Your role in communicating pharmaceutical black box warnings, adverse effects, precautions, and contraindications.

By Regina Patrick, RPSGT

Pharmaceutical warnings issued by the US Food and Drug Administration (FDA) aim to protect the public from the adverse effects of a drug. However, factors such as patient illiteracy or improper physician-to-patient communication can thwart this goal. An illiterate patient, unable to read dosing instructions, may rely on their memory of the doctor’s verbal instruction; the results can be fatal if the patient remembers the verbal instructions incorrectly. Physicians often mistakenly believe a patient clearly understands medical terms when explaining dosing instructions or drug warnings to the patient; a patient may too overwhelmed or embarrassed to admit their ignorance and may pretend that they understood clearly. This means that when a patient goes home, they may guess at how to take the medication—with potentially deadly results if the patient guesses wrong. Because of these factors, it is sometimes difficult to determine if an adverse effect is due to improper physician communication or patient error, or if an adverse effect is truly caused by the drug itself and warrants an FDA-approved warning.

In the early morning hours of Thursday, May 4, 2006, US Representative Patrick Kennedy unintentionally brought to public awareness a little-known side effect of the anti-insomnia medication Ambien1,2 (generic name, zolpidem). That day, Kennedy was traveling at a high rate of speed with his headlights off; he drove into the wrong lane and struck a curb, nearly missing a police car in the process. The police pursued and signaled for Kennedy to stop, but he continued to drive at a slower speed and ultimately drove into a security barrier. At the scene, police noted he had red, watery eyes, slurred speech, and unsteady gait. Kennedy explained to the police that he was on his way to cast a vote in the House of Representatives. In actuality, the vote had taken place 6 hours before. Later, he publicly explained that he had taken Ambien and an antinausea drug, Phenergen (promethazine) before going to bed Wednesday evening but he had no memory of getting out of bed, driving, being stopped by police, or being given three traffic citations.

This high profile event and other reports3,4 of sleep-driving after taking zolpidem led the FDA on March 14, 2007 to request that all manufacturers of sedative-hypnotic drugs revise their literature to include stronger language about the risk of complex sleep-related behavior such as sleep-driving when taking the drugs. This warning affected 13 drugs: the barbiturate drugs secobarbital and butabarbital; the benzodiazepine drugs flurazepam, triazolam, quazepam, estazolam, and temazepam; and the non-benzodiazepine drugs zolpidem, eszopiclone, ramelteon, and zaleplon.

Sedative-hypnotic drugs, which are used to treat insomnia, are not the only medications used for sleep disorders that have strong FDA warnings. Medications used to treat hypersomnia (excessive sleepiness) and parasomnias (events or behavior that occur during sleep such as sleepwalking) also have problematic effects that have warranted FDA-approved warnings.


In 2007, the FDA directed manufacturers to include black box warnings—the strongest warning possible—for amphetamines and methylphenidate drugs.5 These stimulant drugs are used to counteract hypersomnia in narcolepsy or other disorders. Both classes of drugs now contain black box warnings for: 1) increased risk of heart-related problems such as high blood pressure, stroke, increased heart rate, and sudden death in people with known heart problems; 2) increased risk of thought changes (eg, suicidal ideation), mood changes (eg, depression), or behavioral changes (eg, increased hostility); and 3) increased risk of experiencing a psychotic episode (eg, hearing voices, hallucinations, or becoming overly suspicious).

In 2004, the FDA first issued a black box warning concerning children taking the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs.6 Children taking this class of antidepressants may have an increased risk of developing suicidal ideation or attempting suicide. There is also some suspicion that some adults may have an increased risk of developing suicidal ideation or attempting suicide with SSRI use. SSRI antidepressant drugs are sometimes used to treat cataplexy (sudden temporary loss of skeletal muscular tone) in narcolepsy and sleepwalking.

Sodium oxybate,7 a form of gamma-hydroxybutyrate (GHB) that is currently used to treat cataplexy in narcolepsy, carries a bold-lettered warning concerning drug dependence and drug craving, while methylphenidate and amphetamine drugs carry a black box warning concerning addiction.


A patient’s improper use of a drug is often a big factor in why an adverse effect occurs. As in the case of Representative Kennedy, a patient may take a sedative-hypnotic drug with another sedating drug unaware that this will intensify sedation. Such inadvertent adverse drug effects can be avoided by careful reading of the FDA-approved Patient Medication Guide for a drug.

A Patient Medication Guide is a paper handout that the FDA requires be distributed with certain prescription medications. A physician must issue a Patient Medication Guide with a prescribed drug if: 1) an adverse effect is likely if a patient is ignorant of the fact that the drug may cause a fatality or may result in serious harm; 2) information about a known serious adverse effect of the drug is important in the patient’s decision to use the drug; or 3) adhering strictly to directions for the use of a drug is essential to improve the drug’s effectiveness or to prevent a serious adverse effect.

