DOTAREM (Page 4 of 6)

8.5 Geriatric Use

In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 304 patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. In general, use of DOTAREM in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No age-related dosage adjustment is necessary.

8.6 Renal Impairment

No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate can be removed from the body by hemodialysis [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

DOTAREM administered to healthy volunteers and to adult patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with DOTAREM have not been reported. Gadoterate can be removed from the body by hemodialysis [See Clinical Pharmacology (12.3)].

11 DESCRIPTION

DOTAREM (gadoterate meglumine) is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. The chemical name for gadoterate meglumine is D-glucitol, 1-deoxy-1-(methylamino)-,[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceto(4-)-.kappa.N1, .kappa.N4, .kappa.N7, .kappa.N10, .kappa.O1, .kappa.O4, .kappa.O7, .kappa.O10]gadolinate(1-)(1:1); it has a formula weight of 753.9 g/mol and empirical formula of C23 H42 O13 N5 Gd (anhydrous basis).

The structural formula of gadoterate meglumine in solution is as follows:

structure
(click image for full-size original)

CAS Registry No. 92943-93-6

DOTAREM Injection is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine. No preservative is added. Each mL of DOTAREM contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. DOTAREM has a pH of 6.5 to 8.0.

The main physiochemical properties of DOTAREM are provided below:

Table 4: Physicochemical Properties

Parameter

Value

Density @ 20°C

1.1753 g/cm3

Viscosity @ 20°C

3.4 mPa∙s

Viscosity @ 37°C

2.4 mPa∙s

Osmolality

1350 mOsm/kg water

The thermodynamic stability constants for gadoterate (log Ktherm and log Kcond at pH 7.4) are 25.6 and 19.3, respectively.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.

In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:

  1. differences in proton density
  2. differences of the spin-lattice or longitudinal relaxation times (T1)
  3. differences in the spin-spin or transverse relaxation time (T2)

When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

12.2 Pharmacodynamics

Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2 — 1.5 T).

Disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

12.3 Pharmacokinetics

The pharmacokinetics of total gadolinium assessed up to 48 hours following an intravenously administered 0.1 mmol/kg dose of DOTAREM in healthy adult subjects demonstrated a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of DOTAREM followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively).

Distribution

The volume of distribution at steady state of total gadolinium in healthy subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water.

Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known.

Following GBCA administration, gadolinium is present for months or years in brain, bone, skin and other organs [see Warnings and Precautions (5.3)].

Metabolism

Gadoterate is not known to be metabolized.

Elimination

Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0 % and 85.4 ± 9.7 % (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2 % and 92.0 ± 12.0 % recovered in urine within 48 hrs in female and male subjects respectively.

In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.

Specific Populations

Renal ImpairmentA single intravenous dose of 0.1 mmol/kg of DOTAREM was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 µmol/L in the 10-30 mL/min creatinine clearance group and 192 ± 62 µmol/L in the 30-60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ± 4.7% in 24 hrs for subjects with normal renal function.

Table 5: Pharmacokinetic Profile of Total Gadolinium in Normal and Renally Impaired Patients

Population

Elimination Half-life

(hr)

Plasma Clearance

(L/h/kg)

Distribution Volume

(L/kg)

Healthy volunteers

1.6 ± 0.2

0.10 ± 0.01

0.246 ± 0.03

Patients with moderate renal impairment

5.1 ± 1.0

0.036 ± 0.007

0.236 ± 0.01

Patients with severe renal impairment

13.9 ± 1.2

0.012 ± 0.001

0.234 ± 0.01

Gadoterate was shown to be dialyzable after an IV injection of DOTAREM in 10 patients with end-stage renal failure who required hemodialysis treatment. Gd serum concentration decreased over time by 88%, 93% and 97% at 0.5 hr, 1.5 hr, and 4 hrs after start of dialysis, respectively. A second and third hemodialysis session further removed Gd. After the third dialysis, Gd serum concentration decreased by 99.7%.

Pediatric populationThe pharmacokinetics of gadoterate in pediatric patients receiving DOTAREM aged birth (term neonates) to 23 months, was investigated in an open label, multicenter study, using a population pharmacokinetics approach. A total of 45 subjects (22 males, 23 females) received a single intravenous dose of DOTAREM 0.1 mmol/kg (0.2 mL/kg). The age ranged from less than one week to 23.8 months (mean 9.9 months) and body weight ranged from 3 to 15 kg (mean 8.1 kg). Individual level of renal maturity in the study population, as expressed by eGFR ranged between 52 and 281 mL/min/1.73 m2 and 11 patients had an eGFR below 100 mL/min/1.73 m2 (range 52 to 95 mL/min/1.73 m2).

Gadoterate concentrations obtained up to 8 hours after DOTAREM administration were best fitted using a biphasic model with linear elimination from the intravascular space. The mean clearance adjusted to body weight was estimated at 0.16 ± 0.07 L/h/kg and increased with eGFR. The estimated mean elimination half-life was 1.47 ± 0.45 hr.

The body weight adjusted clearance of gadoterate after single intravenous injection of 0.1 mmol/kg of DOTAREM in pediatric subjects aged less than 2 years was similar to that observed in healthy adults.

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