ProHance (Page 2 of 5)

5.2 Hypersensitivity Reactions

Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of ProHance administration and resolved with prompt emergency treatment.

Prior to ProHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. If such a reaction occurs, stop ProHance and immediately begin appropriate therapy. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after ProHance administration.

5.3 Gadolinium Retention

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (e.g. brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].

Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.1)]. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions (6.2)].

While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.

5.4 Acute Kidney Injury (AKI)

In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.

6  ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

  • Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions (5.1)]
  • Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse events described in this section were observed in clinical trials involving 3174 subjects (including 2896 adults and 278 pediatric subjects ages 0 to 17 years) exposed to ProHance. Approximately 48% of the subjects were men and ethnic distribution was 78% Caucasian, 6% Black, 3% Hispanic, 6% Asian, and 2% other. In 5% of the subjects, race was not reported. Average age was 47 years (range from 1 day to 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg.

Overall, approximately 5.8% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after ProHance administration.

Table 2 lists adverse reactions that occurred in ≥ 0.4% subjects who received ProHance.
Table 2: More frequent adverse reactions in clinical trials
Reaction Rate (%)N = 3174
Nausea 1.4%
Dysgeusia 0.9%
Headache 0.7%
Dizziness 0.4%
Urticaria 0.4%
The following additional adverse events occurred in fewer than 0.4% of the subjects:
General disorders and administration site conditions: Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site warmth, pain, pyrexia
Cardiac: Angina pectoris, palpitations, atrio-ventricular block first degree
Ear and labyrinth disorders: Ear discomfort, tinnitus
Eye disorders: Eye pruritis, lacrimation increased
Gastrointestinal disorders: Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingival pain, oral pruritis, swollen tongue, vomiting
Infections and infestations: Gingivitis, rhinitis
Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, blood chloride increased, blood pressure immeasurable, blood urea decreased, hemoglobin decreased, heart rate increased
Metabolism and nutrition disorders: Decreased appetite, hypoglycemia
Musculoskeletal and connective tissue disorders: Back pain, musculoskeletal stiffness
Nervous system disorders: Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness, migraine, paresthesia, presyncope, seizure, syncope, taste disorder
Psychiatric disorders: Anxiety, mental status changes
Respiratory, thoracic and mediastinal disorders: Cough, dry throat, dyspnea, nasal discomfort, throat irritation
Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritis, rash, rash morbilliform
Vascular disorders: Flushing, hypotension, peripheral coldness, vascular rupture, vasodilatation, vasospasm

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of ProHance that were not observed in the clinical trials. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

* Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.
The following adverse drug reactions have also been reported:
General Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.
Cardiac disorders: Cardiac arrest, bradycardia, hypertension
Immune system disorders: Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria [see Warnings and Precautions (5.2)].
Nervous system disorders: Coma, loss of consciousness, vasovagal reaction, tremor
Respiratory, thoracic and mediastinal disorders: Respiratory arrest, pulmonary edema
Renal and urinary system disorders: Acute renal failure *

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