Jorge Orestes Cerdeira, Inst. Sup. Agronomia, 2005Def. Uma sucess˜ao (num´erica) ´e uma aplica¸c˜ao de N (N0) em R. n = an− 1 + an− 2 an = n , an = ( − 1) n , an = 1 ,Se `a medida que n aumenta os termos da sucess˜ao se aproximamde um n´umero a , diz-se que a ´e o limite da sucess˜ao. Mais precisa-Diz-se que a ∈ R ´e o limite da sucess˜ao an , e e
Conversely, injection forms, though being painful and needing help of medical personnel for application, help to quickly achieve necessary concentration of preparation in blood amoxil online Antibiotic is usually chosen in an empiric way (at random). But when choosing one is obligatory guided by definite rules.
Your costs can change dramatically when new medications come to market. So we keep careful watch on new drug launches, as well
as on medications expected to gain approval in the next several months.
The Pipeline Report contains a sampling of the initial assessments of recent and upcoming medication launches from news outlets andexpert analysts around the industry. We try to capture some of the variables that will determine the ultimate impact of a new drug,including whether a medication represents a substantial advance in the science, its relative place within its therapeutic class and othermarket dynamics.
This report contains only a few of the most prominent new medications. If you would like to view a more extensive, more clinically-
oriented list, please click here to download from OptumRx.
If you have questions about our strategies or programs related to the new medications, please contact your OptumRx representative.
[Brand name pending] levomilnacipranForest Laboratories, Inc. and Pierre Fabre Laboratories
The treatment of Major Depressive Disorder (MDD) in adults.1 Current Status
• Cymbalta® (duloxetineHCl)1• Effexor XR®(venlafaxine HCl) 1 Similar Medications
• Pristiq® (desvenlafaxine) 1• Savella® (milnacipran) • One pharmaceutical research firm (Decision Resources) surveyed U.S. psychiatrists who said they would prescribe levomilnacipran to 25 percent of their treatment-resistant depression patients. 2 • This would represent ~5 percent of the drug-treated unipolar depression population in the U.S. in Potential Market
• Datamonitor anticipates levomilnacipran to launch in the US in Q2 2013 and forecasts peak-year • Analysts believe that levomilnacipran will be positioned so that it does not undercut sales of Viibryd® (vilazodone HCl), another drug made by Forest.3 • But that will mean levomilnacipran will have to compete with other, more established medications, including generic formulations of Effexor XR (venlafaxine) and Cymbalta (duloxetine). 3 1. Drug Discovery & Development. Forest Labs Files for Levomilnacipran Approval. Sept. 27, 2012 2. Decision Resources.Surveyed U.S. Psychiatrists Indicate They Would Prescribe Forest Laboratories/Pierre Fabre’s Levomilnacipran to 25 Percent of Their Patients with Treatment-Resistant Depression. January 30, 2012 3. Datamonitor. Forest: data hint at rapid onset for levomilnacipran but competition will remain fierce. 12 March 2012 4. Internal Medicine News Digital Network. Levomilnacipran SR Effective for Major Depressive Disorder. June 14, 2012.
June, 2013 Issue 1
Breo™ Ellipta™ (fluticasone/vilanterol)GlaxoSmithKline and Theravance, Inc
A once-daily inhaled medication for the long-term, maintenance treatment of airflow obstruction in Therapeutic Use
patients with chronic obstructive pulmonary disease (COPD), and for the reduction of COPDexacerbations.1/td> Current Status
• Received FDA approval May 10, 2013. 1 • Advair® (fluticasone propionate and salmeterol) 2• Symbicort ® (budesonide/formoterol fumarate dihydrate) 2 Similar Medications
• Approximately13 million US adults have COPD and another 11 million are undiagnosed or • COPD is the third most common cause of death in the US. 3 Potential Market
• The predicted annual sales for Breo Ellipta as reported by Thomson Reuters is estimated to be The FDA cautions that Breo Ellipta should not be used as a rescue therapy to treat sudden breathing problems (acute bronchospasm) and is not recommended for people younger than 18 years. 1 1. FDA News Release. FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease. May 10, 2013.
