Report ms

Worldwide, Multiple Sclerosis is thought to affect more than 2.1 million people. While the disease is not contagious or directly inherited, ep idem io log i s t s—t he scientists who study patterns of disease—have identified factors in the distribution of MS around the world that may eventually help determine what causes the disease. In the United States today, there are approximately 400,000 people with multiple sclerosis (MS)—with 200 more people diagnosed every week.

Extensive research is going on to find the real cause for multiple sclerosis (MS) but still it is hidden. There are many drugs used for treatment of MS in which the higher percentage is for injectable and very limited options with oral. Both type of treatment options are effective but have acceptable side effect profiles.

Interferons and glatiramer acetate lower the relapse rate by only 30%, do not substantially influence disability progression and are not effective in SPMS or primary progressive multiple sclerosis but not free from side effects.

Natalizumab (TYSABRI ) is used in severe RRMS and lowers the relapse rate by 60%, but the risk of developing PML increases with number of natalizumab infusions, and reports of 31 confirmed cases of PML had been received by the FDA, with about 10 deaths. Instead of all currently available therapeutic options for multiple sclerosis have to be administered parenterally. Several oral substances are currently in the late clinical development stage. One of them, GILENYA [FTY720 (also known as fingolimod)] is approved in September 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability.

Moving towards stable MS free life

9th February, 2012

Research in Multiple Sclerosis

“A step towards safe and

secure MS free world”

Page 1 Let’s restore healthy life..!!

Inside this issue:

MS Overview 2

Approved Drugs 5

Approval Status 6

EXTAVIA & BETASERON

7

AVONEX 8

COPAXONE 9

NOVANTRONE 10

REBIF 11

TYSABRI 13

GILENYA 15

Conclusion 16

Reference 17

Page 2

Multiple Sclerosis (MS) Overview

Courses of Multiple Sclerosis

There are four courses of disease, each of which might be mild, moderate or severe. These courses are as follows:

♦ Relapsing Remitting Multiple Sclerosis.

♦ Primary Progressive Multiple Sclerosis.

♦ Secondary Progressive Multiple Sclerosis.

♦ Progressive Relapsing Multiple Sclerosis.

“Relapses with remissions and no disease

progression, approximately 85% of people

are initially diagnosed with RRMS.”

MULTIPLE SCLEROSIS AND MAIN SYMPTOMS

Multiple Sclerosis (MS) is a chronic disabling disease that attacks the central nervous system (CNS) made up of brain, spinal cord and optic nerves.

This is an autoimmune disease in which body’s own defense system attacks the myelin sheath or myelin, the fatty substance that surrounds and protects the nerve fibers in CNS that leads to formation of tissue or sclerosis. The nerve fibers themselves can also be damaged. When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing the variety of symptoms which may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision.


Let’s restore healthy life..!!

Page 3

of their new area. Such data suggest that exposure to some environmental agent that occurs before puberty may predispose a person to develop MS later on.

Persons living in areas farther from equator are more prone to MS as it is believed Vitamin D have a beneficial impact on immune function and may help protect against autoimmune diseases like MS and people living near equator have more amount of Vitamin D as they are more exposed to sunlight the natural source of Vitamin D.

Infectious - A variety of viruses and bacteria, including measles, canine distemper, human herpes virus-6, Eps te in -Barr , and Ch lamydia pneumonia have been examined for the demyelination and inflammation of neurons but none has been yet proved.

Genetic - MS is not a hereditary but studies have shown that there is a higher prevalence of certain genes in populations with higher rates of MS and research for new techniques for

It is believed that a combination of several factors may be involved in causing MS but the exact cause of MS is still unknown. Studies are ongoing in the areas of Immunology (the science of the body’s immune system), Epidemiology (that looks at patterns of disease in the population), and genetics in an effort to answer this important question.

Immunology (the science of the body’s immune system) but exact antigen, or target that the immune cells are sensitized to attack, remains unknown in this area.

Epidemiologists - Scientists who study disease patterns are looking at many factors, including variations in geography, demographics (age, gender, and ethnic background), genetics, infectious causes, and migration patterns, in an effort to understand why.

Studies of migration patterns have shown that people born in an area of the world with a high risk of MS who then move to an area with a lower risk before the age of 15, acquire the risk

Etiology of Multiple Sclerosis

A "cluster" of MS defined as the perception that a very high number of cases of MS have occurred over a specific time period and/or in a certain area. Such clusters of MS - or of other diseases where clusters are occasionally reported - are of interest because they may provide clues to environmental or genetic risk factors which might cause or trigger the disease. So far, cluster studies (in the Faroe Islands, Galion, OH, DePue, IL, and El Paso, TX, among others) have not produced clear evidence for the existence of any causative or triggering factor or factors in MS.


relapses or remissions. Rate of progression may vary over time with occasional plateaus and temporary minor improvements. Approximately 10% of people are diagnosed with PPMS.

Secondary Progressive Multiple Sclerosis (SPMS)

People following initial period of RRMS may develop secondary progressive disease course in which the disease worsens more steadily, with or without occasional flare-ups, minor recoveries (remissions), or plateaus. Approximately 50% of people with relapsing-remitting MS developed this form of the disease course within 10 years before disease modifying medications became

Relapsing Remitting Multiple Sclerosis (RRMS)

People with this type experience clearly defined attacks or relapses, flare-ups or exacerbations of worsening neurological functions followed by partial or complete recovery periods (remissions), during which no disease progression occurs.

