Generic Drugs: Bioequivalent and Interchangeable?

Use of generic drugs has the potential to reduce annual consumer spending on prescriptions by billions.  A study published in the New England Journal of Medicine and discussed in the New York Times Economix blog in 2012 looked at Medicare Part D expenditures and correlated them with drug prescribing patterns. The regions of the United States with the highest Medicare expenditures were those where more name brand drugs were prescribed.  But, are generic drugs as safe and effective as name brand drugs?

Generic medications become available after brand name drugs go off patent (usually 10 to 14 years after coming to market). The pharmaceutical industry maintains that the high cost of brand name drugs relates to the research and development required to innovate and bring new products to market.   Advertising and promotion are also, no doubt, a major factor.  

A generic drug is a drug that has been determined to be the bioequivalent of a brand name drug in terms of its active ingredient.   Standards for proving bioequivalence are defined by the FDA and are similar to standards used in Canada, Japan and Europe.  Here’s what the FDA website says about bioequivalence:

“One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug.”

The following graph illustrates the bioavailability of two drugs, Drug A and Drug B. The statistics may be difficult to understand, but to be determined bioequivalent the 90% confidence interval of the ratios of the mean bioavailability, or “area under the curve” (AUC), of the two drugs and their peak concentrations (Cmax) must be in the ranges of 80 to 125%.  In more concrete terms, analyses of numerous studies of bioequivalence have shown that differences in blood concentrations of the active ingredients of branded versus generic drugs are generally less than 4 percent.

Once a generic drug is deemed to be bioequivalent by these statistical standards it is not required to go through the same extensive clinical safety and efficacy trials, as a newly innovated brand name drug applying for its initial patent.

What are some pitfalls of using generics? The inactive ingredients in generics compared with branded drugs are not required to be the same. Therefore allergies to these fillers and inactive compounds can be an issue. Also, special consideration should be taken when changing from a branded drug to a generic drug, or when changing between generics, if the drug has a narrow therapeutic index. Some drugs with narrow therapeutic indices include thyroid medications, anti-epileptics and warfarin.

Here are some examples of issues that come up with generics:

The adhesive contained in a fentanyl transdermal patch differs depending on whether the patch is generic or brand name. Some of my patients have developed allergies to the adhesive in the brand name patch (as opposed to the generic,) others complain that the generics don’t stick as well.

Along the lines of narrow therapeutic index—I can recall two separate instances in which a patient was changed to a new warfarin generic drug product. In each case the patient’s PT and INR (coagulation test) had been stable for months, but after the change their levels of anti-coagulation became too high. This took some detailed history-taking to figure out. One review of the literature suggested that generic warfarin and Coumadin products are equally effective and safe and uphold the FDA’s criteria for bioequivalence, yet the authors still suggested that patients limit switches amongst warfarin products and brand and monitor anti-coagulation after making changes.

If a product is deemed bioequivalent then it is also deemed “interchangeable” and pharmacists are not required to inform physicians when they change a patient from brand to generic, or when they change from one generic to another.

Another patient, who reports a high level of drug sensitivity, noticed that a particular generic of nortriptyline used for chronic insomnia was more effective for him than others.

Thyroid medication is known to vary amongst the generics and Synthroid brand in terms of clinical effects. While the FDA has deemed these various products to be bioequivalent and interchangeable many endocrinologists disagree.  In attempt to address this issue in 2004 a  Joint Statement was issued by the major endocrinology professional societies making recommendations on the topic.

The most recent controversy regarding generics has to do with biological drugs, or “biologics.” Because of the inherent complexity of these innovator drugs, which are derived from living cells, the concept of “biosimilar” has replaced bioequivalent for the generic products being developed.  As reported last week in the New York Times, the pharmaceutical industry is currently engaged intense lobbying to prevent biosimilar generic biologics from coming to market as competition to the numerous, ultra-expensive biologics whose patents will be expiring in the near future. 

The science behind the FDA approval process for generic drugs is rigorous. My advice, it can be smart to try a generic. There is no evidence that these products are of lower quality, or less effective than name brand products—though they are not required to go through clinical efficacy trials. However, be wary of minor fluctuations in the clinical effects of your medications when switching between name brand and generic, and amongst different generics, and be aware that your pharmacist may change your generic from one manufacturer to another without your knowledge (the pill should look different). 

What is your experience with generic medications versus name brand products?

 

 

 

A Lesson on Mental Illness Care: Connecting Two Tragedies

For the past month I’ve been trying to formulate a blog that could capture my thoughts about mental illness and the prevention of violence. At this point my ideas are still not crystallized, but perhaps writing this will help. A few days before Christmas I received a phone call from a former patient’s mother.  She called while I was at the mall with my family doing some last minute shopping—I had taken the day off work.   My patient, who I will call “Mark,” and his family had left the state of Georgia and my care approximately 6 months prior.  Fighting to contain her grief Mark’s mother told me that her son, who was just 25 years old, had taken his own life.

