MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

DATE: May 6, 2003

FROM: Lauren Lee, Pharm.D., Safety Evaluator

Division of Drug Risk Evaluation, HFD-430

THROUGH: Mark Avigan, M.D., Acting Director

Division of Drug Risk Evaluation, HFD-430

TO: Charles Ganley, M.D., Director

Division of Over-The-Counter Drug Products, HFD-560

SUBJECT: ODS Post-Marketing Safety Review (PID# D030159)

Ø Drug: Ipecac

Ø Reactions: All adverse events

I. EXECUTIVE SUMMARY:

This consult is in response to the request from the Division of the Over-The-Counter drug products to search the AERS database and review all adverse event reports involving ipecac syrup.

The AERS searches revealed 17 adverse event reports involving Ipecac. Six of 17 cases revealed ipecac abuse in females between 19 and 33 years of age (mean 25) with anorexia nervosa/bulimia. Ipecac was used as an emetic in 9 of 17 cases for the accidental ingestion or intentional overdose of drugs and other substances. Six of 9 patients were under 16 years of age. The reported adverse events in the above 15 of 17 cases were: myopathy (2), myocarditis (2), eye pain/conjunctivitis (2), pericarditis/skeletal myopathy (1), cerebral hemorrhage (1), massive hernia/cardiopulmonary arrest (1), cardiac arrest (1), seizure/dehydration (1), generalized welts (1), urticaria (1), retching (1), and prolonged vomiting (1). Two of 17 cases did not provide the indication for ipecac use and the descriptions of the adverse event, except that the patients (3 and 4 year olds) died after the ingestion of ipecac. There were 6 other fatalities (total 8/17), of which 4 were due to ipecac abuse and 2 were due to the possible underlying medical conditions in combination with ipecac use as an emetic. Of the remaining 9 cases, three required hospitalization, one of which also experienced permanent heart damage, five recovered without hospitalization, and the outcome was unknown in one.

Since ipecac is an OTC monograph product, there is no requirement for a drug company to submit adverse event reports to the FDA. Therefore, it is not surprising that the above AERS data on ipecac are very limited. However, the reported adverse events involving ipecac are consistent with its characteristic effects. The main alkaloid components of ipecac are emetine, which in cases of overdose may be a contributing factor of skeletal and cardiac muscle toxicity, and cephaeline, which causes emesis. Chronic or acute intoxication of emetine in the body could lead to ipecac poisoning and death. It is noteworthy that 50% of the deaths reported were due to the abuse/overdose of ipecac. In some of the remaining cases where ipecac was not abused but rather used as an emetic, multiple or prolonged vomiting episodes were noted. Since ipecac can cause multiple/prolonged vomiting episodes and the ipecac labeling recommends not giving activated charcoal until after the patient has vomited (so that the charcoal will not adsorb ipecac), a specific time interval for administering activated charcoal after ipecac ingestion is likely to be useful. It is also noteworthy that the ipecac labeling does not contain the maximum total dose or the maximum number of times the dose should be repeated.

II. DRUG LABELING:

Ipecac (OTC Poison Treatment Tentative Final Monograph 1985)

Warnings:

· Do not use in persons who are not fully conscious.

· Do not use this product, unless directed by a health professional, if turpentine, corrosives, such as alkalies (lye) and strong acids, or petroleum distillates, such as kerosene, gasoline, paint thinner, cleaning fluid, or furniture polish, have been ingested.

· Do not administer milk with this product.

· Activated charcoal will adsorb ipecac syrup. Do not give activated charcoal until after the patient has vomited, unless directed by a health professional.

Oral Dosage:

· Adults and children ³ 12 years of age and over – 2 tablespoonsful (30 ml of 1 bottle) followed by 1-2 glasses (8 to 16 ounces) of water or other clear liquid or as directed by a health professional.

· Children 1 to under 12 years of age – 1 tablespoonful (15 ml or ½ bottle) followed by 1 to 2 glasses (8 to 16 ounces) of water or other clear liquid or as directed by a health professional.

· Children 6 months to under 1 year of age – 1 teaspoonful (5 ml) followed by ½ to 1 glass (4 to 8 ounces) of water or other clear liquid or as directed by a health professional.

· If vomiting does not occur within 30 minutes, repeat the dose.

III. SELECTION OF CASE SERIES:

As of 3/31/2003, the AERS database contained 23 adverse event reports for ipecac. Seventeen of 23 cases were selected for further review and the remaining 6 reports were excluded due to the following:

Report image not retrievable	2
Report image not legible	2
Duplicate report	1
Vomiting reported as an adverse event (case excluded since ipecac is an emetic)	1
Total	6

IV. SUMMARY OF CASES:

The AERS searches revealed 17 adverse event reports involving Ipecac. All were domestic reports, of which 6 were published cases. The reported adverse events in 15 of 17 cases in which the reason for use was stated, included the following:

· myopathy (2)

· myocarditis (2)

· eye pain/conjunctivitis (2)

· pericarditis/skeletal myopathy (1)

· cerebral hemorrhage (1)

· massive hernia/cardiopulmonary arrest (1)

· cardiac arrest (1)

· seizure/dehydration (1)

· generalized welts (1)

· urticaria (1)

· retching (1)

· prolonged vomiting (1)

Two of 17 cases did not provide the descriptions of the adverse event or the indication for ipecac use, except that the patients (3 and 4 year olds) died after the ingestion of ipecac. There were 6 other fatalities (total 8/17), of which 4 were due to ipecac abuse and 2 were due to the possible underlying medical conditions in combination with ipecac use as an emetic. Of the remaining 9 cases, three required hospitalization, one of which also experienced permanent heart damage, five recovered without hospitalization, and the outcome was unknown in one.