Relapses with remissions and no disease progression, approximately 85% of people are initially diagnosed with RRMS.

Primary Progressive Multiple Sclerosis (PPMS)

This course is characterized by slowly worsening of neurological functions from the beginning with no distinct

Courses of Multiple Sclerosis

Progressive Relapsing Multiple Sclerosis (PRMS)

This is a rare course of MS where people experience steadily worsening of disease from the beginning with c l ear a t ta ck s ( re lapse s ) o n neurological functions along the way. There may or may not be any from these relapses, but the disease continues to progress without remissions. Approximately 5% of people are diagnosed with this PRMS.


Diagnostic criteria for Multiple Sclerosis In order to make a diagnosis of MS, the physician must:

♦ Find evidence of damage in at least two separate areas of the central nervous system (CNS), which includes the brain, spinal cord and optic nerves AND

♦ Find evidence that the damage occurred at least one month apart AND

♦ Rule out all other possible diagnoses.

Diagnostic Tools for Multiple Sclerosis ⇒ Medical History and Neurological Examination

⇒ MRI

⇒ Visual Evoked Potential (VEP)

⇒ Cerebrospinal Fluid Analysis

⇒ Blood Tests (rule out other conditions that cause symptoms similar to those of MS, including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS.)

⇒ Other Conditions Cause Demyelination (Damage to Myelin)

Possible treatments for Multiple Sclerosis • Modifying the Disease Course

• Treating Exacerbations (cause for this is inflammation commonly treated with high-dose corticosteroids to reduce it.)

• Managing Symptoms

• Promoting Function through Rehabilitation

• The Role of Complementary and Alternative Medicine (CAM)

Page 4



Page 5

S.No

Brand Name Manufacturer

Chemical Name

Primary Usage in MS

Generic Available

Route of Administration

1 AVONEX

(U.S. and Canada) Biogen Idec

Interferon beta-1a

Disease-modifying agent

No

Injectable (Intramuscular Injection)

2

BETASERON;

EXTAVIA

(U.S. and Canada)

Bayer

Healthcare;

Novartis

Interferon beta-1b


No

Injectable (Subcutaneous Injection)

3 COPAXONE

(U.S. and Canada)

Teva

Neuroscience Inc

Glatiramer acetate

[formerly called Copolymer-1]


No


4 GILENYA

(U.S.) Novartis fingolimod

Disease-modifying

No Oral (Capsule)

5 **NOVANTRONE

(U.S. and Canada)

EMD Serono, Inc

Mitoxantrone for injection concentrate


No IV infusion

6 REBIF

EMD Serono

(Co-Marketed by: EMD Serono &

Pfizer Inc)

Interferon

beta-1a


No


7

TYSABRI®

(formerly called Antegren)

Biogen Idec Inc

Natalizumab Disease-modifying agent

No IV infusion

FDA-Approved Disease-Modifying Drugs

TRADEMARKS ♦ TYSABRI is a registered trademark of Elan Pharmaceuticals, Inc.

♦ AVONEX is a registered trademark of Biogen Idec.

♦ BETASERON is a registered trademark of Bayer Schering Pharma

Aktiengesellschaft.

♦ REBIF is a registered trademark of Ares Trading S.A.

♦ TOUCH is a trademark of Biogen Idec and Elan Pharmaceuticals, Inc.

IMPORTANT

◊ Novantrone has not been approved

for the treatment of primary-progressive MS (characterized by progression from disease onset wi th no acute a t tacks or remissions.

◊ Novantrone should be used only in

those with normal cardiac function, once every three months at a dose of 12mg/m2. Periodic cardiac monitoring is required throughout the treatment period.



Page 6

DRUG APPROVALS

NOVANTRONE Original Approval or Tentative Approval Date:

October 13, 2000

FDA Application No: (NDA) 021120

Company: SERONO

COPAXONE Original Approval or Tentative Approval Date:

December 20, 1996


Company: TEVA

AVONEX Original Approval or Tentative Approval Date:

May 17, 1996

FDA Application No: (BLA) 103628

Company: BIOGEN

BETASERON Original Approval or Tentative Approval Date:

July 23, 1993


Company: BAYER HEALTHCARE

TYSABRI Original Approval or Tentative Approval Date:

November 23, 2004


Company: BIOGEN IDEC

REBIF Original Approval or Tentative Approval Date: March

7, 2002


Company: SERONO

GILENYA Original Approval or Tentative Approval Date:

September 21, 2010


Company: NOVARTIS

EXTAVIA Original Approval or Tentative Approval Date: August

14, 2009


Company: NOVARTIS

Important reminder concerning interferon medications (Avonex®, Betaseron®, Extavia®, and Rebif®) and natalizumab

(Tysabri®)

Dr. Aaron Miller, the National MS Society's Chief Medical Officer, emphasizes the need for periodic liver function testing for all patients taking an interferon medication or natalizumab. He recommends obtaining a baseline evaluation and periodic testing thereafter.



