Osmovist (Iotrolan)

OSMOVIST®

Berlex Canada

Iotrolan

Dimeric Nonionic Radiographic Contrast Medium for Myelography

Action And Clinical Pharmacology: Iotrolan is a dimeric, nonionic, hexaiodinated radiocontrast medium. The contrast-giving substance, iotrolan, is a dimer of triiodinated isophthalic acid derivatives, in which the firmly bound iodine absorbs the x-rays. Solutions of iotrolan are isotonic to plasma and cerebrospinal fluid at radiologically useful iodine levels.

After intrathecal administration, iotrolan is absorbed from cerebrospinal fluid (CSF) into the blood stream. The mean half-life of the transfer of iotrolan from the spinal fluid to the blood plasma was found to be 5.7±6 hours in adults. The highest concentration of iodine in plasma occurred 3.5±3.1 hours after intrathecal administration. Plasma protein binding at a concentration of 1.2 mg I/mL is 2.4%. The mean elimination half-life of iotrolan in the plasma is 13.6±13.9 hours (median of 9 hours). Approximately 50 to 80% of the administered dose is excreted unmetabolized by the kidneys within 24 hours after administration, and approximately 90% within 72 hours. Only 0.6% of the dose was found in the feces collected up to 72 hours after dosing.

Total and renal clearance following i.v. injection is 93.5±5 mL/min and 90±4 mL/min, respectively.

In patients with renal impairment, depending on the degree of impairment, decreased renal elimination may cause prolonged iotrolan levels in plasma.

After i.v. administration, the blood-chemical parameters – including those in renally impaired patients (creatinine more than 1.5 mg/dL) – did not display any statistically significant changes compared to the baseline values. The fluctuations lay within the circadian range.

There is no evidence of metabolism, deiodination or biotransformation in rats and humans.

Generally, acceptable diagnostic contrast by conventional radiographic techniques can be achieved for at least 30 minutes following intrathecal injection. Computerized tomography may be performed up to 3 to 5 hours after iotrolan administration depending on the level of injection (cervical, thoracic or lumbar).

Contrast enhancement is directly related to the initial dosage of iotrolan administered and patient positioning.

Indications And Clinical Uses: In adults for lumbar myelography, cervical myelography, total columnar myelography and computerized tomography of spinal and subarachnoid spaces.

Contra-Indications: Iotrolan should not be administered to patients with known hypersensitivity to the drug or to patients with manifest hyperthyroidism.

Intrathecal administration of corticosteroids with iotrolan is contraindicated.

Lumbar and cervical puncture should not be performed in the presence of significant local or systemic infection where bacteremia is likely.

Manufacturers’ Warnings In Clinical States: Contrast media which are related chemically to triiodinated benzoic acid derivatives have been associated with serious and fatal reactions. Therefore, clear indication and evaluation of the risk/benefit ratio for every patient should precede each examination with contrast media. Also, it is of utmost importance that adequate facilities and appropriate personnel be readily available and a course of action be planned in advance for the immediate treatment of any serious untoward reaction.

Diagnostic procedures utilizing a radiopaque contrast medium should be conducted only by a physician with the requisite training and a thorough knowledge of the particular procedure to be performed. The physician must also be thoroughly familiar with the emergency treatment of all adverse events.

If grossly bloody CSF is encountered, the possible benefits of a myelographic procedure should be compared in terms of risk to the patient.

Direct intracisternal or ventricular administration for standard radiography is not recommended. Although seizures were not seen in clinical trials of iotrolan, caution should be observed in patients with epilepsy. Patients who are receiving anticonvulsants should be maintained on that therapy. In patients with a history of seizure activity who are not on anticonvulsant therapy, premedication with barbiturates or phenytoin should be considered.

Caution must be exercised in patients with a reduced seizure threshold. Neuroleptics or antidepressants should be discontinued 48 hours before the examination because they reduce the seizure threshold.

Pregnancy: The safe use of iotrolan during pregnancy has not been established. Therefore, it should not be used unless the benefits outweigh the risks.

Lactation : If the use of iotrolan is considered necessary in a nursing mother, it is suggested to discontinue breast feeding for 48 hours.

Children: The safety and effectiveness of iotrolan in myelography for children has not been established.

Geriatrics: Elderly patients may present a special risk in the use of radiographic contrast media. These patients may have compromised renal and cardiac function and may be taking medication (e.g., b-blockers) which may make them more susceptible to the potentially harmful effects of procedures involving the use of contrast media.