Ipecac abuse

In 6 of 17 cases, ipecac was abused in female patients with eating disorders (e.g. anorexia nervosa/bulimia). Ages ranged from 19 to 33 with a mean of 25 years. The following adverse events were noted in association with ipecac toxicity:

· myopathy (2)

· myocarditis (2)

· pericarditis/skeletal myopathy (1)

· cardiac arrest due to emetine toxicity (1)

In three patients, ipecac was used for 3 weeks, 3 months, and 30 months, respectively. These three patients ingested 60-90 ml/d, 3-4 bottles/d, 60 ml/d, respectively. The first two patients died, and the third patient recovered only to replace ipecac with alcohol use. The dosing information and the duration of use were not reported in the three remaining cases. Outcomes of these 6 cases included 4 deaths, 1 recovery, and 1 permanent heart damage. All four deaths were related to ipecac toxicity/overdose.

Use as an emetic

Ipecac was used as an emetic in 9 of 17 cases for the ingestion or overdose of the following:

· amaryllis plant (1)

· boric acid (1)

· acetaminophen (2)

· Advil (1)

· Aleve (1)

· Motrin/acetaminophen (1)

· aspirin (1)

· Zithromax (1).

The reported adverse events in these cases included the following:

· eye pain/conjunctivitis (2)

· massive hernia/cardiopulmonary arrest (1)

· cerebral hemorrhage (1)

· seizure/dehydration (1)

· retching (1)

· generalized welts (1)

· urticaria (1)

· vomiting (1)

Six of 9 patients were under 16 years of age. Outcomes were 2 deaths, 2 hospitalizations, 4 recoveries, and 1 unknown.

The first case of death involved a 14 month old child who was given ipecac for the ingestion of an amaryllis plant and experienced vomiting for 42 hours. Although she was seen by a physician and sent home, she experienced cardiopulmonary arrest during a subsequent transportation to the hospital. Postmortem examination revealed 50 ml of bilious fluid in the left pleural space as well as the stomach and pylorus, which had herniated through the esophageal hiatus in the diaphragm. The reporter discussed two plausible contributory causes for this event; the first is that the child may have had a congenital diaphragmatic defect, and the second is that herniation occurred in response to the emetic action of either the amaryllis leaf or ipecac or both. The second case of death involved an 84 year old female with a past medical history of angina, tachycardia, and aortic valvular stenosis, who was given ipecac followed by activated charcoal for boric acid ingestion. She vomited 7 times over 3 hours. She experienced hemiplegia, decreased level of consciousness, and aspiration. She died of cerebral hemorrhage. According to the reporter, it is possible that the patient’s cerebral bleeding may have occurred prior to ipecac administration. However, since her symptoms occurred after ipecac administration and subsequent vomiting, the act of vomiting may have caused changes in intracerebral venous and arterial pressure that triggered the intracerebral hemorrhage.

In 2 of 9 cases where ipecac was used as an emetic, ipecac was administered to 2 and 4 year olds, respectively, for the accidental ingestion of acetaminophen. However, during the administration of ipecac, the drug was inadvertently splashed into the eyes and caused ocular pain and conjunctivitis. The 2 year old recovered, but the outcome of the 4 year old was not provided. In 2 other cases, generalized welts and urticaria were noted after the administration of ipecac for accidental ingestion of acetaminophen/Motrin and intentional aspirin overdose, respectively. The temporal onsets of these two events suggest that the reported reactions could be due to either ipecac or the ingested drugs that caused the overdose. Both patients recovered. Seizure and hypoglycemia were reported in a 2 year old male who accidentally ingested Advil and was given ipecac. The reporting physician thought that the seizure was due to dehydration. However, since the child suffered from the flu at the time of the overdose, the role of vomiting from ipecac may not have been the sole source of dehydration in this patient. One of 2 remaining cases involved retching subsequent to ipecac administration, leading to hospitalization. The last case involved an inappropriate administration of ipecac for a false overdose of Zithromax. This patient experienced vomiting for hours but the outcome was not serious.

V. DISCUSSION/CONCLUSION:

However, the reported adverse events involving ipecac are consistent with its characteristic effects. The main alkaloid components of ipecac are emetine, which in cases of overdose may be a contributing factor of skeletal and cardiac muscle toxicity, and cephaeline, which causes emesis. Chronic or acute intoxication of emetine in the body could lead to ipecac poisoning and death. It is noteworthy that 50% of the deaths reported were due to the abuse/overdose of ipecac. In some of the remaining cases where ipecac was not abused but rather used as an emetic, multiple or prolonged vomiting episodes were noted. Since ipecac can cause multiple/prolonged vomiting episodes and the ipecac labeling recommends not giving activated charcoal until after the patient has vomited (so that the charcoal will not adsorb ipecac), a specific time interval for administering activated charcoal after ipecac ingestion is likely to be useful. It is also noteworthy that the ipecac labeling does not contain the maximum total dose or the maximum number of times the dose should be repeated.

_______________________

Lauren Lee, Pharm.D.

Safety Evaluator

Concur:

_______________________

Claudia Karwoski, Pharm.D.

Safety Evaluator Team Leader