Important Safety Information
- Because OLYSIO® 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 and Precautions:
Risk of Hepatitis B Virus Reactivation in Patients Coinfected With HCV and HBV: 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 OLYSIO®. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with OLYSIO® and during posttreatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
Serious Symptomatic Bradycardia When Coadministered With Sofosbuvir and Amiodarone: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered 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 OLYSIO® in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be coadministered OLYSIO® 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 OLYSIO® 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 OLYSIO® 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 OLYSIO® 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 OLYSIO® and these events have not been established.
OLYSIO® is not recommended for patients with moderate or severe hepatic impairment (Child‐Pugh B or C).
In clinical trials of OLYSIO®, 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 OLYSIO® 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 OLYSIO® 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 OLYSIO® 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 OLYSIO®. Warnings and precautions related to these drugs also apply to their use in OLYSIO® combination treatment.
Photosensitivity: Photosensitivity reactions have been observed with OLYSIO® combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO® 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 OLYSIO®. Avoid use of tanning devices during treatment with OLYSIO®. Discontinuation of OLYSIO® 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 OLYSIO® in the setting of a photosensitivity reaction, expert consultation is advised.
Rash: Rash has been observed with OLYSIO® 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 OLYSIO® have been reported in subjects receiving OLYSIO® in combination with Peg‐IFN‐alfa and RBV. Most of the rash events in OLYSIO®‐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, OLYSIO® should be discontinued. Patients should be monitored until the rash has resolved.
Sulfa Allergy: OLYSIO® 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 OLYSIO®.
- Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: Coadministration of OLYSIO® 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. The potential for drug-drug interactions must be considered prior to and during treatment.
- Use With Sofosbuvir: The most common (all grades, ≥10%) adverse events reported during 12 or 24 weeks of treatment with OLYSIO® in combination with sofosbuvir were headache (17% and 23%), fatigue (16% and 32%), nausea (14% and 13%), rash (including photosensitivity)(12% and 16%), diarrhea (6% and 16%), and dizziness (3% and 16%), respectively.
- Use With Peg‐IFN‐alfa and RBV: Adverse reactions (all grades, ≥3% higher frequency) for OLYSIO® with Peg‐IFN‐alfa and RBV vs. Peg‐IFN‐alfa and RBV alone during the first 12 weeks of treatment were rash (including photosensitivity) (28% vs. 20%), pruritus (22% vs. 15%), nausea (22% vs. 18%), myalgia (16% vs. 13%), and dyspnea (12% vs. 8%).
Use in Specific Populations:
Pregnancy: If OLYSIO® 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 OLYSIO® for information on use in pregnancy. No adequate human data are available to establish whether or not OLYSIO® poses a risk to pregnancy outcomes. Pregnant women should be advised of potential risk to the fetus.
Race: Patients of East Asian ancestry exhibit higher plasma simeprevir exposures, but no dosage adjustment is required based on race.
Renal Impairment: No dosage adjustment of OLYSIO® is required in patients with mild, moderate, or severe renal impairment. The safety and efficacy of OLYSIO® 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.
Hepatic Impairment: No dosage adjustment of OLYSIO® is required in patients with mild hepatic impairment (Child‐Pugh A). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C). In clinical trials of OLYSIO® 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 OLYSIO® combination therapy.
The safety and efficacy of OLYSIO® have not been studied in liver transplant patients.
Not a complete list of Uses in Specific Populations.
Consult the PI for Peg‐IFN‐alfa and RBV or sofosbuvir before starting your patients on therapy with OLYSIO®. Safety information related to these drugs also applies to their use in OLYSIO® combination treatment.