NEWER DRUGS APPROVED BY US-FDA FOR 2014: A DEEP INSIGHT(PART-I)PRESENTED BY:VISHNU.R.NAIR,4TH YEAR PHARM.D,NATIONAL COLLEGE OF PHARMACY(NCP)

GENERAL INTRODUCTION INNOVATION drives PROGRESS As far as INNOVATION regarding development of new drugs & therapeutic biological products is concerned, FDA’S CENTER FOR DRUG EVALUATION & RESEARCH(CDER) supports the pharmaceutical industry at every step of the process

With its understanding of the science used to create new products, testing & manufacturing procedures, along with the diseases & conditions, that new products are designed to treat, FDA provides SCIENTIFIC & REGULATORY ADVICE, required to bring new therapies to market

Thus, I am going to present 20(out of 41) NEWER DRUGS APPROVED BY US-FDA for the year 2014……………………………………………………

NEWER DRUGS APPROVED BY US-FDA FOR 2014……………………………………………

1. DAPAGLIFLOZIN(FARXIGA):i. CLASS : ANTI-DIABETICS; SGLT-2 INHIBITORSii. APPROVED ON: 8/1/2014iii. INDICATION: To improve GLYCEMIC CONTROL, along with diet & exercise, in

adults with TYPE-II DIABETES MELLITUSiv. MOA:- SGLT-2(Sodium glucose transporter-2) present in PCT Responsible for MAXIMUM REABSORPTION of GLUCOSE from tubular lumen Harmful for DM patients

- Drug BLOCKS SGLT-2 REDUCES GLUCOSE REABSORPTION REDUCES RENAL THRESHOLD FOR GLUCOSE REDUCES URINARY GLUCOSE EXCRETION

v. ADRs:- RENAL IMPAIRMENT (>10%)- UTI (4.3-5.7%)- DYSLIPIDAEMIA (2.1-2.5%)

vi. DRUG INTERACTION:- DRUG + CHLORPROPAMIDE Increased risk of HYPOGLYCEMIAvii. CONTRAINDICATIONS:- GFR < 30 ml/min/1.73 meter sq.- ESRD- Patients , on DIALYSISviii. DOSE:- INITIAL DOSE: 5 mg PO every day, in morning, with/ without food- Increase dose to 10 mg PO every day(if GFR > 60 ml/min)…………..

2. TASIMELTEON(HETLIOZ):i. APPROVED ON : 31/01/2014ii. CLASS : SEDATIVE/ HYPNOTICS; MELATONIN RECEPTOR AGONISTSiii. INDICATION : To treat NON-24 –HOUR SLEEP-WAKE DISORDER, in

TOTALLY BLIND INDIVIDUALSiv. MOA:- NON-24 : “CHRONIC, CIRCADIAN RHYTHM(body clock) disorder(in the blind); associated with PROBLEMS in SLEEP TIMINGS”

- Daily exposure to LIGHT-DARK CYCLE SYNCHRONIZES CIRCADIAN CLOCK , with the 24-hour day

- Absence of light perception SLEEP-WAKE CYCLES SHIFT DESYNCHRONIZATION of CIRCADIAN CLOCK OCCURS

- DRUG binds, with HIGH AFFINITY to MT-1 & MT-2 receptors in SUPRACHIASMATIC NUCLEUS of BRAIN Causes SYNCHRONIZATION of body’s MT & CORTISOL CIRCADIAN RHYTHMS Alleviates NON-24 HOUR DISORDER

v. ADRs:- Headache (10%)- Increased ALT levels (10%)- Nightmares/ abnormal dreams (10%)vi. INTERACTION:- DRUG + FENTANYL Increased risk of SEDATION, RESPIRATORY DEPRESSION & COMA

vii. DOSE:- 20 mg PO, every day, before bedtime, at the SAME TIME EVERY NIGHT…………………