A Patient Medication Guide contains black box and other types of warnings for a medication. It also gives a general description of the drug, lists the ingredients in the drug, explains how the drug works, and gives directions on how to properly take the drug. Other types of warnings found in a Patient Medication Guide are in the “Adverse Effects,” “Warnings,” “Precautions,” and “Contraindications” sections of the Guide. The differences between these and a black box warning are as follows.

  • The black box warning is often the first warning seen in a Patient Medication Guide. It is enclosed within a box (hence, “black box”) and prominently highlights that the drug has one or more of the following three factors. One, an adverse effect of the drug may cause permanent disability, may be life-threatening, or may cause death. Two, a drug’s serious adverse effects can be lessened by: using the drug in conjunction with another medication; restricting its use to a certain patient population; monitoring it carefully to avoid toxicity; or avoiding certain substances (eg, herbal remedies, medications, specific foods) while using the drug. Three, use of the drug must be restricted to assure its safe usage–for example, limiting the amount of refills for a highly addictive drug. A boxed warning may direct the patient to the “Adverse Effects,” “Warnings,” “Precautions,” and “Contraindications” sections for further details.
  • The “Adverse Effects” section describes the common and not-so-common side effects that occur with use of a drug. Adverse effects may range from minor discomfort (eg, rash) to more severe reactions (eg, angioedema [swelling of the face and tongue]).
  • The “Warnings” section may elaborate on the black box warning. This section also describes other potentially harmful effects of a drug. For example, some antidepressants (eg, sertraline, paroxetine, and bupropion) list in their warning sections that they can lower the seizure threshold in some people (increase the risk of the person having a seizure).
  • The “Precautions” section list the patients in whom or the conditions for which the drug should be used carefully. For example, the combined use of some SSRIs (eg, fluoxetine) with an anticonvulsant medication may cause therapeutic blood levels of the anticonvulsant medication to become toxic in some people with a seizure disorder. Therefore, patients with a seizure disorder taking antidepressants need to be carefully monitored to avoid this reaction.
  • The “Contraindications” section describes patients for whom and conditions for which taking the drug would be harmful or ineffective. For example, sedative-hypnotic drugs may cause fetal harm and are therefore contraindicated for use by pregnant women.

The physician plays a crucial role in preventing a patient from suffering an adverse effect of a drug. Once a physician prescribes a medication for insomnia, hypersomnia, or a parasomnia, the patient needs to be monitored for side effects.

Sedatives-hypnotics used to treat insomnia, stimulant drugs used to treat hypersomnia, and sodium oxybate used to treat cataplexy can be addictive. A physician may be able to avert a patient’s becoming dependent or addicted to a drug by questioning the patient about their use of the drug during each visit. Some issues a physician may need to address or note in patients taking these potentially addictive drugs are: Is the patient taking the drug as prescribed? Does the patient ever use the drug at other than prescribed times and for reasons other than for the sleep disorder (for example, does the patient use the drug during the daytime “to calm my nerves”)? Is the patient needing ever-increasing doses of the medication? Does the patient become extremely defensive when questioned about their use of the drug? Are the patient’s family members reporting uncharacteristic mood, thought, or behavior changes in the patient?

Since sedatives-hypnotics have been associated with the manifestation of complex behaviors during sleep, physicians need to assess if this potentially dangerous behavior is occurring in patients who are prescribed these drugs. Some issues a physician may need to address or note in a patient taking sedatives-hypnotics are: Has the patient ever awakened in a different setting without knowing how he got there? Have family members ever told the person about conversations or odd behavior while appearing half-asleep or “out of it”? Has this behavior started since beginning the medication? Is the person taking the medication as prescribed? Is the patient taking alcohol or other sedating medications with the sedative-hypnotic? Is the person taking the drug when they have 8 hours or more to devote to sleep?

Thought changes (eg, suicidal ideation) or mood changes (eg, major depression, mania) can occur in patients taking stimulant drugs. To avert possible suicide or avert injury to self or others due to mania, a physician may need to ask patients taking these medications about symptoms of depression or mania. Some issues a physician may need to address or note in patients taking stimulant drugs are: Has the patient been struggling with depression? Does the patient complain of “racing” thoughts? Does the patient describe suicidal ideation?

In addition, stimulant drugs are associated with increased cardiovascular problems. Physicians may need to monitor the patient’s blood pressure to determine if hypertension is occurring. Other issues a physician may need to note or address are: Is the patient complaining of heart palpitations or skipped heart beats? Is the patient complaining of chest pains?

