Hepatitis c

HEPATITIS

C

• “Hepa” means Liver• “Titis” means Inflammation• Hepatitis is an inflammation of

the liver.• Infectious (i.e. viral, bacterial,

fungal, and parasitic organisms)• Non-infectious (e.g. alcohol).

INTRODUCTION

TYPES OF HEPATITIS

• Hepatitis C is a contagious liver disease that results from infection with the Hepatitis C virus (HCV).

• Two types:1 Acute Short-term illness Occurs within the first 6 months after someone is exposed to the HCV.

2 Chronic: Acute infection leads to chronic infection. Long-term health problems, or even death.

HEPATITIS C

SOURCES OF INFECTION FORPERSONS WITH HEPATITIS C

*Nosocomial; Health-care work; Perinatal

Source: Centers for Disease Control and PreventionDr.T.V.Rao MD

EPIDEMIOLOGY

• The WHO estimates about 3% of the world’s population has been infected with HCV.

• More than 170 million chronic carriers who are at risk of developing liver cirrhosis and/or liver cancer.

• Severe morbidity in 20-30% of infected persons.

Source: Centers for Disease Control and Prevention

TREATMENT & MEDICATIONS

HCV PROTEASE INHIBITORS

SIMEPREVIR

Brand Names Olysio Galexos

Pharmacokinetics

Absorption:Food increases systemic exposure by 60-70%

Distribution:Protein bound

>99.9%

Metabolism:Liver

Excretion:Hepatobiliaryt1/2 : 41 hr (HCV+); 10-13 hr (HCV-)

Pharmacodynamics Inhibit the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases.

Dosing forms & strengths:

Capsule 150mg.

Indications and Dosing

Chronic Hepatitis C (genotype 1)

Treatment-naïve and prior relapsed patients

150 mg PO qD for 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin FOLLOWED by an additional 12 weeks of peginterferon alfa and ribavirin( with cirrhosis).

Treatment-naïve or experienced

150 mg PO qD plus sofosbuvir 400 mg for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis).

Administration Oral• Administer with food. • Maintain adequate fluid intake.• Swallow capsules whole.

Dosing Considerations

Must not be used as monotherapy; if sofosbuvir, peginterferon alfa, or ribavirin is discontinued for any reason, simeprevir must also be discontinued.

Adverse Effects Fatigue, headache ,dizziness, insomnia, Skin rash, pruritus, Nausea , diarrhea, Increased serum bilirubin, Myalgia, Dyspnea

Contraindications Hypersensitivity, Pregnancy

Drug Interactions • Simeprevir may increase the serum concentration of Atorvastatin, Cisapride, CYP3A4 Substrates, Cyclosporine (Systemic).

• CYP3A4 Inducers may decrease the serum concentration of Simeprevir. • Atazanavir and CYP3A4 Inhibitors may increase the serum concentration of

Simeprevir.

Storage Store below 30°C (86°F). Store in the original bottle. Protect from light.

HCV POLYMERASE INHIBITORS

SOFOSBUVIR

Brand Names Sovaldi

Pharmacokinetics Absorption: Well absorbed

Distribution: Plasma bound

61-65%

Metabolism: Hepatic

Excretion: Urine

t1/2 : 0.4hr

Pharmacodynamics Inhibitor of HCV NS5B RNA-dependent polymerase; hence suppresses viral replication.

Dosing forms & strengths Tablet 400mg.


Chronic Hepatitis CGenotype 1 or 4 400 mg PO qDay plus ribavirin and peginterferon alfa for 12

weeks.

Genotype 2 400 mg PO qDay plus ribavirin for 12 weeks.Genotype 3 400 mg PO qDay plus ribavirin for 24 weeks.

Administration Oral Take with or without food.


Must not be used as monotherapy; if peginterferon alfa, or ribavirin is discontinued for any reason, sovaldi must also be discontinued.

