Omeprazole Drug Profile

INTRODUCTION

INTRODUCTION

Drug Omeprazole Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease (PUD),

gastroesophageal reflux disease (GORD/GERD),

laryngopharyngeal reflux (LPR), and

Zollinger-Ellison syndrome. It was first marketed in the US in 1989 by AstraZeneca under the brand names Losec and Prilosec, and is now also available from generic manufacturers under various brand names. AstraZeneca markets omeprazole as Losec, Antra, Gastroloc, Mopral, Omepral, and Prilosec. Omeprazole is marketed as Zegerid by Santarus, Prilosec OTC by Procter & Gamble and Zegerid OTC by Schering-Plough. In India it is available as OMEZ (FGP). Omeprazole is one of the most widely prescribed drugs internationally and is available over the counter in some countries.

Pharmacology Omeprazole is a racemate. It contains a tricoordinated sulfur atom in a pyramidal structure and therefore can exist in equal amounts of both the S and R enantiomers. In the acidic conditions of the +

+

stomach, both are converted to achiral products, which react with a cysteine group in H /K ATPase,

thereby inhibiting the ability of the parietal cells to produce gastric acid.

Name change In 1990, at the request of the U.S. Food and Drug Administration (FDA), the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide). Unfortunately, the new name has led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.

Clinical use Use in Helicobacter pylori eradication Omeprazole is combined with the antibiotics clarithromycin and amoxicillin (or metronidazole in penicillin-hypersensitive patients) in the 7-14 day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is the causative factor in the majority of peptic and duodenal ulcers.

Side effects Some of the most frequent side effects of omeprazole (experienced by over 1% of those taking the drug) are headache, diarrhea, abdominal pain, nausea, dizziness, trouble awakening and sleep deprivation, although in

clinical trials the incidence of these effects with omeprazole was mostly

comparable to that found with placebo. Proton pump inhibitors may be associated with a greater risk of hip fractures, and clostridium difficile-associated diarrhea.

]

Patients are frequently administered the drugs in intensive care as a

protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia. Other side effects may include bone rebuild interference and B12 vitamin reduction.

Interactions Omeprazole is a competitive inhibitor of the enzymes CYP2C19 and CYP2C9, and may therefore interact with drugs that depend on them for metabolism, such as diazepam, escitalopram, and warfarin; the concentrations of these drugs may increase if they are used concomitantly with omeprazole.Clopidogrel (Plavix) is an inactive

prodrug that partially depends on CYP2C19 for

conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects and potentially increasing the risk of stroke or heart attack in people taking clopidogrel to prevent these events.Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs. Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazole or atazanavir) will be poorly absorbed, whereas drugs that are broken down in acidic environments (such as erythromycin) will be absorbed to a greater extent than normal. St. John's wort (Hypericum perforatum) and

Gingko biloba significantly reduce plasma

concentrations of omeprazole through induction of CYP3A4 and CYP2C19.

Absorption and distribution The absorption of omeprazole takes place in the small intestine and is usually completed within 3– 6 hours. The systemic

bioavailability of omeprazole after repeated dose is about 60%. Omeprazole

bioavailability is significantly impaired by the presence of food and, therefore, patients should be advised to take omeprazole before eating. The capsule should be taken immediately before a meal. The MUPS tablet may be taken with or without food. The powder for oral suspension should be taken on an empty stomach at least 1 hour before a meal. Plasma protein binding is about 95%.

Metabolism and excretion Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver. Identified metabolites are the sulfone, the sulfide and hydroxy-omeprazole, which exert no significant effect on the acid secretion. About 80% of an orally given dose is excreted as metabolites in the urine and the remainder is found in the feces, primarily originating from bile secretion.

FORMULATIONS AND DOSAGE FORMS Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10 mg, 20 mg, 40 mg, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating enteric-coated granules within capsules, enteric-coated tablets, and the multipleunit pellet system (MUPS). It is also available for use in injectable form (I.V.) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Multiple unit pellet system Omeprazole tablets manufactured by AstraZeneca (notably Losec/Prilosec) are formulated as a "multiple unit pellet system" (MUPS). Essentially, the tablet consists of extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell. When the tablet is immersed in an aqueous solution, as happens when the tablet reaches the stomach, water enters the tablet by osmosis. The contents swell from water absorption causing the shell to burst, releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional entericcoated preparations. Patients for which the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia) because the tablets can be mixed with

water ahead of time, releasing the granules into a slurry form, which is easier to pass down the feeding tube or to swallow than the pill. The granules are manufactured in a fluid air bed system. Sugar spheres in suspension are sequentially sprayed with aqueous suspensions of omeprazole, a protective layer, an enteric coating and an outer layer to reduce granule aggregation.

Marketing & pharmaceutical marketing Pharmaceutical marketing, sometimes called medico-marketing or pharma marketing in some countries, is the business of advertising or otherwise promoting the sale of pharmaceuticals or drugs. There is some evidence that marketing practices can negatively affect both patients and the health care profession. Many countries have measures in place to limit advertising by pharmaceutical companies. Pharmaceutical company spending on marketing far exceeds that spent on research. In Canada, $1.7 billion was spent in 2004 to market drugs to physicians; in the United States, $21 billion was spent in 2002. In 2005 money spent on pharmaceutical marketing in the US was estimated at $29.9 billion with one estimate as high as $57 billion. When the US numbers are broken down, 56% was free samples, 25% was detailing of physicians, 12.5% was direct to user advertising, 4% on hospital detailing, and 2% on journal ads. The marketing of medication has a long history. The sale of miracle cures, many with little real potency, has always been common. Marketing of legitimate non-prescription medications, such as pain relievers or allergy medicine, has also long been practiced, although, until recently, mass marketing of prescription medications has been rare. It was long believed that since doctors made the selection of drugs, mass marketing was a waste of resources; specific ads targeting the medical profession were thought to be cheaper and just as effective. This would involve ads in professional journals and visits by sales staff to doctor’s offices and hospitals. An important part of these efforts was marketing to medical students

To health care providers Marketing to health care providers takes four main forms: gifting, detailing, drug samples, and sponsoring continuing medical education (CME).Of the 237,000 medical sites representing 680,000

physicians surveyed in SK&A's 2010 Physician Access survey, half said they prefer or require an appointment to see a rep (up from 38.5% preferring or requiring an appointment in 2008), while 23% won't see reps at all, according to the survey data. Practices owned by hospitals or health systems are tougher to get into than private practices, since appointments have to go through headquarters, the survey found. 13.3% of offices with just one or two doctors won't see reps, compared with a no-see rate of 42% at offices with 10 or more docs The most accessible physicians for promotional purposes are allergists/immunologists – only 4.2% won't see reps at all – followed by orthopedic specialists (5.1%) and diabetes specialists (7.6%). Diagnostic radiologists are the most rigid about allowing details – 92.1% won't see reps – followed by pathologists and neuroradiologists, at 92.1% and 91.8%, respectively. Edetailing is widely used to reach "no see physicians"; approximately 23% of primary care physicians and 28% of specialists prefer computer-based edetailing, according to survey findings reported in the April 25, 2011, edition of American Medical News (AMNews), published by the American Medical Association (AMA).

New pharma code & guidelines The Pharmaceutical Research and Manufacturers of America (PhRMA) released updates to its voluntary Code on Interactions with Healthcare Professionals on July 10. The new guidelines take effect January 2009." In addition to prohibiting small gifts and reminder items such as pens, notepads, staplers, clipboards, pill boxes, etc., the revised Code: 1. Prohibits company sales representatives from providing restaurant meals to healthcare professionals, but allows them to provide occasional meals in healthcare professionals’ offices in conjunction with informational presentations"

2. Includes new provisions requiring companies to ensure their representatives are sufficiently trained about applicable laws, regulations, and industry codes of practice and ethics. 3. Provides that each company will state its intentions to abide by the Code and that company CEOs and compliance officers will certify each year that they have processes in place to comply 4. Includes more detailed standards regarding the independence of continuing medical education. 5. Provides additional guidance and restrictions for speaking and consulting arrangements with healthcare professionals. However, the Good Works Health government-approved platform offers physicians and other health care professionals the opportunity to direct donations to charities of their choice in exchange for participation in pharmaceutical promotional/educational programs.

Free samples Free samples have been shown to affect physician prescribing behaviour. Physicians with access to free samples are more likely to prescribe brand name medication over equivalent generic medications. Other studies found that free samples decreased the likelihood that physicians would follow standard of care practices. Receiving pharmaceutical samples does not reduce prescription costs. Even after receiving samples, sample recipients remain disproportionately burdened by prescription costs. It is argued that a benefit to free samples is the “try it before you buy it” approach. Free Samples give immediate access to the medication and the patient can begin treatment right away. Also, it saves time from going to a pharmacy to get it filled before treatment begins. Since not all medications work for everyone, and many do not work the same way for each person, free samples allow patients to find which

dose and brand of medication works best before having to spend money on a filled prescription at a pharmacy.

Sale and techniques of sales To become a successful sales representative you need to have a solid understanding of selling concepts. These concepts give you the foundation to understand why customers act the way they do and provide a guide as to how to use your selling skills to overcome obstacles and increase sales. Successful Selling Steps If we consider the steps most successful sales representatives go through to increase their effectiveness on sales calls, we will see there are three general areas for consideration: 1. 2. 3.

