CLARISCAN: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine.

Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay.

No impairment of male or female fertility and reproductive performance was observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug.

13.2 Animal Toxicology and/or Pharmacology

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting [see Warnings and Precautions (5.5)].

Toxicity of gadoterate meglumine was evaluated in neonatal and juvenile (pre- and post-weaning) rats following a single or repeated intravenous administration at doses 1, 2, and 4 times the MHD based on BSA. Gadoterate meglumine was well tolerated at all dose levels tested and had no effect on growth, pre-weaning development, behavior and sexual maturation.

14 CLINICAL STUDIES

CNS Imaging

Efficacy and safety of gadoterate meglumine were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either gadoterate meglumine or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received gadoterate meglumine, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and “paired pre- and post-contrast”) were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received gadoterate meglumine. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component’s patient-level visualization score.

Among the adult patients, 245 received gadoterate meglumine and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other.

Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater “better”, or same/worse “not better” than the pre- contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. Gadoterate meglumine provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images.

Table 6: Study A. Improvement in Patient-level Lesion Visualization Scores, Paired versus Pre-contrast Images *
Lesion Scores Reader 1 Reader 2 Reader 3
n = 231 n = 232 n = 237
*
Better: number of patients with paired (pre-and post-contrast) score greater than the pre-contrast scoreNot better: number of patients with paired score same as or worse than the pre-contrast scoreMissing: number of patients with missing score
Difference = paired mean score minus pre-contrast mean score
Statistically significant improvement by paired t-test
Border Delineation
Better 195 (84%) 215 (93%) 132 (56%)
Not Better 28 (12%) 7 (3%) 88 (37%)
Missing 8 (4%) 10 (4%) 17 (7%)
Difference in Mean Score 2.26 2.89 1.17
Internal Morphology
Better 218 (94%) 214 (93%) 187 (79%)
Not Better 5 (2%) 8 (3%) 33 (14%)
Missing 8 (4%) 10 (4%) 17 (7%)
Difference in Mean Score 2.74 2.75 1.54
Contrast Enhancement
Better 208 (90%) 216 (93%) 208 (88%)
Not Better 15 (6%) 6 (3%) 12 (5%)
Missing 8 (4%) 10 (4%) 17 (7%)
Difference in Mean Score 3.09 3.69 2.92

In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. Gadoterate meglumine lesion visualization scores were similar to those for gadopentetate dimeglumine. Gadoterate meglumine imaging results in the pediatric patients were also similar to those seen in adults.

In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in a previously conducted clinical trial. Gadoterate meglumine administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with gadoterate meglumine.

CNS Imaging in the Sub-population of Pediatric Patients < 2 years old

A non-randomized study (Study C) with 28 pediatric patients under 2 years of age who were referred for contrast MRI of the CNS supported extrapolation of CNS efficacy findings from adults and older children. CNS lesions were identified in 16 of these 28 patients on paired pre- and post-contrast images compared to 15 patients on pre-contrast images alone. In the 16 patients who had identifiable lesions, the scores for the co-endpoints of lesion visualization were improved for at least one lesion on paired pre- and post-contrast images compared to pre-contrast images in 8 out of 16 (50%) patients for lesion border delineation, 8 out of 16 (50%) patients for lesion internal morphology, and 14 out of 16 (88%) patients for lesion contrast enhancement.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clariscan Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials and pre-filled syringes.

  • Clariscan Injection is supplied in 10 mL vials containing 5 mL or 10 mL of solution and in 20 mL vials containing 15 mL or 20 mL of solution.

Each single-dose vial is closed with a rubber stopper and sealed with an aluminum cap and the contents are sterile. Vials are packaged in a box of 10, in the following configurations:

2.5 mmol per 5 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-06)
5 mmol per 10 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-01)
7.5 mmol per 15 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-02)
10 mmol per 20 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-05)
  • Clariscan Injection is supplied in 20 mL plastic pre-filled syringes containing 10 mL, 15 mL, or 20 mL of solution.

Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are individually packaged in a box of 10, in the following configurations:

5 mmol per 10 mL (0.5 mmol per mL) in plastic pre-filled syringe (NDC 0407-2943-12)
7.5 mmol per 15 mL (0.5 mmol per mL) in plastic pre-filled syringe (NDC 0407-2943-17)
10 mmol per 20 mL (0.5 mmol per mL) in plastic pre-filled syringe (NDC 0407-2943-22)

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature].

Pre-filled syringes must not be frozen. Frozen syringes should be discarded.

Should solidification occur in the vial because of exposure to the cold, bring Clariscan to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, Clariscan should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are dissolved and that the container and closure have not been damaged. Discard the vial if solids persist.

17 PATIENT COUNSELING INFORMATION

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide)

17.1 Nephrogenic Systemic Fibrosis

Instruct patients to inform their healthcare provider if they:

  1. have a history of kidney disease, or
  2. have recently received a GBCA.

GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:

  • Describe the clinical manifestations of NSF.
  • Describe procedures to screen for the detection of renal impairment.

Instruct the patients to contact their physician if they develop signs or symptoms of NSF following Clariscan administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.

17.2 Common Adverse Reactions

Inform patients that they may experience:

  • Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site.
  • Side effects of headache, nausea, abnormal taste and feeling hot.

17.3 General Precautions

  • Pregnancy: Advise pregnant women of the potential risk of fetal exposure to gadoterate [see Use in Specific Population (8.1)].
  • Gadolinium Retention: Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].

Distributed by GE Healthcare Inc.
Marlborough, MA 01752 U.S.A.Product of Norwegian Origin.

GE and the GE Monogram are trademarks of General Electric Company.

1199343 BK

MEDICATION GUIDE
CLARISCAN™ (kla-ri’-skan)(gadoterate meglumine) injection for intravenous use
What is Clariscan?
  • Clariscan is a prescription medicine called a gadolinium-based contrast agent (GBCA). Clariscan, like other GBCAs, is injected into your vein and used with a magnetic resonance imaging (MRI) scanner.
  • An MRI exam with a GBCA, including Clariscan, helps your doctor to see problems better than an MRI exam without a GBCA.
  • Your doctor has reviewed your medical records and has determined that you would benefit from using a GBCA with your MRI exam.

What is the most important information I should know about Clariscan?

  • Clariscan contains a metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for a long time (several months to years).
  • It is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.
  • Rarely patients have reported pains, tiredness, and skin, muscle or bone ailments for a long time, but these symptoms have not been directly linked to gadolinium.
  • There are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist or MultiHance. Gadolinium stays in the body the least after Clariscan, Dotarem, Gadavist or ProHance.
  • People who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.
  • Some people with kidney problems who get gadolinium medicines can develop a condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Clariscan.
Do not receive Clariscan if you have had a severe allergic reaction to Clariscan.
Before receiving Clariscan, tell your healthcare provider about all your medical conditions, including if you:
  • have had any MRI procedures in the past where you received a GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.
  • are pregnant or plan to become pregnant. It is not known if Clariscan can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if a GBCA such as Clariscan is received during pregnancy.
  • have kidney problems, diabetes, or high blood pressure.
  • have had an allergic reaction to dyes (contrast agents) including GBCA.
What are possible side effects of Clariscan?
The most common side effects of Clariscan include: nausea, headache, pain, or cold feeling at the injection site, and rash. These are not all the possible side effects of Clariscan.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective uses of Clariscan. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your healthcare provider for information about Clariscan that is written for health professionals.
What are the ingredients in Clariscan? Active ingredient: gadoterate meglumine Inactive ingredients: DOTA, water for injection Manufactured by: GE Healthcare AS Oslo, Norway GE and the GE Monogram are trademarks of General Electric Company. For more information, go to www.GEHealthcare.com or call 1-800-654-0118.
This Medication Guide has been approved by the U.S. Food and Drug Administration. 11/2019

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