Omnipaque Injection

Dosage Form: injection

140   180   240   300   350

140

350

NOT FOR INTRATHECAL USE

OMNIPAQUE in REDIFLO™ (prefilled cartridges) NOT FOR INTRATHECAL USE

Section I — Intrathecal

Section II — Intravascular

Section III — Oral/Body Cavity Use

Omnipaque Injection Description

Iohexol,N,N´ - Bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)-acetamido]-2,4,6-triiodo-isophthalamide, is a nonionic, water-soluble radiographic contrast medium with a molecular weight of 821.14 (iodine content 46.36%). In aqueous solution each triiodinated molecule remains undissociated.

The chemical structure is:

OMNIPAQUE is provided as a sterile, pyrogen-free, colorless to pale-yellow solution, in the following iodine concentrations: 140, 180, 240, 300, and 350 mgI/mL. OMNIPAQUE 140 contains 302 mg of iohexol equivalent to 140 mg of organic iodine per mL; OMNIPAQUE 180 contains 388 mg of iohexol equivalent to 180 mg of organic iodine per mL; OMNIPAQUE 240 contains 518 mg of iohexol equivalent to 240 mg of organic iodine per mL; OMNIPAQUE 300 contains 647 mg of iohexol equivalent to 300 mg of organic iodine per mL; and OMNIPAQUE 350 contains 755 mg of iohexol equivalent to 350 mg of organic iodine per mL. Each milliliter of iohexol solution contains 1.21 mg tromethamine and 0.1 mg edetate calcium disodium with the pH adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Unused portions must be discarded. Iohexol solution is sensitive to light and therefore should be protected from exposure.

The available concentrations have the following physical properties:

Concentration (mgI/mL)	Osmolality* (mOsm/kg water)	Osmolarity (mOsm/L)	Absolute Viscosity (cp)		Specific Gravity
			20°C	37°C	37°C
* By vapor-pressure osmometry.
140	322	273	2.3	1.5	1.164
180	408	331	3.1	2.0	1.209
240	520	391	5.8	3.4	1.280
300	672	465	11.8	6.3	1.349
350	844	541	20.4	10.4	1.406

OMNIPAQUE 140, OMNIPAQUE 180, OMNIPAQUE 240, OMNIPAQUE 300, and OMNIPAQUE 350 have osmolalities from approximately 1.1 to 3.0 times that of plasma (285 mOsm/kg water) or cerebrospinal fluid (301 mOsm/kg water) as shown in the above table and are hypertonic under conditions of use.

SECTION I

CLINICAL PHARMACOLOGY—Intrathecal

Iohexol is absorbed from cerebrospinal fluid (CSF) into the bloodstream and is eliminated by renal excretion. No significant metabolism, deiodination, or biotransformation occurs.

In five adult patients receiving 16 to 18 milliliters of iohexol (180 mgI/mL) by lumbar intrathecal injection, approximately 88 (73.1-98.2) percent of the injected dose was excreted in the urine within the first 24 hours after administration. The renal and body clearances were 99 (47-137) milliliters per minute and 109 (52-138) milliliters per minute. The mean maximal plasma concentration was 119 (72-177) micrograms of iohexol per milliliter and occurred after 3.8 (2-6) hours. The volume of distribution was 557 (350-849) milliliters per kilogram. In one patient with a large spinal cord tumor, excretion was delayed (67 percent of the dose appeared in the urine within the first 24 hours) with no difference in the total overall recovery in the urine after 48 hours. The delay in excretion appeared to be related to a decrease in the rate of transfer of iohexol from the cerebrospinal fluid to the blood (plasma maximal concentration was approximately 30 micrograms/mL).

The initial concentration and volume of the medium, in conjunction with appropriate patient manipulation and the volume of CSF into which the medium is placed, will determine the extent of the diagnostic contrast that can be achieved.

Following intrathecal injection in conventional radiography, OMNIPAQUE 180, OMNIPAQUE 240, and OMNIPAQUE 300 will continue to provide good diagnostic contrast for at least 30 minutes. Slow diffusion of iohexol takes place throughout the CSF with subsequent absorption into the bloodstream. Once in the systemic circulation, iohexol displays little tendency to bind to serum or plasma proteins. At approximately 1 hour following injection, contrast of diagnostic quality will no longer be available for conventional myelography. If computerized tomographic (CT) myelography is to follow, consideration should be given to a delay of several hours to allow the degree of contrast to decrease.