Business Planning The Sales Call (pre-call, sales call, post-call) Follow-Up

Business planning is a critical step in ensuring your selling skills are most effective. Sales representatives in the healthcare industry manage their territories as if they were running their own business. To be successful in your sales territory you need to fully understand it before you attempt to call on customers. This includes knowing which customers drive your business, what their “buying” style is so you can match your selling style to it, managing an investment budget, managing your daily and weekly schedule, and working with your team to implement the territory business plans. You can view the business planning process as creating a blueprint for success. Most healthcare companies will give you a territory, a list of target customers, the sales tools needed to influence your target customers and a budget. It is up to you and your territory team to come up with a plan that will most effectively make use of these resources to increase sales. Following the business planning process, there are three main steps to consider to improve your sales call effectiveness: 1.

Pre-call planning (before you meet the customer)

2.

The sales call (face to face with the customer)

3.

Post-call analysis and follow-up (after your sales call)

Pre-call planning done prior to meeting your customer involves several steps such as reviewing past customer call notes, setting call objectives and preparing sales tools to be most effective in the short time with your customer. This will be covered in more detail shortly.

During the actual sales call itself, there are several steps to be aware of: opening, presenting features and benefits, probing, objection handling, etc. Making an effective sales call involves excellent skills within each of these areas and we will cover them more in-depth in the coming chapters. After leaving each and every sales call, post-call analysis needs to be completed, and any follow-up required accurately recorded and completed. These notes which you make post-call are what you will be reviewing prior to your next appointment with your customers. Without having these notes, your effectiveness on the next call will not be as high. One major goal of a healthcare sales representative is to be seen as a valued consultant by customers. Once you are viewed by your target customers as an excellent and credible resource (and not just another sales representative) you will have increased access and time with them – and increased face-to-face selling time is a key ingredient for success in healthcare sales. Ensuring timely follow-up to customer requests in a professional manner will go a long way in ensuring you become that value added consultant in their practices. The Sales Cycle A sales cycle is the stages that a typical customer goes through before agreeing to purchase or use your product. Although the ultimate goal is a sale, there are several stages which you must take the customer through before you can ask for the business. In the first stage, called Introduction and Awareness, the customer is not yet aware that you or your products exist. They may not even know about any problems they are currently facing because they have not taken the time to consider them. Your goal with a customer at this stage is to introduce your products and services and try to identify any problem areas which your product can solve for them, their patients or the healthcare system. Moving a customer through this stage is sometimes not easy and requires certain sales techniques. Techniques used to move a customer from this stage to the next one are rapport building, probing, objection handling, and gaining feedback. Throughout this book you will learn how to improve each of these skills to be successful in a healthcare sales role. The second stage is Identification. At this stage you need to convince the customer that a problem does indeed exist. This is sometimes the hardest stage to get through as many customers will tell you that they are happy with their current product. To move the customer through this stage, sales skills such as presenting features and benefits, probing, gaining feedback, and the ability to handle objections will be needed. In the third stage, the Knowledge stage, you must educate the customer on what your company and products offer using the features and benefits of your products and or services. Without the proper knowledge of what you and your company can offer (to the customer, the patient or the healthcare system), the customer will not be able to evaluate his options properly. Excellent use of features and benefits, probing, and objection handling will help you to move the customer through this stage to the evaluation stage.

The Evaluation stage is where the customer takes the time to compare your product to that which he is currently using. It is sometimes extremely difficult to change the habits of a customer, so persuasion and persistence is needed. Realizing where the customer is at within this sales cycle will help you to maintain perspective and use the appropriate sales skills to move him along the sales cycle. This is where your needs analysis is critical, as you want to ensure you are reinforcing, on a frequent basis, the benefits your product or service offers versus your competition in addressing THAT particular customer’s needs. To move the customer through this stage you need to present strong features and benefits, use excellent competitive selling techniques in addition to probing and strong skills. In the final stage, the customer makes a Decision to use your product or service or your competitors. If he has chosen your product, you can feel good about taking your customer through the sales cycle and convincing him of the benefits of your product versus the competition. If the customer does not choose your product or service, then your job will be to take him back to the evaluation stage so he can reevaluate the options and reconsider your product. Sometimes this is very difficult to do, as they may be very happy with what they are currently using. You may have to take them all the way back to the identification stage to find new opportunities or problems which your product can address and your competitor cannot. This is a very dynamic model, and each customer you deal with will be at a different stage in this cycle. It is your job to identify where that customer is and try to get him to the next stage using effective selling techniques. Think of the sales cycle as a series of steps that you are climbing. Before you reach the top step (the sale), you have to walk the customer up each of the lower steps first. It is very rare that you will meet a customer for the first time and walk away with a sale. You need to complete the steps in the cycle and earn the right to ask for the business. Another concept to keep in mind is that the time needed to move a customer through the sales cycle varies based on several factors: 1. Type of product – Healthcare sales products which are more expensive (such as capital equipment for use in hospitals) often requires consensus from a committee before the contract is signed. As a result, to get all members of the committee to agree takes quite a bit longer than a sale where only one customer needs to say “yes”. 2. Frequency of sales calls – The more frequently you are able to get face to face selling time with a customer, the quicker you will be able to move them through the sales cycle…IF you have developed excellent selling skills. 3. Representative selling skills – Without effective selling skills, you will not be able to move customers through the sales cycle. To move them more quickly through the sales cycle, you must continually develop and improve on all of the sales skills listed in this book. Of the three listed here, representative selling skills is by far the most important one which affects the time needed to move a customer through the sales cycle.

The Customer Environment Before we discuss each stage and the selling skills needed, we will consider the customer environment. The healthcare customer environment and selling into it requires a significant amount of planning, preparation, persistence and versatility to be effective. As you will learn, time is a very valuable commodity in the healthcare office or clinic, and making effective use of your time is critical to move that customer along the sales cycle to a decision which is favorable for your product or service. The key to success in this environment is ensuring you are calling on the right customer, the right number of times using the right message! Why is it getting more difficult to get time with our customers? Over the past several years, it has been getting more and more difficult to access customers in the healthcare industry, and those that can be accessed are giving less and less time to sales representatives. We will now have a look at some of the main reasons this is occurring: 1. Time Pressures – Today’s professionals try to squeeze more work into a day. Some physicians see between 30 and 60 patients per day. In addition to seeing patients, physicians need to finish patient charts, fill out insurance and lawyer’s reports, return phone calls and attend meetings. This is in addition to trying to have a life outside the office and spending quality time with their families. Five minutes with a representative is five minutes they could have spent completing other tasks. 2. Lack of Monetary Gain – Physicians do not get paid to see representatives but they do get paid to see patients. If they could see a patient in the time it takes to talk to a representative then they are losing money every time they talk to a representative. This reiterates the fact that you must provide value to your target customers on each and every call if you want to continue to get face time with them. 3. Number of Representatives – In many offices that see representatives, it is not uncommon for six or more representatives to visit on any given day. The sheer number representatives can be overwhelming, not only to the physician, but to the medical office assistants who have to deal with the patients in the waiting room. 4. Lack of Value Seen – This is the most important factor to keep in mind as you work on your territory. If a physician truly believes that seeing a particular sales representative will add value to his practice, he will take the time away from his patients to hear what that representative has to say. However, if he feels that a representative will bring no value, he will likely not spend any time with him or her. There can be various reasons for this, but the number one reason is that only the best representatives take the time to identify “true” needs of each customer and sell to that particular need. There are a lot of representatives who do not take the time to identify needs, involve the customer in the sales call, or prepare for each call to ensure value is seen every time. Without providing value to your key customers you will not be able to get adequate selling time to be effective.

Key Terms To be most successful as a healthcare sales representative, you must understand two key terms: targeting and frequency. Targeting: The Right Customer When considering who your target customers are, there are two key questions to ask: how important is this customer to your business and how accessible is the customer to you? How important is this customer to your business? When considering this factor you need to look at not only how busy their practice is, but also what their patient demographics are. Yes, you must call on customers who see many patients per day, but if they are not the right types of patients for your products, then you are wasting your time. For example, if you are selling a medication for high blood pressure and you are calling on a busy physician who sees mainly younger women and children, this is not likely a good use of your time. It is crucial that you look at both how busy your customer is and what types of patients they most commonly treat. Generally speaking, the more patients a customer sees the better, as long as these are the types of patients your product will help. How does a representative find out what types of patients a customer may see? There are many ways including viewing the waiting room to profile the patients waiting to see the physician, looking to see what types of product samples are on the shelves, and asking the medical office assistant or local pharmacist what types of patients the area services. If all else fails, ask your physician! They will usually give you a straight up answer as to the types of patients they look after. Just remember, it’s not just the busy physicians who are important to you – they may be busy, but may not be seeing your targeted patient population. If this is the case, they may not be a true target physician for you. How accessible is your customer? If you have a customer who is extremely busy and services the types of patients that would be a great fit for your product, it makes sense that they should be a target for you. However, what if this physician is not willing to see you as a sales representative even though you have tried many ways to see him or her? In this situation, it may be wiser to take them off your target list and replace them with another customer that you have access to. However, it is important to remember that just because you have tried a couple of times to see this customer and have not had success, it does not mean they are not accessible. You need to try every means possible (using all of the activities you read about in the Introduction to the Pharmaceutical Sales Industry from PharmaCareer) to ensure that there is not some way that you can access this customer. There are many times a customer seems inaccessible but somehow, someway, you manage to make contact with them. These can end up being your best supporters as much of your competition may have given up calling on them, giving you the opportunity to sell to them in a less

