Are Nuplazid and Other FDA-Approved Drugs Really Safe and Effective?

Nuplazid (pimavanserin) is a fascinating example of the FDA’s confusing drug authorization process. We suspect that many people think a stamp of approval from the Food and Drug Administration means a medication has received very thoughtful review and passed high hurdles with flying colors. Sometimes, though, the way in which drugs get a green light is a lot more complicated.

Safe and Effective? What Does That Mean?

The FDA’s fundamental criteria for approving new drugs is surprisingly simple. Manufacturers must prove that a medicine is “safe and effective” before they can market it. This is a key component of the Food Drug and Cosmetic Act.

The problem with this concept is that no one bothers to define what “safe” or “effective” really means. This vagueness creates confusion in the minds of many consumers and health professionals.

Every night on television, people watch prescription drug commercials that mention a long list of serious drug side effects. Not infrequently they hear about adverse reactions such as depression, suicidal thoughts, confusion, weight gain, trouble breathing, heart attacks, cancer, fatal infections and death.

Nuplazid Commercial:

The concern over drug safety and effectiveness bubbled up recently in Congressional hearings on a medicine called pimavanserin (Nuplazid). It was approved by the FDA two years ago to treat hallucinations and delusions associated with Parkinson’s disease.

Here is a link to a Nuplazid “commercial” that is not a Nuplazid commercial. It’s what the industry refers to as a disease awareness campaign. Nowhere in the ad is the drug Nuplazid mentioned.

What you see is an older man in a dark room. While eerie music plays in the background and voices whisper in the background you hear the man saying:

“They appear out of nowhere…my secret visitors. Appearing next to me in plain sight.”

A cat dashes past and disappears. While the eerie music continues to play the announcer says:

“Hallucinations and delusions. These are the unknown parts of living with Parkinson’s disease.”

The man in shadows then says:

“What stories they tell…but for my ears only. What plots they unfold but only in my mind.”

The voice-over announcer then shares:

“Over 50 percent of people with Parkinson’s will experience hallucinations or delusions during the course of their disease and these can worsen over time, making things even more challenging.”

Sounds scary! Then the reassuring female announcer’s voice tells us:

“But there are advances that have led to treatment options that can help.”

The viewer is told to “Talk to your Parkinson’s specialist” and

“Learn more at MORETOPARKINSONS.com”

Nowhere during the commercial is Nuplazid mentioned. Because disease awareness campaigns do not tell you to ask your doctor if the drug is right for you, they don’t have to mention Nuplazid side effects.

Nuplazid Side Effects:

Here is what you will find in the official Nuplazid prescribing information:

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
• NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.

“Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6- to 1.7-times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.

“Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.”

Other Nuplazid Side Effects:

Nuplazid side effects include fluid buildup in extremities (peripheral edema), digestive upset (nausea, constipation), confusion and unsteadiness (gait disturbance). Other adverse reactions may include sleepiness, skin rash and tongue swelling.

Institute for Safe Medication Practices (ISMP):

QuarterWatch (Nov. 2, 2017) (an independent drug industry watchdog publication of ISMP) reported on the safety and effectiveness of Nuplazid. This report noted that the initial approval of this drug was based on one clinical trial:

“Three previous trials had failed to demonstrate a benefit in reducing hallucinations and other symptoms of psychosis. FDA’s medical reviewer recommended against the approval of Nuplazid. He noted that, although other psychiatric drugs were often approved with limited evidence of benefit, in the case of Nuplazid, treatment had more than doubled the risk of death and/or serious adverse events in its only positive trial.”

Despite the FDA’s own reviewer’s objections, the agency decided that the potential benefits outweighed the risks for this drug.

A CNN Report:

Since then, concerns about this drug’s safety and effectiveness have mounted. Hundreds of people have died while taking Nuplazid. The FDA points out, however, that many of these patients were old and sick and taking other medications as well. Consequently, the agency is investigating to see whether this drug was directly responsible for their deaths.

The FDA reviewer, Dr. Paul Andreason, has left the agency. In a CNN report he is quoted as saying:

“This is exactly what I thought was going to happen.”

Questions have also been raised about its effectiveness. According to CNN, more than 1,000 reports have been submitted to the FDA claiming that the drug did not eliminate hallucinations.

Congressional Hearings:

U. S. Representative Rosa DeLauro questioned the Commissioner of the Food and Drug Administration during recent hearings:

“How many more adverse events do we have to have reported? How many people, quite frankly, have to die? Why does the industry always take precedence over public health and safety?”

The Commissioner, Dr. Scott Gottlieb, told Congress that the agency would “take another look” at the safety profile of Nuplazid. We wish the FDA would take another look at a lot of other medications as well.

The FDA and “Safe and Effective”:

If all FDA-approved drugs are supposed to be safe and effective, why do so many come with warnings about deadly adverse effects? The FDA seems to believe it’s off the hook as long as the official prescribing information contains cautions about potential hazards. The idea is that informed physicians and patients will be able to make balanced decisions based on this kind of data.

Long lists of scary side effects can quickly overwhelm physicians and pharmacists as well as patients, even sophisticated ones. Frequent exposure to such recitations in commercials may desensitize people to the dangers of drugs.

The FDA considers it a patient’s responsibility to be informed about the risks of any medicine she takes. One could argue that in the case of Nuplazid, elderly patients who are hallucinating and may be cognitively impaired should not be expected to shoulder this burden. Even desperate family members may not be qualified to assess the balance of benefits and harms. Isn’t that what the FDA should be doing?

Past Disasters:

Despite the assurance that a drug must be proven safe and effective before it is approved, the FDA has a long track record of problem medications. The arthritis drug Vioxx (rofecoxib) flamed out because of an association with heart attacks and strokes. It was removed from the market after about five years.

Bextra (valdecoxib) was somewhat similar to Vioxx. It disappeared after almost four years.

The cholesterol-lowering drug Baycol (cerivastatin) caused severe muscle breakdown (rhabdomyolysis) and was also linked to an excessive number of deaths. It took roughly four years before Baycol was pulled.

The diabetes drug Rezulin (troglitazone) bit the dust after about three years. The FDA reviewer who analyzed the original safety data did not recommend approval. He was concerned about liver toxicity. He was overruled by the agency. Eventually, the drug’s potential to cause serious liver toxicity was proven and Rezulin disappeared from the market.

How Do You Interpret Words Such as “Safe and Effective”?

What does the phrase “safe and effective” mean to you? We really want to understand how patients and family members perceive safety and effectiveness. If a drug “works” in 4 out 10 patients and a placebo sugar pill works in 3 out of 10 patients, the FDA might consider the medicine effective, even if 6 out of 10 got no benefit at all. Would you consider that drug effective?

Even if a medicine causes potentially life-threatening reactions like suicidal thoughts, heart attacks, strokes or cancer, the FDA might well consider it “safe.” Would you? Please share your thoughts in the comment section below.