Adverse Reactions

ADVERSE REACTIONS – Q & A

What are adverse drug reactions?

Adverse reactions are undesirable effects, reasonably associated with use of a drug, which may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. ⁽⁴⁾

 An adverse drug reaction (ADR) is harm directly caused by the drug at normal doses, during normal use. ⁽⁵⁾

An adverse drug event (ADE) is an undesirable experience or injury resulting from the use of a drug in a patient. ^(5) (6)

All adverse events may not be observed during use of a drug, only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event. ⁽⁴⁾

Adverse Drug Reactions (ADRs) are believed to be among the top 10 leading causes of death. ⁽⁷⁾

Many ADRs are discovered only after a drug has been on the market for years. ⁽⁸⁾

Why should adverse drug reactions be documented and reported? ⁽⁵⁾

The purpose of documenting and reporting adverse drug reactions is to prevent future injuries for patients. 

New adverse drug reactions are often discovered when drugs are used in larger or in different populations than studied during initial clinical trials. Documentation and reporting becomes a crucial element in clarifying the side effect profile of a drug.

What types of adverse drug reactions should be documented? ⁽⁵⁾

Of particular importance to the U. S. Food and Drug Administration (FDA) are suspected adverse drug reactions for a new drug and suspected severe adverse drug reactions for any drug, no matter when the drug entered the market.

Health care providers should document adverse drug reactions that have caused harm or altered therapeutic care and/or where future use of the drug might cause danger or harm to a patient.

How does the U. S. Food and Drug Administration find out about adverse drug events or side effects?

The U.S Food and Drug Administration (FDA) relies on the voluntary reporting of serious adverse events by consumers and healthcare professionals through its MedWatch reporting program. ⁽⁹⁾

Approximately 10 percent of the reports the FDA receives comes directly to them through an adverse event reporting system called MedWatch from physicians, consumers, anyone who wishes to report an adverse event. ⁽¹⁰⁾

In the United States, the initiator of the report does so on a voluntary basis. ⁽¹⁰⁾

The vast majority of adverse reports come to the manufacturer or sponsor of the pharmaceutical agent. ⁽¹⁰⁾

Ninety percent of the reports that the FDA receives comes from a physician, pharmacist, health care institution, or other provider who reports to the manufacturer, who follows up on that case and then reports to the FDA. ⁽¹⁰⁾

Adverse drug reactions reported through MedWatch can act as “signals” which are then investigated to determine their clinical significance and potential public health impact. ⁽⁵⁾

This may lead to regulatory action, including mandatory warnings and labeling changes, manufacturer-sponsored post-marketing studies, journal publications, “Dear Health Care Professional” letters warning clinicians of possible drug associated events, modified indications, and/or dosing schedules, or rarely, product withdrawal. ⁽⁵⁾

The event is serious and should be reported to FDA when the patient outcome is: ⁽⁶⁾

• Death
• Life-threatening
• Hospitalization (initial or prolonged)
• Disability or Permanent Damage
• Congenital Anomaly/Birth Defect
• Required Intervention to Prevent Permanent Impairment or Damage (Devices)
• Other Serious (Important Medical Events)

What percentage of adverse drug events may be reported to the pharmaceutical companies or to the FDA?

A variety of studies have looked at the rate at which the FDA receives adverse event reports. ⁽¹⁰⁾

Commonly, the FDA states that between 1 to 10 percent of all adverse drug events are reported. ^(10) (11)

There also have been studies that have looked at serious adverse events. For many of those, the actual reporting rate is somewhat higher. ⁽¹⁰⁾

Depending on the nature of the adverse event and the drug, the FDA may receive somewhere between a third and a half of those serious reports, compared to the 1 to 10 percent of all reports. ⁽¹⁰⁾

“The vital component to drug post-marketing surveillance in this country is the voluntary compliance and active engagement by the health care community in recognizing and reporting adverse events.” ⁽¹⁰⁾

Steven Galson of the FDA in a Frontline interview in 2003 stated: ⁽¹¹⁾

• “But the system is imperfect. Without being able to require people to make those reports, if we don't have the authority to do that, it's hard to increase it beyond that. Again, we could do better if we had more case reports. But we're trying to do the best with the system that we have.”

How adequate is the U.S. FDA MedWatch system for monitoring drugs once they’ve been approved and they’re on the market?