competitive environment. It is important to remember that on average you will need to make contact with your targeted customers six to twelve times a year to make an impact. Seeing a customer once every two years is not going to make much of an impact on your sales! Frequency: The Right Number of Times A physician or other healthcare professional’s accessibility will affect another key aspect in healthcare sales, which is called frequency. Frequency is simply how often, or how many times during the course of a month, quarter, or year you should be in front of a customer selling your products’ messages. Frequency must be established for each target customer by realistically evaluating how often you can access that customer. Each customer you call on will have an effective frequency which you will identify over time and will dictate how you manage your sales territory on a day to day basis. Not only do you have to call on your customers the right number of times with the right frequency and the right message, but you must identify which activities are best suited for each customer as there are many different ways of accessing them. Here is a list of activities that you can do with each of your customers or physicians. The goal is to find out who responds best to each activity and then use this knowledge to develop your business plan around each customer to ensure you are seeing them often enough to make an impact. ·

appointments

·

drop-in calls

·

video lunches or lunch and learns

·

journal clubs

·

symposia

·

CME (continuing medical education) programs

·

conferences

·

hospital rounds

·

hospital displays

·

business development or public relation events

Value or Needs Based Selling

The key to value selling is to ensure that you are selling based on what is important to your customer and NOT just what is important to you. During the training process, you will be given every possible advantage of the product you are going to be selling. The key to success on territory is finding which of those advantages are most important for each individual physician you call on. Many sales trainers talk about finding the physicians “hot button.” The hot button is a product’s features and benefits which are most important to a particular physician. Many new representatives just out of training will do a “data dump” or “product puke” which simply means trying to present two weeks of product training in five minutes. Instead of doing this, spend time trying to find out what is important to your customer (using your excellent probing skills) and then using the two or three features/benefits of your product that are most relevant.

Consultative selling simply means selling as a consultant by involving your customer in discussion to ensure you are talking about areas that are important to them. Most adults do not like being talked “to” and would rather be involved in a discussion. Plus, this will allow you to gain much more information than if you were doing all of the talking. Based on the information you have received through consultative selling and probing, you will then use the appropriate sales tools to highlight the features and benefits your product offers which best match the customer hot buttons.

Features and Benefits

Features are simply things that are built into a product or service and cannot be changed. Examples of typical features of a healthcare sales product include: efficacy, safety and price. Efficacy answers the question “does the product do what is says it will do?” If a medication was designed to lower cholesterol by a certain percentage, efficacy is a measure of whether or not it does so in the manner described in the literature and communicated by a sales representative. Comparing the efficacy of two medications by a physician will often lead to him developing a preference for one over the other. Safety is another area where products may differ. Safety is simply a comparison of the adverse effect profile between medications (contraindications, cautions, side effects). Price is self explanatory. Products rarely cost the same, and often higher priced products need to be sold more assertively to convince customers they are worth the extra money paid.

Features by themselves do not sell a product. It is the benefit attached to a particular feature which will impact the customer and sell your product. The benefit explains to the customer why a feature is important and how it will help him, the patient, or the health care system. For example, consider a product which costs one dollar a day for a patient. This feature ($1.00) will not sell the product. However, the benefit may be that the price is 25% less than the competitor’s product and this means that the physician’s patients (who may all live in a lower income neighborhood) may have more money in their pockets for other living necessities. Conversely, the $1.00 price tag may be more than what the competitors charge. However, your product may have data (which the other product does not have) which shows it reduces heart attacks by 30% which means a savings to the total healthcare system. As a sales representative, your goal is to find the feature that is MOST important to your customer (hot button)

and then focus on explaining how the benefits of this feature are better or more pronounced than the competition.

When deciding whether or not you have presented a feature or a benefit, ask yourself “so what”? If there is an answer to the “so what” question that you just asked yourself, then you may have presented a feature and will need to go one step further to present a benefit. Keep asking yourself “so what” until you really have trouble answering it. You need to take a benefit down to a very basic level and be able to communicate it in a clear and effective way – using a visual aid to reinforce your message.

In addition, to make your features and benefits more impactful, many successful healthcare sales representatives “paint the patient picture.” Painting the patient picture means helping the physician visualize exactly which type of patient in his practice will most benefit from your product. If you do this successfully, the next time that patient comes in, he or she may get your product and your sales will increase.

Relationship between Sales and Marketing

Most people confuse between sales and marketing. It’s actually pretty straightforward: Marketers create demand, and the sales team execute accordingly to fulfill that demand. Similar to design and marketing, both teams share a symbiotic relationship – one cannot benefit without the other, yet they don’t speak the same language. Each have their own jargons and lingoes they throw around one other, and it’s not helping your company to grow. How can you put an end to the ceaseless sales and marketing dispute? Let’s take a closer look at their dynamics. We all know that poor communication discourages any form of relationship. A disconnect between your teammates discourages your business efforts to maximize value for both your company and your customers. Common conflicts include: Losing focus You may think that joint metrics in sales and marketing saves time, money, and energy. On the contrary, this culture is exactly what’s causing that blurry distinction between sales and marketing – when they’ve led a successful campaign, everyone shares the reward. When all else fails, team members blame one another. Separatistic culture Each team is too focused on individual tasks. Marketers work out the grand plan, sales wants to close the deal ASAP. Marketers work behind the desk, sales are out in the field. Marketers are strategic thinkers who are highly analytical and data-oriented, and they’re motivated by providing creative solutions for the

long haul. Sales wants to generate maximum revenue as they’re usually compensated by commissions, quotas, bonuses, and so on.

What about the customers? We’re living in the digital era, and as a business leader it’s your responsibility for everyone in your team to understand that consumers’ buying behaviors are changing. For your product or service to successfully penetrate the new demand, you need to redesign your strategy through a coherent series of campaigns, promotions, advertising, and other efforts. This is where your marketing and salesforce must learn to cooperate, because no matter how brilliant the plan is, your company will never profit when people simply don’t buy. There are 4 essential steps a customer goes through before they decide to buy from you:

1.

Awareness They know your existence. They look forward to seeing you again.

2.

Consideration They go home and think about you – a sign that you’ve addressed their needs and you promise to deliver.

3.

Preference They like you more than your competitors, thanks to your excellent presentations and proposals.

4.

Conversion They’re ready to negotiate contracts and proceed to sales.

Converting leads to sales is tricky, and identifying qualified leads takes time. To foster strong customer relationships, it takes a collaborative effort from every department of your company.

Teamwork: Two heads are better than one True, your marketing plan should be solid, but it must also be flexible enough to integrate its functions with the sales team. Similarly, salesforce must have a clear understanding of what is expected out of each campaign. When both teams start speaking the same language, they’re more engaged in executing every step of the process from start to finish. Align your sales and marketing operations to build on the following equities: •

Loyalty This is the foundation for word-of-the-mouth marketing. At this point, your focus is to educate and nurture first-time and regular customers. You’ve earned their trust, and you’ve got to maintain that by giving quality service and continuous support.

•

Advocacy When customers are loyal to your brand, they help you build referrals for future prospects. Consider it a success when your users, fans, and customers supports your brand more than anything else.

In a nutshell, it’s your job as a leader to encourage effective communication among your teammates. Instead of blaming one another, shift their focus on customers instead: What are their wants and needs? Once demands are clearly outlined, it gets easier to guide your teams and define exactly you expect out of each team.

Ultimately, your goal as a leader is to manage a stable brand and reputation. Everyone in your company must commit and connect to remain consistent with your vision and mission.

INDIAN PHARMACEUTICAL INDUSTRY Globalization is widely seen as a dominating phenomenon of 21st century encompassing worldwide integration of financial systems, trade liberalization, deregulation and market opening resulting in a global market and patterns of industrial development. In last few decades it is evident that firms and institutions from peripheral countries or developing world are making sustained and deliberate effort to take advantage of the new opportunities. The rise of East Asia followed by growth in China and India has led to emergence of new breed of Multinational Enterprises (MNEs) from these countries. By the end of 2004 China emerged as fifth largest outward direct foreign investor with a total US $ 37 billion and was the third largest exporter after Germany and the US (Child and Rodrigues, 2005). Similarly albeit on a smaller scale in the last decade Indian economy saw a dramatic growth in overseas investment by the Indian industry. The firms from latecomer countries are making inroads in sectors such as manufacturing (steel and pharmaceuticals) and services (IT) and trading as well as high technology sectors like semiconductors. Some of the firms such as Infosys, Lenovo, Ranbaxy and Espat are now competing at a global level. Multinational enterprises from developing countries are a clear representation of a sustained increase in outward Foreign direct investment (FDI) from developing countries which has risen from $60 billion in 1980 to $ 869 billion in 2000 and to a total in excess of $1trillion for the first time in 2004 (UNCTAD, 2004). Outward FDI from developing countries accounts for more than 10 percent of the world’s outward FDI. The rise of outward FDI and new MNEs that embody it, from economies such as India, China, Korea, Singapore, Malaysia and Taiwan is a key phenomenon for the world economy in last decade. It shows that firms from developing countries are rising to compete at the frontiers of the world market and this research also focusing on the strategies they have adopted to achieve that.