After administration into the lumbar subarachnoid space, computerized tomography shows the presence of contrast medium in the thoracic region in about 1 hour, in the cervical region in about 2 hours, and in the basal cisterns in 3 to 4 hours.

In patients with renal impairment, depending on the degree of impairment, prolonged plasma iohexol levels may be anticipated due to decreased renal elimination.

INDICATIONS AND USAGE—Intrathecal

OMNIPAQUE 180, OMNIPAQUE 240, and OMNIPAQUE 300 are indicated for intrathecal administration in adults including myelography (lumbar, thoracic, cervical, total columnar) and in contrast enhancement for computerized tomography (myelography, cisternography, ventriculography).

OMNIPAQUE 180 is indicated for intrathecal administration in children including myelography (lumbar, thoracic, cervical, total columnar) and in contrast enhancement for computerized tomography (myelography, cisternography).

CONTRAINDICATIONS—Intrathecal

OMNIPAQUE should not be administered to patients with a known hypersensitivity to iohexol.

Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.

Intrathecal administration of corticosteroids with OMNIPAQUE is contraindicated.

Because of the possibility of overdosage, immediate repeat myelography in the event of technical failure is contraindicated (see DOSAGE AND ADMINISTRATION).

WARNINGS—General

SEVERE ADVERSE EVENTS—INADVERTENT INTRATHECAL ADMINISTRATION

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that OMNIPAQUE 140 and 350 are not administered intrathecally. (All other concentrations of OMNIPAQUE are approved for intrathecal administration.)

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

Caution is advised in patients with a history of epilepsy, severe cardiovascular disease, chronic alcoholism, or multiple sclerosis.

Elderly patients may present a greater risk following myelography. The need for the procedure in these patients should be evaluated carefully. Special attention must be paid to dose and concentration of the medium, hydration, and technique used.

Patients who are receiving anticonvulsants should be maintained on this therapy. Should a seizure occur, intravenous diazepam or phenobarbital sodium is recommended. In patients with a history of seizure activity who are not on anticonvulsant therapy, premedication with barbiturates should be considered.

Prophylactic anticonvulsant treatment with barbiturates should be considered in patients with evidence of inadvertent intracranial entry of a large or concentrated bolus of the contrast medium since there may be an increased risk of seizure in such cases.

Drugs which lower the seizure threshold, especially phenothiazine derivatives, including those used for their antihistamine properties, are not recommended for use with OMNIPAQUE. Others include MAO inhibitors, tricyclic antidepressants, CNS stimulants, and psychoactive drugs described as analeptics, major tranquilizers, or antipsychotic drugs. While the contributory role of these medications has not been established, the use of such drugs should be based on physician evaluation of potential benefits and potential risks. Physicians have discontinued these agents at least 48 hours before and for at least 24 hours postprocedure.

Care is required in patient management to prevent inadvertent intracranial entry of a large dose or concentrated bolus of the medium. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (eg, by active patient movement). Direct intracisternal or ventricular administration for standard radiography (not CT) is not recommended.

In most reported cases of major motor seizures with nonionic myelographic media, one or more of the following factors were present. Therefore avoid:

• Deviations from recommended procedure or in myelographic management.


• Use in patients with a history of epilepsy.


• Overdosage.


• Intracranial entry of a bolus or premature diffusion of a high concentration of the medium.


• Medication with neuroleptic drugs or phenothiazine antinauseants.


• Failure to maintain elevation of the head during the procedure, on the stretcher, or in bed.


• Excessive and particularly active patient movement or straining.

PRECAUTIONS—General

Diagnostic procedures which involve the use of radiopaque diagnostic agents 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 reactions 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 severe delayed reactions have occurred. (See ADVERSE REACTIONS.)

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). Dehydration in these patients seems to be enhanced by the osmotic diuretic action of contrast agents. Patients should be well hydrated prior to and following administration of any contrast medium, including iohexol.

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid, cardiovascular or central nervous system reactions, should always be considered (see ADVERSE REACTIONS). Therefore, it is of utmost importance that a course of action be carefully planned in advance for the immediate treatment of serious reactions, and that adequate and appropriate facilities and personnel be readily available in case of any reaction.