Adverse Effects Fatigue, headache, dizziness, insomnia, Skin rash, pruritus, Nausea , diarrhea, chills, anemia, Myalgia, Dyspnea, asthenia

Contraindications Hypersensitivity, Pregnancy or planning pregnancy, CrCl < 50 mL/min, pancreatitis, hemoglobinopathy.

Drug Interactions Modafinil, Oxcarbazepine, P-glycoprotein/ABCB1 Inducers, Rifabutin, Rifapentine may decrease the serum concentration of Sofosbuvir.

Storage Store below 30°C (86°F). Dispense only in original container.

COMBINATION PRODUCTS

LEDIPASVIR/SOFOSBUVIR Brand Names Harvoni

PharmacokineticsAbsorption:

Well absorbedDistribution:

Protein bindingLedipasvir:>99.8%;

Metabolism: Ledipasvir: 47 h Sofosbuvir: ~0.5 h

Excretion: •Feces•Urine

Pharmacodynamics• Ledipasvir: Inhibits HCV NS5A protein, which is required for viral replication.• Sofosbuvir: Inhibitor of HCV NS5B RNA-dependent polymerase; hence

suppresses viral replication.Dosing forms & strengths Tablet 90mg/400mg.


Chronic Hepatitis C (Genotype 1)

Treatment-naïve 1 tablet (90mg/400mg) PO qDay for 12 weeks (with or without cirrhosis)

Treatment-experienced 1 tablet (90mg/400mg) PO qDay for 12 weeks (without cirrhosis)

Treatment-experienced 1 tablet (90mg/400mg) PO qDay for 24 weeks (with cirrhosis)

Administration Oral May take with or without food.


8 weeks can be considered in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL.

Adverse Effects Fatigue, headache, dizziness, insomnia, Increased bilirubin, Increased lipase.

Cautions Do not use with other products that contain sofosbuvir (Sovaldi).

Drug Interactions

• Sofosbuvir may enhance the bradycardic effect of Amiodarone.• Antacids, H2-Antagonist & PPIs may decrease the serum concentration of Ledipasvir.• Sofosbuvir may increase the serum concentration of Topotecan, Vincristine, rifaximin &

rosuvastatin.

Storage Store below 30°C (86°F). Dispense in original container.

HCV NS5A INHIBITORS

DACLATASVIR

Brand Names Daklinza

Pharmacokinetics

Absorption: Bioavailability

67%

Distribution:Protein binding

99%

Metabolism: Hepatic by CYP3A

Excretion: •Feces•Urine

Pharmacodynamics Inhibits NS5A, a nonstructural protein encoded by HCV, suppress viral replication.

Dosing forms & strengths Tablet 30mg/60mg.


Chronic Hepatitis C (Genotype 3) 60 mg (plus sofosbuvir 400 mg) PO qDay for 12 weeks.

Administration Oral May take with or without food.


If sofosbuvir is permanently discontinued in a patient receiving daclatasvir with sofosbuvir, then daclatasvir should also be discontinued.

Adverse Effects Headache , Fatigue , Nausea , Diarrhea , Elevated lipase.

Contraindications Coadministration with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of daclatasvir efficacy.

Drug Interactions • Daclatasvir may enhance the bradycardic effect of Amiodarone.• CYP3A4 inducers may decrease the serum concentration of Daclatasvir.• CYP3A4 inducers may increase the serum concentration of Daclatasvir.• Daclatasvir may increase the serum concentration of HMG-CoA Reductase Inhibitors.

Storage Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

INTERFERONS & RIBAVARIN

INTERFERON ALFA-2B

Brand Names Intron-A

Pharmacokinetics

Absorption:Bioavailability•IM: 83%•SC: 90%

Distribution:•Vd: 31 L•IFN does not penetrate the CSF

Metabolism:Renal

Excretion:Elimination H.L •IV: 2 hours •IM: 2-3 hours•SC: 2-3 hours

PharmacodynamicsInhibits HBV replication; immunomodulatory actions; may induce gene transcription; interferes with oncogene expression, may change cell surface antigen expression; cytotoxic activity of macrophages increases.