Reporting of adverse events from the point of care is voluntary in the United States. FDA receives some adverse event and medication error reports directly from health care professionals (such as physicians, pharmacists, nurses and others) and consumers (such as patients, family members, lawyers and others). ⁽¹²⁾

Healthcare professionals and consumers (See Your Guide to Reporting Problems to the FDA)  may also report these events to the products’ manufacturers. If a manufacturer receives an adverse event report, it is required to send the report to FDA as specified by regulations. ⁽¹²⁾

Concern exists over the ability of the Food and Drug Administration (FDA) and pharmaceutical manufacturers to identify serious adverse events and to notify physicians about these findings. ⁽⁷⁾

Serious adverse drug reactions (ADRs) can go unrecognized if initial safety signals are unclear. New approaches to identifying unexpected pharmaceutical toxic effects are needed. ⁽⁷⁾

One concern is that current pharmacovigilance efforts are hindered by low reporting rates, and when ADRs are reported the information is of variable quality. ⁽⁷⁾

Steven Galson of the FDA in a Frontline interview in 2003 stated:

•  “Some of the main strengths are that we do get a lot of reports, and hundreds of thousands are in the system. We get a lot every year.” ⁽¹¹⁾
•  “The weaknesses of the system are that the quality of the reports aren't that great. They come from many different sources. They may have a lot of detail. They may have a little detail.” ⁽¹¹⁾
•  “Sometimes we can't get back to the reporter to get the details that we need to really fill in the cases. The other problem is that the actual reporting rate is low, which means [that of] a lot of the cases of adverse events that happen, we really only see a fairly small proportion of them.” ⁽¹¹⁾
•  “So there are strengths and weaknesses. We think that there are improvements that should be made, and we will make them.” ⁽¹¹⁾

What don't we know about a drug at the time it's approved?

There are a lot of things the FDA does not know about a drug at the time that it's approved. First of all, because of the limited number of people who were studied during the clinical trial phase, rare adverse events are often difficult to pick up during that phase. ⁽¹⁰⁾

Once a drug is marketed and used in tens [of thousands], hundreds of thousands, or even millions of individuals, it's more likely for a rare adverse event to occur. ⁽¹⁰⁾

Are consumers safe and protected by the U.S. FDA’s drug safety system? ⁽¹³⁾

"Every time a consumer or patient puts a pill in their mouth, especially a new pill that they've never taken before, it's an experiment."

How big an experiment depends on the pill and how well the drug has been studied. Unfortunately, many of the pills that are taken have not been studied adequately.

Even the drugs that health care professionals think they know a lot about, something may have been missed along the way.

The average medicine only works and has the right effect in only about 60 percent of people.

Raymond Woosley, M.D., in an Frontline interview in 2003 stated:

• “Many people have side effects. We didn't know how many until we started looking carefully, and some of those side effects are deadly.”
• “We don't have a safety system in this country. We've got a good voluntary reported system, but it is not a full system.”
• “We know that for every adverse event that is reported to the FDA, about 100 that never get sent in. We only get 1 percent of serious reports ever sent in, and many of those are sketchy. That's why it takes a while, too long a while, to detect these problems.”

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More Information:

• Dangerous Prescription, The FDA: Hazardous to Your Health
• Reporting Serious Problems to FDA
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program
• U.S. FDA, What is a Serious Adverse Event?
• How to Use the Consumer Complaint System and MedWatch
  
• Your Guide to Reporting Problems to the FDA
  

POSTMARKETING ADVERSE EVENTS IN U.S. WOMEN WHO USED MIFEPRISTONE FOR TERMINATION OF PREGNANCY

What has the FDA recently announced about the risks of adverse events associated with medical abortion?

Since mifepristone’s approval in September 2000, the Food and Drug Administration has received reports of serious adverse events, including deaths, in the United States following medical abortion with mifepristone and misoprostol.

On April 30, 2011 the FDA released a new report called the "Mifepristone U.S. Postmarketing Adverse Events Summary."

The report briefly  outlines the serious health risks of medical abortion when mifepristone and misoprostol is used to terminate early pregnancy.

The FDA report revealed the following details:

• 2,207 cases of women's injuries were reported of any adverse event of mifepristone and misoprostol medical abortion.
• 1.52 million women have been estimated to have had a medical abortion with mifepristone and misoprostol
• 14 women Died as a result of medical abortion.
• 612 women were Hospitalized.
• 339 women experienced a blood loss that required a Blood Transfusion.
• 256 women experienced Infections.
• 48 women experienced Severe Infections.