The possibility of an idiosyncratic reaction in susceptible patients should always be considered (see ADVERSE REACTIONS). The susceptible population includes, but is not limited to, patients with a history of a previous reaction to contrast media, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity: bronchial asthma, hay fever, and food allergies.

The occurrence of severe 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 media, 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 (see ADVERSE REACTIONS). Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

In patients with severe renal insufficiency or failure, compensatory biliary excretion of the drug is anticipated to occur, with a slow clearance into the bile. Patients with hepatorenal insufficiency should not be examined unless the possibility of benefit clearly outweighs the additional risk.

Administration of contrast media should be performed by qualified personnel familiar with the procedure and appropriate patient management (see PATIENT MANAGEMENT). Sterile technique must be used with any spinal puncture.

When OMNIPAQUE is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately.

If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is present, do not use.

Repeat Procedures: If in the clinical judgment of the physician sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY).

Information for Patients (or if applicable, children)

Patients receiving injectable radiopaque diagnostic agents should be instructed to:

1. Inform your physician if you are pregnant (see CLINICAL PHARMACOLOGY).


2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disorder (see WARNINGS).


3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS—General).


4. Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you are administered this drug.

Drug Interactions

Drugs which lower seizure threshold, especially phenothiazine derivatives including those used for their antihistaminic or antinauseant properties, are not recommended for use with OMNIPAQUE. Others include monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, CNS stimulants, psychoactive drugs described as analeptics, major tranquilizers, or antipsychotic drugs. Such medications should be discontinued at least 48 hours before myelography, should not be used for the control of nausea or vomiting during or after myelography, and should not be resumed for at least 24 hours postprocedure. In nonelective procedures in patients on these drugs, consider prophylactic use of anticonvulsants.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenesis, or whether OMNIPAQUE can affect fertility in men or women.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with up to 100 times the recommended human dose. No evidence of impaired fertility or harm to the fetus has been demonstrated due to OMNIPAQUE. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known to what extent iohexol is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast media are administered to nursing women. Bottle feedings may be substituted for breast feedings for 24 hours following administration of OMNIPAQUE.

Pediatric Use

Pediatric patients at higher risk of experiencing adverse events during contrast medium administration may include those having asthma, a sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age.

ADVERSE REACTIONS—Intrathecal

The most frequently reported adverse reactions with OMNIPAQUE are headache, mild to moderate pain including backache, neckache and stiffness, nausea, and vomiting. These reactions usually occur 1 to 10 hours after injection, and almost all occur 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.

Transient alterations in vital signs may occur and their significance must be assessed on an individual basis. Those reactions reported in clinical studies with OMNIPAQUE are listed below in decreasing order of occurrence, based on clinical studies of 1531 patients.

Headaches: The most frequently occurring adverse reaction following myelography has been headache, with an incidence of approximately 18%. Headache may be caused by either a direct effect of the contrast medium or by CSF leakage at the dural puncture site. However, in managing the patient, it is considered more important to minimize intracranial entry of contrast medium by postural management than attempting to control possible CSF leakage (see PATIENT MANAGEMENT).

Pain: Mild to moderate pain including backache, neckache and stiffness, and neuralgia occurred following injection with an incidence of about 8%.

Nausea and Vomiting: Nausea was reported with an incidence of about 6%, and vomiting about 3% (see PATIENT MANAGEMENT). Maintaining normal hydration is very important. The use of phenothiazine antinauseants is not recommended. (See WARNINGS—General.) Reassurance to the patient that the nausea will clear usually is all that is required.

Dizziness: Transient dizziness was reported in about 2% of the patients.

Other Reactions: Other reactions occurring with an individual incidence of less than 0.1% included: feeling of heaviness, hypotension, hypertonia, sensation of heat, sweating, vertigo, loss of appetite, drowsiness, hypertension, photophobia, tinnitus, neuralgia, paresthesia, difficulty in micturition, and neurological changes. All were transient and mild with no clinical sequelae.

Pediatrics

In controlled clinical trials involving 152 patients for pediatric myelography by lumbar puncture, adverse events following the use of OMNIPAQUE 180 were generally less frequent than with adults.