Dosing forms & strengths

• Injectable solution 6 / 10 million International Units/mL (3.8 / 3.2 mL vial respectively)

• Multi dose pen; 6 doses each; (22.5 / 37.5 / 75 million International Units/1.5mL)

• Powder for injection (10 / 18 / 50 million International Units/vial)Indications and Dosing

Chronic Hepatitis C 3 million units IM/SC 3 times/wk for16 wk.Acute Hepatitis C 5 million Units SC/IM qd for 4 wk, then 3 times/wk for 20 wk.

Administration IV, IM, SC OR Intralesional.Dosing Considerations

For chronic hepatitis:•If ALT normalized after 16 wk, continue treatment for 18-24 mo.•If ALT not normalized or high levels of HCV RNA after 16 wk, consider discontinuing treatment.For acute hepatitis:•If severe adverse reactions develop reduce dose by 50% or temporarily withhold until adverse reactions abate.•If intolerance persists discontinue permanently.

Adverse Effects Fatigue, Fever, Neutropenia, Flu-like syndrome, Myalgia, anorexia, nausea, weakness.Contraindications Hypersensitivity, Autoimmune hepatitis, Decompensated liver diseaseDrug Interactions • may increase the serum concentration of Methadone.

• may enhance the adverse/toxic effect of Ribavirin. Hemolytic anemia has been observed.

Storage • Refrigerate intact vials.• Powder & premixed solutions are stable at room temp for 7 d & for 30 d if

refrigerated.

INTERFERON ALFACON 1 Brand Names Infergen

Pharmacokinetics

• Pharmacokinetic studies have not been conducted on patients with chronic hepatitis C.

• Time to peak: Healthy volunteers: 24-36 hours.

Pharmacodynamics Release immunomodulatory cytokine that enhances phagocytic activity of macrophages and cytotoxic activity of lymphocytes for target cells.

Dosing forms & strengths: Injectable solution : 9mcg/0.3mL & 15mcg/0.5mL.


Chronic Hepatitis C (Genotype 3)

• 9 mcg SC 3 times/week for 24 wk.• 15 mcg SC with ribavirin qDay for up to 48 weeks.

<75 kg: ribavirin 1 g PO divided q12hr. ≥75 kg: ribavirin 1.2 g PO divided q12hr.

Administration• SC, 3 times/week, with at least 48 hours between doses. • Allow to reach room temperature just prior to administration.


• If severe toxicity occurs: Reduce to 7.5 mcg SC 3 times/week or discontinue.• Monitor: Hgb, WBC, Plt, LFTs, creatinine, thyroid.

Adverse Effects Headache, Fatigue, Fever, Rigors, Myalgia, Body pain, Back pain, Arthalagia.

Contraindications • Hypersensitivity • Decompensated liver disease• Autoimmune hepatitis

Drug Interactions • Interferons may decrease the metabolism of Theophylline Derivatives.• Interferons may enhance the adverse/toxic effect of Zidovudine. • Interferons may decrease the metabolism of Zidovudine.

Storage • Store in refrigerator 2°C to 8°C. Do not freeze. • Avoid exposure to direct sunlight. • Do not shake vigorously.

PEGYLATED INTERFERON ALFA-2A

Brand Names Pegasys

Pharmacokinetics• Elimination Half-life:160 hours• Time to peak serum: 72 to 96 hours

Pharmacodynamics Release immunomodulatory cytokine that enhances phagocytic activity of macrophages and cytotoxic activity of lymphocytes for target cells.

