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iopamidol injection, solution
ISOVUE-M (Iopamidol Injection) formulations are stable, aqueous, sterile, and nonprrogenic solutions for intrathecal administration. Each mL of ISOVUE-M 200 (lopamidol Injection 41%) provides 408 mg iopamidol with 1mg tromethamine and 0.26 mg edetate calcium disodium. The solution contains approximately 0.029 mg (0.001mEq) sodium and 200 mg organically bound iodine per mL. Each mL of ISOVUE-M 300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg (0.002 mEq) sodium and 300 mg organically bound iodine per mL. The pH of ISOVUE-M contrast media has been adjusted to 6.5-7.5 with hydrochloric acid and/or sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE-M (lopamidol Injection) is hypertonic as compared to plasma and cerbrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).
The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation occurs. Iopamidol is rapidly absorbed into the bloodstream from cerebrospinal fluid (CSF); following intrathecal administration, iopamidol apperrs in plasma within one hour and virtually all of the drug reaches the systemic circulation within 24 hours, Iopamidol is excreted mainly through the kidneys following intrthecal administration, and the drug is essentially undetectable in the plasma 48 hours later. In patients with impaired renal function, the elimination half-life is prolonged dependent upon the degree of impairment. In the absence of renal dysfunction, the cumulative urinary excretion for iopamidol, expressed as a percentage of administered intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after admininstration. In normal subjects approximately 1 percent or less of the administered dose appears in cumulative 72- to 96-hour fecal specimens. Iopamidol displays little tendency to bind to serum or plasma proteins. No evidence of in vivo complement activation has been found in normal subjects. Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent following intravascular administration.
Indications and Usage
ISOVUE-M (Iopamidol Injection) is indicated for intrathecal administration in adult neuroradiology inculding myelography(lumbar, thoracic, cervical, total columnar), and for contrast enhancement of computed tomographic (CECT) cisternography and ventriculography. ISOVUE-M 200 (lopamidol Injection) is indicated for thoraco-lumbar myelography in children over the age of two years.
Intrathecal administration of corticosteroids with iopamidol is contraindicated. Because of overdosage considerations, immediate repeat myelography in the event of technical failure is contraindicated (see interval recommendation under DOSAGE AND ADMINISTRATION). Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.
The need for myelographic examination should be
carefully evaluated. Iopamidol should be administered with caution in
patients with increased intrcranial pressure or suspicion of
intracranial tumor, abscess or hematoma, those with a history of
convulsive disorder, severe cardiovascular disease, chronic alcoholism,
or multiple sclerosis, and elderly patients. Particular attention must
be given to state of hydration, concentration of medium, dose, and
technique used in these patients. Contrast media may promote sickling
in individuals who are homozygous for sickle cell disease when injected
intravenously or intra-arterially. Although ISOVUE-M is not injected
intravascularly, measurable plasma levels are attained after
intrathecal administration of iopamidol. If frankly bloody
cerebrospinal fluid is observed, the possible benefits of a
myelographic examination should be considered in terms of risk to the
Patients on anticonvulsant medication should be maintained on this therapy.
Direct intracisternal or ventricular administration for standard radiography (without computerized tomographic enhancement) is not recommended. Inadvertent intracranial entry of a large or concentrated bolus of the contrast medium, which increase the risk of neurotoxicity, can be prevented by careful patient management. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (e.g., by active patient movement). If such intracranial entry of the medium occurs, prophylactic anticonvulsant treatment with diazepam or barbiturates orally for 24 to 48 hours should be considered.
Use of medications that may lower the seizure thresnold (phenothiazine derivatives, including those used for their antihistaminic properties; tricyclic antidepressants; MAO inhibitors; CNS stimulants; analeptics; antipsychotic agents) should be carefully evaluated While the contributory role of such medications has not been established, some physicians have discontinued these agents at least 48 hours before and for at least 24 hours following intrathecal use.
Focal and generalized motor seizures have been reported after intrathecal use of water-soluble contrast agents including iopamidol. In several of those cases reported with iopamidol, higher than recommended doses were employed. Therfore avoid:
Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since sever delayed reactions may occur.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Patients should be well hydrated prior to and following iopamidol administration.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Patients should be well hydrated prior to following iopamidol administration.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered (see ADVERSE REACTIONS). Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a know sensitivity to iodine per se, and patients with a know clinical hypersensitivity (bronchial asthma, hay fever, and food allergies). The occurrence of sever idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered (see CONTRAINDICATIONS).
Reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.
The possibility of inducing bacterial meningitis in patients during intrathecal procedures should always be considered. To avoid bacterial contamination during spinal puncture, a sterile field should be maintained at all times.
If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.
Information for Patients
Patients receiving injectable radiopaque diagnostic agents should be instructed to:
1. Inform your physician if you are pregnant.
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.