Deaths were associated with sepsis in eight of the 14 reported fatalities (7 cases tested positive for Clostridium sordellii, 1 case tested positive for Clostridium perfringens). All but one fatal sepsis case reported vaginal misoprostol use; buccal misoprostol use was reported in one case. The six remaining U.S. deaths involved unique events. There were five additional deaths in women from foreign countries (non-US) who used mifepristone for termination of pregnancy.
Infections includes:

• endometritis (involving the lining of the womb),
• pelvic inflammatory disease (involving the nearby reproductive organs such as the fallopian tubes or ovaries), and
• pelvic infections with sepsis (a serious systemic infection that has spread beyond the reproductive organs).

The report did not include women with reported sexually transmitted infections such as Chlamydia infections and gonorrhea, cystitis and women with toxic shock syndrome not associated with a pelvic infection.

Severe infections generally involve:

• death or hospitalization for at least 2-3 days,
• intravenous antibiotics for at least 24 hours,
• total antibiotic usage for at least 3 days, and
• any other physical or clinical findings, laboratory data or surgery that suggest a severe infection.

Ectopic Pregnancy: Administration of mifepristone and misoprostol is contraindicated in patients with confirmed or suspected ectopic pregnancy (a pregnancy outside the uterus).

Vaginal Bleeding: As stated in the approved Mifeprex (mifepristone) labeling, bleeding or spotting can be expected for an average of 9-16 days, and may last for up to 30 days.  

More Information – Post Marketing Surveillance Programs: ⁽¹⁴⁾

The U.S. Food and Drug Administration (FDA) maintains a system of postmarketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug approval process. FDA monitors adverse events such as adverse reactions and poisonings.

The Agency uses this information to update drug labeling, and, on rare occasions, to reevaluate the approval or marketing decision.

The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products.

The MedWatch program is for health professionals and the public to voluntarily report serious reactions and problems with medical products, such as drugs and medical devices. It also ensures that new safety information is rapidly communicated to the medical community thereby improving patient care.

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More Information:

• Mifepristone U.S. Postmarketing Adverse Events Summary through 04/30/2011 ⁽¹⁾
• U.S. Food and Drug Administation Postmarketing Surveillance Programs
• Mifeprex (mifepristone) Information
  

ADVERSE REACTIONS – MIFEPRISTONE

What types of adverse reactions should a women expect after taking mifepristone for medical abortion? ⁽²⁾

The treatment procedure is designed to induce the vaginal bleeding and uterine cramping necessary to produce an abortion.

Nearly all of the women who receive Mifeprex (mifepristone) and misoprostol will report adverse reactions, and many can be expected to report more than one such reaction.

About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure.

Those adverse events that occurred with a frequency greater than or equal to 1% in the U.S. and French trials are shown in Table 3.

Vaginal bleeding and uterine cramping are expected consequences of the action of Mifeprex as used in the treatment procedure.

Following administration of mifepristone and misoprostol in the French clinical studies, 80 to 90% of women reported bleeding more heavily than they do during a heavy menstrual period (see WARNINGS, Vaginal Bleeding).

Women also typically experience abdominal pain, including uterine cramping. Other commonly reported side effects were nausea, vomiting and diarrhea.

Some adverse reactions reported during the four hours following administration of misoprostol were judged by women as being more severe than others: the percentage of women who considered any particular adverse event as severe ranged from 2 to 35% in the U.S. and French trials. After the third day of the treatment procedure, the number of reports of adverse reactions declined progressively in the French trials, so that by day 14, reports were rare except for reports of bleeding and spotting.

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More Information:

•  Mifeprex (mifepristone), Prescribing Information

TYPE OF REPORTED ADVERSE EVENTS FOLLOWING ADMINISTRATION OF MIFEPRISTONE AND MISOPROSTOL IN THE U.S. AND FRENCH TRIALS

TYPE OF ADVERSE EVENT	U.S. TRIALS	FRENCH TRIALS
Abdominal Pain (cramping)	96%	NA
Uterine Cramping	NA	83%
Nausea	61%	43%
Headache	31%	2%
Vomiting	26%	18%
Diarrhea	20%	12%
Dizziness	12%	1%
Fatigue	10%	NA
Back Pain	9%	NA
Uterine Hemorrhage	5%	NA
Fever	4%	NA
Viral Infections	4%	NA
Vaginitis	3%	NA
Rigors (chills/shaking)	3%	NA
Dyspepsia	3%	NA
Insomnia	3%	NA
Asthenia	2%	1%
Leg Pain	2%	NA
Anxiety	2%	NA
Anemia	2%	NA
Leukorrhea	2%	NA
Sinusitis	2%	NA
Syncope	1%	NA
Endometritis/Salpingitis/Pelvic Inflammatory Disease	1%	NA
Decrease in hemoglobin greater than 2 g/dl	NA	6%
Pelvic Pain	NA	2%
Fainting	NA	2%

*Only adverse reactions with incidence ≥1% are included.