3. ELOSULFASE ALFA(VIMIZIM):i. APPROVED ON: 14/02/2014ii. INDICATION: To treat MUCOPOLYSACCHARIDOSIS TYPE “IV A”(MORQUIO

‘A’ SYNDROME)iii. CLASS : ENZYMES, METABOLICiv. MOA:- MORQUIO ‘A’ SYNDROME is a RARE, INHERITED DISORDER, that affects major

organ systems in the body- Disease is a form of MUCOPOLYSACCHARIDOSIS, which is a type of LYSOSOME STORAGE DISEASE

- People born with MORQUIO ‘A’ Can’t break down GAG(Glycosaminoglycans) molecules, due to DEFICIENCY of N-ACETYL, GALACTOSAMINE-6-SULFATASE (GALNS)

- GALNS Breaks down/ recycles materials that the body CAN’T USE- Enzyme deficiency INCREASES ACCUMULATION of GAG SUBSTRATES (KERATIN SULFATE (KS); CHONDROITIN SULFATE (C6S)) in LYSOSOMAL compartment of cells causes WIDESPREAD ORGAN DYSFUNCTION

- DRUG Provides EXOGENOUS ENZYME GALNS GALNS is taken up into LYSOSOMES Increases CATABOLISM of KS & C6S

v. ADRs:- Pyrexia (33%)- Headache (31%)- Abdominal pain (21%)vi. DOSE:2 mg/kg i.v, infused for 3.5-4.5 hours………………………………….

A PERSON, AFFECTED BY MORQUIO ‘A’ SYNDROME

4. DROXIDOPA (NORTHERA):i. APPROVED ON: 18/02.2014ii. INDICATION : To treat NEUROGENIC ORTHOSTATIC HYPOTENSION

(NOH)iii. CLASS : ALPHA & BETA-ADRENERGIC AGONISTiv. MOA:- NOH is a sign of CARDIOVASCULAR AUTONOMIC DYSFUNCTION, that is caused by FAILURE of NORADRENERGIC NEUROTRANSMISSION, caused by AUTONOMIC DYSREGULATION

- Associated with sustained fall of(within 3 minutes of standing):• SYSTOLIC B.P by 20 mm Hg• DIASTOLIC B.P by 10 mm Hg- DRUG NOREPINEPHRINE PRECURSOR Metabolized by DOPA-DECARBOXYLASE to NE distributed throughout body raises SYSTOLIC & DIASTOLIC B.P

v. ADRs:a. Headache (13.2%)b. Dizziness (9.6%)c. HTN (7%)vi. CONTRAINDICATION:d. Hypersensitivityvii. DRUG INTERACTION :e. DRUG + AMPHETAMINE PHARMACODYNAMIC SYNERGISM

Raises BP & HRviii. DOSE: 100 mg TID ;P.O…………………………………..

5. METRELEPTIN FOR INJECTION(MYALEPT):i. CLASS : LEPTIN ANALOGUEii. APPROVED ON : 24.02.2014iii. INDICATION: To treat COMPLICATIONS of LEPTIN DEFICIENCYiv. MOA:- LEPTIN is a hormone, secreted by ADIPOSE TISSUE- LEPTIN informs CNS of status of ENERGY STORES in body- Deficiency of ADIPOSE TISSUE Causes LEPTIN DEFICIENCY Causes LIPODYSTROPHY, HYPERTRIGLYCERIDEMIA, & FAT DEPOSITION in non-adipose tissues (liver, muscle) causes metabolic abnormalities, including insulin resistance

- DRUG RECOMBINANT ANALOG of hormone LEPTIN- DRUG binds to human LEPTIN RECEPTOR Activates it alleviates LIPODYSTROPHY MANIFESTATIONS.

- ADRs:a. Headache (13%)b. Hypoglycemia (13%)c. Reduced weight (13%)- DRUG INTERACTION:a. DRUG + CHLORPROPAMIDE increased risk of HYPOGLYCEMIA- CONTRAINDICATION:a. Hypersensitivity- DOSE :a. For males/females <40 kg weight : 0.06 mg/kg s.cb. For males > 40 kg : 2.5 mg s.cc. For females > 40 kg : 5 mg s.c……………………………..