Drug Description

Biotechnological product, manufactured by a biotechnological process from one of the naturally-occurring interferons (a type of protein) made up of exactly the same amino acids (major components of proteins) as the interferon beta found in the human body.

It has been proved in a study of 372 ambulatory patients with relapsing-remitting MS taking recommended dose of the medication experienced fewer exacerbations with longer intervals in between than those having lower dose of the medication. Additionally, patients on interferon beta-1b had no increase in total lesion area, as shown on MRI, in contrast to the placebo group that had a significant increase.

Approval Status

BETASERON and EXTAVIA are approved by the FDA for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. Relapsing forms of MS include individuals with secondary-progressive MS who continue to experience relapses or acute attacks.

BETASERON and EXTAVIA are also approved for use in individuals who have experienced a first clinical episode (clinically-isolated syndrome) and have MRI features that are consistent with multiple sclerosis.

Dosage and Administration

EXTAVIA

Recommended dose of EXTAVIA is 0.25 mg taken every other day through manual subcutaneous injection or with the EXTAVIA Auto-Injector II.

EXTAVIA doesn't need to be refrigerated as an unmixed powder. After mixing, however, EXTAVIA must be used right away or refrigerated and used within 3 hours.

Physician will start treatment on a smaller dose of 0.0625

mg and increase your dosage gradually over a 6-week period to 0.25 mg.

BETASERON

The recommended dose of Betaseron is 0.25 mg injected subcutaneously every other day. Generally, patients should be started at 0.0625 mg (0.25 mL) subcutaneously every other day, and increased over a six week period to 0.25 mg (1.0 mL) every other day.

BETASERON should be stored at room temperature 25°C (77°F). Excursions of 15 to 30°C (59 to 86°F) are permitted. Do not freeze.

Warnings

FDA has added warnings and precautions to the prescribing information for

this medication: Depression and suicide, Liver problems, Allergic reactions, Seizures.

Because of the potential of Interferon beta 1b (BETASERON; EXTAVIA) to affect the thyroid gland, and to alter the levels of white blood cells, red blood cells, and platelets in a person’s system, blood tests are recommended at regular intervals.

Side Effects

Injection site reaction, Flu-like symptom complex, Excessive fatigue, Headache, Pain, Increased muscle tone, Fever, Muscle pain, Rash, Chills, Trouble sleeping, Incoordination, Abdominal pain, Decreased white blood cells, Tissue swelling, Urinary urgency, Skin disorder, Chest pain, Vaginal bleeding, Impotence, High blood

EXTAVIA NOVARTIS & BETASERON BAYER HEALTHCARE

PHARMACEUTICALS

Page 7

EXTAVIA EXACTLY SAME

PRODUCT

AS

BETASERON

(BETAFERON FOR OUR NON-US FRIENDS),

INTERFERON BETA-1B.

BETASERON (WHICH IS

MANUFACTURED BY BAYER

SCHERING PHARMA AG) IS THE

OLDEST OF THE DISEASE-MODIFYING THERAPIES FOR MS,

KNOWN AS THE

“CRAB”

(COPAXONE, REBIF, AVONEX AND

BETASERON) DRUGS

Interferon beta-1b

IMPORTANT

Do not take EXTAVIA two days in a row

Do not reuse any vials, syringes, or needles

Change your injection site each time you inject EXTAVIA to avoid serious skin reactions

Avoid injecting EXTAVIA into an area of skin that is sore, red, infected, or has other

problems.

NOTE:

Should not be used during

pregnancy or by any woman who is

trying to become pregnant. Women

taking BETASERON or EXTAVIA

should use birth control measures

at all times.



Drug Description

Biotechnological product, manu fac t u r ed by a biotechnological process from one of the naturally-occurring interferons (a type of protein) made up of exactly the same amino acids (major components of proteins) as the interferon beta found in the human body. Various studies have p roved AVONEX , a clinically definite diagnosis of MS.

This medication had reduced the risk of disability progression with fewer exacerbations, and showed a reduction in number and size of active lesions in the brain (as shown on MRI) when compared with the group taking a placebo in relapsing MS patients taking medication in controlled trials.

A l s o A VONE X h a d significantly delayed the time to second exacerbation in patients who had experienced a single demyelinating event in the optic nerve, spinal cord, or brainstem, and had lesions typical of MS on brain MRI.

Approval Status

FDA has approved AVONEX for the treatment of patients with relapsing forms of MS to slow the accumulation of physical disability and decrease the frequency of cl in ical exacerbations. AVONEX is approved for use in people who have experienced a first attack and have lesions consistent with MS on their MRI.


Once-a-week intramuscular (IM) injection usually in the large muscles of the thigh, upper arm or hip is prescribed.

AVONEX is available in two forms as a liquid in a pre-filled syringe and as a powder in a single-use vial.

Prefilled syringe: Prefilled syringes of AVONEX should be refrigerated at 36-46°F (2-8°C). If refrigeration is unavailable, vials should be stored up to 77°F (25°C) for up to 7 days.

About 30 minutes before taking AVONEX, it is recommended that you remove your syringe from the refrigerator and allow it t o wa rm t o r o om temperature. Do not use external heat sources such as hot water to warm your AVONEX in a prefilled syringe.