3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of substance used for x-ray procedures (see PRECAUTIONS-General).
4. Inform your physician about any other medications you are currently taking, including nonprescription drug, before you have this procedure.
Other drugs should not be admixed with iopamidol (see CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION, Drug Incompatibilities).
Drug/Laboratory Test Interactions
The results of PBI and radioactive iodine uptake studies, which depend on iodine estimations, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media. However, thyroid function tests not depending on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected. Any test which might be affected by contrast media should be performed prior to administration of the contrast medium.
Laboratory Test FindingsIn vitro studies with animal blood showed that many radiopaque contrast agents, including iopamidol, produced a slight depression of plasma coagulation factors including prothrombin time, partial thromboplastin time, and fibrinogen, as well as a slight tendency to cause platelet and /or red blood cell aggregation.
Transitory changes may occur in red cell and leucocyte counts, serum calcium, serum creatinine, serum glutamic oxalacetic transaminase (SGOT), and uric acid in urine; transient albuminuria may occur.
These findings have not been associated with clinical manifestations.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in vitro tests.
Pregnancy: Teratogenic Effects
Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 2.7 and 1.4 times the maximum recommended human dose (1.48gl/kg in a 50kg individual). respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol. There are, however, no adequate and well-control studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only id clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when iopamidol is administered to a nursing woman.
See DOSAGE AND ADMINISTRATION section.
The most frequently reported adverse reactions
following intrathecal administration of iopamidol are headache, nausea,
vomiting, and musculoskeletal pain. These reactions usually occur 1 to
10 hours after injection, almost all occurring within 24 hours. They
are usually mild to moderate in degree, lasting for a few hours and
usually disappearing within 24 hours. Rarely, headaches may be severe
or persist for days. Headache is often accompanied by nausea and
vomiting, and tends to be more frequent and persistent in patients not
optimally hydrated. Backache, neck stiffness, numbness and
paresthesias, leg or sciatic-type pain occurred less frequently, often
in the form of a transient exacerbation of preexisting symptomatology.
Transient alterations in vital signs may occur and their significance
must be assessed on an individual basis.
The following table of incidence of reactions is based on clinical studies with ISOVUE-M (lopamidol Injection) in about 686 patients.
Major motor seizures have been reported in the clinical literature and since market introduction in th eUnited States. Early onset of seizures (less than two hours) is indicative of early substantial intrcranial entry. Transitory EEG changes occur and usually take the form of slow wave activity.
While not observed in controlled clinical studies with ISOVUE-M (Iopamidol Injection), the following adverse reactions may occur because they have been reported with ISOVUE-M and other nonionic water soluble contrast agents: cardiovascular (arrhythmias); pulmonary (apnea); bacterial meningitis, and aseptic meningitis syndrome; allergy or idiosyncrasy (chills, pruritus, nasal congestion, Guillain_Barre syndrome); CNS irritation (psycho-organic syndrome : mild and transitory perceptual aberrations such as depersonalization, anxiety, deppression, hyperreflexia or areflexia, hypertonia or flaccidity, restlessness, tremor, echoacousia,echolalia, asterixis or dysphasia have occurred). Profound mental disturbances have rarely been reported (various forms and degrees of aphasia, mental confusion or disorientation); the onset is usually at 8 to 10 hours and lasts for about 24 hours without aftereffects. However, occasionally they have been manifest as apprehension, agitation or progressive withdrawal to the point of stupor or coma. In a few cases, these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances (believed subjective or delusional). Persistent cortical loss of vision in association with convulsions, and ventricular block have been reported. Rarely, persistent though transitory weakness in the leg or ocular muscles has been reported. Peripheral neuropathies have been rare and transitory. They include sensory and/or motor or nerve root disturbances, myelitis, persistent leg muscle pain or weakness, or sixth nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, paralysis, or spasticity are unusual.
General Adverse Reactions To Contrast Media
Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of other water-soluble intrvascularly administered contrast agents are mild to moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Reported incidences of death from the administration of other iodinated contrast media range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. During intrathecal use, there is a lower incidence of electroencephalographic changes as well as neurotoxicity by virtue of the intrinsic properties of the iopamidol molecule.
Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that for the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents appear within one to three minutes after the start of injection, but delayed reactions may occur (see PRECAUTIONS-GENERAL).
Because measurable plasma levels are attained following the intrathecal administration of lopamidol, adverse reactions reported with the use of intravascular contrast agents are theoretically possible. These include:
Cardiovascular: vasodilation (feeling of warmth), cerebral hematomas, hemodynamic disturbances, sinus brady cardia, transient electrocardiographic abnormalities, ventricular fibrillation, pentechiae.
Digestive: nausea, vomiting, severe unilateral or bilateral swelling of the parotid and submaxillary glands.
