Label Drug Use Useless, Costly

¶ … Label Drug Use

USELESS, COSTLY or FATAL

Off-Label Drug Use

In November, 2003, the Knight-Ridder news service conducted an investigation on a practice called "off-label prescribing (Devitt 2006)." It found that doctors wrote up to 115 million prescriptions per year for drugs for off-label or unapproved uses. The concern has been that 8,000 to 80,000 people could develop serious reactions to these drugs. The May 8th issue of the Archives of Internal Medicine published a report about the practice. It said that more than one in every five prescriptions given out in the United States has been for unapproved or unproven use. One out of seven is intended for purposes with "little or no scientific" basis or support. The drug is either not approved by the Food and Drug Administration or prescribed for another condition. The drug may, for example, be indicated for cancer but prescribed for hypertension. Or the doctor may change the dosage or duration of the treatment or use. These are examples of off-label prescribing (Devitt).

When the FDA approves a particular drug for a particular ailment, doctors can legally prescribe it for another ailment (Devitt 2006). Drug manufacturers do not have to get approval for all the conditions for which a particular drug may be useful. Furthermore, doctors do not have to inform patients that the drug being prescribed is for off-label use. The American Medical Association endorses their members' autonomous clinical decision-making authority over off-label drug use as long as it is drawn from "sound medical opinion and strong scientific evidence." This is the provision of AMA policy H. 120-988 (Devitt).

A research on the 100 most popularly prescribed drugs in the U.S. And 60 randomly selected medications from the Archives of Internal Medicine (Devitt 2006). These 160 drugs were approximately 56% of all prescribed drugs used in 2001 alone. The purpose of the research was to determine how many of these drugs were FDA-approved, off-label but with sound scientific support, or off-label with limited or without scientific support. Analysis of the findings showed that the majority of the prescribed drugs were FDA-approved but a large number lacked FDA approval for conditions they were used for. In addition, 15% of them lacked the appropriate scientific basis for the use. Off-label prescriptions were most often used for cardiac drugs and anticonvulsants. Findings showed that 46% of all drugs prescribed for these conditions were off-label. As to volume, 35.5 million antimicrobials were prescribed for psychiatric treatment as antidepressants, anxiolytics and anti-psychotics. A third of all off-label prescriptions were cardiac medications and anticonvulsants. The most frequently prescribed off-label at 83% was gabapentin. It is an anticonvulsant medication approved for epileptic seizures but often prescribed for nerve pain caused by the herpes virus. In addition, only 20% of these off-label prescriptions had the required strong scientific support for the alternative use. In 2004, the manufacturer of gabapentin pleaded guilty to two counts of criminal fraud for which it paid more than $430 million for the charges and civil liabilities. Other frequent off-label prescriptions were made for the antidepressant amitriptyline hydrochloride at 81% and the oral steroid dexamethasone (Devitt).

The Knight-Ridder study conducted in 2003 found that off-label drugs sold at approximately $12.9 billion or almost a quarter of those on retail (Devitt 2006). Yet the Knight-Ridder examined only 45 of these drugs and did not include those for cancer and pediatric uses. The Archives researched used only 160 of these and only for 2001. Of the thousands of drugs sold in the U.S., one cannot possibly measure the financial and human costs entailed by off-label prescribing as to their wasteful use, insurance billing and paperwork in addition to the incalculable risks to human safety and health (Devitt).

Issues on off-label drug use center on effectiveness and safety (Nightingale 2003). In practical terms, these issues relate to the administration, contraindications, warnings, precautions, abuse and dependence of these drugs as they used in ways other than those approved by FDA. Problems arise from the authority and wisdom for their un-approved uses, and the risks incurred in prescribing, reimbursement and coverage, physician liability and the conditions on the manufacturer's dissemination of the literature of these drugs. Effective patient care requires that a physician be authorized and free to use and prescribe drugs as he sees fit. When he uses or prescribes off-label, he assumes the responsibility of being well-informed about the drug and the possession of sound medical evidence and judgment. The lack of approval for off-label use may be the company's lack of interest in acquiring that approval for its own commercial or financial reasons. Or the company may have included off-label use but the FDA did not approve this (Nightingale).

