On Jan. 10, 2013, the Food and Drug Administration (FDA) issued a drug safety communication concerning most sleeping pills containing the drug zolpidem because of new data showing that the levels of drug remaining in the blood the morning after use may be high enough to impair activities requiring mental alertness, including driving. Though the drug’s newest formulation, INTERMEZZO, was not specifically included in the FDA’s safety communication, the FDA twice rejected it for approval due...
On Jan. 10, 2013, the Food and Drug Administration (FDA) issued a drug safety communication concerning most sleeping pills containing the drug zolpidem because of new data showing that the levels of drug remaining in the blood the morning after use may be high enough to impair activities requiring mental alertness, including driving. Though the drug’s newest formulation, INTERMEZZO, was not specifically included in the FDA’s safety communication, the FDA twice rejected it for approval due to these same concerns.
INTERMEZZO was approved in November 2011 as a formulation of zolpidem that dissolves under the tongue. Until its formulation, the idea behind insomnia drugs was to assist one in getting to sleep at his or her normal bedtime. INTERMEZZO differs from the rest of the group in that it is for people who wake up in the night and still have four hours left before they are to rise in the morning. As such, it is designed to work for a shorter period of time than typical sleeping pills. But even with its shorter action time, INTERMEZZO presents some of the same serious safety concerns as earlier formulations of zolpidem.
Overview of zolpidem
Zolpidem originated in 1992 as the familiar and controversial sleeping pill AMBIEN, and it has since morphed into four more variations (see table).
AMBIEN and the four formulations that followed it all contain the same chemical, zolpidem tartrate. The differences between the five formulations are either in the length of time the drug is effective (extended time or limited time) or mechanism of delivery (oral tablet, oral spray or sublingual tablet).
Zolpidem is one of the three so-called “Z drugs” used to treat insomnia (the other two being eszopiclone [LUNESTA] and zaleplon [SONATA]), all of which are categorized as Do Not Use on Public Citizen’s WorstPills.org. They all belong to a drug class called nonbenzodiazepine hypnotics.
“Nonbenzodiazepine” means that the drugs are allegedly not like VALIUM or similar drugs. (Most of the benzodiazepines are also categorized as Do Not Use. One listed as Limited Use is oxazepam [SERAX].) Although zolpidem and the other Z drugs are not benzodiazepines, they have many of the same effects of this family of drugs, including the potential to cause dependence. The WorstPills.org website provides a wealth of information on the use of these drugs.
Formulations of Zolpidem Tartrate
|AMBIEN CR*||Oral tablet|
|EDLUAR*||Sublingual tablet (8 hrs)|
|INTERMEZZO*||Sublingual tablet (4 hrs.)|
*Do Not Use
A history of safety concerns
In September 2008, Transcept Pharmaceuticals, Inc., submitted its original application to the FDA for drug approval of INTERMEZZO. This was followed by an FDA rejection in October 2009 due to concerns about mental alertness, including an impaired ability to drive the morning after the drug was taken. These safety concerns were related to high levels of the drug remaining in the blood the next morning.
The company resubmitted its application and was again turned down by the FDA, in July 2011, because the FDA reviewers remained concerned about the same safety issues.
However, two months later, on Sept. 14, 2011, the FDA review team, along with two of the FDA’s top management staff, met with the pharmaceutical company. Two weeks later, on Sept. 27, 2011, the FDA received a new submission from the company. At this point, the director of the FDA division that reviewed INTERMEZZO stated that the team was “convinced by the sponsor’s re-analysis and presentation of the pharmacokinetic data.”
The result was that INTERMEZZO was finally approved on Nov. 23, 2011, despite limited efficacy and the many safety concerns associated with its use. Some of the risks of all formulations of zolpidem include:
- Impairment of alertness and motor coordination. In a driving study for INTERMEZZO, next-day driving was statistically significantly impaired at three hours after taking the drug and, while not statistically significant, was poorer than placebo at four hours after taking the drug. These risks are especially relevant to women, whose bodies eliminate zolpidem more slowly than men.
- Severe anaphylactic reaction. Reactions have occurred in people allergic to zolpidem or its ingredients and include swelling of the face, lips and throat, which can cause difficulty breathing and swallowing. (Nausea and vomiting also are signs of such allergic reactions.)
- Next-day memory loss of activities performed the night before. These can include texting, making and eating food, engaging in sex, and sleepwalking.
- Worsened depression or suicidal thinking.
- Respiratory depression.
- Drug abuse and dependence. There have been post-marketing reports of drug abuse, dependence and withdrawal. Those with a history of addiction to drugs or alcohol are at increased risk and should be carefully monitored. To avoid adverse effects of abdominal and muscle cramps, vomiting, sweating, tremors and convulsions, it is important to not abruptly stop taking zolpidem.
- Harmful interactions with alcohol and other drugs. Patients are advised not to drink alcohol the day they plan to take the drug as alertness is impaired. Impaired alertness also can occur when patients are also taking imipramine (an antidepressant), chlorpromazine (an antipsychotic) or ketoconazole (an antifungal).
- Fetal harm. There were abnormalities in fetal bone formation in the skull in studies in rats and rabbits.
- Neonatal withdrawal. Babies born to mothers taking hypnotic drugs may be at risk for withdrawal symptoms.
- Breastfeeding risks. Zolpidem is excreted in human milk, putting infants at risk.
- Harm to geriatric patients. Geriatric patients experienced an increase in falls. Of 30 non-U.S. patients receiving zolpidem formulations and reporting falls, 28 (93 percent) were 70 years of age or older.
In clinical trials, the measured outcomes for those taking the drug compared with those taking a placebo sublingual tablet were rather small. The one study done in a sleep lab, in which sleep times could be carefully monitored, showed that women taking a 1.75-milligram (mg) dose of INTERMEZZO after awakening during the night fell back to sleep only 12 minutes sooner than those taking a placebo. Men in the study who took a 3.5-mg dose fell back to sleep 16 minutes sooner than those taking a placebo.
What You Can Do
Given some of the risks presented by zolpidem and by sleeping pills in general, it is probably a good idea to try nondrug approaches to getting to sleep before approaching your doctor for a pharmaceutical solution. Avoid the use of caffeine, nicotine and alcohol, especially after noon. Establish a routine for getting ready to go to bed, including relaxation techniques. Pursue regular physical activity, such as walking or gardening, but avoid vigorous exercise too close to bedtime.
If you and your doctor decide that you would benefit from a prescription for sleeping pills, which you should use for only short periods of time, consider oxazepam. See the “Sleeping Pills and Tranquilizers” section of WorstPills.org for information on safer use of this drug.