subject ( < 1%), leading to treatment discontinuation; none of the subjects experienced Grade 4 rash.

Most photosensitivity reactions were of mild severity (Grade 1); Grade 2 photosensitivity reactions were reported in 2 of 317 subjects ( < 1%). No Grade 3 or 4 photosensitivity reactions were reported and none of the subjects discontinued treatment due to photosensitivity reactions.

Laboratory Abnormalities

Among subjects who received Galexos in combination with sofosbuvir, the most common Grade 3 and 4 laboratory abnormalities were amylase and lipase elevations  (Table 5). Most elevations in amylase and lipase were transient and of mild or moderate severity. Amylase and lipase elevations were not associated with pancreatitis.

Table 5: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) in Amylase, Hyperbilirubinemia and Lipase in Subjects Receiving 12 or 24 Weeks of Galexos in Combination with Sofosbuvir±

Galexos In Combination With Peg-IFN-alfa And RBV

The safety profile of Galexos in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection is based on pooled data from three Phase 3 trials (QUEST-1, QUEST-2 and PROMISE). These trials included a total of 1178 subjects who received Galexos or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive Galexos 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks.

In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with Galexos in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving Galexos in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving Galexos in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of Galexos or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving Galexos with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively.

Table 6 lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects with HCV genotype 1 infection receiving Galexos 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy.

Table 6: Adverse Reactions (all Grades) that occurred ≥ 3% Higher Frequency Among Subjects with HCV Genotype 1 Infection Receiving Galexos Combination with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo in Combination with Peg-IFN-alfa and RBV During the First 12 Weeks of Treatment in Subjects with Chronic HCV Infection* (Pooled Phase 3†)

Rash and Photosensitivity

In the Phase 3 clinical trials of Galexos or placebo in combination with Peg-IFN-alfa and RBV, rash (including photosensitivity reactions) was observed in 28% of Galexos-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with Galexos or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the Galexos group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in Galexos-treated subjects were of mild or moderate severity (Grade 1 or 2). Severe (Grade 3) rash occurred in 1% of Galexos-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of Galexos or placebo due to rash occurred in 1% of Galexos-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures.

All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of Galexos-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with Galexos or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in Galexos-treated subjects were of mild or moderate severity (Grade 1 or 2). Two Galexos-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported.

Dyspnea

During the 12 weeks of treatment with Galexos or placebo in combination with Peg-IFN-alfa and RBV, dyspnea was reported in 12% of Galexos-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in Galexos-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with Galexos due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with Galexos.

Laboratory Abnormalities

Among subjects who received Galexos or placebo plus Peg-IFN-alfa and RBV, there were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in Galexos-treated subjects than in placebo-treated subjects are listed in Table 7.

Table 7: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in Galexos-Treated Subjects (Pooled Phase 3*; First 12 Weeks of Treatment)

Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of Galexos. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.

Adverse Reactions In HCV/HIV-1 Co-infection

Galexos in combination with Peg-IFN-alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV-1 co-infection (C212). The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono-infected subjects.

Adverse Reactions In HCV Genotype 4 Infection

Galexos in combination with Peg-IFN-alfa and RBV was studied in 107 subjects with HCV genotype 4 infection (RESTORE). The safety profile of Galexos in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection.

Adverse Reactions In East Asian Subjects

Galexos in combination with Peg-IFN-alfa and RBV was studied in a Phase 3 trial conducted in China and South Korea in treatment-naïve subjects with chronic HCV genotype 1 infection (TIGER). The safety profile of Galexos in East Asian subjects was similar to that of the pooled Phase 3 population from global trials; however, a higher incidence of the laboratory abnormality hyperbilirubinemia was observed in patients receiving 150 mg Galexos plus Peg-IFN-alfa and RBV compared to patients receiving placebo plus Peg-IFN-alfa and RBV. Elevation of total bilirubin (all grades) was observed in 66% (99/151) of subjects treated with 150 mg Galexos plus Peg-IFN-alfa and RBV and in 26% (40/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. Bilirubin elevations were mainly Grade 1 or Grade 2. Grade 3 elevations in bilirubin were observed in 9% (13/151) of subjects treated with 150 mg Galexos plus Peg-IFN-alfa and RBV and in 1% (2/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. There were no Grade 4 elevations in bilirubin. The bilirubin elevations were not associated with increases in liver transaminases and were reversible after the end of treatment.

Postmarketing Experience

The following adverse reactions have been reported during post approval use of Galexos. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.

Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen.

Hepatobiliary Disorders: hepatic decompensation, hepatic failure.

Human experience of overdose with Galexos is limited. There is no specific antidote for overdose with Galexos. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed.

Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.

Cardiac Electrophysiology

In a thorough QT/QTc study in 60 healthy subjects, simeprevir 150 mg (recommended dose) and 350 mg (2.3 times the recommended dose) did not affect the QT/QTc interval.

The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once-daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2-to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In Phase 3 trials with Peg-IFN-alfa and RBV in HCV-infected subjects, the geometric mean steady-state pre-dose plasma concentration was 1009 ng/mL (geometric coefficient of variation [gCV] = 162%) and the geometric mean steady-state AUC24 was 39140 ng.h/mL (gCV = 98%).

Absorption

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of Galexos in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post-dose.

In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.

Effects of Food on Oral Absorption

Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric breakfast (928 kcal) and by 69% after a normal-caloric breakfast (533 kcal), and delayed the absorption by 1 hour and 1.5 hours, respectively.

Distribution

Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.

Metabolism

Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of Galexos with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir.

Following a single oral administration of 200 mg (1.3 times the recommended dosage) ¹⁴C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.

Elimination

Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg ¹⁴C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.

The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg (1.3 times the recommended dosage) of simeprevir.