May 3, 2016
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Olysio

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Olysio

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 is co-administered with sofosbuvir in combination with another HCV direct-acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving 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 co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.

Co-administration 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 co-administered 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 co-administration 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 [see ADVERSE REACTIONS and DRUG INTERACTIONS].

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 has not been established [see ADVERSE REACTIONS].

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS]. 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 [see ADVERSE REACTIONS]. 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

Co-administration 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 [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Patient Counseling Information

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 [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and DRUG INTERACTIONS].

Pregnancy

Advise patients taking OLYSIO to avoid pregnancy during treatment. In addition, when OLYSIO is taken with ribavirin, advise patients to avoid pregnancy during treatment and within 6 months of stopping ribavirin and to notify their healthcare provider immediately in the event of a pregnancy [see Use In Specific Populations].

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 [see WARNINGS AND PRECAUTIONS].

Photosensitivity

Advise patients of the risk of photosensitivity reactions related to OLYSIO 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 OLYSIO.

Advise patients to contact their healthcare provider immediately if they develop a photosensitivity reaction. Inform patients not to stop OLYSIO due to photosensitivity reactions unless instructed by their healthcare provider [see WARNINGS AND PRECAUTIONS].

Rash

Advise patients of the risk of rash related to OLYSIO 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 OLYSIO due to rash unless instructed by their healthcare provider [see WARNINGS AND PRECAUTIONS].

Administration

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

Advise patients to take OLYSIO every day at the regularly scheduled time with food. Inform patients that it is important not to miss or skip doses and to take OLYSIO for the duration that is recommended by the healthcare provider. Inform patients not to take more or less than the prescribed dose of OLYSIO 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 OLYSIO 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 approximately 0.2 times the mean AUC in humans.

If OLYSIO 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

Because OLYSIO is administered in combination with other antiviral drugs, refer to prescribing information of the drugs used in combination with OLYSIO for information regarding use in pregnancy.

Pregnancy Category C

Risk Summary

Adequate and well-controlled trials with OLYSIO have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. OLYSIO should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

If OLYSIO is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy.

Animal Data

Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily.

In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose.

In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once-daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once-daily dose. 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 a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once-daily dose. Subsequent survival, behavior and reproductive capacity were not affected.

Nursing Mothers

It is not known whether OLYSIO or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with OLYSIO, taking into account the importance of the therapy to the mother.

If OLYSIO is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen. Refer to RBV prescribing information for additional information on use in nursing mothers.

Pediatric Use

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

Geriatric Use

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

Race

Patients of East Asian ancestry exhibit higher simeprevir plasma exposures, but no dosage adjustment is required based on race [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY and Clinical Studies].

Renal Impairment

No dosage adjustment of OLYSIO is required in patients with mild, moderate or severe renal impairment [see CLINICAL PHARMACOLOGY]. 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 [see CLINICAL PHARMACOLOGY].

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

Hepatic Impairment

No dosage adjustment of OLYSIO is required in patients with mild hepatic impairment (Child-Pugh Class A) [see CLINICAL PHARMACOLOGY].

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class 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 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY].

The safety and efficacy of OLYSIO have not been established in liver transplant patients.

See the Peg-IFN-alfa prescribing information regarding its contraindication in patients with hepatic decompensation.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/31/2016

Warnings
Precautions

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