FDA: New mineral toxicity: gadolinium dx in CRF (fwd)

[Guest guest]

Another reason not to agree to any contrast dyes....

Subject: FDA: New mineral toxicity: gadolinium dx in CRF

Gadolinium

RN: 7440-54-2

is used as non-iodinated contrast for MR studies and has previously been

considered safe.

The new concern is for patients with renal failure, suffering " Nephrogenic

Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NSF/NFD) " after

gadolinium administration.

http://www.fda.gov/cder/drug/infopage/gcca/default.htm

Information on Gadolinium-Containing Contrast Agents

The FDA is evaluating important safety information about

gadolinium-containing contrast agents and a disease known as Nephrogenic

Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NSF/NFD) that occurs

in patients with kidney failure.

- Public Health

Advisory<http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm>

- http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm

- Questions and Answers

[html<http://www.fda.gov/cder/drug/infopage/gcca/qa.htm>]

[PDF <http://www.fda.gov/cder/drug/infopage/gcca/qa_gcca.pdf>]

- Healthcare Professional Sheet

[html<http://www.fda.gov/cder/drug/InfoSheets/HCP/gccaHCP.htm>]

[PDF <http://www.fda.gov/cder/drug/InfoSheets/HCP/gccaHCP.pdf>]

- " Dear Healthcare

Professional<http://www.fda.gov/medwatch/safety/2006/gadolinium_NFD-NSF_dhcp.pdf\

>

" letter from GE Healthcare (6/6/2006)

*Gadolinium-Containing Contrast Agents*

- Gadobenate Dimeglumine (marketed as MultiHance)

- Regulatory History of MultiHance and Labeling Information from

Drugs@FDA<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseac\

tion=Search.SearchAction & SearchTerm=MultiHance & SearchType=BasicSearch>

- Gadodiamide (marketed as Omniscan)

- Regulatory History of Omniscan from

Drugs@FDA<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseac\

tion=Search.SearchAction & SearchTerm=Omniscan & SearchType=BasicSearch>

- Gadopentetate Dimeglumine (marketed as Magnevist)

- Regulatory History of Magnevist and Labeling Information from

Drugs@FDA<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseac\

tion=Search.SearchAction & SearchTerm=Magnevist & SearchType=BasicSearch>

- Gadoteridol (marketed as ProHance)

- Regulatory History of ProHance and Labeling Information from

Drugs@FDA<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseac\

tion=Search.SearchAction & SearchTerm=ProHance & SearchType=BasicSearch>

- Gadoversetamide (marketed as OptiMARK)

- Regulatory History of OptiMARK and Labeling Information from

Drugs@FDA<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseac\

tion=Search.SearchAction & SearchTerm=OptiMARK & SearchType=BasicSearch>

*Public Health Advisory

*Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI):

Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance

The FDA is evaluating imortant safety information about

gadolinium-containing contrast agents and a disease known as Nephrogenic

Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NSF/NFD) that occurs

in patients with kidney failure. New reports have identified a possible link

between NSF/NFD and exposure to gadolinium containing contrast agents used

at high doses for a procedure called Magnetic Resonance Angiography (MRA).

An MRA test uses magnetic resonance imaging to take pictures of blood

vessels. During an MRA test, a drug known as a gadolinium-contrast agent is

injected into a patient's vein so blood vessels can be distinguished from

other nearby tissues.

The FDA has learned of 25 cases of NSF/NFD in patients with kidney failure

who received Omniscan®, a gadolinium-containing contrast agent, and took the

MRA test. The FDA is actively investigating whether exposure to a

gadolinium-contrast agent for MRA is associated with the development of

NSF/NFD. While FDA conducts its investigation, the following recommendations

are being provided to health care providers and patients:

· Gadolinium-containing contrast agents, especially at high doses, should be

used only if clearly necessary in patients with advanced kidney failure

(those currently requiring dialysis or with a Glomerular Filtration Rate

(GFR) = 15 cc/min or less).