A physician who is contemplating on prescribing an off-label drug for a particular patient may be guided by guidelines for pertinent indications, diseases or population groups (Nightingale 2003). He may review the FDA's updated labeling, such as black-box warnings, contraindications, interactions and side effects, especially those relating to off-label use. He may also consider higher doses, use among different groups, use in patients with other medical conditions or taking other medications. It will be an advantage to gather information on how long the particular drug has been in the market and the extent of off-label use and its status in other countries with a modern regulatory system for drugs. The physician has the pivotal role in the matter. If he possesses reliable and detailed knowledge of the medical history and status of the patient, the physician may decide on the appropriateness of an off-label drug for a condition and in that setting. The drug may prove to be more or less effective, safer or less safe, than the drug officially approved for the condition. The drug may otherwise be ineffective and unsafe. Information about off-label prescribing is accessible from medical literature, professional associations, pharmacies and the FDA online. This accessibility will help the physician reach or form appropriate decision on off-label drug use (Nightingale).

The consequences of high-profile drug safety controversies have been changing the environment of drugs and marketing of drugs (Business Editors 2005). They also tend to reduce potential profits of companies from the off-label use of these products. The U.S. And the European Union regulatory reform reduced indication expansion as a protection strategy. Indication expansion will differentiate the new use and prevent off-label use in the new indication. A company needs to identify the best indication management strategy for its brand of drugs. It must discover and understand the impact of regulatory reform and increased drug safety awareness about off-label drug use. It also needs to know the best timing for the launching, competitive position, pricing and what market factors influence the effectiveness of the selected indication expansion strategy (Business Editors).

An injectable drug, called Byetta, can now allow diabetics reduce blood sugar to normal levels slowly and steadily (Wilson 2005). Byetta was recently approved by the FDA. These benefits can lower blood pressure and cholesterol and the need to take other medications, according to Dr. Carol Wysham. Dr. Wysham, an endocrinologist at Rockwood Clinic, was a major researcher of a study on the effects of Byetta. She described the drug as the biggest breakthrough in the control of diabetes in the past 10 years. Present FDA-approved medications are injected by the patients themselves before breakfast and before supper. In diabetes, the pancreas does not produce enough insulin to make glucose enter the cells freely. Glucose is the source of body energy. Glucagon-like popypeptide or GLP-1 is produced in the intestines of healthy persons and stimulates the secretion of insulin. Diabetics lack this hormone. Other drugs are administered in the early stages of the disease to raise the level of secretion of insulin or improve sensitivity to insulin. Insulin in injection form is resorted to only when there is no other way the patient can have enough of it as the body needs. It is still unknown why diabetics have less GLP than non-diabetics at 30 to 40%. The new drug, Byetta, fills these needs. It more than supplies the insulin the pancreas cannot secrete. It also does not produce additional insulin when the sugar level reaches the normal range. While current injections are done twice daily, Byetta injections are used only once a week (Wilson).

Approximately eight years ago, Dr. John Eng, a hormone researcher in New York, found the chemical composition of the saliva of a Gila monster as almost identical to that of GLP-1 (Wilson 2005). The Gila monster is a poisonous lizard, which lives in the deserts of Southwestern U.S. And Mexico. Amylin Pharmaceuticals took advantage of Dr. Eng's finding and synthesized the Gila monster's saliva. FDA subjected it to prescribed trials and later federally approved it as Byetta. Researchers have been familiar with GLP-1, Byetta's model. But it fades quickly after being introduced into the body. Hence, it could not be used to cure diabetes. There is a steady flow of GLP-1 in non-diabetic bodies, which keeps the pancreas active in secreting insulin at normal levels. The structure of Byetta is similar to that of GLP-1 and performs the same functions. Both promote decreased appetite (Wilson).

Dr. Wysham was an observer at a study conducted on 20 Rockwood diabetic patients who were taking conventional diabetic medication for their uncontrolled blood sugar (Wilson 2005). She was not informed about their glucose levels for several months after the tests began. About two-thirds of the respondents were given different injectible doses of Byetta to incorporate into their medication plan, while the rest were given placebos. All of them were instructed and trained to do the injections at certain times twice daily for a month. Then they were subjected to a physical exam. Dr. Wysham closely monitored their liver, kidney, blood counts, and other functions. She observed that the patients consistently lose weight while taking Byetta. The average respondent-patient lost 15 pounds in the duration of the study, 5 lost more than 20 and two, more than 40 (Wilson).

