Elbasvir and Grazoprevir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Zepatier: Elbasvir 50 mg and grazoprevir 100 mg

Pharmacology

Mechanism of Action

Elbasvir is an inhibitor of HCV NS5A, which is essential for viral replication and virion assembly.

Grazoprevir is an inhibitor of HCV NS3/4A protease, necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.

Pharmacokinetics/Pharmacodynamics

Absorption

Not affected by meals.

Distribution

Elbasvir: Distribution into most tissue including hepatic; Grazoprevir: Predominantly hepatic distribution

V_d: Elbasvir: ~680 L; Grazoprevir: ~1,250 L

Metabolism

Elbasvir, Grazoprevir: Hepatic (partial oxidative metabolism via CYP3A); metabolites not detected in plasma

Excretion

Feces (>90%); urine (<1%)

Time to Peak

Elbasvir: Median: 3 hours (range: 3 to 6 hours); Grazoprevir: Median: 2 hours (range: 30 minutes to 3 hours)

Half-Life Elimination

Elbasvir: ~24 hours; Grazoprevir: ~31 hours

Protein Binding

Elbasvir: >99.9% (albumin, alpha-1 acid glycoprotein); Grazoprevir: 98.8% (albumin, alpha-1 acid glycoprotein)

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adults; used with ribavirin in certain patient populations.

Use: Off Label

Chronic hepatitis C (genotype 3)yes

Based on the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, elbasvir/grazoprevir, in combination with sofosbuvir, is an effective and recommended treatment of genotype 3 HCV in peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C); history of prior hepatic decompensation; concurrent use with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations and strong inducers of CYP3A. Concurrent use of drugs that are contraindicated include, but are not necessarily limited to: atazanavir, carbamazepine, cyclosporine, darunavir, efavirenz, lopinavir, phenytoin, rifampin, saquinavir, St. John's wort, tipranavir. If used with ribavirin, contraindications of ribavirin also apply. See ribavirin prescribing information.

Canadian labeling (not in US labeling): Hypersensitivity to elbasvir, grazoprevir, or any component of the formulation. If used with sofosbuvir, contraindications of sofosbuvir also apply. See sofosbuvir prescribing information.

Dosage and Administration

Dosing: Adult

Chronic hepatitis C (genotype 1a or 1b) (monoinfection or coinfection with HIV-1): Oral:

Genotype 1a:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) without baseline NS5A polymorphisms: One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) with baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2018).

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and without baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class) and with baseline NS5A polymorphisms (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2018).

Genotype 1b:

Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Peginterferon + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) (alternative agent): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Chronic hepatitis C (genotype 3) (off-label use): Oral: Peginterferon alfa + ribavirin treatment-experienced with compensated cirrhosis (Child-Pugh class A): One tablet once daily with concomitant sofosbuvir for 12 weeks (AASLD/IDSA 2018).

Chronic hepatitis C (genotype 4): Oral:

Treatment naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced virologic relapse after prior peginterferon/ribavirin therapy: One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced prior on-treatment failure while on peginterferon/ribavirin (alternative agent): One tablet once daily with concomitant ribavirin for 16 weeks (AASLD/IDSA 2018).

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer without regard to meals.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Keep in original blister pack until time of use; protect from moisture.

Drug Interactions

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. Consider therapy modification

Antidiabetic Agents: Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Grazoprevir. Avoid combination

AtorvaSTATin: Grazoprevir may increase the serum concentration of AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

AtorvaSTATin: Elbasvir may increase the serum concentration of AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

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. Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Cobicistat: May increase the serum concentration of Grazoprevir. Avoid combination

Cobicistat: May increase the serum concentration of Elbasvir. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Elbasvir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Grazoprevir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Elbasvir. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Darunavir: May increase the serum concentration of Grazoprevir. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Efavirenz: May decrease the serum concentration of Grazoprevir. Avoid combination

Efavirenz: May decrease the serum concentration of Elbasvir. Avoid combination

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluvastatin: Elbasvir may increase the serum concentration of Fluvastatin. Monitor therapy

Fluvastatin: Grazoprevir may increase the serum concentration of Fluvastatin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Elbasvir. Avoid combination

Ketoconazole (Systemic): May increase the serum concentration of Grazoprevir. Avoid combination

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lopinavir: May increase the serum concentration of Grazoprevir. Avoid combination

Lovastatin: Elbasvir may increase the serum concentration of Lovastatin. Monitor therapy

Lovastatin: Grazoprevir may increase the serum concentration of Lovastatin. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors: May increase the serum concentration of Grazoprevir. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Avoid combination