6. FLORBETABEN F-18 INJECTION (NEURACEQ):i. CLASS : DIAGNOSTIC IMAGING AGENTSii. APPROVED ON : 19.03.2014iii. INDICATION : For PET imaging of brainiv. MOA:- Agent binds to BETA-AMYLOID PLAQUES in brain produces POSITRON SIGNAL Detected by PET SCANNER

v. ADRs:- Injection site pain (3.9%)- Injection site erythema (1.7%)vi. DOSE:300 mBq, by slow i.v bolus………………………………………

7. MILTEFOSINE (IMPAVIDO):i. CLASS : ANTI-LEISHMANIASIS AGENTSii. APPROVED ON: 19.3.2014iii. INDICATION: To treat a tropical disease called LEISHMANIASISiv. MOA:- LEISHMANIASIS is a disease, caused by PROTOZOAN PARASITES of GENUS LEISHMANIA

- Spread by bites of SANDFLIES (Female PHLEBOTOMINE)- Causatives include:a. L. donovanib. L. infantumc. L. chagasi, etc

- Drug interacts with MEMBRANE LIPIDS, PHOSPHOLIPIDS & STEROLS of LEISHMANIA species inhibits CYTOCHROME ‘C’ OXIDASE found in MITOCHONDRIA causes APOPTOSIS-LIKE CELL DEATH……………………..

v. ADRs:- Increased transaminase levels (94%)- Reduced platelet counts (62%)- Motion sickness (29.2%)vi. CONTRAINDICATIONS:- Pregnancy- Hypersensitivity- SJOGREN-LARSSON SYNDROME ( Condition, characterized by DRY, SCALY SKIN[ICHTHYOSIS]; NEUROLOGICAL PROBLEMS; & EYE PROBLEMS)

vii. DOSE:- For weight > 45 kg : 50 mg PO, TID, for 4 weeks- For weight < 45 kg : 50 mg PO, BID, for 4 weeks………………………………

A PERSON, AFFECTED WITH SJOGREN-LARSSON SYNDROME

8. APREMILAST (OTEZLA):i. CLASS : DMARD; PDE-4 INHIBITORSii. APPROVED ON : 21.03.2014iii. INDICATION : To treat adults with ACTIVE PSORIATIC ARTHRITISiv. MOA:- PSORIATIC ARTHRITIS is a type of INFLAMMATORY ARTHRITIS, found in people with PSORIASIS

- Associated with PAIN, SWELLING & STIFFNESS in 1/ more joints- DRUG INHIBITS PDE-4 Increases CYCLIC-AMP Levels Alleviates PSORIATIC ARTHRITIS

v. ADRs:- Diarrhea (7.7-9.3%)- Nausea (7.4-8.9%)- Headache (4.8-5.9%)

vi. INTERACTION:- DRUG + CBZ Reduces drug levels and effectsvii. CONTRAINDICATION:- Hypersensitivityviii. DOSE :- DAY 1 : 10 mg in AM- DAY 2 : 10 mg in AM & PM- DAY 3 : 10 mg in AM , & 20 mg in PM- DAY 4 : 20 mg in AM & PM- DAY 5 : 20 mg in AM & 30 mg in PM- DAY 6 , and thereafter : 30 mg PO BID………………………………………

9. ALBIGLUTIDE(TANZEUM):i. APPROVED ON : 15.04.2014ii. INDICATION : To improve GLYCEMIC CONTROL, along with diet in

exercise, in adults, with type II DMiii. CLASS : ANTIDIABETICS; GLP-1 AGONISTSiv. MOA:- DRUG Agonizes GLP-1 RECEPTOR increases GLUCOSE-DEPENDANT INSULIN SECRETION

v. ADRs:- URTI (13%)- Diarrhea (10.5%)vi. INTERACTION :- DRUG + ARIPIPRAZOLE ANTAGONISTIC EFFECT

vii. CONTRAINDICATIONS:a. Hypersensitivityb. Personal/family history of MEDULLARY THYROID CARCINOMAc. MULTIPLE ENDOCRINE NEOPLASIA TYPE-II(MEN-II)viii. DOSE:30 mg s.c; once weekly increase to 50 mg once weekly(if glycemic control is not established)………………………….