2. Wall Street Journal. Glaxo, Theravance Lung Drug Breo Ellipta Face FDA Panel Wednesday. April 15, 2013.
3. American Lung Association, COPD Fact Sheet, February 2011.
4. The Telegraph. GSK lung 'wonder drug' gets green light. 18 Apr 2013.
[brand name pending] suvorexantMerck 1
Accepted for review by FDA in Nov., 2012 1 Currently, the U.S. market for insomnia drugs is largely dominated by generic medications 3• zolpidem (generic Ambien®, Ambien CR®) Similar Medications
• zaleplon (generic Sonata)• temazepam (Restoril®) U.S. insomnia sales were reported at $1.6 billion annually in 2012.3But analysts doubt suvorexant willmake a significant impact on the insomnia market:• While side-effects may be reduced, efficacy for suvorexant is roughly comparable to existing drugs.
• Generic Ambien (zolpidem), costs less than 1/4 the price of branded sleep drugs.3• Suvorexant sales are forecast at $350 million by 2016. 3 • Existing sleep aids such as zolpidem (generic Ambien) and zaleplon (generic Sonata) may cause side effects like memory loss and sleepwalking. 2,3 Suvorexant allows patients to go to sleep more quickly and to sleep throughout the night, with fewerside-effects. 2,3 1. Business Wire. Merck Announces FDA Acceptance of New Drug Application for suvorexant, an Investigational Insomnia Medicine. November 08, 2012.
2. Fierce Biotech. Can Merck use animal data to make its case against Lunesta, Ambien? April 4, 2013 3. Forbes. Can a Safer Ambien Make Billions? Merck Aims to Find Out. November 19, 2012.
June, 2013 Issue 1
LiptruzetTM(atorvastatin/ezetimibe)MerckCombines generic Lipitor® (atorvastatin) with Zetia®
• Vytorin®is another combination medication marketed by Merck containing generic Zocor® Similar Medications
• U.S. market for all cholesterol-lowering drugs worth $18.5-billion in 2011. 3 Potential Market
1. U.S. Food and Drug Administration. NDA Approval letter: NDA 200153. May 3, 2013. Accessed May 8, 2013.
2. Business Week. Merck’s Liptruzet Wins U.S. FDA Approval to Lower Cholesterol. May 3, 2013.
3. Nature. Cholesterol limits lose their lustre; Revised guidelines for heart health are set to move away from target-based Specialty medications
Tecfidera (dimethyl fumarate)Biogen Idec
Oral medication used to treat adults with the most common form of multiple sclerosis (MS).1/td> Current Status
U.S. Food and Drug Administration approved March 27, 2013.1 Prior to 2010, most MS disease-modifying therapies were injectable therapies:• Betaseron (interferon beta-1a (IFNβ-1a)) was introduced in 1993 and subsequent versions of interferon beta have been approved since then2 • Copaxone® (glatiramer acetate injection), a non-interferon based therapy, was approved in Similar Medications
• 2010: Gilenya®, (fingolimod) first oral agent for the treatment of MS 2• 2012: Aubagio® (teriflunomide) second oral agent for MS 2 • MS affects nearly 400,000 individuals in the United States. Onset typically occurs between age 20 • Analysts expect Tecfidera to be a blockbuster because of its combination of efficacy and relative safety plus the convenience of being a pill.3 • On price, Tecfidera is priced midway among the current oral MS treatments at $54,900 (wholesale) per patient per year. That is slightly less than 10% below Gilenya and 14% above Aubagio.2 • Note that all of these prices are considerably higher than for earlier treatments. The average cost to treat an MS patient in 2010 was $24,113. 4 • During the clinical studies of Tecfidera the side effects experienced appeared to be relatively mild Potential Market
by comparison to existing drugs. 5 And while its ability to reduce the rate of relapse is similar to thecompeting oral drugs, it is much better than that of the existing injectibles.5 • Reports indicate that doctors with early MS patients may be waiting for this treatment to become available.5 In part due to this, financial analysts expect that Tecfidera could capture as much as20% of the MS market in its first year.7 • Subsequent projections have sales growing rapidly by 2018, with consensus global sales at around • Currently, the world market for MS drugs is $14 billion per year.3 June, 2013 Issue 1
• Among existing therapies, the various interferon formulations and glatiramer acetate (GA) have • Even today, no single MS agent has emerged as the consensus “first-line” treatment. 2 • Now with a third oral agent on the market, some speculate that the traditional injectable therapies will begin to be replaced by the oral medications– even at a much at a higher cost. 2 1. U.S. Food and Drug Administration News Release. FDA approves new multiple sclerosis treatment: Tecfidera. March 2. American Journal of Managed Care. The Changing Management of Multiple Sclerosis—Dimethyl Fumarate (Tecfidera) for MS. April 22nd, 2013.