Repeat Procedure: A minimal interval of 72 hours should be allowed before repeat examinations with iotrolan; however, a 5 to 7 day interval is recommended (see Dosage).

Precautions: Before any contrast medium is injected, the patient should be questioned for a history of previous reaction to a contrast medium, a known sensitivity to iodine or known clinical hypersensitivity (bronchial asthma, hay fever and food allergies). The reported incidence of adverse reactions to contrast media are higher in patients with these conditions. Most adverse reactions to contrast agents appear within 30 minutes after the start of their injection, but a delayed reaction may occur. Premedication with antihistamines (except phenothiazine derivatives, see Drug Interactions) or corticoids may be considered in order to avoid or minimize possible allergic adverse reactions. However, antihistamines or corticosteroids should not be mixed in the same syringe with any contrast medium because of potential chemical incompatibility.

Caution must be exercised in the case of hypersensitivity to iodinated contrast media, latent hyperthyroidism, severe cardiovascular disease and bland nodular goitre. Experience shows that patients with an allergic disposition suffer more frequently from hypersensitivity reactions.

Hypersensitivity reactions to contrast media including shock cannot be ruled out but are expected to be rare in the proposed indications. The susceptible population includes especially patients with a history of a previous reaction to contrast media, with a known sensitivity to iodine, or with known clinical hypersensitivity.

The use of a test dose of the contrast medium before injection of the full dose has been employed to predict severe or fatal reactions. These provocative tests may themselves cause severe, even fatal, reactions and are unreliable in predicting patients at special risk.

Care in patient management should be taken to prevent inadvertent intracranial entry of a large or concentrated bolus of contrast medium, which increases the risk of neurotoxicity. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (e.g., by active patient movement).

Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients and susceptible nondiabetic patients (often elderly patients with pre-existing renal disease). Patients should be well hydrated before and after iotrolan administration.

Assessment of thyroid function may be obscured for several weeks following the administration of iotrolan.

Drug Interactions: Intrathecal administration of corticosteroids with iotrolan is contraindicated.

Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, concurrent drugs should not be physically admixed with contrast agents.

Drugs which lower the seizure threshold, especially phenothiazine derivatives, including those used for their antihistamine properties, should not be used with iotrolan. Other drugs lowering the seizure threshold to be avoided include MAO inhibitors, tricyclic antidepressants, CNS stimulants and psychoactive drugs described as analeptics, or antipsychotic drugs. Such medication should be discontinued at least 48 hours before myelography, should not be used for the control of nausea and vomiting, and should not be resumed for at least 24 hours after the procedure.

Hypersensitivity reactions can be aggravated in patients on b-blockers. The prevalence of delayed reactions (e.g., fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.

Adverse Reactions: General: Careful patient observation for adverse reactions is recommended in the use of all contrast media. Reactions accompanying use may vary with the dosage, the technique of administration, the procedure and the underlying condition of the patient. Adverse reactions generally occur within 30 minutes after injection and some may be of long-lasting nature. These reactions include: laryngospasm, bronchospasm, wheezing, dyspnea, and status asthmaticus; angioedema, subglottic edema and signs of airway obstruction; anaphylactic shock; cardiovascular collapse with peripheral vasodilation, hypotension, tachycardia, dyspnea, cyanosis, sweating, pallor, ventricular fibrillation and cardiac arrest; CNS stimulation or depression with agitation, convulsions, coma and death. Severe life-threatening reactions to iodinated contrast media require appropriate emergency measures. Temporary renal failure may occur in rare cases. Delayed reactions can occasionally occur.

Many life-threatening reactions begin with only mild symptoms such as nasal congestion, sneezing, watery eyes, skin erythema, or a vague sense of discomfort. It is therefore extremely important that all patients be watched closely until their symptoms have abated. The symptoms, which occur regardless of the amount of contrast medium administered and the mode of administration, can indicate incipient shock. Administration of the contrast medium must then be interrupted immediately and, if necessary, specific therapy initiated i.v. In the case of i.v. administration, use of a flexible indwelling catheter is therefore recommended.

Hypersensitivity reactions to the contrast medium including shock cannot be ruled out, but are expected to be rare in the proposed indications.

As after the use of other myelographic agents, cell count increases can be expected after administration of iotrolan into the CSF. No cases of arachnoiditis have been reported.

The most frequent subjective complaints are headaches, nausea and vomiting; however, experience shows that their incidence is no higher than after the loss of pressure in the subarachnoid space resulting from puncture of the spinal canal. In view of this, an effort should be made to remove only as much fluid as is being replaced by the contrast medium solution. On the other hand, a volume of contrast medium in excess of the amount of fluid removed does not lead to an increase of pressure in the subarachnoid space.

