SAURABH WANI

PGDPM

GARWARE COLLEGE

ASSIGNMENT – OVERVIEW OF MEDICINE

CARING AND CURING

INTRODUCTION

Novartis (NYSE: NVS) is a world leader in the research and development of products to protect and improve health and well-being. The company has core businesses in pharmaceuticals, vaccines, consumer health, generics, eye care and animal health

Headquartered in Basel, Switzerland, Novartis employs nearly 115 000 people in over 140 countries worldwide to help save lives and improve the quality of life. The Group is present in India through Novartis India Limited,

listed on the Mumbai Stock Exchange and its wholly owned subsidiaries Novartis Healthcare Private Limited, Sandoz Private Limited and Chiron Behring Vaccines Private Limited.

HISTORY OF NOVARTIS

Novartis was created in 1996 through the merger of Ciba-Geigy and Sandoz,

two companies with a rich and diverse corporate history. Throughout the

years, Novartis and its predecessor companies have discovered and

developed many innovative products for patients and consumers worldwide.

Novartis has been in India since 1947. The Group operates in India through

four entities namely Novartis India Limited, listed on the Mumbai Stock

Exchange, Novartis Healthcare Private Limited, Sandoz Private Limited and

Chiron-Behring Vaccine Private Limited. In India Novartis has a presence in

pharmaceuticals, generics (pharmaceutical products that are off patent),

Vaccines, OTC (over-the-counter medicines), eyecare and Animal Health.

PRESENT STATUS

Novartis India has reported a standalone sales turnover of Rs 212.85 crore and a net profit of Rs 24.41 crore for the quarter ended Mar '13. Other income for the quarter was Rs 22.30 crore.For the quarter ended Mar 2012 the standalone sales turnover was Rs 204.48 crore and net profit was Rs 32.91 crore., and other income Rs 27.96 crore.Novartis India shares closed at 575.60 on May 14, 2013 (BSE) and has given -14.13% returns over the last 6 months and -18.31% over the last 12 months

REMARKABLE ACHIVEMENTS

{1} Novartis Pharmaceutical US chosen for 2013 list of best employers for mothers .

{2} Novartis was accredited as the first global CEO Cancer Gold Standard employer by the CEO Roundtable on Cancer .

{3} Award of Excellence for Innovations in Diversity

{4} Fortune 500 rated Novartis as the third largest healthcare company worldwide.

{5} Novartis enters the list of the 50 preferred employers among European Engineering/IT students .

{6} SMS for Life has been recognized by Sustainia to Novartis as one of the world's top 100 innovative, sustainable solutions for 2013

{7} Novartis Pharmaceuticals Corporation recognized among the best employers for diversity in the US in Diversity Inc's Top 50 Companies for Diversity

{8} Novartis ranked top pharmaceutical company in Fortune's World's Most Admired Companies 2013 for the third time in a row.

{9} Novartis recognized as having the "Most Innovative Pipeline" for the third consecutive year.

{10} Novartis is a member of the 2012/13 Dow Jones Sustainability World Index, which recognizes the leading sustainability-driven companies worldwide.

{11} Novartis awarded two of the prestigious SCRIP Awards for excellence in innovation and R&D

{12} Novartis is the greenest healthcare company worldwide

{13} Novartis ranked no. 11 on Science's Top 20 Employers list.

{14} Novartis brand ranks no. 39 globally and no. 2 in Switzerland.

{15} Novartis named one of the top 50 most attractive employers worldwide for engineering students by Universum .

{16} Novartis named the most transparent large healthcare company by Transparency International

{17} Novartis wins Ethical Corporation Award for Best Corporate/NGO Partnership for SMS for Life

{18} Novartis ranks again as the most respected healthcare company in "The World's Most Respected Companies" by US business magazine Barron's

{19} Novartis again ranked No. 1 employer in Switzerland for students in Natural Science by Swiss business magazine Bilanz and Universum

{20} Novartis is No. 2 in Pharm Exec's 2012 ranking of the top 50 pharma companies based on Rx sales.

{21} Novartis CEO Joseph Jimenez receives "CEO in Action" award for commitment and engagement in Novartis Diversity & Inclusion initiatives.

MOST VISIBLE PRODUCTS OF NOVARTIS

{1} GALVUS - PRICE OF GALVUS 50 mg RS 586.04

Galvus® (vildagliptin) is approved in more than 100 countries across Europe, Asia Pacific, Africa and Latin America . It is indicated for the treatment of type 2 diabetes as a monotherapy and in combination with metformin, a sulphonylurea, a thiazolidinedione or insulin. Specific indications vary by country.

SALES OF GALVUS Novartis believes that Galvus will be one of the drugs that will offset the loss of revenues from patent expirations, notably on its biggest-seller, the blood pressure lowerer Diovan (valsartan). Galvus generated sales of $677 million, a rise of 66% and this despite not being available in the USA.

