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Sofosbuvir 400mg Velpatasvir 100mg

Velpaclear

Strength/Dose (in mg or ml) Strength - 400 Mg / Dosage form - Tablets

Velpaclear

Each film coated tablet contains:
Sofosbuvir 400 mg
Velpatasvir 100 mg
Excipients q.s.
Colours: Indigo Carmine Aluminium Lake, Brilliant Blue FCF Aluminium Lake & Titanium Dioxide I.P.

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DESCRIPTION :


Sofosbuvir :

Sofosbuvir is a nucleotide analog hepatitis C virus nonstructural protein 5B (HCV NS5B) polymerase inhibitor. The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5 (2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy) (phenoxy)phosphorylamino)propanoate. It has a molecular formula of C H FN O P and a molecular weight of 529.45.

Velpatasvir :

Velpatasvir is a HCV NS5A inhibitor. The IUPAC name for velpatasvir is Methyl {(1R)-2-[(2S,4S)-2-(5-{2 [(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5 -methylpyrrolidin-2-yl] 1,11- dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4 (methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate. It has a molecular formula of C H N O and a molecular 49 54 8 8 weight of 883.0.

PHARMACOLOGIC PROPERTIES :

CLINICAL PHARMACOLOGY:

Mechanism of Action:

Sofosbuvir :

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. Velpaclear is a GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir :

Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. Velpaclear Tablets In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

DOSAGE FORM :

Velpaclear Tablets for oral use :

INDICATION :

Velpaclear Tablets are indicated for the treatment of adult patients with chronic Hepatitis C Virus, Genotype 1,2,3,4,5 or 6 infection:
* Without cirrhosis or with compensated cirrhosis
* With decompensated cirrhosis for use in combination with Ribavirin

DOSAGE AND ADMINISTRATION :

The recommended dosage of velpaclear is one tablet taken orally, once daily with or without food.
Recommended treatment and duration for all HCV Genotypes
* When administered with Velpaclear , the recommended dosage of ribavirin is based on weight (administered with food): 1000 mg per day for patients less than 75 kg and 1200 mg for those weighing at least 75 kg, divided and administered twice daily. The dosage of ribavirin can be adjusted based on hemoglobin and creatinine clearance. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
Patients without cirrhosis and patients with compensated cirrhosis - Sofosbuvir + Velpatasvir for 12 weeks Patients without cirrhosis and patients with compensated cirrhosis - Sofosbuvir + Velpatasvir + ribavirin* for 12 weeks

Pharmacokinetics :

Absorption :

The pharmacokinetic properties of the Sofosbuvir, GS-331007 and Velpatasvir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C infection.
Following oral administration of Velpaclear (sofosbuvir/velpatasvir) sofosbuvir was absorbed quickly and the peak median plasma concentration was observed 1 hour post dose. Median peak concentration of GS-331007 was observed 3 hours post dose.
Velpatasvir median peak concentrations were observed at 3 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected patients, mean steady-state AUC0-24 for sofosbuvir (n = 982), GS-331007 (n = 1,428) and velpatasvir (n = 1,425) were 1,260, 13,970 and 2,970 ng.h/mL, respectively. Steady-state Cmax for sofosbuvir, GS-331007 and velpatasvir were 566, 868 and 259 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively in HCV-infected patients.

Effects of food :

Relative to fasting conditions, the administration of a single dose of sofosbuvir and velpatasvir with a moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal resulted in a 34% and 21% increase in velpatasvir AUC respectively, and a 31% and 5% increase in velpatasvir C , respectively. The moderate or high fat meal increased sofosbuvir AUC by 60% and 78%, respectively, but did not 0-¥, max 0-¥ substantially affect the sofosbuvir C . The moderate or high fat meal did not alter GS-331007 AUC but resulted in a 25% and 37% decrease in its Cmax, respectively. The response rates in Phase 3 studies max 0-¥, were similar in HCV-infected patients who received Velpaclear (sofosbuvir and velpatasvir) with food or without food. Sofosbuvir and velpatasvir can be administered without regard to food.

Distribution :

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 mg/mL to 20 mg/mL. Protein binding of GS-331007 was minimal 14 14 in human plasma. After a single 400 mg dose of [ C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [ C]-radioactivity was approximately 0.7.Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 mg/mL to 1.8 mg/mL. After a single 100 mg dose of [14C]-velpatasvir in healthy 14 subjects, the blood to plasma ratio of [ C]-radioactivity ranged between 0.52 and 0.67.

Metabolism :

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosysthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total systemic exposure.

Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug. The monohydroxylated and desmethylated velpatasvir were the metabolites identified in human plasma. Unchanged velpatasvir is the major species present in faeces.

Excretion :

14 Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the [ C]-radioactivity was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Sofosbuvir/Velpatasvir were 0.5 and 25 hours, respectively. 14 Following a single 100 mg oral dose of [14C]-velpatasvir, mean total recovery of the [ C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the faeces and urine, respectively. Unchanged velpatasvir was the major species in faeces accounting for a mean of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and desmethylated velpatasvir (3.0%). These data indicate that biliary excretion of parent drug was a major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of sofosbuvir and velpatasvir was approximately 15 hours

CONTRAINDICATIONS :

Hypersensitivity to the sofosbuvir or velpatasvir or to any of the excipients of the product.
Sofosbuvir and velpatasvir with ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated.