10. RAMUCIRUMAB (CYRAMZA):i. APPROVED ON : 21.04.2014ii. INDICATION : To treat patients with ADVANCED STOMACH CANCER /

GASTROESOPHAGEAL JUNCTION ADENOCARCINOMAiii. CLASS : ANTINEOPLASTICS; VEGF-INHIBITORiv. MOA:- DRUG specifically binds to VEGF RECEPTOR TYPE 2 Blocks binding of VEGFR ligands (VEGF-A; VEGF-C; VEGF-D) inhibition of LIGAND- STIMULATED ACTIVATION of VEGF-2 Inhibits PROLIFERATION & MIGRATION of ENDOTHELIAL CELLS

v. ADRs:- Fatigue (57%)- Neutropenia (54%)- Stomatitis (37%)

vi. DOSE:a. For NON- SMALL CELL LUNG CANCER (NSCLC) 10 mg/kg i.v;

infused over 1 hour prior to DOCETAXEL (75 mg/meter sq.) infusion on DAY 1 of a 21-day cycle

b. For GASTRIC CANCER : 8 mg/kg i.v every 2 weeks; infused over 1 hour; along with PACLITAXEL (80 mg/meter sq.) ………………………….

11. SILTUXIMAB(SYLVANT):i. APPROVED ON: 23.04.2014ii. INDICATION : To treat patients with MULTICENTRIC CASTLEMAN’S

DISEASE(MCD)iii. CLASS : IMMUNOMODULATORS; ANTINEOPLASTICS; MONOCLONAL

ANTIBODYiv. MOA:- MCD is a LYMPHOPROLIFERATIVE DISORDER that involves HYPERACTIVATION of the immune system, excessive release of CYTOKINES, proliferation of B & T CELLS and MULTIPLE ORGAN SYSTEM DYSFUNCTION

- May be localized to a SINGLE LYMPH NODE/ MULTIPLE- Associated with LYMPH NODE HYPERPLASIA, AUTOIMMUNE DISORDERS, & MALIGNANCIES

- Also known as LYMPHOID HAMARTOMA, ANGIOFOLLICULAR LYMPH NODE HYPERPLASIA , etc.

- DRUG is an IL-6 blocker- DRUG binds to IL-6 Prevents binding of IL-6 to its receptors alleviates symptoms of CASTLEMAN’S DISEASE

v. ADRs:- Pruritus (28%)- Hyperuricemia (11%)- Thrombocytopenia (9%)vi. INTERACTION:- DRUG + CHOLERA VACCINE Increases risk of INFECTION, by IMMUNOSUPPRESSIVE EFFECTS

vii. CONTRAINDICATION :- Severe hypersensitivityviii. DOSE:11 mg/kg i.v every 3 weeks; infused for 1 hour……………………..

12. CERITINIB(ZYKADIA):i. APPROVED ON: 29.4.2014ii. INDICATION : To treat patients, with LATE-STAGE (METASTATIC) NSCLCiii. CLASS :ANTINEOPLASTICS; ANAPLASTIC LYMPHOMA KINASE

INHIBITORiv. MOA:- NSCLC is any type of EPITHELIAL LUNG CANCER, other than SMALL CELL LUNG CARCINOMA (SCLC)

- Usually INSENSITIVE to CHEMOTHERAPY, and treated with SURGERY- Types include SQUAMOUS CELL CARCINOMA; LARGE CELL CARCINOMA; & ADENOCARCINOMA

- DRUG is a TYROSINE KINASE INHIBITOR- DRUG Binds to ALK(ANAPLASTIC LYMPHOMA KINASE) inhibits AUTOPHOSPHORYLATION & ALK-MEDIATED PHOSPHORYLATION required for PROLIFERATION of ALK-DEPENDANT CANCER CELLS

v. ADRs:- Diarrhea (86%)- Reduced hemoglobin (84%)- Increased ALT & AST (80%)vi. INTERACTION:DRUG + FLIBANSERIN Severe HYPOTENSION/ SYNCOPEvii. DOSE:750 mg PO every day……………………..