It came as a shock, though admittedly during the brief time that I doctored Mark I had been very concerned about his well-being.  His mother said that she wanted me to know because I had worked so hard to help her son. As I listened to the story of the months leading up to his suicide I was flooded with questions:  Could I have prevented this? How did he kill himself? Had he found another physician after he moved? Had he been seeing a psychiatrist, as I had recommended?

I had only cared for Mark for three or four months. When we first met, early in 2012, his mother and he were desperate.  She called me one evening after clinic hours. I was at my son’s saxophone lesson and stepped outside to take the call. She found my medical practice and phone number on Google. She thought I might be able to help. He’d had a tough childhood. His sister was severely disabled. Then, he suffered a traumatic life event in college. Mark, though obviously very intelligent, had dropped out, unable to function.  While he was my patient Mark confided that he was desperate to be independent and get back to normal functioning, but felt crippled by his health.  He was a very likable young man who I connected with.

He described multiple symptoms—head pressure, mental fogginess, intense pain and burning all over his body coursing from his center outward and down his extremities, nausea, heartburn, post-nasal drip, an intensely dry mouth, insatiable thirst, difficulty swallowing, loss of appetite, change in his bowel habits, weight loss and muscle wasting.   Mark felt that he was dying from a medical condition that remained undiagnosed. As he explained it, his trouble had started while was under the care of a psychiatrist. He attributed some of his symptoms to a medication, a serotonin re-uptake inhibitor, Effexor, which he felt had permanently changed him.

He asked if I could test him for permanent damage caused by traces of the drug that might remain in his blood stream months after his last dose. He had left his psychiatrist’s care wanting another opinion and a thorough evaluation of these physical symptoms that were relentless and incapacitating.  

I embarked on a very thorough medical evaluation—including a plethora of blood tests, an MRI of his brain, a neurology and an allergy and immunology consultation.  I knew all the while that the root problem was very likely his underlying psychiatric condition. Mark acknowledged ongoing depressed mood and severe long-standing anxiety, but was primarily concerned about his physical health. I asked to speak with his psychiatrist, but his preference was that I evaluate his condition independently, and he refused.  When questioned about thoughts of self-harm or harming others Mark stated, “I could never do that to my mother.”

After frequent lengthy office visits and phone calls over a period of several months I was not able to arrive at a unifying medical diagnosis that explained my patient’s condition. I was, however, increasingly concerned about his psychological health and referred him to another psychiatrist. I had become aware of underlying paranoid overtones in his affect, which I felt were delusional. He had been concerned about a pharmacy contaminating his prescriptions with a substance that made him ill. He asked me if I knew what the substance was (I had never heard of it), and asked me to investigate it. He expressed suspicion about various commercial labs and preferred that I send his lab specimens to a smaller lab that he had researched and chosen. He felt this lab would do a more accurate job with his lab testing. He asked me my opinion on his future career—he said he was very interested in the military, and asked if I thought that might be a good direction for him.  Inwardly I cringed at the thought, and tried to steer him toward a more flexible career choice, and one that would not involve use of firearms.

After several months of working closely with Mark his mother informed me that the family would be moving out of state.  Although the timing was not ideal, his father could not turn down the job opportunity and Mark could not stay on his own. Despite my referrals he had never established with a new psychiatrist.  In a last ditch attempt to get him some help, I made a phone call to a psychiatrist who I knew and trusted. The psychiatrist agreed to see Mark several times prior to his move—it was the best we could think of.

 I felt that I needed to clearly articulate my clinical impression to Mark’s mother prior to their departure, which was that my patient was suffering from a psychiatric condition that caused a disorder of thinking in the form of paranoia and delusions.   I mentioned schizophrenia. Mark’s mother acknowledged that this diagnosis had been previously suggested, but that she and Mark wanted another opinion. 

At the time of his last visit Mark brought in a fairly organized list of the symptoms he was suffering from and how they impacted his ability to function. He wanted me to write a letter attesting to the fact that he was unable to work or go to school because of his condition. I agreed to write a letter describing his condition, which was difficult given the fact that there was no psychiatrist involved and his diagnosis appeared to be primarily psychiatric—I explained this to Mark and had a direct conversation with him about my clinical impression.

The visits to my psychiatrist referral never occurred. My patient moved later that summer and I had no further contact until the phone call in December. The news about my patient’s tragic suicide came one week after the shooting at Newtown, where, as we all know, another young man with significant psychiatric illness inexplicably sacrificed not only his life, but the lives of 26 children and teachers. I immediately wondered if my patient had shot himself, but somehow during our brief phone conversation, I could not bring myself to ask his mom how he died—it seemed irrelevant to her grief at the time. These two events cast a shadow over my holiday season.  