If your AVONEX prefilled syringe has been exposed to conditions other than those recommended, do not use the product. Instead, discard your prefilled syringe and call your pharmacist.

Powder: Single use Vials of AVONEX s hou ld be refrigerated at 36-46°F (2-8°C). If refrigeration is unavailable, vials should be stored up to 77°F (25°C) for up to 7 days.

Do not expose the vials of AVONEX to high or freezing temperatures. After mixing the powder, AVONEX solution should be used immediately or within 6 hours if stored in the

refrigerator.

Warnings

Prior to taking AVONEX, be sure to tell your physician if you have ever had any of the following medical problems: Depress ion , anxiety, or trouble sleeping, Problems with your thyroid gland, Blood problems such as bleeding or bruising easily, anemia, low white

AVONEX BIOGEN Idec

Page 8

Flu-like symptoms are a fairly common side effect during the initial weeks of AVONEX treatment. It is recommended that you take your AVONEX injection before bedtime. Immediately before your injection, and for the 24 hours that follow the injection, patients have found that use of over the counter pain and fever reducing medications can help with this common side

IMPORTANT

Should not be used during pregnancy or by any

woman who is trying to become pregnant. Women

taking AVONEX should use birth control measures at all times. If you want to become pregnant while

being treated with AVONEX, discuss the

matter with your physician. If you become pregnant

while using AVONEX, stop the treatment and contact

your physician.

Side Effects

● Common Side Effects are

injection-site reactions (ISRs) and flu-like symptoms (FLS).

● More severe ISRs include:

● Lipoatrophy, or loss of fat cells,

resulting in a dent in your skin. Necrosis or death of tissue around the site of the injection.

● Flu like symptoms includes

fatigue, chills, fever, muscle aches, and sweating. Most of these will disappear after the initial few weeks of treatment but if they still persist and become more severe, or cause you significant discomfort, be sure to talk them over with your physician.

● Other Side Effects includes

depression, including ongoing sadness, anxiety, loss of interest in daily activities, irritability, low se l f -es tee m, gu i l t , poor concentration, indecisiveness, confusion, and eating and sleep disturbances, should be reported promptly to your doctor.

Interferon beta-1a



Drug Description

COPAXONE is a synthetic protein that simulates myelin basic protein, a component of the myelin that insulates nerve fibers in the brain and spinal cord. This drug seems to block myelin-damaging T-cells through a mechanism that is not completely understood.

It has been observed in controlled clinical trials that RRMS taking the glatiramer acetate had a significant reduction in annual relapse rate and a reduction in new lesions as shown on magnetic resonance imaging (MRI) compared to control subjects taking placebo.

Approval Status

COPAXONE is approved by the U.S. Food and Drug Administration (FDA) to reduce the frequency of relapses in patients with relapsing-remitting MS and for use in individuals who have experienced a first clinical episode (clinically-isolated syndrome) and have MRI features that are consistent with multiple sclerosis.


Once a day subcutaneous injection, usually in the fat layer just under the skin and the muscles beneath is prescribed.

Pre-filled syringes are also used for drug administration and should be kept refrigerated. If refrigeration is not available, the drug may be safely stored at room temperature for up to one month.

Warnings

Do not use a pre-filled syringe that appears cloudy or contains particles.

Do not change the dose or dosing schedule of this medication without consulting your physician.

Glatiramer acetate is not recommended for use during pregnancy. Women who wish to become pregnant s h o u l d d i s c u s s t h i s medication, and all others they are taking, with their physician. If you become pregnant while on the medication, inform your phys i c ian . Glat i ramer acetate is a Pregnancy Category B medication, meaning that although no adverse effects have been found in animal studies, no adequate, well-controlled studies have been done in pregnan t women to demonstrate its safety in humans.

It is not known whether glatiramer acetate passes into the breast milk. Nursing women should discuss the use of this medication with their physician.

Side Effects

Injection-site reactions (e.g. swelling, the development of a hardened lump, redness, tenderness , increased warmth of the skin, itching at the site of the injection), runny nose; tremor; unusual tiredness or weakness; weight gain are some of the side effects but don’t need any attention unless severe.

Hives (an itchy, blotchy swelling of the skin) or severe pain at the injection

site type of unusual side effects must be discussed as soon as possible with physician.

Possible immediate post-i n j e c t i o n r e a c t i o n : Approximately 13% of i n d i v i d u a l s u s i n g COPAXONE will experience, at one time or another, a transient (very temporary) reaction immediately after injecting glatiramer acetate. This reaction, which usually occurs only once, includes flushing or chest tightness with heart palpitations, anxiety, and difficulty breathing. During the clinical trials, these reactions occurred very rarely, usually within minutes of an injection. They lasted approximately 15 minutes and resolved without further problem.

Page 9

COPAXONE TEVA Neuroscience Inc Glatiramer Acetate

IMPORTANT

♦ COPAXONE is light-sensitive; protect it from light when not injecting.

♦ Do not reuse any syringes, or needles

♦ Change your injection site each time you inject COPAXONE to avoid serious skin reactions

♦ Avoid injecting COPAXONE into an area of skin that is sore, red, infected, or has other problems.