The FDA relies on medical professionals to relay pharmaceutical warnings to patients. However in relaying the information, medical professionals often make the mistake of assuming that a person clearly understands medical terminology or that the patient is literate. If a professional simply gives a patient a Patient Medication Guide sheet and instructs the patient to read it, the patient may be unwilling and ashamed to admit that they do not understand medical terminology or that they are functionally illiterate (have low reading skills). To reduce this likelihood, a sleep professional should review a drug’s adverse effects, warnings, and precautions verbally with all patients when prescribing a medication. To ensure that a patient is understanding the information and warnings of a medication, the sleep professional may have the patient explain in their own words their understanding of the information.


The FDA currently consists of several centers that oversee various aspects of drug safety. One center is the Center for Drug Evaluation and Research (CDER). The CDER evaluates the safety of a drug from its preclinical trials through its clinical trials and, finally, during its postmarketing phase. Postmarketing surveillance often identifies adverse events that did not appear during the preclinical and clinical trials. The CDER gains postmarketing information about a drug by collecting adverse events reports submitted by drug companies, patients, or physicians to FDA’s MedWatch program. The CDER also works with drug companies to reduce medication errors that can occur because of confusing labeling, drug packaging, or drug names that look or sound alike.

To further assure the safety of a drug, several advisory committees make recommendations to the FDA concerning a drug. One committee is the Drug Safety and Risk Management Advisory Committee.8 This committee advises the FDA on how to manage the risks of taking a drug and how to communicate a drug’s risk (eg, should the drug have a warning, should the warning be black boxed, which warning section—precaution, contraindication, etc—should an adverse event be listed under). It collects and evaluates reports (eg, adverse events reports) for drugs that are under the regulatory control of the FDA. The committee also advises the FDA regarding the safety, efficacy, and abuse potential of drugs based on all available scientific and medical information. It recommends actions to be taken concerning the marketing, investigation, and control of such drugs.


Approximately 300,000 preventable adverse events occur in American hospitals every year9 Many of these events occur because the severity of a warning is unclear. This confusion is because of the fact that the prescribing information for drugs, particularly newly approved drugs, has become increasingly more complex. Even physicians often have difficulty finding specific information in a drug’s package insert (a package insert is the prescription drug information written specifically for physicians). If a physician can not effectively find information to relay to patients, this increases patients’ risk of suffering adverse drug effects. Therefore, in 2006 the FDA revised how it prioritizes warning information in package inserts.9

One significant change is the inclusion of the Highlights section in the physician information package about a drug. This section is prominently displayed at the top of the page. It contains Boxed Warnings and summaries of the “Indications and Usage” and “Dosage and Administration” sections. The Highlights section also includes a list of all important recent changes concerning a medication made within the year to ensure health care professionals have immediate access to the most up-to-date information about the drug before prescribing it. With this and other revisions, the FDA hopes to improve a physician’s ability to relay to patients pertinent information about the adverse effects of a drug.

At times, it is difficult to determine if an adverse effect is because of patient error, physician-to-patient miscommunication, or the result of the drug itself. For this reason, the FDA may take many months or longer to determine whether it is necessary to add stronger warning for a drug recommended by an advisory committee. Improved educational efforts aimed at preventing patient dosing error and physician-to-patient miscommunication will help not only in reducing the incidence of an adverse drug effect and the consequences of an adverse effect (eg, hospitalization) but potentially may help in more accurately determining the true risk of a prescription drug.

Regina Patrick, RPSGT, is a contributing writer for Sleep Review. 

  1. Rep. Kennedy to enter rehab for addiction: Announcement comes after early morning car crash near Capitol. MSNBC Online. May 5, 2006. Accessed December 26, 2011.
  2. Barrett T, Todd B. Rep. Kennedy entering rehab after crash. Capitol Police: Initial probe of incident “improper.” CNN Online. May 5, 2006. Accessed December 26, 2011.
  3. Gupta S. American Morning. “Sleep Driving” segment. CNN transcript. CNN, Atlanta. 2006 May 15. Accessed December 26, 2011.
  4. Unsafe sleepwalking, sleep driving linked to pills. CBC News Online. April 19, 2007. Accessed December 26, 2011.
  5. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events (Press Release). FDA News & Events. Item ID no: P07-26. February 21, 2007. Accessed December 26, 2011.
  6. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). FDA launches a multi-pronged strategy to strengthen safeguards for children treated with antidepressant medications (Press Release). FDA News & Events. Item ID no: P04-97. October 15, 2004. Accessed December 26, 2011.
  7. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Patient Medication Guide: Xyrem (sodium oxybate). Item ID no: NDA 21-196/S-005. November 18, 2005. Accessed December 26, 2011.
  8. Brodsky JD. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Drug Safety and Risk Management Advisory Committee. Committee Charter: Drug Safety and Risk Management—Drugs Advisory Committee. May 19, 2006. [removed][/removed](last accessed 12–26–2011).
  9. United States. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). FDA announces new prescription drug information format to improve patient safety (Press Release). FDA News. Item ID no: P06–08. 2006 Jan 18. Can be accessed at: (last accessed on 12–26–2011).