· It may be prudent to institute prompt dialysis in patients with advanced

kidney dysfunction who receive a gadolinium contrast MRA. Although there are

no data to determine the utility of dialysis to prevent or treat NSF/NSD in

patients with decreased kidney function, average excretory rates of

gadolinium are 78%, 96%, and 99% in the first to third hemodialysis

sessions, respectively (Okada, et al, Acta Radiologica, vol 42 p. 339, May

2001). Five gadolinium-containing contrast agents are FDA-approved for use

during magnetic resonance imaging (MRI), a test that can look at internal

body organs and tissues. The trade names of the U.S. approved

gadolinium-containing contrast agents are: Omniscan, OptiMARK, Magnevist,

ProHance, and MultiHance. None of these drugs are FDA approved for MRA. The

dose of gadolinium-containing contrast agent given to patients undergoing an

MRA test is often higher (up to three times) than the approved dose for MRI.

NSF/NFD appears to occur in patients with kidney failure along with high

levels of acid in body fluids a condition known as acidosis that is common

in patients with kidney failure. Patients with NSF/NFD have tight and rigid

skin making it difficult to bend joints. NSF/NFD may also result in

fibrosis, or scarring, of body organs resulting in the inability of body

organs to work properly and can lead to death. Diagnosis of NSF/NFD is done

by looking at a sample of skin under a microscope.

Scientists first identified NSF/NFD in 1997 and the cause of NSF/NFD is

unknown. Worldwide, there are approximately 200 reports of NSF/NFD.

The 25 cases of NSF/NFD were reported on May 29, 2006, by the Danish

Medicines Agency. Among these, 20 cases occurred in Denmark and five cases

occurred in Austria. The patients developed NSF/SFD within 3 months (range 2

weeks to 3 months) after receiving the gadolinium-containing contrast agent.

The five patients from Austria are described in a publication: Grobner T.

Gadolinium – a specific trigger for the development of nephrogenic fibrosing

dermopathy and nephrogenic systemic fibrosis Nephrol dial Transplant.

21(4):1104-8.

The FDA has not yet determined whether exposure by patients with kidney

failure to gadolinium-containing contrast agents during an MRA test causes

NSF/NFD. The FDA is gathering additional information about NSF/NFD and

investigating whether other patients who received gadolinium-containing

contrast agents developed NSF/NFD.

The FDA urges health care providers and patients to report adverse event

information to the FDA via the MedWatch program by phone (1-800-FDA-1088),

by fax (1-800-FDA-0178), or by the Internet at

http://www.fda.gov/medwatch/index.html.

= -- = -- = --

Ovid MEDLINE® 1966 to June Week 2 2006

# Search History Results

1 Gadolinium/ae, po, to [Adverse Effects, Poisoning, Toxicity] 174

Unique Identifier 15824364

Authors Maramattom BV. Manno EM. Wijdicks EF. Lindell EP.

Authors Full Name Maramattom, Boby Varkey. Manno, M. Wijdicks,

Eelco F M. Lindell, P.

Institution Division of Critical Care Neurology, Department of Neurology,

Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Title Gadolinium encephalopathy in a patient with renal failure.

Source Neurology. 64(7):1276-8, 2005 Apr 12.

Abstract Gadolinium chelates are extensively used in MRI studies.

Neurotoxicity due to gadolinium chelates is minimal and uncommon. A

57-year-old woman in renal failure developed a subacute encephalopathy after

inadvertent repetitive gadolinium contrast administration. An unusual MRI

appearance with CSF hyperintensity due to gadolinium diffusion into the CSF

is also shown.

= -- = -- = --

Unique Identifier 16119797

Authors Narumi Y. Nakamura H.

Authors Full Name Narumi, Yoshifumi. Nakamura, Hironobu.

Title [Frequency of severe adverse reactions and fatal cases to non-ionic

iodine-based contrast media and gadolinium-based contrast media]. [Japanese]

Source Nippon Igaku Hoshasen Gakkai Zasshi - Nippon Acta Radiologica.