Dosing forms & strengths

• Vial for single use: 180mcg/ml• Prefilled syringe for single use: 180mcg/0.5ml• Autoinjector for single use: 135 or 180 mcg/0.5ml


C H C

• With other anti viral drugs: 180 mcg SC once weekly

• Without other anti viral drugs: Genotypes 1, 4: 48 weeks Genotypes 2, 3: 24 weeks Genotypes 5, 6: Insufficient data to recommend use

Administration• SC. Abdomen or thigh. Rotate injection site. • Administration should be done on the same day and at approximately the same time

each week.Dosing Considerations

• Only indicated for the treatment of patients with CHC with compensated liver disease if there are contraindications or significant intolerance to other HCV antiviral drugs.• Not recommended for treatment of patients with CHC who previously failed therapy

with an interferon-alfa.• Not recommended for treatment of patients with CHC who have had solid organ

transplantation.Adverse Effects Headache, Fatigue, Rigors, Insomnia, Anxiety, Alopecia, Pruritis.

Contraindications Pregnancy, Autoimmune hepatitis, Hypersensitivity, Decompensated liver disease.

Drug Interactions • may diminish the therapeutic effect of BCG (Intravesical).• may enhance the adverse/toxic effect of CloZAPine. Agranulocytosis may be

increased.Storage • Store in refrigerator at 2°C to 8°C. Do not freeze. Do not leave out of the refrigerator

for more than 24 hours. • Do not shake.• Discard any unused portion. Protect from light.

RIBAVIRIN

Brand Names Rebetol, Virazole, Copegus, Moderiba, Ribasphere

Pharmacokinetics


Oral: 64%

Distribution: Protein binding

Oral: None

Metabolism:•Hepatically •Intracellularly

Excretion:•Inhalation:

Urine (40%)•Oral capsule:

Urine (61%)

PharmacodynamicsMay inhibit the initiation and elongation of RNA fragments by inhibiting polymerase activity, which in turn results in the inhibition of viral protein synthesis.

Dosing forms & strengths:

• Tablet (200mg 400mg 600mg).• Inhalation solution (6g/vial).• Oral solution (40mg/mL).


C H C (Genotype 1 to 6)

• Body weight dependent dosing. Varied.• Period: 24 to 48 hours.

AdministrationOral Administer with food.

Inhalation In well ventilated rooms.


Dose reductions/interruptions recommended if Hgb falls.

Adverse Effects Headache, Fatigue, Fever, Rigors, Myalgia, Body pain, Back pain, Arthalagia.

Contraindications Pregnancy, Autoimmune hepatitis, Hypersensitivity, Decompensated liver disease.

Drug Interactions • Ribavirin may enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors. Lactic acidosis may occur.

• Diminish the therapeutic effect of Influenza Virus Vaccine.

Storage • Store vials in a dry place at 15°C to 30°C.• Store tablets at 25°C.• Solution are refrigerated at 2°C to 8°C.

THROMBOPOIETIN-RECEPTOR AGONISTS

ELTROMBOPAGBrand Names Promacta

Pharmacokinetics


•Tablets: 52%•Suspension: increased by 22 %

Distribution: Protein binding:

> 99%

Metabolism:In liver

Excretion:•In feces•In urine

Pharmacodynamics Interacts with transmembrane domain of human TPO receptor and induces megakaryocyte proliferation and differentiation from bone marrow progenitor cells.

Dosing forms & strengths Tablet: 12.5 mg 25 mg 50 mg 75 mg


Chronic Hepatitis C-Associated Thrombocytopenia

25 mg PO QD

Administration: Oral 1 hour before or 2 hours after a meal.


• Used in patients whose degree of thrombocytopenia prevents the initiation of interferon-based therapy.

• Monitor CBCs with differentials (including platelet counts) qWeek. • Not safe in combination with direct-acting antiviral agents.• Used without interferons.

Adverse Effects Influenza-like symptoms, Headache, Rigor, Fatigue, Nausea, Arthralgia, Myalgia.

Contraindications Not documented.

Drug Interactions Aluminium hydroxide, Fe salts, Mg salts & calcium salts may decrease its serum concentration.

Storage • Store oral suspension at 20°C to 25°C.• Store oral tablets at 20°C to 25°C.

THANKYOU

Hepatitis c

Health & Medicine

Transcript of Hepatitis c