RifAMPin: May decrease the serum concentration of Grazoprevir. Conversely, single doses of Rifampin may increase Grazoprevir concentrations. Avoid combination

Rosuvastatin: Grazoprevir may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Rosuvastatin: Elbasvir may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Saquinavir: May increase the serum concentration of Grazoprevir. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simvastatin: Elbasvir may increase the serum concentration of Simvastatin. Monitor therapy

Simvastatin: Grazoprevir may increase the serum concentration of Simvastatin. Monitor therapy

St John's Wort: May decrease the serum concentration of Grazoprevir. Avoid combination

St John's Wort: May decrease the serum concentration of Elbasvir. Avoid combination

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. Consider therapy modification

Tacrolimus (Systemic): Grazoprevir may decrease the serum concentration of Tacrolimus (Systemic). Grazoprevir may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tipranavir: May increase the serum concentration of Grazoprevir. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Consider therapy modification

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification

Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a BCRP inhibitor. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Direct Acting Antiviral Agents (HCV) may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (11%), headache (10% to 11%)

Gastrointestinal: Nausea (11%)

1% to 10%: Hepatic: Increased serum alanine aminotransferase (1% to 2%)

<1%, postmarketing, and/or case reports: Acute hepatic failure (FDA Safety Alert, August 28, 2019), angioedema, decreased hemoglobin, increased serum bilirubin, reactivation of HBV, severe hepatic disease (FDA Safety Alert, August 28, 2019)

Warnings/Precautions

Concerns related to adverse effects:

• ALT elevations: ALT elevations (>5 times ULN) have been observed generally at week 8 or beyond; changes have been mostly asymptomatic and resolved with ongoing or completed therapy. Females, Asian patients, and patients ≥65 years of age may be at greater risk for ALT changes. Patients should report fatigue, weakness, decreased appetite, nausea/vomiting, jaundice, or discolored feces. Monitor liver function tests prior to therapy, at treatment week 8, and as clinically indicated. Consider discontinuing therapy if ALT levels remain persistently >10 times ULN. Discontinue therapy if accompanied by signs/symptoms of hepatic inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.

Disease-related concerns:

• Diabetes: Rapid reduction in hepatitis C viral load during direct-acting antiviral (DAA) therapy for hepatitis C may lead to improvement in glucose metabolism in patients with diabetes, potentially resulting in symptomatic hypoglycemia if antidiabetic agents are continued at the same dose. Monitor for changes in glucose tolerance and inform patients of the risk of hypoglycemia during DAA therapy, particularly within the first 3 months. Modification of antidiabetic therapy may be necessary (Ciancio 2018; Dawood 2017; Hum 2017).
• Hepatic impairment: Cases of hepatic decompensation and failure, some fatal, have been reported in patients without cirrhosis and in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh class B or C). Use is contraindicated in moderate or severe impairment (Child-Pugh class B or C) and with a history of prior hepatic decompensation. Monitor hepatic function tests and for signs and symptoms of hepatic decompensation more frequently in patients with compensated cirrhosis (Child-Pugh class A) or evidence of advanced liver disease (eg, portal hypertension); discontinue if hepatic decompensation or failure develops.
• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of treatment; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustments, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Resistance testing prior to treatment initiation in HCV genotype 1a: Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to treatment initiation to determine regimen and duration. Sustained virologic response rates were lower after 12 weeks in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.

Monitoring Parameters

Baseline (within 12 weeks prior to treatment initiation) CBC, INR, hepatic function (albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), calculated GFR; baseline (obtain any time prior to treatment initiation) HCV genotype and subtype, quantitative HCV viral load. During treatment, monitor CBC, serum creatinine, calculated GFR (after 4 weeks of therapy and as clinically indicated); hepatic function (treatment week 4, 8, and 12 [if treatment duration is 16 weeks]); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) (AASLD/IDSA 2018). 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. In genotype 1a patients, testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to treatment initiation.

In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia (Ciancio 2018; Dawood 2017; Hum 2017).

Pregnancy

Pregnancy Considerations

Use in combination with ribavirin is contraindicated in pregnant women and males whose female partners are pregnant.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2018). When HCV infection is detected during pregnancy, treatment should be deferred until after delivery. Direct-acting antiviral medications should not be used in pregnant females outside of clinical trials until safety and efficacy information is available (SMFM [Hughes 2017]).

If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Refer to the ribavirin monograph for additional information.

Patient Education

What is this drug used for?

• It is used to treat or prevent eye infections.
• This drug may be used with other drugs to treat hepatitis C. If you are also taking other drugs to treat hepatitis C, talk with the doctor about the risks and side effects that may happen.

Frequently reported side effects of this drug

• Nausea
• Diarrhea
• Headache
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.