13. VORAPAXAR(ZONTIVITY):i. APPROVED ON : 08.05.2014ii. INDICATION : To reduce the risk of STROKE & HEART ATTACKS in

HIGH-RISK PATIENTSiii. CLASS : ANTIPLATELET AGENTS; CARDIOVASCULAR; PROTEASE

ACTIVATED RECEPTOR-1 (PAR-1) INHIBITORS ; THROMBIN INHIBITORS

iv. MOA:- DRUG Reversibly blocks PAR-1 RECEPTOR (expressed on PLATELETS)

- DRUG inhibits THROMBIN RECEPTOR AGONIST PEPTIDE (TRAP)-induced PLATELET AGGREGATION

v. ADRs:- Anemia (5%)- Depression (2.4%)

vi. INTERACTION:DRUG + DEFIBROTIDE PHARMACODYNAMIC SYNERGISMvii. CONTRAINDICATION:- Active pathological bleedingviii. DOSE : 2.08 mg PO every day (in combination with ASPIRIN/ CLOPIDOGREL)…………….

14. VEDOLIZUMAB(ENTYVIO):i. APPROVED ON : 20.05.2014ii. INDICATION : To treat adult patients with moderate-severe ULCERATIVE

COLITIS & CROHN’S DISEASEiii. CLASS: IBD AGENTS; MONOCLONAL ANTIBODIES; INTEGRIN

BLOCKERSiv. MOA:- DRUG Recombinant humanized monoclonal antibody- DRUG binds specifically to ALPHA-4;BETA-7 INTEGRIN Blocks interaction of above INTEGRIN with MAdCAM-1(Mucosal adhesion addressin cell adhesion molecule) inhibits migration of MEMORY-T-LYMPHOCYTES across endothelium , into inflamed gastrointestinal parenchymal tissue

v. ADRs:- Nasopharyngitis (13%)- Headache (12%)

vi. INTERACTION:DRUG + ADALIMUMAB increased IMMUNOSUPPRESSIVE EFFECTS increased risk of INFECTIONSvii. CONTRAINDICATION:- Hypersensitivityviii. DOSE: a. Initially 300 mg i.v at weeks 0,2,6 b. Maintenance dose : 300 mg i.v ; every 8 weeks…………………..

15. DALBAVANCIN (DALVANCE):i. APPROVED ON : 23.05.2014ii. INDICATION : To treat adults with skin infectionsiii. CLASS : GLYCOPEPTIDE ANTIBIOTICSiv. MOA:- DRUG Binds to D-ALANYL-D-ALANINE TERMINUS of PENTAPEPTIDE in cell wall PEPTIDOGLYCAN of susceptible organism prevents CROSS-LINKING Interferes with CELL-WALL SYNTHESIS BACTERICIDAL EFFECT

- Usually BACTERICIDAL against STAPHYLOCOCCUS AUREUS & STREPTOCOCCUS PYOGENES

v. ADRs:- Nausea (5.5%)- Eosinophilia (<2%)- Hematochezia (<2%)

vi. CONTRAINDICATION:- Hypersensitivityvii. DOSE:- 1500 mg i.v; infused over 30 minutes…………………………

16. EFINACONAZOLE(JUBLIA):i. APPROVED ON: 06.06.2014ii. INDICATION : To treat mild-moderate ONYCHOMYCOSISiii. CLASS : TOPICAL ANTIFUNGALS; TRIAZOLESiv. MOA:- ONYCHOMYCOSIS, also known as TINEA UNGUIUM, is a fungal infection of the NAIL