Headache:       9%

Vomiting:        6%

Backache:    1.3%

Other Reactions: Other reactions occurring with an individual incidence of less than 0.7% included: fever, hives, stomachache, visual hallucination, and neurological changes. All were transient and mild with no clinical sequelae.

General Adverse Reactions to Contrast Media

Physicians should remain alert for the occurrence of adverse effects in addition to those discussed above, particularly the following reactions which have been reported in the literature for other nonionic, water-soluble myelographic media, and rarely with iohexol. These have included, but are not limited to, convulsion, aseptic and bacterial meningitis, and CNS and other neurological disturbances.

An aseptic meningitis syndrome has been reported rarely (less than 0.01%). It was usually preceded by pronounced headaches, nausea and vomiting. Onset usually occurred about 12 to 18 hours postprocedure. Prominent features were meningismus, fever, sometimes with oculomotor signs and mental confusion. Lumbar puncture revealed a high white cell count, high protein content often with a low glucose level and with absence of organisms. The condition usually started to clear spontaneously about 10 hours after onset, with complete recovery over 2 to 3 days.

Allergy or Idiosyncrasy: Chills, fever, profuse diaphoresis, pruritus, urticaria, nasal congestion, dyspnea, and a case of Guillain-Barre syndrome.

CNS Irritation: Mild and transitory perceptual aberrations such as hallucinations, depersonalization, amnesia, hostility, amblyopia, diplopia, photophobia, psychosis, insomnia, anxiety, depression, hyperesthesia, visual or auditory or speech disturbances, confusion and disorientation. In addition, malaise, weakness, convulsion, EEG changes, meningismus, hyperreflexia or areflexia, hypertonia or flaccidity, hemiplegia, paralysis, quadriplegia, restlessness, tremor, echoacousia, echolalia, asterixis, cerebral hemorrhage, and dysphasia have occurred.

Profound mental disturbances have also rarely been reported. They have usually consisted of 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 in several instances to the point of somnolence, stupor, and coma. In a few cases these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances (believed subjective or delusional), including unilateral or bilateral loss of vision which may last for hours. In one case, persistent cortical loss of vision has been reported in association with convulsions. Ventricular block has been reported; amnesia of varying degrees may be present for the reaction event.

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, 6th nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, or spasticity is unusual and has responded promptly to a small intravenous dose of diazepam.

In general, the reactions which are known to occur upon parenteral administration of iodinated contrast agents are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of water-soluble contrast agents are mild to moderate in degree. However, severe, life-threatening, anaphylactoid and fatal reactions, mostly of cardiovascular origin and central nervous system origin, have occurred.

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 media, the dose, and speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category.

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 dose injected, the speed 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 of 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 injectable contrast media appear within 1 to 3 minutes after the start of injection, but delayed reactions may occur.

Overdosage

Clinical consequences of overdosage with OMNIPAQUE have not been reported. However, based on experience with other nonionic myelographic media, physicians should be alert to a potential increase in frequency and severity of CNS-mediated reactions. Even use of a recommended dose can produce effects 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 medium.

The intracisternal LD50 value of OMNIPAQUE (in grams of iodine per kilogram body weight) is greater than 2.0 in mice.

DOSAGE AND ADMINISTRATION — Intrathecal

The volume and concentration of OMNIPAQUE 180, OMNIPAQUE 240, or OMNIPAQUE 300 to be administered will depend on the degree and extent of contrast required in the area(s) under examination and on the equipment and technique employed.

OMNIPAQUE 180 at a concentration of 180 mgI/mL, OMNIPAQUE 240 at a concentration of 240 mgI/mL, or OMNIPAQUE 300 at a concentration of 300 mgI/mL is recommended for the examination of the lumbar, thoracic, and cervical regions in adults by lumbar or direct cervical injection and is slightly hypertonic to CSF.

OMNIPAQUE 180 at a concentration of 180 mgI/mL is recommended for the examination of the lumbar, thoracic, and cervical regions in children by lumbar injection and is slightly hypertonic to CSF.

A total dose of 3060 mg iodine or a concentration of 300 mgI/mL should not be exceeded in adults and a total dose of 2700 mg iodine or a concentration of 180 mgI/mL should not be exceeded in children in a single myelographic examination. This is based on clinical trial evaluation to date. As in all diagnostic procedures, the minimum volume and dose to produce adequate visualization should be used. Most procedures do not require either maximum dose or concentration.