Severe headaches lasting several days may occur.

There have been very rare cases of aseptic meningitis with fever, stiff neck, headaches and an increased cell count in the CSF following administration of hydrosoluble nonionic contrast media for myelography. In most cases, all the symptoms disappeared within a week.

Severe side effects are extremely rare when the contrast medium is administered in the proper manner.

The safety of iotrolan was evaluated in 2 000 patients during clinical trials for myelography. Iotrolan was generally well tolerated. The most frequently reported adverse events were headache (27.5%), neck pain (13.5%), nausea (6.7%), vomiting (3.3%), stiff neck (2.8%), circulatory dysregulation (2.5%), giddiness (2.3%), back pain (2.2%), pain – localized (2.1%), dizziness (1.9%), sweats (1.9%) and tinnitus (1.1%).

Spontaneous Adverse Events having an Incidence of

Allergic/Cutaneous: allergoid reaction, cellulitis.

CNS: root pain/radicular symptoms, pain – radiating, paresthesia, clouding of sensorium, hyperesthesia, sensation of warmth, disturbed vision, anxiety, sensation of cold, shivering, chills, nystagmus, somnolence, transient change neurobehavior, very brief nonspecific EEG changes, speech disorder.

Gastrointestinal: constipation, abdominal cramps, indigestion, diarrhea, dry mouth.

Musculoskeletal: myoclonia, dystonia/hypertonia, myasthenia.

Other: fever, urinary tract disorder, viral syndrome/URI, hepatitis, crying, bleeding from gums and nose, dyspnea, ear ache, sub-xyphoid pressure.

Treatment of Adverse Effects: Contrast media should be injected only by physicians thoroughly familiar with emergency treatment of all adverse reactions to contrast media. The assistance of other trained personnel such as cardiologists, internists and anesthetists is required in the management of severe reactions.

A guideline for the treatment of adverse reactions is presented below. This outline is not intended to be a complete manual on the treatment of adverse reactions to contrast media or on cardiopulmonary resuscitation. The physician should refer to the appropriate texts on the subject.

It is also realized that institutions or individual practitioners will already have appropriate systems in effect and that circumstances may dictate the use of additional or different measures.

Minor Allergic Reactions: When treatment is considered necessary, the i.v. or i.m. administration of an antihistamine such as diphenhydramine HCl 25 to 50 mg is generally sufficient (contraindicated in epileptics). The resulting drowsiness makes it imperative to ensure that outpatients neither drive nor go home unaccompanied.

Major or Life-threatening Reactions: A major reaction may be manifested by signs and symptoms of cardiovascular collapse, severe respiratory difficulty and nervous system dysfunction. Convulsions, coma and cardiorespiratory arrest may ensue. The following measures should be considered: Start emergency therapy immediately, carefully monitoring vital signs. Have emergency resuscitation team summoned, do not leave patient unattended. Ensure airway is patent, guard against aspiration. Commence artificial respiration if patient is not breathing. Administer oxygen if necessary. Start external cardiac massage in the event of cardiac arrest. Establish route for i.v. medication by starting infusion of appropriate solution (i.e., 5% dextrose in water). Judiciously administer specific drug therapy as indicated by the type and severity of the reaction. Careful monitoring is mandatory to detect adverse reactions of all drugs administered: Acute allergic-anaphylactoid reactions: Soluble hydrocortisone 500 to 1 000 mg i.v. and/or epinephrine injection USP 1:1 000 solution, 0.2 to 0.4 mL s.c. In the presence of anoxia, this may cause ventricular fibrillation. Caution is required in patients on adrenergic beta-blockers. In extreme emergency, 0.1 mL/min, appropriately diluted, may be given i.v. until the desired effect is obtained. Do not exceed 0.4 mL. Cardiac arrest: epinephrine injection USP 1:1 000 solution, 0.1 to 0.2 mL, appropriately diluted, may be given intracardially. Hypotension: Monitor blood pressure carefully. Phenylephrine HCl 0.1 to 0.5 mg appropriately diluted by slow i.v. injection or by slow infusion, or norepinephrine 4 mL of 0.2% solution in 1 000 mL of 5% dextrose by slow drip infusion. Acidosis: Sodium bicarbonate 5%; 50 mL i.v. every 10 minutes as needed to combat post-arrest acidosis. Sinus bradycardia: Atropine 0.4 to 0.6 mg i.v. may also reverse 2dor 3ddegree block. Convulsions: Phenobarbital sodium 50 mg in fractional doses by slow i.v. injection (contraindicated if cyanosis is present) or diazepam 5 to 10 mg by slow i.v. injection, titrating the dose to the response of the patient. Defibrillation, administration of antiarrhythmics and additional emergency measures and drugs may be required. Transfer patient to intensive care unit when feasible for further monitoring and treatment.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: An overdose of iotrolan should be treated by support of vital functions and prompt institution of symptomatic therapy. On inadvertent overdosage or in greatly limited renal function, iotrolan can be removed from the body by extracorporeal dialysis.