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More Information:

• Mifeprex (mifepristone), Prescribing Information

POSTMARKETING EXPERIENCE – MIFEPRISTONE

What other types of adverse reactions have been reported after mifepristone was approved for medical abortion?⁽²⁾

The following adverse reactions have also been reported during post-approval use of Mifeprex (mifepristone) and misoprostol:

• Allergic reaction (including rash, hives, itching),
• hypotension (including orthostatic),
• light­headedness, loss of consciousness,
• post-abortal infection (including endomyometritis, parametritis, pelvic infection),
• ruptured ectopic pregnancy,
• shortness of breath,
• tachycardia (including racing pulse, heart palpitations, heart pounding), and
• hematometra.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

No causal relationship between these events and Mifeprex and misoprostol has been established.

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More Information – Causal Relationships: ⁽⁴⁾

The drug’s labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established.

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More Information:

• Mifeprex (mifepristone), Prescribing Information
• Code of Federal Regulations. Title 21, Part 201, Labeling

ADVERSE REACTIONS – MISOPROSTOL

What types of adverse reactions have been reported with misoprostol use? ⁽³⁾

The following have been reported as adverse events in subjects receiving Cytotec:

Gastrointestinal:

In subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain.

The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14–40% and in all studies (over 5,000 patients) averaged 13%.

Abdominal pain occurred in 13–20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo.

Gynecological:

Women who received Cytotec during clinical trials reported the following gynecological disorders:

• spotting (0.7%),
• cramps (0.6%),
• hypermenorrhea (0.5%),
• menstrual disorder (0.3%) and
• dysmenorrhea (0.1%).

Postmenopausal vaginal bleeding may be related to Cytotec administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See Boxed WARNINGS.)

Incidence greater than 1%:

In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Cytotec and may be causally related to the drug:

• nausea (3.2%),
• flatulence (2.9%),
• headache (2.4%),
• dyspepsia (2.0%),
• vomiting (1.3%), and
• constipation (1.1%).

However, there were no significant differences between the incidences of these events for Cytotec and placebo.

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Information – Indications and Usage of Misoprostol:

Cytotec (misoprostol) is indicated for reducing the risk of NSAID (nonsteroidal antiinflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer.

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More Information:

• Cytotec (misoprostol) Tablets Labeling, 9/2009

ADVERSE EVENTS, CAUSAL RELATIONSHIP UNKNOWN – MISOPROSTOL

What other types of adverse reactions have been reported after misoprostol was approved? ⁽³⁾

The following adverse events were infrequently reported. Causal relationships between Cytotec and these events have not been established but cannot be excluded:

• Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes.
• Skin: rash, dermatitis, alopecia, pallor, breast pain.
• Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache.
• Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis.
• Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA).
• Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase.
• Hypersensitivity: anaphylactic reaction
• Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase.
• Genitourinary: polyuria, dysuria, hematuria, urinary tract infection.
• Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion.
• Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain.
• Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased.

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More Information – Causal Relationships:

The drug’s labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established.

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More Information:

• Cytotec (misoprostol) Tablets Labeling, 9/2009

OVERDOSAGE

Overdosage: Mifepristone ⁽²⁾

No serious adverse reactions were reported in tolerance studies in healthy non-pregnant female and healthy male subjects where mifepristone was administered in single doses greater than threefold that recommended for termination of pregnancy.

If a patient ingests a massive overdose, she should be observed closely for signs of adrenal failure.

The oral acute lethal dose of mifepristone in the mouse, rat and dog is greater than 1000 mg/kg (about 100 times the human dose recommended for termination of pregnancy).

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Overdosage: Misoprostol ⁽³⁾

The toxic dose of Cytotec in humans has not been determined.

Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported.

In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system.

Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy.

It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.

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More Information:

• Mifeprex (mifepristone), Prescribing Information
• Cytotec (misoprostol) Tablets Labeling, 9/2009