The results of the study led Dr. Wysham to believe that Byetta could slow down or even terminate the progression of diabetes before a patient requires insulin therapy (Wilson 2005). Injecting insulin and injecting Byetta had almost the same results. Byetta even made patients lose weight. This was the finding of a recently concluded six-month study. It compared patients who took insulin and patients who took Byetta both as injectibles and twice daily. Dr. Wysham commented that 102-week extension trials confirmed the trend. While she noted that Byetta does not work in all cases. But the results of an 82-week study showed that 62% of the respondents met clinically-established glucose standards, which they previously failed to meet. Dr. Wysham said that 90% of all diabetics are overweight and the benefits deriving from Byetta have understandably drawn diabetics to it. It is expensive yet compares with the price of other conventional diabetic drugs. It is covered by most health insurance plans. She estimated that Byetta costs $150 a month at wholesale (Wilson).

Eli Lilly's Byetta, indicated for Type 2 diabetes (Johnsen 2005).Its generic name is exenatide, considered an incretin mimetic agent. It imitates the action of insulin in the intestines in stimulating insulin production without the risk of hypoglycemia. This risk is associated with insulin injections. Byetta is the synthetic exendin-4 hormone from the saliva of the Gila monster. This lizard eats only four times a year. When not eating, its pancreas is inactive. When it does, the exendin-4 found in its saliva reactivates the pancreas. Byetta imitates the mechanisms of insulin, which is similar to extendin-4. Byetta remains in the blood system and works only when blood sugar levels are too high. Observers projected the sales of Byetta to exceed $800 million next year. Its manufacturer, Eli Lilly, was working for the approval of a long-acting release version last year. This new formulation was predicted to reach $1.5 billion in sales (Johnsen).

Exenatide injection is indicated only for Type-2 diabetes but not as a substitute for insulin (Ezzo and Ambizas 2006). The biggest clinical test of exenatide therapy investigated 733 patients who used exenatide with metformin and a sulfonylurea for 30 weeks. The most commonly observed adverse reaction was gastrointestinal in nature. The combination of xenatide and metformin did not increase the incidence of hypoglycemia. But there was a 3.3-14.4% increase when sulf0nylurea was added to exenatide (Ezzo and Ambizas).

In studies on the tolerability of exenatide when combined with current therapy, 7% of the respondents backed out because of nausea and vomiting (Ezzo and Ambizas 2006). Other common reactions were diarrhea, dizziness, headache and shaking. The patients lost an average of 4.9 pounds in the 30 weeks of study. Another study, which combined exenatide and insulin glargine, 1 in 10 withdrew because of the adverse effects of the combination. These effects were 57% nausea and 17% vomiting. As to effectiveness, studies showed that a combination of exenatide would result in 7% or less of A1C in 24 to 46% of patients with an initial A1C of more than 7%. Exenatide reduced fasting plasma glucose levels by 5 to 10 mg per dL. This did not increase weight. A pre-filled pen containing 60 doses of exenatide for a month would cost approximately $191 to 223. A vial of 10 ml of insulin glargine would cost approximately $69 for a month's use. And exenatide is sold as a sterile solution for subcutaneous injection at 250 mcg per mL. It is available in 1.2-mL prefilled pen and in 2.4-ml prefilled pen forms. This should be injected into the thigh, abdomen or upper arm. It should be refrigerated and protected from light. It should be disposed of 30 days after the first use. The first dosage must be injected subcutaneously two times daily within 60 minutes before the morning and evening meals, not after. The dose may be increased to 10 mcg twice daily after a month of treatment. When added to metformin, exenatide may be continued. When added to a sulfonylurea, the dose of sulfonylurea should be reduced to avoid or reduce the risk of hypoglycemia (Ezzo and Ambizas).

Exenatide injectible for Type-2 diabetes requires that the patient be educated in its use (Ezzo and Ambizas 2006). Glucose levels should be strictly monitored because of the difficulty of use. Exenatide is costly and inconvenient. It is still believed not to have proven benefits over other drugs used to treat diabetes, such as insulin (Ezzo and Ambizas).

The other off-label drug used in the treatment of Type-2 diabetes is Januvia, a product of Merck & Co., Inc. (Business Editors 2007). It was the first and only depeptidyl peptidase-4 inhibitor or DPP-4 to be accepted and used by the European Commission. It is said to enhance the body's ability to reduce blood sugar levels when it goes higher than normal. In treating Type 2 diabetes, Januvia improves glycemic control when combined with metformin. This is the recourse when diet, exercise and metformin have not effected sufficient glycemic control. Patients with Type-2 diabetes and using a PPAR gamma agonist may find it useful. All 27 countries of the EU have adopted its use. The drug was to be launched in the 42 EU countries, including Mexico, the U.S. And the Philippines (Business Editors).