Dosage And Administration: Iotrolan is indicated for intrathecal use only.

General Information: As with all radiopaque contrast agents, the minimum concentration and volume to produce adequate visualization should be used. Factors such as age, body size, anticipated pathology and degree and extent of opacification required, structure(s) or area to be examined, disease process, equipment and technique to be employed should be considered. If the equipment available allows films in all necessary projections without having to move the patient and allows instillation under fluoroscopic control, the iodine concentrations and volumes at the lower limit of each specified range are sufficient. Higher concentrations are indicated if it is necessary to reposition the patient since the contrast medium dilutes more quickly due to turbulence.

The dose and concentration used in the spinal area influence the ultimate intracranial concentrations.

After every examination of the subarachnoid space, particularly thoracic/cervical sections, the contrast medium should be drained as far as possible into the lumbar region by sitting the patient up for a few minutes. Then the patient should rest in bed for at least 24 hours, the first 6 hours of which should be spent with the trunk horizontal and the head raised 15°.

Recent evidence suggests that maintaining the patient in an upright position (wheelchair or ambulation) after the myelographic procedure may help minimize adverse effects. The upright position may help to delay dispersion of the medium and to maximize the spinal arachnoid absorption.

Anesthesia is not necessary if thin puncture needles are used, and premedication with sedatives is usually not needed.

The patient should be fasting but adequately hydrated on the day of the examination. Disorders of water and electrolyte balance must be corrected.

Experience has shown that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensified contrast medium-related reactions. They can be counteracted by calm management of the patient and the use of suitable medication.

Solutions of iotrolan, like those of other radiopaque contrast media, should be at or close to body temperature when injected. As with other sterile parenteral products, iotrolan should not be transferred from the vial to other delivery systems except immediately prior to use.

Withdrawal of contrast media from their containers should be accomplished under aseptic conditions with sterile syringes. Spinal puncture must always be performed under sterile conditions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Iotrolan should be used only if particulate free and within the normal colorless to pale yellow range.

Iotrolan should not be drawn into the syringe until immediately before use. Any unused portion should be discarded.

Vials containing contrast medium solutions are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The use of cannulas with a long tip and a maximum diameter of 18 G is recommended for piercing the stopper and drawing up the contrast medium.

Recommended Dosages: The dosage recommendations for conventional radiography or computed tomography are intended as general guidelines.

Rate of Injection: To avoid excessive mixing with CSF and consequent loss of contrast, as well as premature dispersion, injection must be made slowly over 1 to 2 minutes.

Repeat Procedure: A minimal interval of 72 hours should be allowed before repeat examinations with iotrolan; however, a 5 to 7 day interval is recommended.

Note: Higher concentrations are indicated if it will be necessary to reposition the patient during myelographic examination, since the medium becomes diluted more quickly as a result of turbulence, and the clarity of detail deteriorates.

Availability And Storage: Osmovist 240: Each mL of sterile, colorless to slightly yellow, odorless, pyrogen-free, aqueous solution contains: iotrolan 513 mg equivalent to 240 mg of organically bound iodine. Nonmedicinal ingredients: edetate calcium disodium, sodium bicarbonate, sodium chloride and sodium hydroxide to adjust pH and water for injection. pH is adjusted to 6.4 to 8.0. Preservative-free.  Vials of 10 mL, units of 10.

Osmovist 300: Each mL of sterile, colorless to slightly yellow, odorless, pyrogen-free, aqueous solution contains: iotrolan 641 mg equivalent to 300 mg of organically bound iodine. Nonmedicinal ingredients: edetate calcium disodium, sodium bicarbonate, sodium hydroxide to adjust pH and water for injection. pH is adjusted to 6.4 to 8.0. Preservative-free.

Store at room temperature (15 to 30°C). Protect from light. Do not freeze. It should be visually inspected and used only if clear and colorless to slightly yellow and free of particulate matter. Discard unused portions.

OSMOVIST® Berlex Canada Iotrolan Dimeric Nonionic Radiographic Contrast Medium for Myelography

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