65(3):300-1, 2005 Jul.

= -- = -- = --

Unique Identifier 15840670

Authors Mark PB. Mazonakis E. Shapiro D. Spooner RJ. Stuart C Rodger R.

Authors Full Name Mark, B. Mazonakis, Emmanouil. Shapiro, .

Spooner, J. Stuart C Rodger, R.

Institution Renal Unit, Western Infirmary, Dumbarton Road, Glasgow G11

6NT, UK. pm124p@...

Title Pseudohypocalcaemia in an elderly patient with advanced renal

failure and renovascular disease.

Source Nephrology Dialysis Transplantation. 20(7):1499-500, 2005 Jul.

= -- = -- = --

Unique Identifier 15609057

Authors Webb JA. Thomsen HS. Morcos SK. Members of Contrast Media Safety

Committee of European Society of Urogenital Radiology (ESUR).

Authors Full Name Webb, Judith A W. Thomsen, Henrik S. Morcos, Sameh K.

Members of Contrast Media Safety Committee of European Society of Urogenital

Radiology (ESUR).

Institution Department of Diagnostic Imaging, St. Bartholomew's Hospital,

London, UK.

Title The use of iodinated and gadolinium contrast media during pregnancy

and lactation.

Source European Radiology. 15(6):1234-40, 2005 Jun.

Abstract The use of iodinated or gadolinium-based contrast media in

pregnant or lactating women often causes concerns in the radiology

department because of the principle of not exposing a fetus or neonate to

any drugs. Because of the uncertainty about the use of contrast media during

pregnancy and lactation, the Contrast Media Safety Committee of the European

Society of Urogenital Radiology decided to review the literature and draw up

guidelines. An extensive literature search was carried out and summarized in

a report. Based on the limited information available, simple guidelines have

been drawn up. The report and guidelines were discussed at the 11th European

Symposium on Urogenital Radiology in Santiago de Compostela, Spain.

Mutagenic and teratogenic effects have not been described after

administration of gadolinium or iodinated contrast media. Free iodide in

radiographic contrast medium given to the mother has the potential to

depress fetal/neonatal thyroid function. Neonatal thyroid function should be

checked during the 1st week if iodinated contrast media have been given

during pregnancy. No effect on the fetus has been seen after gadolinium

contrast media. Only tiny amounts of iodinated or gadolinium-based contrast

medium given to a lactating mother reach the milk, and only a minute

proportion entering the baby's gut is absorbed. The very small potential

risk associated with absorption of contrast medium may be considered

insufficient to warrant stopping breast-feeding for 24 h following either

iodinated or gadolinium contrast agents.

Unique Identifier 15280530

Authors Erley CM. Bader BD. Berger ED. Tuncel N. Winkler S. Tepe G.

Risler T. Duda S.

Authors Full Name Erley, Christiane M. Bader, Birgit D. Berger, Elke D.

Tuncel, Nurdan. Winkler, Sabine. Tepe, Gunnar. Risler, Teut. Duda, Stephan.

Institution University of Tubingen, Department of Internal Medicine,

Section for Nephrology and Hypertension, Germany. christiane.erley@...

Title Gadolinium-based contrast media compared with iodinated media for

digital subtraction angiography in azotaemic patients.

Source Nephrology Dialysis Transplantation. 19(10):2526-31, 2004 Oct.

