Simeprevir (Olysio) is a direct-acting oral antiviral drug that inhibits the HCV NS3/4A protease. It is used in combination with sofosbuvir and ribavirin for the treatment of chronic active hepatitis C, Genotype 1 and 4 in particular.
Simeprevir (Olysio) Uses:
-
Chronic hepatitis C:
- Treatment of genotype 1 chronic hepatitis C in adjunct to sofosbuvir in adults without cirrhosis
- Limitations of use:
- Not recommended for use in patients who have previously failed a simeprevir containing therapy or another regimen containing HCV protease inhibitors.
-
Off Label Use of Simeprevir in Adults:
- Chronic hepatitis C, genotype 1 and 4 (post-liver transplantation)
Simeprevir (Olysio) Dose in Adults
Note:
- If other concurrent treatment (sofosbuvir or peginterferon and ribavirin) is stopped for any reason, simeprevir must also be stopped.
- Do not decrease simeprevir dose or interrupt therapy; if therapy must be interrupted because of side effects or incomplete response, do not start again.
- In patients with genotype 1a and compensated cirrhosis, screening for HCV with the NS3 Q80K polymorphism may be considered before starting therapy.
- Screening is strongly recommended before starting combination treatment with peginterferon alfa and ribavirin in patients with genotype 1a;
- Consider alternative therapy in patients infected with HCV genotype 1a containing the Q80K polymorphism.
Simeprevir (Olysio) Dose in the treatment of chronic hepatitis C (CHC): Oral:
-
Genotype 1, treatment-naive or peginterferon + ribavirin treatment-experienced without cirrhosis (alternative regimen):
- 150 mg once daily combined with sofosbuvir for 12 weeks.
-
Genotype 1 or 4, liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) (alternative regimen; off-label use):
- 150 mg once daily combined with sofosbuvir with or without ribavirin for 12 weeks.
Use in Children:
Not indicated.
Pregnancy Risk Category: N (not assigned)
- In animal reproduction studies, side effects were observed.
- Simeprevir should not be used as a single therapy; Simeprevir combination therapy with Ribavirin is contraindicated for pregnant females and males who are married to pregnant female partners.
- All warnings regarding ribavirin use in conjunction with ribavirin must be observed.
- For more information, see the ribavirin monograph.
- Hepatitis C treatment is not recommended for pregnant women or to reduce the chance of mother-to child transmission.
- To reduce the risk of HCV transmission, HCV-infected women with childbearing potential may want to postpone pregnancy until treatment is completed.
- Treatment should be delayed until after the delivery if HCV infection is discovered during pregnancy.
- Until safety and efficacy data is available, direct-acting antiviral medication should not be administered to pregnant women.
Simeprevir use during breastfeeding:
- It is not known if simeprevir can be found in breast milk.
- According to the manufacturer, when deciding whether to continue or stop breastfeeding during therapy, consider the risks to infant exposure, the benefits to the infant and the benefits to the mother.
- The spread of the hepatitis C viruses is not associated with breastfeeding. However, if nipples crack or bleed, it is not recommended to breastfeed. Instead, express your milk and throw it away.
- HIV co-infection means that breastfeeding is not recommended.
Simeprevir (Olysio) Dose in Kidney Disease:
- CrCl >30 mL/minute:
- No dose adjustment required.
- CrCl ≤30 mL/minute:
- There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
- End-stage renal disease (ESRD), including hemodialysis patients:
- There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
- Dialysis is unlikely to cause significant removal of simeprevir.
Simeprevir (Olysio) Dose in Liver disease:
- Mild impairment (Child-Pugh class A):
- No dose adjustment required.
- Moderate or severe impairment (Child-Pugh class B or C):
- Use is not recommended.