Anesthesia is not necessary. Premedication sedatives or tranquilizers are usually not needed (see PRECAUTIONS). Patients should be well hydrated prior to and following contrast administration. Seizure-prone patients should be maintained on anticonvulsant medication.

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.

Rate of Injection: To avoid excessive mixing with CSF and consequent dilution of contrast, injection should be made slowly over 1 to 2 minutes.

Depending on the estimated volume of contrast medium which may be required for the procedure a small amount of CSF may be removed to minimize distention of the subarachnoid spaces.

The lumbar or cervical puncture needle may be removed immediately following injection since it is not necessary to remove OMNIPAQUE after injection into the subarachnoid space.

Adults: The usual recommended total doses for use in lumbar, thoracic, cervical, and total columnar myelography in adults are 1.2 gI to 3.06 gI as follows:

Procedure	Formulations	Concentration (mgI/mL)	Volume (mL)	Dose (gI)
Lumbar Myelography (via lumbar injection)	OMNIPAQUE 180	180	10-17	1.8-3.06
	OMNIPAQUE 240	240	7-12.5	1.7-3.0
Thoracic Myelography (via lumbar or cervical injection)	OMNIPAQUE 240	240	6-12.5	1.7-3.0
	OMNIPAQUE 300	300	6-10	1.8-3.0
Cervical Myelography (via lumbar injection)	OMNIPAQUE 240	240	6-12.5	1.4-3.0
	OMNIPAQUE 300	300	6-10	1.8-3.0
Cervical Myelography (via C1-2 injection)	OMNIPAQUE 180	180	7-10	1.3-1.8
	OMNIPAQUE 240	240	6-12.5	1.4-3.0
	OMNIPAQUE 300	300	4-10	1.2-3.0
Total Columnar Myelography (via lumbar injection)	OMNIPAQUE 240	240	6-12.5	1.4-3.0
	OMNIPAQUE 300	300	6-10	1.8-3.0

Pediatrics: The usual recommended total doses for lumbar, thoracic, cervical, and/or total columnar myelography by lumbar puncture in children are 0.36 gI to 2.94 gI (see table below). Actual volumes administered depend largely on patient age and the following guidelines are recommended.

Age	Conc. (mgI/mL)	Volume (mL)	Dose (gI)
0 to < 3 mos.	180	2-4	0.36-0.72
3 to < 36 mos.	180	4-8	0.72-1.44
3 to < 7 yrs.	180	5-10	0.9-1.8
7 to < 13 yrs.	180	5-12	0.9-2.16
13 to 18 yrs.	180	6-15	1.08-2.7

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 products should be inspected visually for particulate matter or discoloration prior to administration. If particulate matter or discoloration is present, do not use.

Repeat Procedures: If in the clinical judgment of the physician sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. An interval of at least 48 hours should be allowed before repeat examination; however, whenever possible, 5 to 7 days is recommended.

PATIENT MANAGEMENT—Intrathecal

Suggestions for Usual Patient Management

Good patient management should be exercised at all times to minimize the potential for procedurally related complications.

Preprocedure

• Discontinuance of neuroleptic drugs (including phenothiazines, eg, chlorpromazine, prochlorperazine, and promethazine) at least 48 hours beforehand should be considered.


• Maintain normal diet up to 2 hours before procedure.


• Ensure hydration-fluids up to procedure.

During Procedure

• Use minimum dose and concentration required for satisfactory contrast (see DOSAGE AND ADMINISTRATION).


• In all positioning techniques keep the patient's head elevated above highest level of spine.


• Do not lower head of table more than 15° in moving contrast medium cranially.


• In patients with excessive lordosis, consider lateral position for injection and movement of the medium cephalad.


• Inject slowly (over 1 to 2 minutes) to avoid excessive mixing.


• To maintain as a bolus, move medium to distal area very slowly. Use fluoroscopic monitoring.


• Avoid intracranial entry of a bolus.


• Avoid early and high cephalad dispersion of the medium.


• Avoid abrupt or active patient movement to minimize excessive mixing of medium with CSF. Instruct patient to remain passive. Move patient slowly and only as necessary.

Postprocedure

• Raise head of stretcher to at least 30° before moving patient onto it.