Nervous: paresthesia, dizziness, convulsions, paralysis, coma.
Respiratory: increased cough, asthma, dyspnea, laryngeal edema, pulmonary edema, bronchospasm, rhinitis.
Skin and Appendages: injection site pain usually due to extravasation and/or erythematous swelling, skin necrosis, urticaria.
Urogenital: osmotic nephrosis of proximal tubular cells, renal failure, pain.
Special Senses: perversion of taste; bilateral ocular irritation; lacrimation; itching; conjunctival chemosis, infection, and conjunctivitis.
The following reactions may also occur: neutropenia, thrombophlebitis, flushing, pallor, weakness, severe retching and chocking, wheezing, cramps, tremors, and sneezing.
A dose of 3000 mgl in adults and 2400 mgl in children is sufficient for
most myelographic procedures. Doses above these levels may result in
an increased frequency and severity of adverse reactions including
seizures. However, in myelography, even use of a recommended dose can
produce mental aberrations tantamount to overdosage, if incorrect
management of the patient during or immediately following the procedure
permits inadvertent early intracranial entry of a large portion of the
Dosage and Administration
In adults a solution that is approximately isotonic (ISOVUE-M 200) is recommended for examination of the lumbar region. For movement of the contrast medium to distant target areas the more concentrated ISOVUE-M 300 preparation should be used to compensate for dilution of ISOVUE-M (lopamidol Injection) with cerebrospinal fluid.
In pediatric patients, a solution that is approximately isotonic (ISOVUE-M 200) is recommended for all intrathecal procedures. In children, loss of contrast due to mixing on movement of the medium is less apt to occur because of their shorter spinal cord.
The usual recommended pediatric dose range for iopamidol is 1400-2400 mg iodine. Iopamidol formulated to contain more than 200 mgl/ml should not be used. See pediatric dosage table for recommended dosage.
It is desirable that solutions of radio paque diagnostic agents for intrathecal use be at body temperature when injected. In the even that crystallization of the medium has occurred, place the vial in hot (60 degree to 100 degree C) water for about five minutes, then shake gently to obtain a clear solution. Cool to body temperature before use.
Discard vial without use if solids persist.
Withdrawal of contrast agents 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 discolorationprior to administration, whenever solution and container permit. Iopamidol solutions should be used only if clear and within the normal colorless to pale yellow range.
Patients should be well hydrated prior to and following ISOVUE-M (Iopamidol Injection) administration.
Suggestions for Usual Patient Management
* See WARNINGS regarding discontinuation of neuroleptic agents
* Maintain normal diet up to 2 hours before procedure
* Ensure hydration-fluids up to time of procedure
* Use minimum dose and concentration required for satisfactory contrast.
* Inject slowly over 1 to 2 minutes to avoid excessive mixing.
* Abrupt or active patient movement causes excessive mixing with CSF.
* Instruct patient to remain passive. Move patient slowly and only as necessary.
* To maintain as a bolus, move medium to distal area very slowly under fluoroscopic control.
* In all positioning techniques keep the patient's head elevated above highest level of spine.
* Do not lower head of table more than 15 degrees during thoraco-cervical procedures.
* In patients with excessive lordosis, consider lateral position for injection and movement of the medium cephalad.
* Avoid intracranial entry of a bolus.
* Avoid early and high cephalad dispersion of the medium.
* At completion of direct cervical or lumbo-cervical procedures, raise head of table steeply (45 degrees) for about 2 minutes to restore medium to lower levels.
* Raise head of stretcher to at lease 30 degrees before moving patient onto it.
* Movement onto stretcher, and off the stretcher to bed, should be done slowly with patient completely passive, maintaining head up position.
* Before moving patient onto bed, raise head of be 30 degree to 45 degree and maintain the patient in this position under close observation for 12 to 24 hours.
* Advise patient to remain still in bed, in head up position for the first 24 hours.
* Obtain visitors cooperation in keeping the patient quiet and in head up position, especially in first few hours.
* Encourage oral fluids and diet as tolerated.
* Antinauseants of the phenothiazine class should not be administered to treat the postprocedural nausea or vomiting (see WARNINGS). Since persistent nausea and vomiting may result in dehydration, prompt consideration of volume replacement by intravenous fluids is recommended.
Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.
ISOVUE-M 200 (Iopamidol Injection 41%)
Ten 10mL single dose vials (NDC 0270-1411-11)
Ten 20mL single dose vials (NDC 0270-1411-25)
ISOVUE-M 300 (Iopamidol Injection 61%)
Ten 15mL single dose vials (NDC 270-1412-15)
StorageStore at 20-25 degrees C (68-77 degrees F). [See USP]. Protect from Light
Revised: 11/2004 General Injectables & Vaccines, Inc.
Reproduced with permission of U.S. National Library of Medicine
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