The first wave MNEs from the developing world documented by authors such as Kumar and mcleod (1981) and Lall (1983) succeeded as international players despite many difficulties. Their success was due as much to the difficulties encountered at home as to the incentives driving internationalization. One of the most salient features of first wave MNE activity is the direction and motivation of FDI compared to western MNEs. Much empirical work on first MNEs indicated strong and marked trend investments in neighboring and other countries which were at a similar or earlier stage of their development. Prominent first wave countries such as India, Philippines, Argentina and Columbia did not show any significant increase in either the level of the total outward FDI, nor a significant shift towards developed country hosts. But the arrival of the second wave MNEs from developing countries represents quite a different phenomenon. First wave countries experienced very low or negative economic growth rate whereas second wave countries grew rapidly over the intervening decade and half. This has been further enhanced by fundamental changes in the world economy which were a direct result of globalization. Globalization has created a more broad and competitive market across countries due to convergence of production and industrial patterns. As a result firms need to have 4 competitive advantages that are globally viable rather than domestically. Most of these developing countries also went through a fundamental shift in the policy orientation from an import substituting role to an export oriented outward economy. Firms in these countries now faced competition in domestic market with global firms and needed upgrade their capabilities to survive. These changes had a profound impact in creating a second wave of MNEs from developing countries. Therefore Mathews (2006) argues that analysis of second wave requires different perspectives that differ from those created to account for outward FDI from developed countries, and the

first wave of MNEs from developing countries. Initial analysis of second wave of MNEs reveals that overseas move of firms in the second wave is a result of the ‘pull factors’ that are drawing firms into global connections unlike ‘push factors’ that drove firms as stand alone players in the first wave (Mathews, 2006). Dunning et al. (1997) suggest that in the case of second wave of MNEs from EastAsian countries such as Taiwan and Korea were subsidized by governments with government policy interacting with firm strategies. The rise of second wave MNEs from emerging countries is less driven by cost factors per se, but more by a search for markets and technological innovations to compete successfully in the Global economy (Yueng, 2000). The sudden appearance of the second wave of firms and their capacity to create competitive positions to existing incumbents has raised interesting questions as they are not simply occupying space vacated by incumbents instead in many cases they are creating new economic space by their organizational and strategic innovation. Thus the changes in the world economy, specifically its globally interlinked character is responsible for driving the new approaches to and patterns of internationalization in firms from peripheral countries. Therefore Mathews (2006) suggests that existing theories and framework of internationalization have failed to capture organization and strategic innovations adopted by developing country MNEs for new modes of internationalization. In this context the Indian pharmaceutical industry provides an ideal case to investigate approaches and motives of second wave MNEs firms from developing countries. From the beginning of the 1990s, the Indian government started liberalization by removing restrictions on trade such as regulations on FDI and opened Indian market to overseas firms. As a result of liberalization policy Indian Economy witnessed dramatic growth, changes in domestic market and firm activities specifically in relation to overseas expansion strategies. The cumulative number of overseas project approved during the 1990s is estimated to be 2652, a nearly 11 fold increase from the number of projects permitted during 1975-90 (230) (Pradhan,2004). The growth of overseas investment is been characterized by significant changes in

location and sectoral distribution. In the 1990s the majority of investments has originated from the service sector and was increasingly developed country-oriented with majority ownership in most cases. The most important destination of Indian outward FDI to date is the USA which accounted for 19% of total cumulative outflows from 1996-2003. In 2005 Indian firms acquire 136 firms overseas with a total value of US $4.3 billion. The Indian pharmaceutical Industry is at the forefront in international expansion compared to other manufacturing sectors in the Indian Economy.

The Indian pharmaceutical industry is the thirteenth largest in the world in terms of market output; accounting for a market of about US$ 2.5 billion (Ramani, 2002). It is ranked as the most advanced pharmaceutical industry amongst developing countries and is one of India’s best science-based industries. Indian firms have been investing abroad for many years but it is only since the late-1990s that outward FDI flows have risen considerably. The liberalization of government policies and relaxation of regulations on FDI abroad have helped Indian firms to expand internationally. In the last decade some Indian pharmaceutical firms have successfully internationalized their operations and emerged as a major producers and suppliers of generic drugs all over the world. This study of internationalization motives and strategies adopted by Indian Pharmaceutical firms. In the absence of more systematic longitudinal firm level data this research is based on case study evidence. The findings suggest that Indian pharmaceutical firms are accessing advanced markets and acquiring new technology through the process of internationalization. Indian firms augmenting existing skills in production capabilities and process R&D by acquiring technology focused firms in advance markets. The analysis suggests that Indian pharmaceutical firms have adapted to the realities of globalization and are finding new niche through the process of internationalization.

The Indian pharmaceutical industry:

India currently represents just US $6 billion of the $550 billion global pharmaceutical industry, its share is increasing at 10 % a year. The organized sector of India’s pharmaceutical industry consists of 250 to 300 companies, which accounts for 70 % of the market, with the top ten companies representing 30%. The Indian pharmaceutical industry has developed wide ranging capabilities in the complex field of drug process Development and production technology. It is well ahead of other developing countries in process R&D capabilities and the range of technologically complex medicines manufactured. The Indian government adopted a new Patents Act in 1970, which laid the foundations of the modern Indian Pharmaceutical industry. It removed product patents for pharmaceuticals, food and agro-chemicals, allowing patents only for production processes. The statutory term for production processes was shortened to five years from grant or seven years from application. The 1970 Patent Act greatly weakened intellectual property protection in India, particularly for pharmaceutical innovations. It started the era of reverse engineering where firms developed new products by changing their production processes like Dr. Reddy. Trained manpower, comparative ease of imitation and a strong chemistry base among Indian research institutes supported manufacturers and gave the Indian pharmaceutical industry its current profile. The industry’s exports were worth more than US $ 492.30 in 2005-06 and they have been growing at a compound annual rate of 22.7 percent over the last few years (National pharmaceutical policy, 2006).

The value of the Indian Pharmaceutical industry’s overseas acquisition has grown from just US $8 million in 1997 to $116 million in 2004. Indian firms have acquired over US $1 billion worth of pharmaceutical companies overseas in 2005. There are 3 developments which are pushing expansion of the Indian pharmaceutical industry into overseas markets; A. Opportunities opened in the US generic market due to the Hatch-Waxman Act, B. Increasing outsourcing by MNC pharmaceutical firms and C. Strengthening of patent laws in the domestic market. D. Implement all these techniques in India for producing good medicines.

These three developments are creating new challenges and opportunities for Indian industry and internationalization is one of route adopted by Indian to succeed in this new environment. The generic opportunity is a result of the passing of the Hutch Waxman Act in the US in 1984. Under this new law, manufacturers of generic drugs no longer had to go through a lengthy period of extensive clinical trials in order to market a generic drug - demonstration of bio-equivalence was sufficient to acquire a patent on a generic drug. procedures were established for the resolution of disputes between branded drug manufacturers and generic manufacturers. Western markets were a lucrative business opportunity and the low cost advantage enjoyed by Indian firms on account of the cheap availability of scientific labour combined with scale economies inherent in the manufacture of bulk chemicals made for big margins. Between 1999 and 2005 drugs worth $ 64 million went off patent allowing generic companies to take advantage of better business opportunities. In the generics industry prescription drugs worth $40 billion in the US and $25 billion in Europe are due to loose patent protection by 2007-08. In 2004 the US senate passed the Greater Access to Affordable Medicine Act diluting some of the proinnovator provisions of 1984 Hatch-Waxman Act, giving a big boost to the

generic business in the US. Similarly Europe is emerging as a key market and a potential growth driver. The size of market in 2006 was US $ 14.2 billion with Germany, France, the UK and Italy accounting for more than 50% of market. Governments in Europe are trying to reduce healthcare costs by embracing generic drug companies. Liberalization facilitated the ability of Indian firms to exploit this opportunity to market generics drugs to the US and other Western economies. Indian firms are preparing themselves to take a share of this increasing global market. Indian drug manufacturers currently export their products to more than 65 countries worldwide; the US being the largest customer. However Indian firms face some difficult challenges such as non tariff barriers, decreasing profits in the generics market, competitive threats from big pharma MNEs and reputation in western markets. For example, US regulation disqualifies Indian firms from bidding for government contracts and Indian firms have to submit separate Applications for each state even when firms have FDA approved products and facilities. Another challenge is the reduction in profit margin due to intense competition from Chinese and Eastern European manufacturers as well as authorized generics produced by main manufacturer. Currently Indian industry is estimated to account for 22% of generics in the world market. Indian firms are aiming to move up the value chain by developing capabilities to produce ‘super generics’ rather than ‘generics generics’ to branded generics. Furthermore, stronger patent protection under the new patent law of 1999 has shut down the avenues for exploitation of generics opportunity in domestic market, but promised large rewards to Indian firms that could leverage their reverse engineering capabilities in advanced markets. The stronger patent law restricts reverse engineering of newly patented molecule, thus affecting an important source of growth for Indian firms. Also

multinational pharmaceutical firms have entered India after 2005 and using the same resource base as Indian firms to compete in the Indian domestic market further increasing pressure on profit margins of Indian firms. The contract research and manufacturing services (CRAM) market has emerged as huge opportunity for the Indian pharmaceutical industry. According to Frost and Sullivan (2005), the global outsourcing market is worth $37 billion and growing at almost 11%; 50% of the contract manufacturing market is in North America, 40% in Europe and just 10% in Asia and the rest of the world. Indian firms possess requisite capabilities to cater for the requirements of outsourcing markets, still India accounts for barely 1.5% of the global CRAM industry. Due to untested patent protection law and lack of data protection MNC firms are reluctant to outsource early stage R&D work to Indian firms. Therefore Indian firms are trying to increase their share in the outsourcing market by moving closer to the market.