• Movement onto and off the stretcher should be done slowly with the patient completely passive, maintaining head-up position.


• Before moving patient onto bed, raise head of bed 30° to 45°.


• Advise patient to remain still in bed, in a sitting or semisitting position, especially in the first few hours.


• Maintain close observation for at least 12 hours after myelogram.


• Obtain visitors' cooperation in keeping the patient quiet and in head-up position, especially in first few hours.


• Encourage oral fluids. Diet as tolerated.


• If nausea or vomiting occurs, do not use phenothiazine antinauseants. Persistent nausea and vomiting will result in dehydration. Therefore, prompt consideration of replacement by intravenous fluids is recommended.

Alternative Postprocedure Method

• Recent evidence with nonionic, water-soluble contrast media suggests that maintaining the patient postmyelography in an upright position (via wheelchair or ambulation) may help minimize adverse effects. The upright position may help to delay upward dispersion of the medium and to maximize the spinal arachnoid absorption.

How is Omnipaque Injection Supplied

OMNIPAQUE 180

  10 mL glass vial, 180 mgI/mL, boxes of 10 (NDC 0407-1411-10)

  20 mL glass vial, 180 mgI/mL, boxes of 10 (NDC 0407-1411-20)

OMNIPAQUE 240

  10 mL glass vial, 240 mgI/mL, boxes of 10 (NDC 0407-1412-10)

  20 mL glass vial, 240 mgI/mL, boxes of 10 (NDC 0407-1412-20)

OMNIPAQUE 300

  10 mL glass vial, 300 mgI/mL, boxes of 10 (NDC 0407-1413-10)

Storage: Protect vials of OMNIPAQUE from strong daylight and direct exposure to sunlight. Do not freeze. Omnipaque should be stored at controlled room temperature, 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

SECTION II

CLINICAL PHARMACOLOGY—Intravascular

Following intravascular injection, iohexol is distributed in the extracellular fluid compartment and is excreted unchanged by glomerular filtration. It will opacify those vessels in the path of flow of the contrast medium permitting radiographic visualization of the internal structures until significant hemodilution occurs.

Approximately 90% or more of the injected dose is excreted within the first 24 hours, with the peak urine concentrations occurring in the first hour after administration. Plasma and urine iohexol levels indicate that the iohexol body clearance is due primarily to renal clearance. An increase in the dose from 500 mgI/kg to 1500 mgI/kg does not significantly alter the clearance of the drug. The following pharmacokinetic values were observed following the intravenous administration of iohexol (between 500 mgI/kg to 1500 mgI/kg) to 16 adult human subjects: renal clearance—120 (86-162) mL/min; total body clearance—131 (98-165) mL/min; and volume of distribution—165 (108-219) mL/kg.

Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal passages may begin as early as 1 minute after intravenous injection. Urograms become apparent in about 1 to 3 minutes with optimal contrast occurring between 5 to 15 minutes. In nephropathic conditions, particularly when excretory capacity has been altered, the rate of excretion may vary unpredictably, and opacification may be delayed after injection. Severe renal impairment may result in a lack of diagnostic opacification of the collecting system and, depending on the degree of renal impairment, prolonged plasma iohexol levels may be anticipated. In these patients, as well as in infants with immature kidneys, the route of excretion through the gallbladder and into the small intestine may increase.

Iohexol displays a low affinity for serum or plasma proteins and is poorly bound to serum albumin. No significant metabolism, deiodination or biotransformation occurs.

OMNIPAQUE probably crosses the placental barrier in humans by simple diffusion. It is not known to what extent iohexol is excreted in human milk.

Animal studies indicate that iohexol does not cross an intact blood-brain barrier to any significant extent following intravascular administration.

OMNIPAQUE enhances computed tomographic imaging through augmentation of radiographic efficiency. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid intravenous injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about ten minutes; thereafter, the fall becomes exponential.

The pharmacokinetics of iohexol in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest immediately after bolus administration (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (ie, dynamic computed tomographic imaging). Utilization of a continuous scanning technique (ie, dynamic CT scanning) may improve enhancement and diagnostic assessment of tumor and other lesions such as abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared; the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other nonvascular lesion.

Because unenhanced scanning may provide adequate diagnostic information in the individual patient, the decision to employ contrast enhancement, which may be associated with risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.