Abstract BACKGROUND: To determine whether gadolinium-based contrast media

(CM) could be used safely for angiographies in patients with renal

dysfunction we investigated renal function after gadobutrol exposure and

compared the results with standard iodinated CM (iohexol) in a randomized

clinical study. METHODS: Twenty-one patients (aged 67+/-11 years, nine

female and 12 male) with severely impaired renal function [mean serum

creatinine 3.2+/-1.3 mg/dl, mean glomerular filtration rate (GFR) 31+/-16

ml/min/1.73 m(2)] who needed to have angiography because of severe

peripheral vascular disease, renal artery stenosis or aortic aneurysms were

randomized to receive in a blinded manner either gadobutrol (Gadovist

1.0mmol/ml) or iohexol (Omnipaque 350) as contrast agents. GFR was

measured by

CM clearance (Renalyzer) at baseline and 48 h after CM administration. The

primary end point was the mean change of GFR from baseline at 48 h, the

secondary one the incidence of CM-induced acute renal failure, defined as a

decrease in GFR of >50% from baseline within 48 h of CM administration.

RESULTS: In the gadobutrol group (n = 10) we observed a statistically

significant decrease in GFR of 10.6+/-13.8 ml/min/1.73 m(2) within 48 h

after CM administration (P<0.05, paired t test). The incidence of CM-induced

ARF amounted to 50%. In comparison, the iohexol group (n = 11) also showed a

statistically significant GFR reduction of 8.7+/-8.8 ml/min/1.73 m(2) (P<

0.05, paired t test), and of ARF by 45%. The percentile of differences of

GFR decreases between the two groups was not significant (P = 0.70). No

patient demonstrated other adverse effects of gadobutrol or iohexol

administration, apart from GFR reduction. Despite the decline in GFR, no

patient required haemodialysis in the 10 following days. CONCLUSIONS: In our

study, gadolinium-based angiography showed no benefit over iohexol

angiography with respect to preventing GFR reduction in patients with

severely impaired renal function.

= -- = -- = --

Unique Identifier 15371610

Authors Leyendecker JR. Gorengaut V. Brown JJ.

Authors Full Name Leyendecker, R. Gorengaut, Vladislav. Brown,

J.

Institution Department of Radiology, Wake Forest University Baptist

Medical Center, Medical Center Blvd, Winston-Salem, NC 27157, USA.

jleyende@...

Title MR imaging of maternal diseases of the abdomen and pelvis during

pregnancy and the immediate postpartum period. [Review] [51 refs]

Source Radiographics. 24(5):1301-16, 2004 Sep-Oct.

Abstract Magnetic resonance (MR) imaging provides multiplanar large

field-of-view images of the body with excellent soft-tissue contrast and

without ionizing radiation. As a result, MR imaging is increasingly being

used to image the maternal abdomen and pelvis during and immediately after

pregnancy. Results of rapid T1- and T2-weighted imaging are often

diagnostic, and blood vessels, ductal structures, and the urinary tract can

frequently be visualized without intravenous administration of contrast

material. Until more conclusive safety data become available, MR imaging

should be reserved for cases in which results of ultrasonography are

inconclusive and patient care depends on further imaging. In the setting of

acute abdomen during pregnancy, MR imaging allows identification of areas of

inflammation, abscess formation, hemorrhage, and bowel obstruction. MR

imaging also helps determine the organ of origin, extent, and composition of

maternal neoplasms and is useful in evaluation of mullerian duct anomalies

and abnormalities of placental formation, position, and implantation. Many

postpartum complications such as retained products of conception and uterine

dehiscence may be diagnosed with MR imaging when results of other modalities

are indeterminate. Copyright RSNA, 2004 [References: 51]

= -- = -- = --

Unique Identifier 15221265

Authors Thomsen HS.

Authors Full Name Thomsen, Henrik S.

Institution Department of Diagnostic Radiology 54E2, Copenhagen

University Hospital at Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark.

heth@...

Title Gadolinium-based contrast media may be nephrotoxic even at approved

doses.

Source European Radiology. 14(9):1654-6, 2004 Sep.

Abstract It is generally believed that gadolinium-based contrast media

are not nephrotoxic at the approved doses for MR (<0.3 mmol/kg body weight).

