DRUG INTERACTIONS-

 • Drug Interactions: Coadministration of DAKLINZA can alter the concentration of other drugs and other drugs may alter the concentration of daclatasvir. Consult the full prescribing information before use for contraindicated drugs and other potential drug-drug interactions. (

Novel Drug Approvals for 2015

1.Name       -  ODOMZO

2. Active Ingredient-     Sonidegib

3. Indication-      To treat patients with locally advanced basal carcinom

Date of Approval     July  2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use DAKLINZA safely and effectively. See full prescribing information for DAKLINZA. DAKLINZA? (daclatasvir) tablets, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

 DAKLINZA is a hepatitis C virus (HCV) NS5A inhibitor indicated for use with sofosbuvir for the treatment of chronic HCV genotype 3 infection.

(1) Limitations of Use: • Sustained virologic response (SVR) rates are reduced in patients with cirrhosis.

ADVERSE REACTIONS---

 Most common adverse reactions (=10%) observed with DAKLINZA in combination with sofosbuvir were headache and fatigue.

CONTRAINDICATIONS-

 • Strong inducers of CYP3

WARNINGS AND PRECAUTIONS--

 • Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Serious symptomatic bradycardia may occur in patients taking amiodarone with sofosbuvir in combination with another HCV direct-acting agent, including DAKLINZA, particularly in patients also receiving beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease.

Coadministration of amiodarone with DAKLINZA in combination with sofosbuvir is not recommended. In patients with no alternative treatment options, cardiac monitoring is recommended.

DOSAGE AND ADMINISTRATION--

 • 60 mg taken orally once daily with or without food in combination with sofosbuvir. (2.1) • Recommended treatment duration: 12 weeks.

 • Dose modification: Reduce dosage to 30 mg once daily with strong CYP3A inhibitors and increase dosage to 90 mg once daily with moderate CYP3A inducers.

DOSAGE FORMS AND STRENGTHS--

• Tablet: 60 mg and 30 mg 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the potential for drug interactions with DAKLINZA, and that some drugs should not be taken with DAKLINZA

Symptomatic Bradycardia-                                                                                         When Used in Combination with Sofosbuvir and Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia, such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems

DAKLINZA Combination Therapy with Sofosbuvir -

Inform patients that DAKLINZA should not be used alone to treat genotype 3 chronic hepatitis C infection. DAKLINZA should be used in combination with sofosbuvir for the treatment of genotype 3 HCV infection 

Missed Doses-                                                                                                                   Instruct patients that if they miss a dose of DAKLINZA, the dose should be taken as soon as possible if remembered within the same day.

However, if the missed dose is not remembered within the same day, the dose should be skipped and the next dose taken at the appropriate time.

For instructions for missed doses of other agents in the regimen, refer to the respective prescribing information.

Hepatitis C Virus Transmission -

Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment should be taken.

Manufactured for: Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Ireland DAKLINZA is a trademark of Bristol-Myers Squibb C

CLINICAL PHARMACOLOGY

1. Mechanism of Action Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus 

2. Pharmacodynamics-                                                                                          Cardiac Electrophysiology-                                                                                                   At a dose 3 times the maximum recommended dose, daclatasvir does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                    The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV.

Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in Cmax, AUC, and Cmin up to 60 mg once daily

Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects.

Population pharmacokinetic estimates for daclatasvir 60 mg once daily in chronic HCV-

Absorption and Bioavailability-                                                                                       In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%.

Effect of Food on Oral Absorption-                                                                                 In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir Cmax and AUC(0-inf) by 28% and 23%, respectively, compared with fasted conditions.

A food effect was not observed with administration of a daclatasvir 60 mg tablet after a low-fat, low-caloric meal (approximately 277 total kcal, 41 kcal from fat, 190 kcal from carbohydrates, 44 kcal from protein) compared with fasted conditions

Distribution-                                                                                                                         With multiple dosing, protein binding of daclatasvir in HCV-infected subjects was approximately 99% and independent of dose at the dose range studied (1-100 mg). In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg [ 13C,15N]-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 L.

Metabolism-                                                                                                                    Daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism.

Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, the majority of radioactivity in plasma was predominately attributed to parent drug (97% or greater). Reference ID: 3797248 12

Elimination-                                                                                                                 Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% of the dose as unchanged daclatasvir)

Following multipledose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg [ 13C,15N]-daclatasvir intravenous dose, the total clearance was 4.2 L/h.

Specific Populations Renal Impairment The pharmacokinetics of daclatasvir following a single 60 mg oral dose was studied in non– HCV-infected subjects with renal impairment.

Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis.

Hepatic Impairment The pharmacokinetics of daclatasvir following a single 30 mg oral dose was studied in non– HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (ChildPugh C) hepatic impairment compared to a corresponding matched control group.

Geriatric Population-                                                                                             pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-79 years) analyzed, age did not have a clinically relevant effect on the pharmacokinetics of daclatasvir 

Pediatric and Adolescent The pharmacokinetics of daclatasvir in pediatric patients has not been evaluated.

Gender Population pharmacokinetic analyses in HCV-infected subjects estimated that female subjects have a 30% higher daclatasvir AUC compared to male subjects. This difference in daclatasvir AUC is not considered clinically relevant.

Race Population pharmacokinetic analyses in HCV-infected subjects indicated that race had no clinically relevant effect on daclatasvir exposure.

Drug Interactions-                                                                                                        Cytochrome P450 (CYP) Enzymes Daclatasvir is a substrate of CYP3A. In vitro, daclatasvir did not inhibit (IC50 >40 µM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.

Daclatasvir did not have a clinically relevant effect on the exposure of midazolam, a sensitive CYP3A substrate. Transporters Daclatasvir is a substrate of P-gp. However, cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir.

Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs used as probes to evaluate potential drug-drug interactions.

The effects of daclatasvir on the Cmax, AUC, and Cmin of the coadministered drug are summarized in Table 5, and the effects of the coadministered drug on the Cmax, AUC, and Cmin of daclatasvir are summarized in Table 6. For information regarding clinical recommendations, 

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary-

No data with DAKLINZA in pregnant women are available to inform a drug-associated risk. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of daclatasvir during organogenesis at doses that produced exposures up to 6 and 22 times, respectively, the recommended human dose (RHD) of 60 mg.

Consider the benefits and risks of DAKLINZA when prescribing DAKLINZA to a pregnant woman.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary-                                                                                               No information regarding the presence of daclatasvir in human milk, the effects on the breastfed infant, or the effects on milk production is available. Daclatasvir is present in the milk of lactating rats 

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAKLINZA and any potential adverse effects on the breastfed infant from DAKLINZA or from the underlying maternal condition.

3. Pediatric Use-                                                                                                              Safety and effectiveness of DAKLINZA in pediatric patients younger than 18 years of age have not been established

4. Geriatric Us-                                                                                                                      Safety was similar across older and younger subjects and there were no safety findings unique to subjects 65 years and older. Sustained virologic response (SVR) rates were comparable among older and younger subjects.

No dosage adjustment of DAKLINZA is required for elderly patients

5. Renal Impairment-                                                                                                       No dosage adjustment of DAKLINZA is required for patients with any degree of renal impairment

6. Hepatic Impairme-                                                                                                         No dosage adjustment of DAKLINZA is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment 

Safety and efficacy of DAKLINZA have not been established in patients with decompensated cirrhosis.

7. Liver Transplant Patients-                                                                                               The safety and efficacy of DAKLINZA combination therapy have not been established  in liver transplant patient

 OVERDOSAGE -

There is no known antidote for overdose of DAKLINZA. Treatment of overdose with DAKLINZA should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status.

Because daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.