Drug Description

ANTINEOPLASTIC drug acts in multiple sclerosis by suppressing the activity of T ce l l s , B ce l l s , and macrophages that are thought to lead the attack on the myelin sheath.

It has been evaluated in a series of European studies over a period of ten years for the treatment of MS. This drug is evaluated in randomized, placebo-controlled, multi-center clinical trial involving patients with secondary-progressive or progressive-relaps ing MS where par t i c ipan ts rece ived 1 2 m g / m 2 o f NOVANTRONE by short IV infusion once every three months for 24 months.

This drug delays the time to first treated relapse and t i m e t o d i s a b i l i t y progression. It also reduced the number of treated relapses and number of new les ions de tec ted by

mag n e t i c r e s o n a n c e imaging.

Approval Status

F D A a p p r o v e d NOVANTRONE for reducing neurological disability and/or the frequency of clinical relapses (attacks) in:

Patients with secondary progressive MS (disease that has changed from relaps ing-remit t ing to progressive at a variable rate).

Progressive-relapsing MS (disease characterized by gradua l i n crease i n disability from onset with clear, acute relapses along the way).

Worsen ing relaps ing-remitting MS (disease characterized by clinical

NOVANTRONE EMD SERONO, Inc

Page 10

ATTENTION!!

NOVANTRONE HAS

NOT BEEN APPROVED

FOR THE TREATMENT

OF PRIMARY-

PROGRESSIVE MS

(CHARACTERIZED BY

PROGRESSION FROM

DISEASE ONSET WITH

NO ACUTE ATTACKS

OR REMISSIONS).


Recommended dose: 12mg/m2 once every three months [Lifetime cumulative dose is limited to 140 mg/m2 (approximately 8-12 doses over two to three years) because of possible cardiac toxicity]

IMPORTANT

Above dose must be given to patients with Normal cardiac function.

NOVANTRONE can increase the risk for infection by decreasing the number of protective white blood cells, blood counts and liver function so it should be evaluated prior to each dose.

SIDE EFFECTS

Side effects that may go away as your body adjusts to the medication and do not require

medical attention unless they continue or are bothersome: nausea, temporary hair loss,

and menstrual disorders in females.

Side effects that should be reported to your physician as soon as possible: fever or

chills, lower back or side pain; painful or difficult urination; swelling of feet and lower

legs; black, tarry stools, cough or shortness of breath; sores in mouth and on lips,

stomach pain.

Mitoxantrone



Drug Description

Biotechnological product, manufactured by a biotechnological process from one of the naturally-occurring interferons (a type of protein) made up of exactly the same amino acids (major components of proteins) as the interferon beta found in the human body.

REBIF is currently available at the 44mcg dose in pre-filled syringes ready for subcutaneous injection.

It has been proved that the two experimental groups of relapsing-remitting MS patients i.e. those receiving 22mcg three times per week and those receiving 44mcg three times a week have a lower relapse rate, prolonged time to first relapse, a higher proportion of relapse-free patients, a lower number of active lesions on MRI and delay in progression of disability in comparison to placebo group in controlled clinical trial.

REBIF EMD SERONO (Co-Marketed by:

EMD SERONO & Pfizer Inc)

Page 11

CARDIOTOXICITY

Person should be carefully evaluated (by examination and medical history) for signs and symptoms of heart disease prior to treatment.

Person whose LVEF is lower than 50% should not be given NOVANTRONE and baseline evaluation of left ventricular ejection fraction (LVEF) should be performed first and if during treatment it falls then also treatment is stopped.

LVEF should be re-tested prior to each dose of

NOVANTRONE.

Factors that are known to increase a person’s risk for cardiotoxicity with

NOVANTRONE are:

Current or prior history of heart disease

Simultaneous use of other medications that can damage the heart

Previous therapy with certain kinds of chemotherapies (anthracyclines or anthracenediones)

SECONDARY ACUTE MYELOGENOUS LEUKEMIA (AML)

AML, a type of cancer, has been reported in MS patients and cancer patients treated with NOVANTRONE.

Regular Checkup during treatment is must. If there is any ongoing medical problem then let your doctor know about it.

No immunizations (vaccinations) with live virus vaccines during treatment. While being treated with this medication, and during the period following treatment, do not have any immunizations (vaccinations) with live virus vaccines without your doctor’s approval. Mitoxantrone may lower your body’s resistance to infection, making you susceptible to the infection that the immunization is designed to help you avoid. Neither you nor anyone in your household should take the oral polio vaccine.

Let your physician know if you are taking any of the following:

Amphotericin B by injection, Antithyroid agents, Azathioprine, Chloramphenicol, Colchicine, Flucytosine, Ganciclovir, Plicamycin, Probenecid, Sulfinpyrazone, Zidovudine

or if you have previously been treated with:

-radiation

-other cancer medications.

IMPORTANT

● For pregnant women or

intending to have children: This medicine may cause birth defects if either the man or woman is receiving it at the time o f c o nc e p t i o n . A pregnancy test i s recommended prior to each treatment for women of child-bearing age. Many medications of this type can cause permanent sterility. Be sure you have discussed this with your physician before taking this medication.

● Breast-feeding should be

discontinued before a woman starts treatment.

