ULTRAVIST Solution for injection Ref.[9475] Active ingredients: Iopromide

General Information

Iopromide behaves in the organism like other highly hydrophilic biologically inert, renally excreted compounds (e.g. mannitol or inulin).

Absorption and distribution

Following intravenous administration, plasma concentrations of iopromide decline rapidly due to distribution into the extracellular space and subsequent elimination. The total distribution volume at steady state is about 16L corresponding roughly to the volume of the extracellular space.

Protein binding is negligible (about 1%). There is no indication that iopromide crosses the intact blood-brain-barrier. A small amount crossed the placental barrier in animal studies (0.3% of the dose were found in rabbit fetuses)

Following administration in the biliary and/or pancreatic duct during Endoscopic Retrograde Cholangiopancreaticography (ERCP), iodinated contrast agents are systemically absorbed and reach peak plasma concentrations between 1 and 4 h post administration. Maximum serum iodine levels following a mean dose of about 7.3 g iodine were about factor 40 lower compared to maximum serum levels reached after respective intravenous doses.

Metabolism

Iopromide is not metabolized.

Elimination

The terminal elimination half-life of iopromide is approximately 2 hours, irrespective of the dose. In the dose range tested, the mean total clearance of iopromide amounts to 106 ± 12 ml/min and is similar to the renal clearance of 102 ± 15 ml/min. Thus, excretion of iopromide is almost exclusively renal. Only about 2% of the dose administered is excreted via the fecal route within 3 days.

Approximately 60% of the dose is excreted within 3 hours after intravenous administration via urine. In the mean 93% of dose was recovered within 12 hours. Excretion is essentially complete within 24 hours.

Following administration into the biliary and/or the pancreatic duct for ERCP urinary iodine serum concentrations returned to pre-dose levels within 7 days.

Linearity/non-linearity The pharmacokinetic parameters of iopromide in humans change dose proportionally (e.g. C_max, AUC) or are dose independent (e.g. V_ss, t_1/2).

Characteristics in special patient populations

Elderly population (aged 65 years and above)

Middle-aged patients (49-64 years) and elderly patients (65-70 years), without significantly impaired renal function, had total plasma clearances between 74 and 114 ml/min (middle aged group, mean 102 ml/min) and between 72 and 110 ml/min (elderly group, mean 89 ml/min), which is only marginally lower than those in young healthy subjects (88 to 138 ml/min, mean 106 ml/min). The individual elimination half-lives were between 1.9-2.9 hours and 1.5-2.7 hours, respectively. Compared to the range of 1.4 to 2.1 h in young healthy volunteers, terminal half-lives are similar. The minor differences correspond to the physiologically reduced glomerular filtration rate with age.

Paediatric Population

Pharmacokinetics of iopromide have not been investigated in the pediatric population (see section 4.2).

Patients with renal impairment

In patients with impaired renal function, the plasma half-life of iopromide is prolonged according to the reduced glomerular filtration rate. The plasma clearance was reduced to 49.4 ml/min/1.73 m² (CV = 53%) in mildly and moderately impaired patients (80> CL_CR >30 ml/min/1.73 m²) and to 18.1 ml/min/1.73 m² (CV = 30%) in severely impaired patients not depending on dialysis (CL_CR = 30–10 ml/min/1.73 m²).

The mean terminal half-life is 6.1 hours (CV = 43%) in mildly and moderately impaired patients (80≥ CL_CR >30 ml/min/1.73 m²) and 11.6 hours (CV = 49%) in severely impaired patients not depending on dialysis (CL_CR = 30–10 ml/min/1.73 m²).

The amount recovered in urine within 6 h post dose was 38% in mildly to moderately impaired patients and 26% in severely impaired patients, compared to more than 83% in healthy volunteers. Within 24 h post dose the recovery was 60% in mildly to moderately and 51% in severely impaired patients, compared to more than 95% in healthy volunteers. Iopromide can be eliminated by hemodialysis. Approximately 60% of the iopromide dose is removed during a 3 hour dialysis.

Patients with hepatic impairment

Elimination is not affected because only about 2% of dose are excreted in faeces.

Preclinical data reveal no evidence of risk for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and reproduction toxicity.

Systemic toxicity

Experimental systemic tolerance studies following repeated daily intravenous administration produced no findings which object to a diagnostic administration of Ultravist to humans.

Genotoxic potential, tumorigenicity

Studies into genotoxic effects (gene-, chromosomal- and genome mutation tests) in vivo and in vitro gave no indication of a mutagenic potential of Ultravist.

Due to the absence of genotoxic effects and taking into account the metabolic stability, pharmacokinetics and the absence of indications of toxic effects on fast-growing tissues as well as the fact that Ultravist was only administered once, there is no evident risk of a tumorigenic effect on humans.

Local tolerance and contact-sensitizing potential

Local tolerance studies following single as well as repeated intravenous administration and single intraarterial, intramuscular, paravenous, intraperitoneal, intrathecal and conjunctival administration indicated that no or only slight adverse local effects are to be expected in blood vessels, paravenous tissue, subarachnoidal space or on the human mucosa.

Studies into contact-sensitizing effect, gave no indication of a sensitizing potential.