Geographically the overseas acquisition by Indian pharmaceutical firms continues to be directed at developed countries specifically the US and Europe (Table 1). Out of 32 acquisitions listed in Table 1 only 6 are in developing markets and the remaining rest of 26 are in advanced markets such as the US and Europe. The major acquisitions are in the area of marketing although some companies are investing in building manufacturing and R&D capacities in developed markets. Indian companies have already established manufacturing plants in the US, Europe, Brazil, Russia and China.

Table 1 Recent acquisition by Indian pharmaceutical firms Company

Focus area

Year

Target

Value

Dishman

Contract

2005

Syprotec (UK)

US $ Million 93.5

Pharma

manufacturing and research

Dr. Reddy’s

service US generics,

2004

Trigenesis (US)

11

Laboratories

speciality

n/a

BMS Laboratories and

16

Meridian

products, APIs, formulations, 2005

Health care Roche’s API Business

59

custom (Mexico) synthesis

2006 2004

Betapharm Kinger Lab ( Brazil)

572 5.2

2005 2005

Uno-Ciclo (Brazil) Servycal SA (Argentina

4.6 n/a

Glenmark

Drug discovery

Pharma

research,

Hikal

formulations API’s contract

2004

Marsin (Denmark)

6 millio for 50%

Jubilant Organosys

manufacturing CRAMS, pharma

2004

PSI (Belgium)

stake 16

2005

Trinity Laboratories (along

20.25 million for

with

75% stake

speciality, chemicals,

subsidiary Trigen

intermediates, 2005

Laboratories ) Target Research Associates

33.5

services CRAMs, generic

2005

MICHEM (China) (JV)

n/a

APIs,

2005

Docpharma (Belgium)

263

2005

Explora Laboratories

n/a

formulations, medical (US) chemistry and clinical Matrix Labs

intermediates and

(Switzerland)

formulations

n/a

Fine Chemicals corp (South

n/a

Nicholas

CRAMS space

2004

Africa) Doubtrex brand acquisition

n/a

Piramal

contract 2004

(US) Rhodia’s inhalation business

14

manufacturing,

Strides lab

(UK)

APIs, branded

2005

Biosyntech (Canada)

6

formulations

2005

Avecia Pharma (UK)

16.9

Generics, OTC and

2005

Manufacturing plant

8

2005

(Poland) Beltapharm (Italy)

EUR 1.6

nutraceuticals

million (70% Sun Pharma

Branded

2005

Two facilities from Valent

1997 2005 2008 2004 n/a

Pharma (Hungary, US) Caraco (US) Able Laboratories (US) Dai Chii Sanque RPG Aventis (France) 18 generic products from

formulations, US generics, APIs Ranbaxy

US and Europe generic Markets

Torrent

Formulations,

Market Contract

Cadilla

manufacturing

Wockhardt

and generics Biogenerics, US

7.5 23.15 84 n/a

Efarmes 2005

S.A. (Spain) Brand –veratide from P&G

5

2005

(Germany) Heumann Pharma

n/a

European generic Zydus

stake) 10

(Germany) 2003

Alpharma (France)

6.6

2003

CP Pharma (UK)

20

and

2004

Esparma (Germany)

11

Europe generic market, Branded generics

The major Indian companies such as Ranbaxy, Dr. Reddy’s Laboratories, Wockhardt and others have established their own brand image in the international market as well as domestic market and are taking steps to consolidate their activities.

Indian firms are compensating for the spiraling cost of selling and marketing in advance countries by setting wholly owned subsidiaries or acquiring local firm. Thus reinforcing the argument that Indian firm’s internationalization through acquisition is directed towards acquiring new knowledge in different areas such as R&D capabilities, regulatory skills and distribution networks.

3. Firms

under investigation

The findings of this research are based on the study of internationalization motives and patterns adopted by five well established Indian pharmaceutical firms, viz. Ranbaxy Laboratories, Dr. Reddy’s Labs, Wockhardt, Nicholas Piramal and Sun Pharmaceuticals Ltd.

Table 2 Firms under investigation

Name of

Year

No. of

No. of

Turnover

% of

the

established

overseas

overseas

(2008)

turnover

Firm

Manufacturing acquisitions RS.

from

IPO

plants

from 1990

Million

8 2 3 5 4

11 4 4 3 3

41205.88 50006 26531.54 28789.1 32776

overseas (2008)

Ranbaxy DRL Wockhardt NPIL Sun

1962 1984 1959 1988 1983

69.90 79.1 70.55 71.67 68.78

1994 2001 2003 2007

All these firms are privately owned business with family ownership and ranked amongst top ten firms in India. Table 2 shows that large part of their turnover comes from overseas markets while advance regions such as US and Europe account for more than 80% of overseas revenue. All these firms raised money through IPOs (Initial Public Offerings) before embarking on the overseas acquisitions.

Omeprazole

BRAND

PACKIN

NAME

COMPOSITION

COMPANY

G

MRP

ABCID cap

Omeprazole 20mg

ARBRO PHARMA

10

36.25

Omeprazole 20mg

SANOFI AVENTIS

10

36.00

Omeprazole 20mg

CHEMO DRUGS

10x20

780.00

cap

Omeprazole 20mg

ADOC PHARMA

10

35.00

ADZOLE

Omeprazole 20mg

ADLEY FORM.

10

N.A.

ACICHEK cap ACIDOF cap ADOLOC

cap ALPHACI D-20 cap

ALPHA Omeprazole 20mg

HEALTHCARE

10

32.00

cap

Omeprazole 20mg

ATOZ PHARMA

10

34.90

AZOL cap

Omeprazole 20mg

D.R. JOHN’S LAB

10

38.50

ATOZOL

BINACID cap

BIOCIN Omeprazole 20mg

HEALTHCARE

10

34.50

Omeprazole 10mg

BIOCHEM

10

19.96

Omeprazole 20mg

BIOCHEM

10

28.80

Omeprazole 40mg

BIOCHEM

10

39.96

Omeprazole 20mg

BIOCHEM

10

N.A.

Omeprazole 20mg

PRG PHARMA

10

35.00

Omeprazole 20mg

CFL

10

39.00

BIOCID cap BIOCID cap BIOCID cap BIOMEZO LE cap BLANCID cap COSZOL cap COZEP

NICHOLAS

cap

Omeprazole 20mg

PIRAMAL

10

37.27

DIOCID

Omeprazole 20mg

INTRA LABS

10

39.00

cap DIOMED cap

Omeprazole 20mg

DYNAMIC

10

N.A.

Omeprazole 20mg

KLOKTER

10

40.00

cap

Omeprazole 20mg

SANDOZ

20x10

700.00

LOKIT cap

Omeprazole 10mg

KOPRAN

10

23.05

LOKIT cap

Omeprazole 20mg

KOPRAN

10

39.88

Omeprazole 10mg

CIPLA

10

22.75

Omeprazole 20mg

CIPLA

10

42.25

cap

Omeprazole 20mg

BIOLOGICAL E.

10

39.00

MAGO cap

Omeprazole 20mg

RAPROSS

10

32.50

cap

Omeprazole 20mg

MARC LAB

10

39.50

OCID cap

Omeprazole 10mg

ZYDUS CADILA

20

54.68

OCID cap

Omeprazole 20mg

ZYDUS CADILA

20

86.28

OLIT cap

Omeprazole 10mg

CADILA PHARMA

10

24.20

OLIT cap

Omeprazole 20mg

CADILA PHARMA

10

42.00

OMAG 20

Omeprazole 20mg

ORDAIN

10

42.40

KLOCID20 cap KULGUT

LOMAC cap LOMAC cap LORESS

MOZAC

cap

HEALTHCARE

OMALCE R cap

Omeprazole 20mg

WOCKHARDT

7

73.39

OMAPIN cap

Omeprazole 20mg

BRAWN LAB

10

20.00

OMECER cap

Omeprazole 20mg

ALPHA LAB

10

32.00

OMELAX cap

Omeprazole 20mg

ZYTRAS LIFE

10

35.50

OMENAT cap

Omeprazole 20mg

NATCO

10

39.87

OMENAT inj

Omeprazole 40mg

NATCO

10ml

43.00

OMEPRALE cap

Omeprazole 10mg

FDC

10

21.15

OMEPRALE cap

Omeprazole 20mg

FDC

10

35.25

OMEPRAZ cap

Omeprazole 20mg

ALKEM

10

46.00

OMEPREN cap

Omeprazole 20mg

BLUE CROSS

10

25.00

cap

Omeprazole 20mg

MESCKON

10

N.A.

OMERON cap

Omeprazole 20mg

AGRON REMEDIES

10

N.A.

OMEROX cap

Omeprazole 20mg

SHINTO BIOTEC

10

N.A.

OMETAB tab

Omeprazole 10mg

INTAS

10

N.A.

