Ledihep (Sofosbuvir & Ledipasvir)

DESCRIPTION

Ledihep  is a fixed dose combination of two most prominent anti-viral agents like Sofosbuvir & Ledipasvir which provides an effective & well accepted one pill once a day regimen for the therapy of genotype I, IV, V or VI caused hepatitis C viral infection in advanced stage. Ledihep  is a one of the directly acting anti-viral medication, which is endorsed by FDA with interferon & ribavirin free drug involved in the treatment of hepatitis C.

Ledihep  is used alone without use of ribavirin in the condition like genotype 1A; this is exceptional in patients who are having cirrhotic & already treated patients. Ledihep  is Sofosbuvir & ledipasvir combination which is pharmacologically classified as NS5B-NS5A inhibitor. Ledihep  is more potent and competent in patients with decompensated cirrhosis condition.

INDICATION

Ledihep  tablets are used to treat chronic hepatitis C viral infection in both adults & pediatric patient with the age of 12 years or older, or weighing of at least 35kg. Ledihep  tablets should be used in; Hepatitis C associated with genotype I, IV, V, or VI with compensated cirrhosis or without cirrhosis. HCV infection related to genotype I infection with decompensated cirrhosis by concomitant use of ribavirin. In liver transplanted patients, HCV associated to genotype I or IV without cirrhosis or with compensated cirrhosis by combining with ribavirin. Ledihep  tablets are used in pediatric patients with HCV infection caused by genotype I, IV, V or VI without cirrhosis or with compensated cirrhosis.

MECHANISM OF ACTION

Ledipasvir is a strong prohibitor of chronic hepatitis C viral associating non structural 5A protein which is a viral phosphoprotein. The vital role of ledipasvir in anti-viral activity mechanism; Inhibition of; Replication Assembly Secretion The mechanism of sofosbuvir involved in anti-viral activity is; Sofosbuvir is prohibitor of nucleotide analogue of hepatitis C viral infection related to non structural 5B polymerase. This enzyme is responsible for intervene the HCV RNA multiplication. The active form of sofosbuvir is in triphosphate form, which involved decreasing the natural cellular uridine nucleotide & is integrated by HCV RNA polymerase into the extended RNA primer strand, which is concluded in viral chain elimination.

ADME PROPERTIES

The pharmacokinetic property of Ledihep  is; The median plasma concentration time of ledipasvir is 4 to 4.5 hours; sofosbuvir is absorbed rapidly and reaches median plasma concentration time is 0.8 to 1 hour; metabolite GS-331007 occurs between 3.5 to 4 hours.

Food should not cause any variation in pharmacokinetic property of Ledihep  . Ledihep  should be taken either with food or without food. Ledihep  is widely distributed in body, the human plasma protein binding capacity of ledipasvir is around >99.8%; sofosbuvir is between 61 to 65%. Ledihep  metabolism is mostly occurred in liver, ledipasvir metabolism is occurred by CYP1A2, 2C8, 2C9, 2C19, 2D6 & 3A4.

The metabolism of sofosbuvir is majorly occurs hepatically and leads by cathepsin A or carboxyl esterase 1. Ledihep  is excreted through feces & urine. Ledipasvir dose are eliminated via urine by 87%.

Sofosbuvir is eliminated by 80% via urine, 14% via feces & 3.5% via exhaled air. Ledipasvir half life period is 47 hours; Sofosbuvir & GS-331007 Half life period is 0.5 to & 27 hours respectively.

DOSAGE MANAGEMENT

DOSING AND ADMINISTRATING

Generally Ledihep  tablet dosage recommended for adults & pediatric age 12 years to <18 years; The prescribed dose of Ledihep  is one tablet should be administered as a single dose by administering with or without food. Recommendation of dosage of Ledihep  in various conditions; including HIV-1 co infected patients Patient without cirrhosis: (adult or pediatric of 12 years of age or older with genotype I, IV, V or VI Chronic HCV) The advised dose of Ledihep  for this condition is one tablet should be administered orally as a single dose for 12 weeks

GENOTYPE I

Without cirrhosis or compensated cirrhosis: Ledihep  should be used alone as a single dose followed for 12 weeks Therapy experienced without cirrhosis: Ledihep  should be used as a single agent for once a day for 12 weeks Therapy experienced with compensated cirrhosis: Ledihep  tablet should be used for 24 weeks In decompensated cirrhosis: Ledihep  with ribavirin should be used followed for 12 weeks

GENOTYPE I TO IV

In liver transplantation patients with compensated cirrhosis or without cirrhosis: Ledihep  tablet should be combined with ribavirin for 12 weeks.