● Higher incidence of

leukemia has been reported in cancer pat ients, previously t r e a t e d w i t h chemotherapy, who were then treated with higher doses of Novantrone than is prescribed for treating MS.

Warning

FDA has added a BLACK BOX WARNING to the prescribing information for this medication. Avoid people with infections.

Interferon beta-1a



Approval Status

FDA has approved REBIF for the treatment of patients with relapsing forms of MS to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.


Three times a week subcutaneous injection usually in the fat layer just under the skin and the muscles beneath is prescribed.

When beginning treatment, it is recommended that you start at 8.8 mcg three times a week and gradually increase over a 4-week period to the 44mcg dose in order to reduce the side effects. A starter kit with 22mcg syringes is available to facilitate the gradual increase in dose.

Important: REBIF should be administered at the same time of day, on the same days of the week, preferably in the late afternoon. Doses must be at least 48 hours apart.

Two injection options for patients:

REBIJECT II

The REBIJECT II auto-injector is designed to make your injections easier than a manual Rebif injection. With the Rebiject II, the needle remains hidden both before and after injecting, which help some people who don't like to see the needle.

REBIF PREFILLED SYRINGE

REBIF can be stored at or below room temperature (25°C/77°F) away from heat and light for up to 30

days.

Since flu-like symptoms are a fairly common side effect during the initial weeks of treatment, it is recommended that the injection be given at bedtime. Taking acetaminophen (Tylenol®) or ibuprofen (Advil®) immediately prior to each injection and during the 24 hours following the injection

will also help to relieve the flu-like symptoms.

Warning

Before beginning treatment, patients should discuss with their doctor the potential benefits and risks associated with REBIF.

Let your doctor know:

If you have a history of depression, seizures, liver disease, thyroid problems, or blood cell count or bleeding problems, or if you have had previous allergic reactions to medications

About all medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. REBIF and other medicines may affect each other, causing serious side effects.

Before you take any new medicines

Important: Not recommended for women

Page 12

IMPORTANT FACTS

Reporting on the outcome of the

EVIDENCE trial, which compared REBIF and AVONEX (both interferon beta-1a), the FDA added the following information to the labeling of REBIF:

“Patients treated with REBIF 44 mcg [micrograms] sc [delivered subcutaneously] tiw [3 times per week] were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with AVONEX 30 mcg im [delivered intramuscularly] qw [once per week].”

Side Effects

Common side effects with REBIF are:

Injection-site reactions, Flu-like symptoms (fever, chills,

muscle aches, tiredness), Depression, Abdominal pain, Increased liver enzymes

Blood cell count decreases (REBIF has a potential to affect the levels of white blood cells, red blood cells, and platelets in a person’s system, blood tests are recommended at regular intervals. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction.)

Potential serious side effects of REBIF include:

Depression and risk of suicide

Liver problems

Risk to pregnancy

Injection-site problems

Severe allergic reactions. Allergic reactions are rare and may be associated with difficulty in breathing and loss of consciousness, which require immediate medical attention.



Drug Description

TYSABRI is a laboratory-produced monoc lona l antibody designed to hamper movement of poten t ia l ly damaging immune cells from the bloodstream, across the “blood-brain barrier” into the brain and spinal cord. It is a prescription medicine approved for adult patients to positively affect key components of MS:

Reduces flare-ups

Slows down the progression of physical disability

TYSABRI may also:

Reduce the number of new brain lesions detectable on MRI

TYSABRI was evaluated in a pair of two-year, controlled clinical trials:

Study I compared TYSABRI to placebo in patients who had not received any i n t e r f e r o n - b e t a o r glatiramer acetate for at least the previous six months.

Study II involved patients who had experienced one or more relapses while on treatment with AVONEX®. Half of the group took TYSABRI in addition to their AVONEX; half of the group took AVONEX plus a placebo.

In both studies, those taking the medication had a reduced risk of disability p r o g r e s s i o n a n d e x p e r i e n c e d f e w e r exacerbations (relapses) compared with the group taking a placebo. TYSABRI has not been studied in people with primary

progressive MS or in children.

Approval Status

U.S. Food and Drug Administration (FDA) in 2006 had approved TYSABRI as a monotherapy (not to be used in combination with another disease-modifying therapy) for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations.


TYSABRI is infused into a vein once every 4 weeks, so you don't need to self-inject. Th i s makes TYSABR I different than other multiple sclerosis medicines.

Due to the risk of PML, TYSABRI is available only through a special distribution program ca l l ed the TOUCH™ Prescr ib ing Program which needs to be learned before starting treatment with TYSABRI. Only physicians, infusion centers, and pharmacies associated with the infusion centers that are registered with the TOUCH program can prescribe, distribute, or infuse the medication.

As part of TOUCH, if you did not qualify for the infusion according to the Pre-infusion Patient Checklist, your doctor will need to decide if you should have another TYSABRI infusion.

Page 13

TYSABRI is DIFFERENT... ♦ TYSABRI is an antibody, not an

interferon (AVONEX® (interferon beta-1a), BETASERON® (interferon beta-1b), EXTAVIA® (interferon beta-1b), REBIF® (interferon beta-1a)) or glatiramer acetate (COPAXONE®).