Use with potent P-gp and potent CYP inducers

Medicinal products that are potent P-glycoprotein (P-gp) or potent cytochrome P450 (CYP) inducers (rifampicin, rifabutin, St. John's wort [Hypericum perforatum], carbamazepine, phenobarbital and phenytoin). Co-administration will significantly decrease sofosbuvir or velpatasvir plasma concentrations and could result in loss of efficacy of sofosbuvir and velpatasvir

WARNINGS AND PRECAUTIONS:

Velpaclear should not be administered concurrently with other medicinal products containing sofosbuvir.

Severe bradycardia and heart block:

Cases of severe bradycardia and heart block have been observed when sofosbuvir used in combination with another direct acting antiviral (DAA), is used with concomitant amiodarone with or without other medicinal products that lower heart rate. The mechanism is not established. The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus DAAs. Cases are potentially life threatening, therefore amiodarone should only be used in patients on sofosbuvir and velpatasvir when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.

Patients who have previously failed therapy with an NS5A-containing regimen.

There are no clinical data to support the efficacy of sofosbuvir and velpatasvir for the treatment of patients who have failed treatment with a regimen containing another NS5A inhibitor. However, on the basis of NS5A resistance associated variants (RAVs) typically seen in patients who have failed therapy with other NS5A inhibitor containing regimens, the in vitro pharmacology of velpatasvir, and the outcomes of sofosbuvir and velpatasvir treatment in NS5A-naïve patients with baseline NS5A RAVs enrolled into the clinical studies, treatment with sofosbuvir + velpatasvir + Ribavirin for 24 weeks can be considered for patients who have failed therapy on an NS5A-containing regimen and who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.
Use with moderate P-gp inducers or moderate CYP inducers : Medicinal products that are moderate P-gp or moderate CYP inducers (e.g. oxcarbazepine, modafinil or efavirenz) may decrease sofosbuvir or velpatasvir plasma concentrations leading to reduced therapeutic effect of sofosbuvir and velpatasvir. Co-administration of such medicinal products with sofosbuvir and velpatasvir is not recommended.

Use with certain HIV antiretroviral regimens :

Sofosbuvir and velpatasvir has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir orcobicistat). The safety of tenofovir disoproxil fumarate in the setting of sofosbuvir/velpatasvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with coadministration of sofosbuvir and velpatasvir with the fixed-dose combination tablet containing elvitegravir / cobicistat/emtricitabine / tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with aboosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving sofosbuvir and velpatasvir concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions.
HCV/HBV (hepatitis B virus) co-infection: There are no data on the use of sofosbuvir and velpatasvir in patients with HCV/HBV co-infection. Clearance of HCV may lead to increased replication of HBV in patients who are HCV/HBV co-infected. HBV levels should be monitored during treatment with sofosbuvir and velpatasvir, and during post-treatment follow-up.

CPT Class C cirrhosis: Safety and efficacy of sofosbuvir and velpatasvir has not been assessed in patients with CPT Class C cirrhosis.

Liver transplant patients : The safety and efficacy of sofosbuvir and velpatasvir in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with sofosbuvir and velpatasvir in accordance withthe recommended posology should be guided by an assessment of the potential benefits and risks for the individual patient.

DRUG INTERACTIONS :

Potential for other drugs to affect sofosbuvir and velpatasvir Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not. Sofosbuvir and velpatasvir may be coadministered with P-gp, BCRP, and CYP inhibitors.

Potential for sofosbuvir and velpatasvir to affect other drugs : Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of sofosbuvir and velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.

USE IN SPECIAL POPULATION

Pregnancy : If sofosbuvir and velpatasvir is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy. No adequate human data are available to establish whether or not sofosbuvir/velpatasvir poses a risk to pregnancy outcomes.
Animal studies have shown a possible link to reproductive toxicity with velpatasvir.
As a precautionary measure, sofosbuvir with velpatasvir use is not recommended during pregnancy.
Breast-feeding : It is unknown whether metabolites of sofosbuvir or velpatasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of sofosbuvir in milk. A risk to the newborns/infants cannot be excluded. Therefore, sofosbuvir and velpatasvir should not be used during breast-feeding.

Paediatric Use : Safety and effectiveness of sofosbuvir/velpatasvir have not been established in pediatric patients.

Geriatric Use : No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of sofosbuvir and velpatasvir is warranted in geriatric patients.

Hepatic Impairment : No dosage adjustment of sofosbuvir and velpatasvir is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).

Renal Impairment : No dosage adjustment of sofosbuvir and velpatasvir is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir and velpatasvir have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or End stage renal disease (ESRD) requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD.

ADVERSE EFFECTS :

The following serious adverse reactions are described below and elsewhere in labeling:
Serious symptomatic bradycardia when Sofosbuvir is co-administered with amiodarone and another HCV direct acting antiviral.
Store protected from moisture at a temperature not exceeding 30°C.
Packing Information
Each Bottle contains 28 Tablets, polyester coil and is closed with a Child-Resistant Closure.

SHELF LIFE

• 24 Months
• Dispense in original container.
• Keep container tightly closed.
• Do not use if seal over bottle opening is broken or missing.
• Keep out of reach of children.