# Presentation: 832161

## Safety Review

**Gerald Faich, MD, MPH**
- President
- Pharmaceutical Safety Assessments
**   **

## Safety Exposure

**Over 2061 subjects dosed**
- 131 given bolus (rapid liver uptake, dropped indication)
- 1930 dosed with dilution and infusion in either50 or 100 ml saline
- 1566 all doses, diluted in 100 ml
- 1236 given the proposed dose and method of administration, 2.6 mg Fe/kg and 100 ml dilution

## Effect of Method of Administration on the Overall Incidence of AEs at all Doses 

| 
Bolus Injection
(N = 131) | Dilution in 50 mland slow infusion
(N = 364) | Diluted in 100 mland slow infusion
(N = 1566) |
| --- | --- | --- |
| 
30.0% | 
17.6% | 
14.2% |

**Bolus development stopped due to an anaphylactic death**

## Adverse Events with 100 ml Dilution in ≥0.5%of the Subjects at a Dose of 2.6 mg Fe/kg:Proposed Dose and Method of Administration 

| Adverse Event | N = 1236 |
| --- | --- |
| Vasodilation | 3.4% |
| Rash | 3.0% |
| Back pain | 2.4% |
| Pruritus | 2.2% |
| Urticaria | 1.7% |
| Dyspnea | 1.3% |
| Nausea | 1.2% |
| Chest pain | 1.1% |
| Pain | 0.8% |
| Sweating | 0.7% |
| Headache | 0.6% |
| Patients with any AE | 15.8% |

## Adverse Events with Proposed Doseand Method of Administration

- There were 69/1236 (5.6%) hypersensitivity events –mainly flushing (vasodilation) including 24 with morethan one symptom
-  4/1236 (0.3%) serious adverse events
- The SAE rate is no greater than found in labeling for nonionic  iodinated contrast media: (0.6 to 1.5%)
- There were no life threatening anaphylactic/anaphylactoid reactions with proposed dose and method of administration

## Immediate Adverse Events

- Immediate hypersensitivity reactions were controlledby stopping the infusion
- The most common reaction was vasodilation
- 38 subjects had the infusion stopped and restarted
- Only 2/38 had recurrence of event and discontinuedthe infusion

## Immediate Hypersensitivity

- 94% of all immediate hypersensitivity reactions werewithin the first 5 minutes after dosing
- Most hypersensitivity reactions were mild to moderatein intensity
- At the proposed dose and method of administration of the4 serious AEs, 2 were immediate hypersensitivity reactions (FDA definition in 1236 patients (0.16%))

## Anaphylactoid Reactions(FDA definition-2 body systems)

- 12/1236 subjects with proposed dose and method of administration
- 2/1236 were considered serious
- 4/12 subjects had the infusion temporarily stopped, then restarted and completed
- The majority included dyspnea and vasodilation –no serious hypotension or respiratory compromise was seen

## Comparative Rates of Serious Adverse Events 

| Contrast Media | Overall AE Rate | Serious AE Rate |
| --- | --- | --- |
| Combidex® (ferumoxtran-10)
Proposed dose and methodof administration | 15.8% | 4/1236 (0.3%) |
| Ultravist® (iopromide) | 32% | 8/708 (1.1%) |
| Comparators to Ultravist:
(iohexol, iopamidol, ioversol) | “Similar” to Ultravist | 4/659 (0.6%) |
| Oxilan® (ioxilan) | 14.3% | 8/531 (1.5%) |
| Comparator to Oxilan:
OmnipaqueTM (iohexol)  | “Similar” to Oxilan | 6/542 (1.1%) |

- Combidex is the trademark of Advanced Magnetics, Inc. Copyright© 2004–2005.All other trademarks and copyrights are the property of their respective owners.

## Anaphylaxis in the USNeugut AI, Ghatak AT, Miller RL. Arch Intern Med. 2001;161:15–21.

**RCM anaphylaxis rate 0.22 to 1%,****may be lower for LOCAs**

## For contrast agents
	Ionic rate 7.1 per 10,000
				 (95% range 4.7-10.6)
	Nonionic 3.5 per 10,000

**	****Ionic rate 7.1 per 10,000**
**	****	****	****	**** ****(95% range 4.7-10.6)**
**	****Nonionic 3.5 per 10,000**

**Risk of anaphylaxis in a hospital populations:****An international study D. W. Kaufman*, *****Pharmacoepidemiol Drug Saf.*****2003 Apr–May;12(3):195–202. **

## Risk Management Program

**Physician education**
- Use of dilution and slow infusion
**Labeling**
- Warnings and Precautions
- “Must be diluted” on vial cap and on label
**Surveillance**
- Target launch to large academic centers
- Enhanced post-launch monitoring
- More frequent safety reporting for first 3 years

## Safety Summary

**Considerable clinical exposure has occurred**
**Hypersensitivity is infrequent and comparable to other contrast agents**
**Risk management is according to established guidelines**

## COMBIDEX®

**COMBIDEX****®**

- (ferumoxtran-10)