CT SCANNING OF THE HEAD

In contrast enhanced computed tomographic head imaging, OMNIPAQUE does not accumulate in normal brain tissue due to the presence of the normal blood-brain barrier. The increase in x-ray absorption in normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in malignant tumors of the brain allows for the accumulation of contrast medium within the interstitial tissue of the tumor. Adjacent normal brain tissue does not contain the contrast medium.

Maximum contrast enhancement in tissue frequently occurs after peak blood iodine levels are reached. A delay in maximum contrast enhancement can occur. Diagnostic contrast enhanced images of the brain have been obtained up to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool, although the mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool.

In patients where the blood-brain barrier is known or suspected to be disrupted, the use of any radiographic contrast medium must be assessed on an individual risk to benefit basis. However, compared to ionic media, nonionic media are less toxic to the central nervous system.

CT SCANNING OF THE BODY

In contrast enhanced computed tomographic body imaging (nonneural tissue), OMNIPAQUE diffuses rapidly from the vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different from that in the brain.

INDICATIONS AND USAGE, GENERAL—Intravascular

OMNIPAQUE 350 is indicated in adults for angiocardiography (ventriculography, selective coronary arteriography), aortography including studies of the aortic root, aortic arch, ascending aorta, abdominal aorta and its branches, contrast enhancement for computed tomographic head and body imaging, intravenous digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels, peripheral arteriography, and excretory urography.

OMNIPAQUE 350 is indicated in children for angiocardiography (ventriculography, pulmonary arteriography, and venography; studies of the collateral arteries and aortography, including the aortic root, aortic arch, ascending and descending aorta).

OMNIPAQUE 300 is indicated in adults for aortography including studies of the aortic arch, abdominal aorta and its branches, contrast enhancement for computed tomographic head and body imaging, cerebral arteriography, peripheral venography (phlebography), and excretory urography.

OMNIPAQUE 300 is indicated in children for angiocardiography (ventriculography), excretory urography, and contrast enhancement for computed tomographic head imaging.

OMNIPAQUE 240 is indicated in adults for contrast enhancement for computed tomographic head imaging and peripheral venography (phlebography).

OMNIPAQUE 140 is indicated in adults for intra-arterial digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels.

OMNIPAQUE 240 is indicated in children for contrast enhancement for computed tomographic head imaging.

Contraindications

OMNIPAQUE should not be administered to patients with a known hypersensitivity to iohexol.

WARNINGS—General

Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been rep

Diflunisal

Diflunisal TABLETS USP

0755

Rx only

Cardiovascular Risk

• NSAIDs* may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).


• Diflunisal tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

*Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.

Diflunisal Description

Diflunisal is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is:

C13H8F2O3 M.W. 250.20

Diflunisal is a stable, white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.

Each tablet, for oral administration, contains 500 mg Diflunisal. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Blue #2 aluminum lake, hypromellose, microcrystalline cellulose, pregelatinized starch, propylene glycol, sodium stearyl fumarate, and titanium dioxide.

Diflunisal - Clinical Pharmacology

Action

Diflunisal is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.

Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, Diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.

The precise mechanism of the analgesic and anti-inflammatory actions of Diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of Diflunisal may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics and Metabolism

Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no Diflunisal is excreted in the feces. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of Diflunisal in plasma is bound to proteins.

As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when Diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of Diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for Diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.

Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of Diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of Diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.

Mild to Moderate Pain

Diflunisal is a peripherally-acting analgesic agent with a long duration of action. Diflunisal produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.

Consistent with its long half-life, clinical effects of Diflunisal mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. Patients treated with Diflunisal, on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. However, Diflunisal produces longer lasting responses than the comparative agents.

Comparative single dose clinical studies have established the analgesic efficacy of Diflunisal at various dose levels relative to other analgesics. Analgesic effect measurements were derived from hourly evaluations by patients during eight and twelve hour postdosing observation periods. The following information may serve as a guide for prescribing Diflunisal.

Diflunisal 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or 650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. Patients treated with Diflunisal had longer lasting responses than the patients treated with the comparative analgesics.

Diflunisal 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. Patients treated with Diflunisal had longer lasting responses than the patients who received acetaminophen with codeine.

A loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effect than an initial 500 mg dose.