Common Side Effects of Simeprevir (Olysio):
-
Central Nervous System:
- Headache
- Fatigue
- Insomnia
- Dizziness
-
Dermatologic:
- Skin Photosensitivity
- Skin Rash
- Pruritus
-
Endocrine & Metabolic:
- Increased Amylase
-
Gastrointestinal:
- Nausea
- Diarrhea
-
Hepatic:
- Increased Serum Bilirubin
- Hyperbilirubinemia
-
Neuromuscular & Skeletal:
- Myalgia
-
Respiratory:
- Dyspnea
Less Common Side Effects of Simeprevir (Olysio):
-
Gastrointestinal:
- Increased serum lipase (with sofosbuvir)
-
Hepatic:
- Increased serum alkaline phosphatase
Contraindications to Simeprevir (Olysio):
- The manufacturer does not recommend any contraindications.
- The contraindications to peginterferon and ribavirin are also applicable when administered in combination with peginterferon and ribavirin. Refer to the Ribavirin or Peginterferon Alfa monographs.
Canadian labeling: Additional contraindications not in US labeling
- Hypersensitivity to simeprevir and any component of the formulation
Warning/Precaution
-
Failure and decompensation of the liver
- In combination therapy with simeprevir, peginterferonalfa and either ribavirin (or sofosbuvir) has been reported hepatic failure and decompensation.
- Patients with advanced or decompensated liver disease were most common in these cases.
- Reports have shown that there have been modest bilirubin increases that did not affect hepatic function. However, post-marketing cases have also been documented of hepatic dysfunction with markedly increased bilirubin levels.
- Monitor hepatic function at baseline, and as clinically indicated. Closely monitor patients with an increase in total bilirubin greater than 2.5 times the ULN.
- If elevated bilirubin is accompanied by liver transaminase increased or clinical signs or symptoms (eg fatigue, weakness and lack of appetite), stop treatment.
-
Photosensitivity
- When combined with ribavirin and peginterferon alfa, photosensitivity reactions have been reported, some even leading to hospitalization.
- This may manifest as an exaggerated sunburn response (burnings, erythema and blistering), which is most common in the first four weeks.
- Avoid too much sun, tanning devices, excessive exposure, and wear loose-fitting clothes, sunscreen.
- If you experience photosensitivity, stop using the product and wait until the reaction is gone.
- Expert consultation is recommended if therapy is to continue with a patient suffering from photosensitivity.
-
Reactions to skin:
- Rash is most commonly observed within the first four weeks of beginning therapy, but it can happen at any time during treatment.
- Combination therapy with peginterferon and ribavirin has been associated with severe rashes and rash which needs to be discontinued.
- Follow up on patients who experience mild to moderate rash.
- Stop taking simeprevir if the rash is severe. Monitor for rash resolution.
-
Sulfa allergy:
- It contains a sulfonamide component.
- Patients with a history sulfa allergy have not experienced an increase in rash or photosensitivity, but the possibility of severe reactions (or even death) cannot be ruled out.
- If hypersensitivity signs develop, stop immediately.
-
Diabetes:
- A rapid reduction in the viral load of hepatitis C during direct-acting antiviral therapy (DAA) for hepatitis C could lead to improved glucose metabolism in patients suffering from diabetes. If antidiabetic drugs are given at the same dosage, this may result in hypoglycemia.
- Monitor glucose tolerance changes and inform patients about the possibility of hypoglycemia while on DAA therapy, especially in the first three months.
- Modifications to anti-diabetic therapy might be required.
-
Hepatic impairment
- Patients with severe or moderate hepatic impairment (Child Puugh class B orC) are not recommended.
-
Hepatitis B virus activation: [US-Boxed Warning]
- Hepatitis B virus reactivation (HBV), has been observed in HCV co-infected patients. These patients were either receiving or had completed treatment using HCV direct-acting antibiotics. Some cases have led to fulminant liver disease, hepatic failure and even death.
- Before initiating simeprevir, test all patients for evidences of HBV infection. Monitor HCV/HBV coinfected patients for flares or HBV reactivation during treatment. Follow up after treatment.