OMETAB tab

Omeprazole 20mg

INTAS

10

32.40

OMEZ cap

Omeprazole 10mg

DR. REDDY’S

10

23.67

OMEZ cap

Omeprazole 20mg

DR. REDDY’S

15

64.80

OMEPRON-20

OMIND-20 cap

Omeprazole 20mg

INDOCO

10

34.50

OMIZAC cap

Omeprazole 10mg

TORRENT

10

23.45

OMIZAC cap

Omeprazole 20mg

TORRENT

10

43.10

CHEMO OMPEP cap

Omeprazole 20mg

BIOLOGICAL

10

37.00

OPAZ cap

Omeprazole 10mg

AGLOWMED

10

N.A.

OPAZ cap

Omeprazole 20mg

AGLOWMED

10

N.A.

10

12.50

DISCOVERY OSKAR-20 cap

Omeprazole 20mg

MANKIND ZOTA

OVEVAR cap

Omeprazole 20mg

HEALTHCARE

10

38.00

PIRAZOLE cap

Omeprazole 20mg

NICHOLAS

10

N.A.

PROMISEC cap

Omeprazole 20mg

ARISTO

10

27.26

PROTOLOC cap

Omeprazole 20mg

USV

10

39.00

PROTOLOC cap

Omeprazole 40mg

USV

10

73.00

PROZEX-20 cap

Omeprazole 20mg

SYNOKEM

10

36.95

RELOC-20 cap

Omeprazole 20mg

RHYDBURG

10

30.00

SANPOL-20 cap

Omeprazole 20mg

SHILAR PHARMA

10

19.50

SIOZOLE cap

Omeprazole 20mg

ALBERT DAVID

10

41.89

SYSTOPIC

10

24.50

EAST AFRICAN (R)

10

37.50

Omeprazole magnesium in TACKO-M tab betacyclodextrin 20mg TRAZ-20 cap

Omeprazole 20mg

ZECID cap

Omeprazole 20mg

ZEE LAB

10x30

1200.00

AUROBINDO ZOLCER cap

Omeprazole 20mg

PHARMA

10

31.89

ZOMEP-20 cap

Omeprazole 20mg

ZOTA PHARMA

10

19.90

Omeprazole

Systematic (IUPAC) name (RS)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) benzo[d]imidazole Clinical data Licence data Pregnancy cat. Legal status Routes Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion

US FDA:link B3 (AU) C (US) Prescription Only (S4) (AU) POM (UK) OTC (US) Oral, IV 35–76%[1][2] 95% Hepatic (CYP2C19, CYP3A4) 1–1.2 hours 80% Renal 20% Faecal

Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Chemical data Formula Mol. mass SMILES[show] InChI[show]

methylsulfinyl)-1H-

73590-58-6 A02BC01 CID 4594 DB00338 4433 KG60484QX9 D00455 CHEBI:7772 CHEMBL1503 C17H19N3O3S 345.4 g/mol

(what is this?) (verify) Omeprazole (INN) (pron.: /oʊˈmɛprəzoʊl/) (Prilosec and generics) is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), laryngopharyngeal reflux (LPR) and Zollinger–Ellison syndrome. Omeprazole is one of the most widely prescribed drugs internationally and is available over the counter in some countries. •

Medical uses See also: Proton pump inhibitor

Used to treat GERD (gastroesophageal reflux disease), gastric and duodenum ulceration and gastritis.

As a therapeutic adjuvant in treating Helicobacter pylori related ulcers Omeprazole is combined with the antibiotics clarithromycin and amoxicillin (or metronidazole in penicillin-hypersensitive patients) in the 7–14 day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is the causative factor in the majority of peptic ulcers.[3]

Adverse effects Some of the most frequent side effects of omeprazole (experienced by over 1% of those taking the drug) are headache, diarrhea, abdominal pain, nausea, dizziness, trouble awakening and sleep deprivation, although in clinical trials the incidence of these effects with omeprazole was mostly comparable to that found with placebo.[4] Other side effects may include iron and vitamin B12 deficiency, although there is very little evidence to support this.[5] Proton pump inhibitors may be associated with a greater risk of osteoporosis related fractures[6][7] and Clostridium difficile-associated diarrhea.[5][8] Antacid preparations (such as omeprazole), by suppressing acid-mediated breakdown of proteins, lead to an elevated risk of developing food and drug allergies. This

happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.[9] Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia. [5][10] The risk of community-acquired pneumonia may also be higher in people taking PPIs.[5] Since their introduction, proton pump inhibitors (especially omeprazole) have been associated with several cases of acute tubulointerstitial nephritis, an inflammation of the kidneys that often occurs as an adverse drug reaction.[5][11][12] PPI use has also been associated with fundic gland polyposis.[13] The following adverse reactions have been identified during post-approval use of Prilosec DelayedRelease Capsules.[14] Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Systemic: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, fever; pain; fatigue; malaise;hair loss; Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: Gynecomastia Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These

polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with Prilosec. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin] Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, hyponatremia, weight gain Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Respiratory: Epistaxis, pharyngeal pain Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), StevensJohnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses: Tinnitus, taste perversion Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis

Interactions Omeprazole is a competitive inhibitor of the enzymes CYP2C19 and CYP2C9, and may therefore interact with drugs that depend on them for metabolism, such as diazepam, escitalopram, and warfarin; the concentrations of these drugs may increase if they are used concomitantly with omeprazole. [15] Clopidogrel (Plavix) is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects and potentially increasing the risk of stroke or heart attack in people taking clopidogrel to prevent these events.[16][17] Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.[18] Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazole or atazanavir) will be poorly absorbed, whereas acid-labile antibiotics (such as erythromycin) will be absorbed to a greater extent than normal due to the more alkaline environment of the stomach.[15] St. John's wort (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.[19]

Mechanism of action Omeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. By acting specifically on the proton pump, omeprazole blocks the final step in acid production, thus reducing gastric acidity.[20]

Pharmacokinetics The absorption of omeprazole takes place in the small intestine and is usually completed within 3–6 hours. The systemic bioavailability of omeprazole after repeated dose is about 60%. Omeprazole bioavailability is significantly impaired by the presence of food and, therefore, patients should be advised to take omeprazole with a glass of water on an empty stomach (i.e., fast for at least 60 minutes before taking omeprazole). Additionally, most sources recommend that after taking omeprazole at least 30 minutes should be allowed to elapse before eating [21][22] (at least 60 minutes for immediaterelease omeprazole plus sodium bicarbonate products, such as Zegerid [23]), though some sources say that with delayed-release forms of omeprazole it is not necessary to wait before eating after taking the medication.[24] Plasma protein binding is about 95%. Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver. Identified metabolites are the sulfone, the sulfide and hydroxy-omeprazole, which exert no significant effect on acid secretion. About 80% of an orally given dose is excreted as metabolites in the urine and the remainder is found in the feces, primarily originating from bile secretion.

Measurement in body fluids Omeprazole may be quantitated in plasma or serum to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients. Plasma omeprazole concentrations are usually in a range of 0.2–

1.2 mg/L in persons receiving the drug therapeutically via the oral route and 1–6 mg/L in victims of acute overdosage. Enantiomeric chromatographic methods are available to distinguish esomeprazole from racemic omeprazole.[25][26]

Chemistry

(S)- and (R)-enantiomers of omeprazole, a racemate (1:1 mixture of both enantiomers)

Omeprazole is a racemate. It contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist in equal amounts of both the (S)- and (R)-enantiomers. In the acidic conditions of the canaliculi of parietal cells, both are converted to achiral products (sulfenic acid and sulfenamide configurations) which reacts with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.

Facing the loss of patent protection and competition from generic drug manufacturers, AstraZeneca developed and heavily marketed esomeprazole (Nexium) as a replacement in 2001.[when?] Esomeprazole is the eutomer [(S)-enantiomer] in the pure form, not a racemate like omeprazole. Omeprazole undergoes a chiral shift in vivo which converts the inactive (R)-enantiomer to the active (S)enantiomer doubling the concentration of the active form.[27] This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers." The proportion of the poor metabolizer phenotype varies widely between populations, from 2–2.5% in African-Americans and white Americans to >20% in Asians; several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status.[28]

History Omeprazole was first marketed in the U.S. in 1989 by Astra AB, now AstraZeneca under the brand names Losec and Prilosec. An over the counter brand, Prilosec OTC, is available without prescription in the US for treatment of heartburn. It is now also available from generic manufacturers under various brand names.