♦ TYSABRI is thought to inhibit white blood cells from getting into the brain and attacking nerves

♦ Keeping these cells from attacking nerves is believed to result in fewer brain lesions that cause multiple sclerosis symptoms.

FACTS REGARDING TYSABRI APPROVAL

● TYSABRI increases the risk of

PROGRESSIVE MULTIFOCAL

LEUKOENCEPHALOPATHY

(PML), a rare brain infection that

usually causes death or severe

disability, TYSABRI is generally

recommended for patients that

have not been helped enough by,

or cannot tolerate, another

treatment for MS.

● TYSABRI does not cure MS and

has not been studied for longer

than two years or in patients with

chronic progressive MS.

TYSABRI IS AN ANTIBODY NOT AN INTERFERON !!!

TYSABRI BIOGEN Idec Inc Natalizumab




Warning

TYSABRI increases your chance of getting a rare brain infection that usually causes death or severe disability. This infection is called P R O G R E S S I V E M U L T I F O C A L LEUKOENCEPHALOPATHY (PML). PML usually happens in people with weakened immune systems.

No one can predict who will get PML.

There is no known treatment, prevention, or cure for PML.

Your chance of getting PML may be higher if you are also being treated with other medicines that can weaken your immune system, including other MS treatments.

Even if you use TYSABRI alone to treat your MS, you can still get PML. Your chance of getting PML increases with a longer period of treatment or if you have received medicines that can weaken your immune system prior to starting TYSABRI.

TYSABRI is available only through a restricted distribution program called the TOUCH® Prescribing Program. In order to receive TYSABRI, you must talk to your doctor, understand the benefits and risks of TYSABRI, and agree to all of the instructions in the TOUCH Prescribing Program.

If you take TYSABRI, it is important that you call your doctor right away if you get any new or worsening medical problems (such as a new or sudden change in your thinking, eyesight, balance, or strength or other problems) that have lasted over several days. If you are pregnant or plan to become pregnant or you are breast feeding. Tell all of your doctors that you are getting treatment with TYSABRI.

Side Effects

Treatment with TYSABRI may come with side effects, including serious side effects. Every person is different and may r eac t t o medications differently. TYSABRI increases your chance of getting a rare brain infection that usually causes death or severe disability. This infection is ca l l ed PROGRESS IVE M U L T I F O C A L LEUKOENCEPHALOPATHY (PML). As of January, 2011, the risk is 0.3/1000 for patients treated up to 24 months; 1.5/1000 for patients treated 25-36 months; 0.9/1000 for patients treated 37-48 months. Data beyond 4 years of treatment are limited.

Allergic reactions

Infections

Liver Damage [Blood tests can be done to check for liver damage. Call your doctor right away if you have symptoms of liver damage.]

Other TYSABRI side effects include:

Headache, Urinary tract infection, Lung infection, Pain in your arms and legs, Vaginitis, Nose and throat infections, Feeling tired, Joint pain, Depression, Diarrhea,

FOR PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

(PML) PATIENTS ONLY

● If you get PML, your

doctor will monitor you for

certain new or worsening

symptoms that can

happen suddenly after

you get PML. Contact

your doctor right away if

you think your general

health status is getting

worse.



GILENYA NOVARTIS Fingolimod

Drug Description

GILENYA ™ is a new class of medication called a sphingosine 1-phosphate receptor modulator, which is thought to act by retaining certain white blood cells (lymphocytes) in the lymph nodes, thereby preventing those cells from crossing the blood-brain barrier into the central nervous system (CNS). Preventing the entry of these cells into the CNS reduces inflammatory damage to nerve cells.

TRANSFORMS one-year study comparing two doses of GILENYA to interferon beta-1a (AVONEX), GILENYA (at the lower, 0.5mg dose) reduced relapses by 52% compared with AVONEX and reduced disease activity as measured by the number of new and newly enlarged T2 lesions on MRI scans compared with AVONEX (1.6 vs 2.6, respectively at one year); reduced brain lesion activity as measured by MRI.

FREEDOMS two-year study comparing two doses of GILENYA to placebo, GILENYA (at the lower, 0.5mg dose) reduced relapses by 54% and reduced the risk of disability progression by 30% compared to placebo. GILENYA also reduced brain lesion activity as measured by MRI.

In both clinical trials, fingolimod showed a reduction in gadolinium-enhancing lesions, which indicate new MS activity.

The data from the TRANSFORMS study indicated that at 12 months, the mean number of gadolinium-enhancing T1 lesions was significantly lower for patients treated with fingolimod at the 0.5 mg dose than for patients taking interferon beta-1a (Avonex), 0.2 vs 0.5 respectively.

In the FREEDOMS trial, the mean number of gadolinium-enhancing T1 lesions was significantly lower at 24 months for the group treated with fingolimod (0.5 mg dose) than for the placebo group, 0.2 vs 1.1.

Page 15

IMPORTANT

TRANSFORMS and FREEDOMS are two large-scale, phase III clinical trials involving people with relapsing-remitting MS, the MRI findings of which were included in an update in the prescribing information for fingolimod and FDA approved it in August 2011.

ATTENTION!!

GILENYA has not been studied in people under

the age of 18 .