- Mainly TOENAILS are affected- DRUG inhibits FUNGAL LANOSTEROL 14-ALPHA DEMETHYLASE inhibits synthesis of ERGOSTEROL cell membrane integrity lost cell death

v. ADRs:- Application site dermatitis (2.2%)- Application site pain (1.1%)

vi. DOSE:For TRICHOPHYTON RUBRUM & TRICHOPHYTON MENTAGROPHYTES infection : 10% topical solution…………………

A PERSON, AFFECTED WITH ONYCHOMYCOSIS

17. TEDIZOLID PHOSPHATE (SIVEXTRO):i. APPROVED ON : 20.06.2014ii. INDICATION: To treat adults with SKIN INFECTIONSiii. CLASS : OXAZOLIDINONE ANTIBIOTICSiv. MOA:- DRUG Binds to 50S subunit of bacterial RIBOSOME Causes inhibition of PROTEIN SYNTHESIS

v. ADRs:- Hemoglobin< 10.1 mg/dl (3.1%)- Reduced platelet count (2.3%)- Palpitations (<2%)vi. DOSE :200 mg PO/ i.v every day; for 6 days…………………….

18. TAVABOROLE (KERYDIN):i. APPROVED ON : 07.07.2014ii. INDICATION : For the topical treatment of ONYCHOMYCOSIS of the

TOENAILSiii. CLASS : TOPICAL ANTIFUNGALS; OXABOROLE DERIVATIVEiv. MOA:- DRUG inhibits AMINOACYL- t-RNA SYTHETASE (AARS) inhibits PROTEIN SYNTHESIS

v. ADRs:- Application site exfoliation (2.7%)- Application site erythema (1.6%)vi. DOSE :0.5% topical solution(apply to affected toenails daily for 48 weeks)………………..

19. EMPAGLIFLOZIN (JARDIANCE) :i. APPROVED ON : 01.08.2014ii. INDICATION : To improve glycemic control in adults with TYPE II DMiii. CLASS : ANTI-DIABETICS; SGLT-2 INHIBITORSiv. MOA:- DRUG Blocks SGLT-2 reduces GLUCOSE REABSORPTION Reduces RENAL THRESHOLD for glucose reduces URINARY GLUCOSE EXCRETION

v. ADRs:- UTI (7.6-9.3%)- Increased urination (3.2-3.4%)- URTI (5.4-6.4%)vi. INTERACTION:DRUG + AMILORIDE PH. SYNERGISM increased URINE VOLUME Increased risk of VOLUME DEPLETION…………….

vii. CONTRAINDICATIONS:- Hypersensitivity- ESRD- Patients on DIALYSISviii. DOSE:- 10 mg PO every day, in the morning, taken with/ without food………………….

20. ORITAVANCIN (ORBACTIV):i. APPROVED ON : 06.08.2014ii. INDICATION : To treat adults with SKIN INFECTIONSiii. CLASS : GLYCOPEPTIDE ANTIBIOTICSiv. MOA:- Shows 3 actions:a. DRUG binds to PEPTIDOGLYCAN RESIDUES Inhibits

POLYMERIZATION step of cell wall biosynthesisb. DRUG Binds to PEPTIDE-BRIDGING SEGMENTS OF CELL WALL

Inhibits TRANSPEPTIDATION(CROSS-LINKING) STEP OF CELL WALL BIOSYNTHESIS

c. DRUG disrupts BACTERIAL MEMBRANE INTEGRITY causes DEPOLARIZATION, INCREASED MEMBRANE PERMEABILITY & CELL DEATH

v. ADRs:- Infusion site phlebitis (2.5%)- Increased ALT (2.8%)- Headache (7.1%)vi. INTERACTION :DRUG + CHOLERA VACCINE PHARMACODYNAMIC ANTAGONISMvii. CONTRAINDICATION:Hypersensitivityviii. DOSE: 1200 mg i.v, given over 3 hours……………………………………

BIBLIOGRAPHY/ REFERENCE www.fda.gov.in www.drugs.com www.drugbank.com www.rxlist.com www.webmd.com

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