In 1990, at the request of the U.S. Food and Drug Administration (FDA), the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide).[29] The new name has led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.[29] AstraZeneca markets omeprazole as Losec, Antra, Gastroloc, Mopral, Omepral, and Prilosec. Omeprazole is marketed as Zegerid by Santarus, Prilosec OTC by Procter & Gamble and Zegerid OTC by Schering-Plough and as Segazole by Star Laboratories in Pakistan.[30][31] In the Philippines, Ajanta Pharma markets omeprazole under the brand name Zegacid. Dr. Reddy's Laboratories markets it as Omez in India, Russia, Romania, and South Africa. In Bangladesh Healthcare Pharmaceuticals Ltd. marketed omeprazole under the brand name Opal. In Bangladesh Apex Pharma also markets omeprazole under the brand name Aspra. It is also available under the brand name Rome 20 marketed by Rephco Pharmaceuticals Ltd. In Bangladesh the brand leader in this market is Seclo. In Argentina it is made by Bago Laboratories S.A. and available there and in Ecuador as Ulcozol. In Indonesia Darya-Varia Laboratories marketed omeprazole as Ozid. In Brazil, omeprazole is produced by Multilab under the name Lozeprel. In Spain it is produced by Cantabria Pharma S.L. under the name emeprotón. In Bangladesh, Eskayef Bangladesh Limited also marketed omeprazole under the brand name Losectil. The Acme Laboratories Limited marketed it under the brand name PPI. In 1999, antiulcerants were the leading class of therapeutic drugs, with $15.6 billion in global sales. Of that, Prilosec accounted for $5.91 billion, making it the best-selling drug on the market.[32] Although Prilosec's U.S. patent expired in April 2001, AstraZeneca was able to delay the introduction of generic versions through lawsuits and peripheral patent claims. It introduced Nexium as a patented replacement drug.[33]

Dosage forms This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (April 2013)

Package of Losec (Omeprazole) 20 mg, purchased in Hong Kong

Omeprazole 10 mg, From U.K.

Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10 mg, 20 mg, 40 mg, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating

enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS). It is also available for use in injectable form (I.V.) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10 ml clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg equivalent to 40 mg of omeprazole.

Multiple unit pellet system Omeprazole tablets manufactured by AstraZeneca (notably Losec/Prilosec) are formulated as a "multiple unit pellet system" (MUPS). Essentially, the tablet consists of extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell. When the tablet is immersed in an aqueous solution, as happens when the tablet reaches the stomach, water enters the tablet by osmosis. The contents swell from water absorption causing the shell to burst, releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional enteric-coated preparations. Patients for which the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia) because the tablets can be mixed with water ahead of time, releasing the granules into a slurry form, which is easier to pass down the feeding tube or to swallow than the pill.[citation needed] The granules are manufactured in a fluid air bed system. Sugar spheres in suspension are sequentially sprayed with aqueous suspensions of omeprazole, a protective layer, an enteric coating and an outer layer to reduce granule aggregation. The granules are mixed with other excipients and compressed into tablets. Finally, the tablets are film-coated to improve the stability and appearance of the preparation. Also available in a liquid suspension form, from a compounding pharmacy. Ideal for infants.

Immediate release formulation In June 2004 the FDA approved an immediate release preparation of omeprazole and sodium bicarbonate that does not require an enteric coating. This preparation employs sodium bicarbonate as a buffer to protect omeprazole from gastric acid degradation. This allows for the production of chewable tablets. This combination preparation is marketed in the United States by Santarus under the brand name Zegerid. Zegerid is marketed as capsules, chewable tablets, and powder for oral suspension. Zegerid is most useful for those patients who suffer from nocturnal acid breakthrough (NAB) or those patients who desire immediate relief. In India it is marketed by Dr. Reddy's Laboratories as powder formulation with the brand name OMEZ-INSTA. It is reported to have additional benefits with patients suffering from alcoholic gastritis and life-style associated gastritis.

BRAND SELECTION Basis of Selction Of Brands This study was taken up as the customer centric approaches and it was kept in mind as to what parameters do customer question while selection of a brand and thus, ultimately result as a major factor affecting the customer over all evaluation process. The company’s interpretation is what is explained in the following text – 1.

Brand rejection. If someone associates a brand with something negative, they will purposely avoid the product. Have you ever experienced bad service somewhere and swore you'd never return to that chain? Have any of your customers said that about your business? Create a logo and slogan that is filled with great benefits to your customer and put that on everything. If public opinion is turning against you or your product, launch a campaign to alter it.

2.

Brand non-recognition. This is where your customers simply don't recognize your brand, probably because it is not clearly differentiated from competitors. Boldly state your product or service's benefits. Always include the full trademark name whenever you refer to your product. Be willing to create brand names for your products or services, just like you've done for your own business. Find the differences in value between your product and your competitors and highlight that difference mercilessly.

3.

Brand recognition. This is a good stage to aim for if you don't have any recognition at all. Brand recognition will help people lean toward your product when given the choice between your product and one they have

never heard of. At the same time, though remember that your competitors are also working on brand recognition, which means their brand could be more recognizable. Continue to differentiate yourself and be sure to add value to your product in order to get to the next stage.

4.

Brand preference. This is where customers - given a choice between two brands - will choose yours over someone else's. It often is the result of a sense of differentiation and that your product or service uniquely serves their needs. As well, you can be sure that any value-added products or services you include help them to choose yours over your competitors. Even though this is a great stage to be in, it's not the final stage. The stage you absolutely want to be in with your brand is!

5.

Brand loyalty.

This is where customers will choose your brand time and time again, even if they experience the occasional poor service or if another product comes along that seems to be better suited to their needs. To achieve brand loyalty, you need to provide a product that is highly differentiated, with plenty of value added, but also you need to offer them remarkable service at a level they will not get anywhere else. Providing this level of service will ensure that they will never switch.

BRANDS SHORTLISTED

PACKING / PRESENTATION

BRAND NAME

COMPANY

COMPOSITION

Ocid – 10

Zydus cadila

Omeprazole -10 mg 10 x 6×10

Omez– 20

Dr. Reddy’s

Omeprazole– 20 mg 5×5×20

OVERVIEW OF COMPANY SELECTION:

Dr. Reddy’s Laboratoriesas Dr. Reddy’s Laboratories Ltd.

Reddy, has

Founded: 1984

Headquar ters

Hyderabad,

Ltd. trading Dr. Reddy's, founded in 1984 by Dr. K. Anji

become

biggest

India’s

second pharmaceutical

Andhra company. Dr. Anji Reddy had worked in the

Pradesh,India

Website: www.drreddys.com

publiclyowne India Drug an Pharmaceut d

n

s

d

icals

Ltd.

Reddy's manufactures and markets a wide range of pharmaceuticals in India and overseas. The company has more than 190 medications ready for patients to take, ingredients for drug manufacture, diagnostic kits,

60active pharmaceutical

critical care and biotechnology

products.

Dr. Reddy’s began as a supplier to Indian drug manufacturers, but it soon started exporting to

other less-regulated markets that had the advantage of not having to spend time and money on a manufacturing plant that that would gain approval from a drug licensing body such as theU.S. Food and Drug Administration (FDA). . By the early 1990s, the expanded scale and profitability from these unregulated markets enabled the company to begin

Cadila

Healthcare

Limited Founded: 1954 Headquarte Ahmedabad, rs:

India http://www.zyduscadila.co

Website: m/ 'Cadi Healthca la re' pharmaceut ical at

a is n Indian hea quarter

company d ed Ahmedabad in o western India.

Gujarat state

f The

company is the fifth largest pharmaceutical company in India,

[1]

with US$290m in

turnover in 2004. It is a significant manufacturer of generic drugs.

Cadila Laboratories was founded in 1952 by Shri Ramanbhai Patel (1925-2001), formerly a lecturer in the L.M. College of Pharmacy, and his business partner Shri Indravadan Modi. The company evolved over the next four decades into one of India's established pharmaceutical companies.

In 1995 the Patel and Modi families split, with the Modi family's share being moved into a new company called Cadila Pharmaceuticals Ltd. and Cadila Healthcare became the Patel family's holding company. Cadila Healthcare did its IPO on the Bombay Stock Exchange in 2000. Its stock code on the Bombay exchange is 532321.

In 2001 the company acquired another Indian pharmaceutical company called German Remedies. On June 25, 2007, the company signed an agreement to acquire 100 per cent stake in Brazils Quimica e Farmaceutica Nikkho do Brasil Ltda (Nikkho) for around 26 million dollars.

Drug Profile Generic Name: Omeprazole

Brand names: Losec & Prilosec

Category: proton pump inhibitor Helicobacter pylori eradication

Molecular formula: C17 H19 N3 O3 S

Chemical name: 6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)

(methylsulfinyl)-1H-benzo[d]imidazole

Chemical structure:

Molecular weight: 345.42

Colour: white to off-white

Solubility in water: 0.25 g/L

Solubility in methanol : 10 g/L.

Melting Point: 200°C

Pka Values: benzimidazole (Omeprazole base)=8.8 and pyridinium ion=4.0 Physical appearance: crystalline powder having 2 to 4 waters of hydration Dose: •

Short-Term Treatment of Active Duodenal Ulcer:

The recommended adult oral dose of PRILOSEC is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

•

Gastric Ulcer:

The recommended adult oral dose is 40 mg once daily for 4-8 weeks.

•

Gastro-esophageal Reflux Disease (GERD):

The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. The recommended adult oral dose for the treatment

of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks. •

Maintenance of Healing of Erosive Esophagitis:

The recommended adult oral dose is 20 mg daily. •

Pediatric Patients

•

For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily dose for pediatric patients 1 to 16 years of age is as follows:

•

Patient Weight

•

5 < 10 kg

5 mg

•

10 < 20 kg

10 mg

•

> 20 kg

•

Omeprazole Daily Dose

20 mg

On a per kg basis, the doses of omeprazole required to heal erosive esophagitis in pediatric patients are greater than those for adults.

•

Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule.

Dosage forms: Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10 mg, 20 mg, 40 mg, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating

enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS).

It is also available for use in injectable form (I.V.) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10 ml clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg equivalent to 40 mg of omeprazole.