Approval Status

FDA approved GILENYA in 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability.


Fingolimod 0.5 mg taken once daily as a single oral capsule either with or without food and Store the medication in a dry place at room temperature.

Precautions to be taken prior to

starting this medication, the

prescribing information for GILENYA

recommends that your doctor do the

following tests:

● A new or recent blood test to establish

lymphocyte (immune cell) count.

● An eye (ophthalmologic) evaluation.

● A new or recent blood test to evaluate

liver enzyme levels.

● A new or recent electrocardiogram in

those using heart medications, those

who have cardiac risk factors, or

those who on examination have slow

or irregular heart beat prior to starting

GILENYA as it may cause your heart

rate to slow down, particularly right

after the first dose, with the drop

being most significant at about six

hours after the dose is taken. So it

needs to be monitored during this six

hour periods.

● Those who do not have a history of

chickenpox or vaccination against

varicella zoster virus (VZV) should be

tested for VZV antibodies, and those

who are negative should consider

vaccination before starting treatment

with GILENYA.

Things to Remember with

GILENYA : -

First dose of the medication

will be given in a doctor’s

office, where you will be

observed for six hours for

signs and symptoms that

may be associated with

decreased heart rate and

other possible heart effects.

Do not stop taking the

medication without talking

with your doctor.

If you re-start GILENYA

after stopping for two or

more weeks, you will need

to take the first dose in the

doctor’s office.


Let Your Doctor Know:

● About all of the medications you are taking, including medicines for heart problems or high blood pressure, vacines, other medications to

control your immune system or treat cancer, or ketoconazole (an anti-fungal) by mouth.

● About any medical conditions you have, including irregular or abnormal heartbeat, a heart rate less than 55 beats a minute, a history of

fainting, a fever or infection, eye problems (especially an inflammation of the eye called uveitis), diabetes, breathing problems, liver

problems, high blood pressure.

● Others:

● May cause your heart rate to slow down, particularly right after the first dose, with the drop being most significant at about six hours after

the dose is taken. So it needs to be monitored during this six hour periods.

● GILENYA lowers the number of lymphocytes in the blood, you may be at greater risk of infection. It is recommended that your doctor

perform a blood test prior to treatment to determine your white blood cell count. After starting treatment, contact your doctor right away if

you have fever, unusual tiredness, body aches, chills, nausea, or vomiting. White blood cell counts generally return to normal approximately

two months after stopping this medication.

● GILENYA can cause a swelling of the macula (a spot in the center of retina of the eye), generally within 3-4 months of starting treatment. It

is recommended that your doctor test your vision before starting treatment and then three to four months later, or any time that you notice

any changes in your vision, including blurriness or shadows in the center of your vision, a blind spot in the center of your vision, sensitivity

to light, or changes in your color vision.

● GILENYA may cause liver problems. Your physician will do a blood test to check your liver functions prior to starting treatment.

● GILENYA may cause shortness of breath in some people. Contact your doctor immediately if you experience any difficulty breathing.

● Patients with infections e.g. chicken pox beware.

● Pregnant women or considering becoming pregnant or breast feeding women: This medication can cause harm to a fetus, so effective birth

control should be used while on the medication and for two months after stopping the medication. Risk of serious reactions in nursing

infants.


Side Effects

☺ Most common side effects in the clinical trials of GILENYA were headache, influenza, diarrhea, back pain, abnormal liver tests, and cough.

Page 16

Conclusion:

This report will help in understanding the available treatments for Multiple Sclerosis as well as the adverse effects helping researchers in development of safe and secure treatment options. There is much improvement needed with the already marketed drugs dosage forms their pharmacological profile.


References:

1. National MS Society: http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/index.aspx 2. REBIF: http://www.rebif.com/pages/home http://www.emdserono.com/cmg.emdserono_us/en/images/rebif_tcm115_19765.pdf 3. COPAXONE: http://www.tevapharm-na.com/Our-Business/Teva-Neuroscience.aspx 4. TYSABRI: http://www.tysabri.com/tysbProject/tysb.portal/_baseurl/threeColLayout/SCSRepository/en_US/tysb/home/about-tysabri/index.xml 5. AVONEX: http://www.avonex.com/prescribing-information-medication-guides.xml http://www.avonex.com/pdfs/pi-syringe.pdf 6. BETASERON: http://www.betaseron.com/ 7. EXTAVIA: http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf 8. New drugs may improve, complicate treatment for multiple sclerosis. Nature Medicine 16, 272 (2010) doi:10.1038/nm0310-272 ; http://www.nature.com/nm/journal/v16/n3/full/nm0310-272.html 9. Fingolimod for Multiple Sclerosis; N Engl J Med 2012; 366:339-347January 26, 2012; http://www.nejm.org/doi/full/10.1056/NEJMct1101691 10. Drug Approval Documents: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm094508.pdf http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1996/ifnbbio051796l.pdf http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/125290s0000ltr.pdf http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/103471s0000_APPROV.pdf http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21120.pdf_Novantrone_Approv.pdf http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/125104_0000_ltr.pdf http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022527s000lbl.pdf



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B. Pharmacy

M.Sc. (Clinical Research and Regulatory Affairs)

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