- As soon as HBV infection is diagnosed, start treatment.
- HBV reactivation has been observed in HBsAg-positive patients and patients with serologic evidence that resolved HBV infections (i.e. HBsAg nil and anti-HBc p). It is characterized as an abrupt increase of HBV replication and a rapid rise in serum HBV DNA levels. Patients with resolved HBV infection may experience a recurrence of HBsAg.
- Patients who are taking immunosuppressants and chemotherapeutic agents may have a greater risk of HBV reactivation.
Simeprevir: Drug Interaction
|
Aminolevulinic Acid (Topical) |
Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). |
|
Antidiabetic Agents |
Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. |
|
Brentuximab Vedotin |
|
|
Celiprolol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. |
|
Clofazimine |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CloZAPine |
CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. |
|
CYP3A4 Substrates (High risk with Inhibitors) |
Simeprevir may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Digoxin |
Simeprevir may increase the serum concentration of Digoxin. |
|
Eltrombopag |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Erdafitinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Escitalopram |
May decrease the serum concentration of Simeprevir. |
|
Everolimus |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. |
|
Flecainide |
Simeprevir may increase the serum concentration of Flecainide. |
|
Fosaprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Gemfibrozil |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions. |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Larotrectinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Larotrectinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. |
|
Lovastatin |
Simeprevir may increase the serum concentration of Lovastatin. |
|
Mexiletine |
Simeprevir may increase the serum concentration of Mexiletine. |
|
Midazolam |
Simeprevir may increase the serum concentration of Midazolam. |
|
Naldemedine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. |
|
Naloxegol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. |
|
Palbociclib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
P-glycoprotein/ABCB1 Substrates |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. |
|
Phosphodiesterase 5 Inhibitors |
Simeprevir may increase the serum concentration of Phosphodiesterase 5 Inhibitors. |
|
Pitavastatin |
Simeprevir may increase the serum concentration of Pitavastatin. |
|
Porfimer |
Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. |
|
Pravastatin |
Simeprevir may increase the serum concentration of Pravastatin. |
|
Propafenone |
Simeprevir may increase the serum concentration of Propafenone. |
|
Prucalopride |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. |
|
Ranolazine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. |
|
RifAXIMin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. |
|
Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Silodosin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. |
|
Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Simvastatin |
Simeprevir may increase the serum concentration of Simvastatin. |
|
Talazoparib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. |
|
Talazoparib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. |
|
Tegaserod |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. |
|
Tenofovir Disoproxil Fumarate |
May decrease the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. |
|
Teriflunomide |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
|
Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Triazolam |
Simeprevir may increase the serum concentration of Triazolam. |
|
Verteporfin |
Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. |
|
Warfarin |
Simeprevir may enhance the anticoagulant effect of Warfarin. |
|
Risk Factor D (Consider therapy modification) |
|
|
Afatinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. |
|
Alpelisib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. |
|
AtorvaSTATin |
|
|
Betrixaban |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. |
|
Bilastine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. |
|
Cladribine |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. |
|
Colchicine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. |
|
Dabigatran Etexilate |
P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. |
|
DOXOrubicin (Conventional) |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. |
|
Edoxaban |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. |
|
Rosuvastatin |
Simeprevir may increase the serum concentration of Rosuvastatin. Management: Limit initial rosuvastatin dose to 5 mg/day when being started in a patient who is also being treated with simeprevir. The maximum rosuvastatin dose should not exceed 10 mg/day with concurrent use of simeprevir. |
|
Stiripentol |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
|
TiZANidine |
CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. |
|
Tolvaptan |
May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. |
|
Venetoclax |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. |
|
Risk Factor X (Avoid combination) |
|
|
Aminolevulinic Acid (Systemic) |
Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). |
|
Asunaprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. |
|
Cisapride |
Simeprevir may increase the serum concentration of Cisapride. |
|
Conivaptan |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CycloSPORINE (Systemic) |
May increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of CycloSPORINE (Systemic). |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of Simeprevir. |
|
CYP3A4 Inducers (Strong) |
May decrease the serum concentration of Simeprevir. |
|
CYP3A4 Inhibitors (Moderate) |
May increase the serum concentration of Simeprevir. |
|
CYP3A4 Inhibitors (Strong): |
May increase the serum concentration of Simeprevir. |
|
Delavirdine |
May increase the serum concentration of Simeprevir. |
|
Dexamethasone (Systemic) |
May decrease the serum concentration of Simeprevir. |
|
Elagolix |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. |
|
Erythromycin (Systemic) |
May increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Erythromycin (Systemic). |
|
Fusidic Acid (Systemic) |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Grazoprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir. |
|
Idelalisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Ledipasvir |
Simeprevir may increase the serum concentration of Ledipasvir. Ledipasvir may increase the serum concentration of Simeprevir. |
|
Milk Thistle |
May increase the serum concentration of Simeprevir. |
|
Nevirapine |
May decrease the serum concentration of Simeprevir. |
|
Oxcarbazepine |
May decrease the serum concentration of Simeprevir. |
|
PAZOPanib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. |
|
PAZOPanib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. |
|
Protease Inhibitors |
May increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. |
|
Revefenacin |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. |
|
St John's Wort |
May decrease the serum concentration of Simeprevir. |
|
Topotecan |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. |
|
Topotecan |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. |
|
VinCRIStine (Liposomal) |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). |
|
Voxilaprevir |
OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. |
Monitoring parameters:
Manufacturer's labeling:
- Bilirubin and liver enzymes (at baseline and during therapy as clinically indicated) at baseline and periodically when clinically advised.
- Liver function tests at baseline and periodically during therapy;
- serum HCV-RNA at baseline, weeks 4, 12, and 24, at end of treatment, during treatment follow-up, and when clinically indicated.
- Screen patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism before beginning treatment.
- Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.
Alternate recommendations:
Baseline (within 12 weeks before beginning antiviral therapy):
- CBC,
- INR,
- hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase),
- calculated GFR.
Baseline (at any time before beginning antiviral therapy):
- HCV genotype and subtype, quantitative HCV viral load, resistance assays (if applicable).
- Screen patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism before starting treatment.
During therapy:
- CBC,
- serum creatinine,
- calculated GFR,
- hepatic function panel (after 4 weeks of therapy and as clinically indicated);
- quantitative HCV viral load testing (after 1 month of therapy and at 3 months after completion of therapy).
- If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 more weeks of treatment (treatment week 6).
In diabetic patients, monitor blood glucose and for signs/symptoms of hypoglycemia.
How to administer Simeprevir (Olysio)?
Oral: Administer with meals. Swallow capsules whole; do not chew, crush, break, cut, or dissolve the capsule.
Mechanism of action of Simeprevir (Olysio):
- Simeprevir is an inhibitor for HCV NS3/4A protease.
- This protease is critical for viral replication.
- It is a direct-acting antiviral medication for HCV.
- Also known as STAT-C, it is a specifically targeted antiviral treatment for HCV.
Absorption:
- Food increases absorption.
Protein binding:
- >99.9% (albumin and alpha 1-acid glycoprotein)
Metabolism: Primarily oxidative metabolism by CYP3A4 (and possibly CYP2C8 and CYP2C19) to unchanged drug and metabolites (minor).
Bioavailability:
- 62% (single dose under fed conditions)
Half-life elimination: Plasma:
- 10 to 13 hours (healthy volunteers);
- 41 hours (HCV-infected patients)
Time to peak, serum:
- 4 to 6 hours
Excretion:
- Feces (~91%);
- urine (<1%)
International Brand Names of Simeprevir:
- Olysio
- Galexos
- Sovriad
Simeprevir Brand Names in Pakistan:
No Brands Available in Pakistan.
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