3. New York Times. 3rd Oral Drug to Treat MS Is Approved by the F.D.A. March 27, 2013.
4. National Multiple Sclerosis Society. Treatments > Medications > Glatiramer Acetate. Accessed May 3, 2013.
5. Center for Studying Health System Change. Research Brief: Limited Options to Manage Specialty Drug Spending.
6. Forbes. Biogen Prices New MS Pill At $55K, Prepares For Marketing Battle. March 29, 2013.
7. Fierce Pharma. Biogen's Tecfidera expected to hit the MS market running. March 28, 2013.
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Intravenous medication used to treat adults common forms of multiple sclerosis (MS).2 • alemtuzumab (previously marketed as Campath®) is licensed to treat leukemia, and has been used off-label in patients with multiple sclerosis for many years.3 • Genzyme pulled Campath off the market in September 2012 to prevent its unauthorized use as an Current Status
• FDA has accepted for review Genzyme’s supplemental Biologics License Application (sBLA). 1• Genzyme expects FDA action in the second half of 2013. 1 There are 5 self-injectable and 2 infused disease-modifying agents on the market: 4Self-injectable:• Avonex® (interferon beta-1a)• Betaseron (interferon beta-1b)• Copaxone® (glatiramer acetate injection (GA)• Extavia® (interferon beta-1b) Similar Medications
• Novantrone® (mitoxantrone)• Tysabri® (natalizumab) Genzyme is pursuing a two-prong strategy to turn alemtuzumab into a major MS drug under theLemtrada brand name:5• ◦ First, it has withdrawn alemtuzumab for leukemia use under the Campath brand in both the U.S.
and in Europe. Campath and Lemtrada are the same drug given at a different dosage.6 ◦ Second, a license extension to approve alemtuzumab for multiple sclerosis opens up a more [For more information see “Pricing the market,” below.]
Pricing the market
• When used for leukemia treatment, alemtuzumab (as Campath) costs around $60,000 for a year’s
treatment (three times a week for up to 12 weeks).
• However, MS patients would need only a fraction of the cancer dosage – just 5 consecutive days and then one year later another 3 days. At that rate, an MS-sized dose of alemtuzumab would cost • As noted in the Tecfidera review above, $6,000 would be just one quarter of the recent average Potential Market
cost of the existing approved injectable MS agents ($24,113/year).
• By eliminating Campath Genzyme prevents cheaper, off-label MS use.
• Obtaining the MS license extension, the company could begin to charge an MS-market price for Lemtrada matched not only against existing injectibles, but also against the newer oral MS drugs, which range from $60,000 to $48,000 per year.
• While Genzyme has not yet released its prices, Lemtrada is expected to grow to between $400 million to $600 million by 2018. By comparison, in 2011 Campath yielded sales of $76 million. 5 1. Specialty News: Specialty Pharma Journal News. Genzyme's Multiple Sclerosis Treatments Receive Positive News 2. The Lancet. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Volume 380, Issue 9856, November 24, 2012.
3. The Lancet. Comment: Alemtuzumab for multiple sclerosis. Volume 380, Issue 9856, Page 1792, 24 November 2012.
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4. American Journal of Managed Care. The Changing Management of Multiple Sclerosis—Dimethyl Fumarate (Tecfidera) for MS. April 22nd, 2013.
5. Fierce Pharma. Sanofi pulls Campath to clear way for higher-priced Lemtrada. August 21, 2012 6. Reuters. Sanofi draws fire over cost of MS drug Lemtrada. October 31, 2012.
7. Center for Studying Health System Change. Research Brief: Limited Options to Manage Specialty Drug Spending.
8. MediLexicon. FDA Approved drugs: Campath. Accessed 04.26.2012 June, 2013 Issue 1
An Inductive Version of Nash-Williams’ Minimal-Bad-Sequence Argument for Higman’s Lemma 1 Mathematisches Institut der Universit¨at M¨unchen2 Department of Computer Science, University of Wales Swansea † Abstract. Higman’s lemma has a very elegant, non-constructive proof due to Nash-Williams using the so-called minimal-bad-sequence argument. The objective of the present pap