I continue to try to make reason of these two tragedies, hoping to arrive at a pithy lesson by connecting the two that I can bring to clinical practice to avoid future heartbreak. What makes it so difficult to get patients with psychiatric illness the help that they need? In this case it was not problems of access, but the underlying disease process itself made my patient resistant to care.  

 I am still searching for broader answers, but perhaps I will start with a call back to my patient’s mother to find out more details. In the meantime, I remain highly skeptical that improved mental health care alone, without restricting access to firearms will be enough to curb gun violence in our country.

Preventing Shingles

Shingles is a common disorder.  It’s caused by the reactivation of the chicken pox virus, varicella zoster virus, which remains dormant in one’s nerves after infection with chicken pox. Anyone who has had chicken pox is at risk.  Shingles is an unpleasant illness.  It causes prodromal nerve irritation, followed by the appearance of a blistering rash that follows the distribution of a nerve root. The rash can be painful and itchy, and can be the source of subsequent bacterial infection.  In some cases, cranial nerves, including nerves that supply the eye and ear, may be affected and this may lead to loss of vision or hearing.

The most unpleasant complication of shingles is the occurrence of “post-herpetic neuralgia,” defined as pain in the distribution of the shingles rash (or affected nerve root), which persists for more than three months after the shingles goes away--this may occur in 10 to 20% of cases.  Early treatment with antiviral therapy may reduce the risk of post-herpetic neuralgia.

One’s risk of developing shingles, and post-herpetic neuralgia as a complication, increases with age.  Immune deficiency, such as infection with HIV/AIDS or treatment with cancer chemotherapeutic drugs, also increases one’s susceptibility to shingles.  It is uncertain how the use of the chicken pox vaccine, now standard in children, will affect their adult risk of shingles compared with those who are unvaccinated.

A vaccine for shingles, Zostavax®, was FDA approved in 2006. In 2008 the CDC recommended that persons over the age of 60 receive the vaccine.  This recommendation is based on the relatively higher prevalence of shingles and its related complication in this age bracket. However, the shingles vaccine is also effective in healthy adults ages 50-59.  At this time the CDC has not recommended routine vaccination of this age group, which is likely related to lower disease incidence (about 4.6% annually in 50 year olds, compared with 7% annually in 60 years olds ,and 9 to 11% in 70 and 80 year olds).

Here are some common questions that patients ask me about the shingles vaccine:

1.       If I have already had shingles should I get a vaccine?

The shingles vaccine has not been tested in those who have already had shingles once. It is speculated that having the condition increases one’s immunity and helps prevent future recurrences. However, there is some research  indicating that those who have already been afflicted may continue to be at significant risk for recurrence. Therefore, it may be reasonable for this population to be vaccinated.

2.       What are the most common side effects related to the shingles vaccine?

According to the CDC, redness, pain, itching, and swelling at the site of the vaccine may occur in 1 out of 3 who receives the vaccine. Headache may occur in 1 out of 70.  More serious allergic reactions to the vaccine components including fever, difficulty breathing and throat swelling, are infrequent.

3.       Will it be safe for me to be around babies, pregnant women, and those with immune compromise after I have had the shingles vaccine? 

Yes, although it is a live attenuated virus vaccine, there have been no described cases of the chicken pox virus being transmitted in this manner from a person inoculated with Zostavax ®to a person who is not immune.

4.       In what population is the shingles vaccine contraindicated?

Although shingles is more common in those with immune compromise, the shingles vaccine is contraindicated in this population, which includes patients with HIV/AIDS, patients on cancer chemotherapy, patients on drugs that affect their immune system (such as oral steroids), and pregnant women. There are case reports describing disseminated shingles resulting from the vaccine in patients with established immune deficiency.

5.       I’m not sure if I had chicken pox, Should I have a shingles vaccine?

Persons who are unsure of whether or not they have had chicken pox should have blood work done to determine their immunity. If there is no evidence of previous exposure then a chicken pox vaccine (Varicella) should be administered in those who are eligible, not a Zostavax®.

6.       After 60, how often does one need a shingles vaccine?

Currently a single vaccine at or after age 60 is recommended.  The shingles vaccine is also FDA approved for patients ages 50-59 years.  However, given the lower disease prevalence and risk in this population the cost and health-benefit is not as well established and at this time the CDC does not specifically recommend it.  It remains uncertain how long the immunity conferred by a single shingles vaccine will last.

7.       What is the cost of a shingles vaccine?

A shingles vaccine costs approximately $200. Many health insurance plans, including Medicare Part D and private insurers, cover the immunization after (but not before) age 60.

For more information visit http://www.cdc.gov/shingles/index.html or http://nihseniorhealth.gov/shingles/aboutshingles/01.html .