Synthesis: preparation of omeprazole which comprises the steps of: # (i) converting 4-nitro-2,3,5-trimethyl pyridine-N-oxide (I) to 4-nitro-3,5-dimethyl-2-(X-substituted methyl) pyridine (II) where X is halogen # (ii) reacting (II) with a substituted benzimidazole of formula (III) to make a compound of formula (IV): # (iii) converting compound (IV) to compound (V) by replacing the nitro group with a methoxy group: # (iv) and oxidising (V) to form omeprazole (VI)

Preferably,

in

step

(i),

the

compound

I

is

acetylated

to

form

4-nitro-3,5-dimethyl-2-

acetoxymethylpyridine (Ia) which, after hydrolysis to compound Ib, is halogenated to form the 2halomethyl derivative (II): where X is halogen.

EP-A-484265 discloses a similar process, but with key differences. At page 32 of EP-A- 484265, production of omeprazole from the intermediate is described, but the N-oxide moiety is retained until

after the condensation reaction with 5-methoxy-2-mercapto-benzimidazole has been performed, thus requiring a subsequent deoxygenation step.

In the above preferred procedure for step (i), the intermediate compounds Ia and Ib are preferably not isolated from the reaction mixture. Also, compound II need not be isolated.

In the most preferred step (i), the acetylation is effected using acetic anhydride, and the halogenation is effected using thionyl chloride. However, other suitable reactants can be used for each of these reactions.

Step (ii) of the process is preferably effected in the presence of sodium hydroxide and a phase transfer catalyst such as, for example, a quaternary ammonium salt, especially one selected from triethyl benzyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate and cetrimide.

Step (iii) of the process of the invention is preferably effected using a mixture of methanol, sodium methoxide and potassium carbonate. However, other reactants can be used such as, for example, potassium hydroxide, sodium hydroxide and potassium bicarbonate. In the most preferred method of performing step (iii), compound IV is reacted with potassium carbonate and sodium methoxide in methanol in the presence of catalytic amounts of anhydrous zinc chloride or magnesium chloride at a temperature above 45°C, preferably at the reflux temperature of methanol.

In step (iv) of the process, the compound of formula V is oxidised to form omeprazole.

Mechanism of Action:

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acidpump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more. Animal Pharmacology

Pharmacodynamics:

Antisecretory Activity: After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.

Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2-6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole.

Serum Gastric Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Enterochromaffin-like (ECL) Cell Effects

Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions.

Other Effects

Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans.

However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment.

Pharmacokinetics Absorption and Distribution: OMEPRAZOLE Delayed-Release Capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to

40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500600 mL/min.

Based on a relative bioavailability study, the AUC and Cmax of OMEPRAZOLE (omeprazole magnesium) for Delayed-Release Oral Suspension were 87% and 88% of those for OMEPRAZOLE Delayed-Release Capsules, respectively.

The bioavailability of omeprazole increases slightly upon repeated administration of OMEPRAZOLE Delayed-Release Capsules.

OMEPRAZOLE Delayed-Release Capsule 40 mg was bioequivalent when administered with and without applesauce. However, OMEPRAZOLE Delayed-Release Capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for OMEPRAZOLE Delayed-Release Capsule 20 mg. The clinical relevance of this finding is unknown.

Distribution Protein binding is approximately 95%.

Metabolism: Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.

Excretion: Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.

Side Effects: The safety data described below reflects exposure to OMEPRAZOLE Delayed-Release Capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from OMEPRAZOLE-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%).

Additional adverse reactions that were reported with an incidence ≥ 1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%).

The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less.

The clinical trial safety profile in pediatric patients who received OMEPRAZOLE Delayed-Release Capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in both the 1 to < 2 and 2 to 16 year age groups (75.0% and 18.5%, respectively). Similarly, fever was frequently reported in the 1 to 2 year age group (33.0%), and accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).[See Use in Specific Populations] Clinical Trials Experience with OMEPRAZOLE in Combination Therapy for H. pylori Eradication

In clinical trials using either dual therapy with OMEPRAZOLE and clarithromycin, or triple therapy with OMEPRAZOLE, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. Dual Therapy (OMEPRAZOLE/clarithromycin)

Adverse reactions observed in controlled clinical trials using combination therapy with OMEPRAZOLE and clarithromycin (n = 346) that differed from those previously described for OMEPRAZOLE alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section). Triple Therapy (OMEPRAZOLE/clarithromycin/amoxicillin)

The most frequent adverse reactions observed in clinical trials using combination therapy with OMEPRAZOLE, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections).

The following adverse reactions have been identified during post-approval use of OMEPRAZOLE Delayed-Release Capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise;

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth. During treatment

with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued.

Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with OMEPRAZOLE. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Metabolic/Nutritional: Hypoglycemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain

Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), StevensJohnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special Senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, doublevision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis

DRUG INTERACTIONS:

Interference with Antiretroviral Therapy:

Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug

resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.

Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. Reduced concentrations of atazanavir and nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased concentrations of saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended

during concurrent use with PRILOSEC. Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. Drugs for Which Gastric pH Can Affect Bioavailability

Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts). In the clinical trials, antacids were used concomitantly with the administration of PRILOSEC. Effects on Hepatic Metabolism/Cytochrome P-450 Pathways

Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by ^oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time.

Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with PRILOSEC.

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole.

Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d. should be considered.

Drugs affecting Omeprazole:

Before taking omeprazole, tell your doctor if you are taking any of the following drugs:

* a blood thinner such as warfarin (Coumadin); * clopidogrel (Plavix); * atazanavir (Reyataz); * disulfiram (Antabuse); * cyclosporine (Gengraf, Neoral, Sandimmune); * tacrolimus (Prograf); * phenytoin (Dilantin); * theophylline (TheoBid, Theo-Dur, Theochron, Theolair, Elixophyllin, Slo-Phyllin); * ketoconazole (Nizoral), voriconazole (Vfend); * ampicillin (Omnipen, Principen); * iron (Feosol, Mol-Iron, Fergon, Femiron, others); or * a medicine for insomnia or anxiety such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan), temazepam (Restoril), clorazepate (Tranxene), chlordiazepoxide (Librium), and others.

Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility:

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times a human dose of 20 mg/day, as expressed on a body surface area

basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to 6.5 times the human dose on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell

chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.

OVERDOSE:

Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience.

Symptoms were transient, and no serious clinical outcome has been reported when PRILOSEC was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.

MISSED DOSE:

If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

CONTRAINDICATIONS: OMEPRAZOLE Delayed-Release Capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed.

RESEARCH METHEDOLOGY

A market research survey has been conducted for the purpose of above study. The research data has been collected through out this procedure.

A. Data collection

The success of any research project depends critically on data. So data collection is the most important aspect of a research project. Primary and secondary data are used in this project.

B. Sample survey:

Survey has been conducted after preparing the questionnaire and the focus was to know the market share of company.

C. Sampling:

a) Nature of Universe

The research was carried on doctors and chemists.

b) Sample Size

Sample size has been 42 chemists of various places in SITAPUR.

c) Secondary Information

Companies documents, various journals, pamphlets and companies portals were studied for relevant information regarding the subject of the projects. These documents were very useful for theoretical, conceptual and organizational background. Detailed analysis of information and data collection was carried on and then it has been possible to complete the task.

d) Question Design

The question was designed keeping in mind the need of the project. The questions were simple and concise. Questions were prepared for chemists.

PRIMARY DATA: Primary data is collected through chemists, questionnaire, and personal interviews of chemists and different employees of DRL (MRs.).

For example: Condition of sale of drugs 

Very Good



Good



Above Average



Average



Below Average



Bad

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13. Lind T. Bioavailability and effect on acid secretion during repeated administration of omeprazole, 20 mg o.m. - comparison between an enteric coated tablet and enteric coated granule formulation. Astra Report No. I-386 1992-09-07 (Data on file). 14. Lind T, et al. Eradication of Helicobacter pylori using one week triple therapies combining omeprazole with two antimicrobials: The MACH1 study. Helicobacter 1996;1(3):138-144.

15. Lloyd-Davies KA, et al. Omeprazole in the treatment of ZES: a 4 year international study. Alimentary Pharmacol and Ther 1988;2:13-32. 16. Logan RPH, Bardhan KD, et al. Eradication of Helicobacter pylori and prevention of recurrence of duodenal ulcer: a randomized, doubleblind, multi-centre trial of omeprazole with or without clarithromycin. Aliment Pharmacol Ther 1995;9:417-423. 17. McArthur KE, Collen MJ, et al. Omeprazole: Effective, convenient therapy for Zollinger-Ellison Syndrome. Gastroenterology 1985;88:939-944. 18. Regardh CG, Gabrielsson M, et al. Pharmacokinetics and metabolism of omeprazole in animals and man - an overview. Scand J Gastroenterol 1985;20(108):79-94. 19. Thomson ABR. Twenty-four-hour gastric pH and pharmacokinetics during treatment with the new omeprazole 20 mg enteric coated tablet and the commercially available Losec® 20 mg capsule in duodenal ulcer patients. Astra Report No. I-1219 1994-05-16 (Data on file). 20. Wallmark B, Lindberg P. Mechanism of action of omeprazole. ISI Atlas of Science: Pharmacology 1987;1:158-