Recently, a patient with diabetic nephropathy required dialysis because of

anuria 6-7 days after MR angiography with 0.14 mmol/kg body weight

gadolinium-DTPA-BMA to assess renal artery stenosis. No special precautions

(e.g., hydration) had been taken. The serum creatinine levels had been

within 200 and 300 micromol/l for the last 3 years with a very slow

increase. This case highlights that gadolinium-based contrast media can

cause contrast medium-induced nephropathy even at doses below 0.2 mmol/kg

body weight in patients with multiple risk factors.

= -- = -- = --

Unique Identifier 14627556

Authors Thomsen HS.

Authors Full Name Thomsen, Henrik S.

Institution Department of Diagnostic Radiology, Copenhagen University

Hospital, Herlev, Denmark. heth@...

Title Guidelines for contrast media from the European Society of

Urogenital Radiology. [Review] [59 refs]

Source AJR. American Journal of Roentgenology. 181(6):1463-71, 2003 Dec.

= -- = -- = --

Unique Identifier 12891113

Authors Sam AD 2nd. Morasch MD. J. Song G. Chen R. Pereles FS.

Authors Full Name Sam, Albert D 2nd. Morasch, Mark D. , .

Song, . Chen, . Pereles, F .

Institution Department of Surgery, Division of Vascular Surgery,

Northwestern Memorial Hospital, Feinberg Northwestern University Medical

School, 201 E Huron Street, Chicago, IL 60611, USA. mmorasch@...

Title Safety of gadolinium contrast angiography in patients with chronic

renal insufficiency.[see comment].

Comments Comment in: J Vasc Surg. 2004 Jul;40(1):204; author reply 204;

PMID: 15218489

Source Journal of Vascular Surgery. 38(2):313-8, 2003 Aug.

Abstract OBJECTIVE: To prevent iodinated contrast medium-induced

nephrotoxicity, gadolinium has been used increasingly for magnetic resonance

angiography (MRA) or conventional digital subtraction angiography (DSA) to

visualize arterial anatomy in patients undergoing vascular surgery who are

considered at high risk because of chronic renal insufficiency. We assessed

the safety of gadolinium-based contrast medium as a substitute for iodinated

contrast medium-enhanced examinations. We determined the incidence of

gadolinium-induced nephrotoxicity in a clinical setting and searched for

contributing risk factors.Patients and methods In a single-center

retrospective study from December 1999 to January 2001, 218 inpatients

underwent MRA and 42 inpatients underwent DSA, with gadolinium as the sole

contrast agent. Patient comorbid conditions, indications for vascular

imaging, contrast dose, urine output, baseline and post-procedure serum

creatinine concentration (SCr), and outcome were recorded for all patients

in whom gadolinium-induced renal failure developed. RESULTS: Of 260 patients

who received gadolinium-based contrast agents, at a dose of 0.25 mmol/kg or

more, 195 patients (75%) had pre-test baseline chronic renal insufficiency.

In 7 of 195 patients (3.5%) acute renal failure developed after

gadolinium-based contrast medium administration, for MRA (n = 153) in 3

patients (1.9%) and DSA (n = 42) in 4 patients (9.5%). Average baseline SCr

in the 195 patients with chronic renal insufficiency was 38.2 +/-

1.6mL/min/1.73 m(2), and in the 7 patients in whom acute renal failure

developed, baseline SCr was 32.5 +/- 7.8 mL/min/1.73 m(2) (P =.33).

Respective intravenous and intra-arterial gadolinium doses in these 7

patients ranged from 0.31 to 0.41 mmol/kg for MRA and 0.27 to 0.42 mmol/kg

for DSA. Acute renal failure did not develop in any of 65 patients with

normal baseline SCr. CONCLUSION: Despite reports of negligible

nephrotoxicity, rarely gadolinium-based contrast agents can cause acute

renal failure in patients with underlying chronic renal insufficiency.

Estimation of creatinine clearance alone does not enable prediction of which

patients are likely to have acute renal failure. Patients at high-risk

should be identified, and prophylactic measures should be taken to reduce

the risk for nephrotoxicity.