MECHANISM OF ACTION OF GALVUS

Vildagliptin is indicated in the treatment of type 2 diabetes mellitus in adults. Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycemic control. Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor. The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

ROUTE OF ADMINISTRATION AND DOSSAGE OF GALVUS

The recommended dose of vildagliptin is 50mg once daily administered in the morning . Doses higher than 100mg are not recommended. If a dose of Galvus is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a thiazolidinedione have not been established . GALVUS is administered by Oral use Galvus can be administered with or without a meal

PHARMACODYNAMICS By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin 50-100mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels. By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion. The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.

{2} DIOVAN 80 mg – PRICE OF DIOVAN RS 616.98

MECHANISM OF ACTION OF DIOVAN Valsartan {DIOVAN} is an oral medication that is used to treat high blood pressure and congestive heart failure. It belongs to a class of drugs called angiotensin receptor blockers (ARBs). Angiotensin, formed in the blood by the action of angiotensin converting enzyme (ACE), is a powerful chemical that attaches to angiotensin receptors found in many tissues but primarily on smooth muscle cells of blood vessels. Angiotensin's attachment to the receptors causes the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Valsartan blocks the angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure.

SALES OF DIOVAN Global sales for DIOVAN 80 Mg were approximately $5000 million

ROUTE OF ADMINISTRATION AND DOSSAGE OF DIOVAN DIOVAN is administered by ORAL routeThe usual dose of valsartan for adults with high blood pressure is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks. For congestive heart failure, the usual dose is 40 mg twice daily. The doses may be increased to 80-160 mg twice daily. The initial dose after a heart attack is 20 mg twice daily. The dose may be increased to 160 mg twice daily if tolerated without side effects

PHARMACODYNAMICS

Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients.Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.

{3} TEGRETOL 100 Mg – PRICE OF TEGRETOL 100 mg RS 10.10

MECHANISM OF ACTION Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to

control the pain of trigeminal neuralgia. The principal metabolite of Tegretol carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established

Sales of TEGRETOL 100mg is $413 million

ROUTE OF ADMINISTRATION AND DOSSAGE OF TEGRETOL100

Tegretol is given orally, usually in two or three divided doses. Tegretol may be taken during, after or between meals, with a little liquid e.g. a glass of water. Tegretol should be taken in a number of divided doses although initially 100-200mg once or twice daily is recommended. This may be followed by a slow increase until the best response is obtained

PHARMACODYNAMICS

Therapeutic class: Anti-epileptic, neurotropic and psychotropic agent Dibenzazepine derivative.

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalisation; generalised tonic-clonic seizures, as well as combinations of these types of seizures.

The mechanism of action of carbamazepine, the active substance of Tegretol, has only been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarised neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine

{4} FEMARA – PRICE OF FEMARA 2.5mg RS 1986.00

MECHANISM OF ACTION LETROZOLE is an oral non - steroidal aromatase inhibitor for the treatment of hormonally responsive breast cancer after surgeryEstrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

SALES TURNOVER OF FEMARA $937 million

ROUTE OF ADMINISTRATION AND DOSSAGE OF FEMARA

The recommended dose of Femara (letrozole tablets) is one 2.5 mg tablet administered once a day, without regard to meals. In patients with advanced disease, treatment with Femara should continue until tumor progression is evident. And Femara is administered orally

PHARMACODYNAMICS

In postmenopausal patients with advanced breast cancer, daily doses of 0.1

mg to 5 mg Femara suppress plasma concentrations of estradiol, estrone,

and estrone sulfate by 75%-95% from baseline with maximal suppression

achieved within two-three days. Suppression is dose-related, with doses of

0.5 mg and higher giving many values of estrone and estrone sulfate that

were below the limit of detection in the assays. Estrogen suppression was

maintained throughout treatment in all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is no

impairment of adrenal steroidogenesis. No clinically-relevant changes were

found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol,

17-hydroxy-progesterone, ACTH or in plasma renin activity among

postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5

mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment

with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any

attenuation of aldosterone or cortisol production. Glucocorticoid or

mineralocorticoid supplementation is, therefore, not necessary. No changes

were noted in plasma concentrations of androgens (androstenedione and

testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5

mg single doses of Femara or in plasma concentrations of androstenedione

among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg.

This indicates that the blockade of estrogen biosynthesis does not lead to

accumulation of androgenic precursors. Plasma levels of LH and FSH were

not affected by letrozole in patients, nor was thyroid function as evaluated

by TSH levels, T3 uptake, and T4 levels

{5} GLIVEC – PRICE OF GLIVEC 400 mg RS 1371.73

MECHANISM OF ACTION OF GLIVEC Imatinib is a small molecule kinase inhibitor. Glivec film-coated tablets contain imatinib mesylate 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl- 1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is

Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity. There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor). In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed

bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity. The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation. Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions. The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.

SALES TURNOVER OF GLIVEC $3100 million

ROUTE OF ADMINISTRATION AND DOSSAGE OF GLIVEC 400

Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg should be administered once daily dose of 800 mg should be administered as 400 mg twice a day. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg

(given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

PHARMACODYNAMICS

Imatinib is an antineoplastic agent used to treat chronic myelogenous leukemia. Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of Abl with Bcr (breakpoint cluster region), termed Bcr-Abl. As this is now a continuously active tyrosine kinase, Imatinib is used to decrease Bcr-Abl activity