GENOTYPE IV, V OR VI

Without cirrhosis or with compensated cirrhosis patients: Ledihep  tablets should be administered alone for 12 weeks The dose of ribavirin should be calculated on the basis of body weight; <75kg: 1000mg; ≥75kg: 1200mg Ribavirin should be administered with food. Ledihep  should be administered with or without food.

PEDIATRICS
GENOTYPE I

Without cirrhosis or with compensated cirrhosis: Ledihep  should be administered orally afor 12 weeks. Therapy experienced without cirrhosis: Ledihep  should be administered orally for 12 weeks. Therapy experienced compensated cirrhosis: Ledihep  tablet should be administered orally for 12 weeks.

GENOTYPE IV, V OR VI

Therapy naïve or experienced without cirrhosis or with compensated cirrhosis: Ledihep  tablet should be administered orally for 12 weeks.

RENAL IMPAIRMENT PATIENTS

Ledihep  dosage adjustment should not be allowed in severe renal damaged condition. Due to greater exposure of sofosbuvir metabolite causes final stage of renal disease (ERSD).

SIDE EFFECTS

SIDE EFFECTS

Elevation of bilirubin Elevation of lipase Elevation of creatine kinase Severe bradycardia HBV reactivation Chest pain Dizziness Trouble in breathing Fatigue Headache Nausea Diarrhea Insomnia

SAFETY PRECAUTION

THE PATIENTS WHO ARE CO INFECTED WITH HBV/HCV WILL CAUSE EXPOSURE OF HEPATITIS B VIRUS REOCCURRENCE

This fatal case occurs in patient who are undergoing anti-viral treatment (during or completion of therapy) or fail to take the anti-hepatitis B drugs. To avoid this problem patient should be examine the HBsAg & anti-HBC counts before start the therapy. Monitor the hepatic function test frequently. Initiation of proper anti-hepatitis B viral therapy occurs.

SEVERE BRADYCARDIA

This severe condition should be produced by concomitant use of Ledihep  with amiodarone. Overcome the problem by stop this combinational treatment. Counsel the patient before starting the treatment about the risk due to this combination. Check ECG periodically. Initiate supportive measures.

EXPOSURE OF ADVERSE EFFECT DUE TO COMBINATION OF LEDIHEP  WITH P-GP INDUCERS

This combination causes loss of therapeutic effect of Ledihep  . To avoid the problem, stop the combination.

EXPOSURE OF ADVERSE EFFECTS ASSOCIATED WITH RIBAVIRIN

Ledihep  ribavirin combination should be avoided. Ribavirin causes fetal damage and concludes as fetal death.

DRUG INTERACTION

Ledipasvir is a component of Ledihep  , which is involved in inhibition of P-gp or BCRP drug transporters. This combination causes elevation of intestinal absorption of these substrates. Ledihep  with P-gp strong inducers, causes decreasing the plasma concentration of component of Ledihep  . Finally leads to loss of effectiveness of Ledihep  . Variation in INR values occurs due to combination of Ledihep  with warfarin. Ledihep  with gastric regulators drug causes decreasing the sofosbuvir & ledipasvir concentration. Avoid this co administration.

Ledihep  with anti-arrhythmic drugs causes increasing the concentration of these drugs. Ledihep  with anti-convulsants or anti-mycobacterials causes decreasing the concentration of both the component of Ledihep  . Ledihep  with anti-retroviral drugs causes increasing the concentration of these retroviral medicines. Ledihep  with herbal supplements like st Johns wort leads to produce the elevation of concentration of st Johns wort and reduced the effect of concentration of Ledihep  and causes loss of therapeutic effect of Ledihep  . Ledihep  with lipid lowering agents causes increasing effect of concentration of these drugs

CONTRAINDICATION

Ledihep  tablet concurrently used with ribavirin should be contraindicated to pregnancy & lactating period. Hypersensitivity reactions should be produced, if patient is contraindicated to the component present in the Ledihep  tablets.

PREGNANCY & LACTATION

Ledihep  pregnancy category is B Ledihep  ribavirin pregnancy category X Ribavirin causes fetal harm and leads to death. Breast feeding should not be recommended.

STORAGE 

The tablet container should be kept at temperature below 30°C Protect from light. Keep the container away from moisture & heat.

OVER DOSAGE

Ledipasvir is more difficult to remove from the body, because it has high protein binding effect. Sofosbuvir circulating metabolite should be eliminate with the range of 54% by undergoing hemodialysis. In case of over dosage of Ledihep  , patient should be; Provide with general supportive measures Monitor the manifestation due to over dosage of Ledihep  Undergo hemodialysis

MISSED DOSE

The missed dose of Ledihep  should be avoided. In case of missed dose, patient must be consult with medical practitioner and follow the instructions. Maintain the regular dosing schedule.