In contrast to the comparative analgesics, a significantly greater proportion of patients treated with Diflunisal did not remedicate and continued to have a good analgesic effect eight to twelve hours after dosing. Seventy-five percent (75%) of patients treated with Diflunisal continued to have a good analgesic response at four hours. When patients having a good analgesic response at four hours were followed, 78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve hours.

Chronic Anti-Inflammatory Therapy in Osteoarthritis and Rheumatoid Arthritis

In the controlled, double-blind clinical trials in which Diflunisal (500 mg to 1000 mg a day) was compared with anti-inflammatory doses of aspirin (2 to 4 grams a day), patients treated with Diflunisal had a significantly lower incidence of tinnitus and of adverse effects involving the gastrointestinal system than patients treated with aspirin (see also Effect on Fecal Blood Loss).

Osteoarthritis

The effectiveness of Diflunisal for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. The activity of Diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal 500 or 750 mg daily was shown to be comparable in effectiveness to aspirin 2000 or 3000 mg daily. In open-label extensions of this study to 24 or 48 weeks, Diflunisal continued to show similar effectiveness and generally was well tolerated.

Rheumatoid Arthritis

In controlled clinical trials, the effectiveness of Diflunisal was established for both acute exacerbations and long-term management of rheumatoid arthritis. The activity of Diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or 3900 mg daily. In open-label extensions of this study to 52 weeks, Diflunisal continued to be effective and was generally well tolerated.

Diflunisal 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In this study, Diflunisal was comparable in efficacy to aspirin.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, Diflunisal 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in effectiveness and tolerability.

In a double-blind multicenter study of 12 weeks' duration, Diflunisal 750 mg daily was comparable in efficacy to naproxen 750 mg daily. The incidence of gastrointestinal adverse effects and tinnitus was comparable for both drugs. This study was extended to 48 weeks on an open-label basis. Diflunisal continued to be effective and generally well tolerated.

In patients with rheumatoid arthritis, Diflunisal and gold salts may be used in combination at their usual dosage levels. In clinical studies, Diflunisal added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.

Antipyretic Activity

Diflunisal tablets are not recommended for use as an antipyretic agent. In single 250 mg, 500 mg, or 750 mg doses, Diflunisal produced measurable but not clinically useful decreases in temperature in patients with fever; however, the possibility that it may mask fever in some patients, particularly with chronic or high doses, should be considered.

Uricosuric Effect

In normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid was observed when Diflunisal was administered at 500 mg or 750 mg daily in divided doses. Patients on long-term therapy taking Diflunisal at 500 mg to 1000 mg daily in divided doses showed a prompt and consistent reduction across studies in mean serum uric acid levels, which were lowered as much as 1.4 mg%. It is not known whether Diflunisal interferes with the activity of other uricosuric agents.

Effect on Platelet Function

As an inhibitor of prostaglandin synthetase, Diflunisal has a dose-related effect on platelet function and bleeding time. In normal volunteers, 250 mg b.i.d. for 8 days had no effect on platelet function, and 500 mg b.i.d., the usual recommended dose, had a slight effect. At 1000 mg b.i.d., which exceeds the maximum recommended dosage, however, Diflunisal inhibited platelet function. In contrast to aspirin, these effects of Diflunisal were reversible, because of the absence of the chemically labile and biologically reactive O-acetyl group at the carbon 4 position. Bleeding time was not altered by a dose of 250 mg b.i.d., and was only slightly increased at 500 mg b.i.d. At 1000 mg b.i.d., a greater increase occurred, but was not statistically significantly different from the change in the placebo group.

Effect on Fecal Blood Loss

When Diflunisal was given to normal volunteers at the usual recommended dose of 500 mg twice daily, fecal blood loss was not significantly different from placebo. Aspirin at 1000 mg four times daily produced the expected increase in fecal blood loss. Diflunisal at 1000 mg twice daily (NOTE: exceeds the recommended dosage) caused a statistically significant increase in fecal blood loss, but this increase was only one-half as large as that associated with aspirin 1300 mg twice daily.

Effect on Blood Glucose

Diflunisal did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or placebo.

Indications and Usage for Diflunisal

Carefully consider the potential benefits and risks of Diflunisal tablets and other treatment options before deciding to use Diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following:

1. Mild to moderate pain


2. Osteoarthritis


3. Rheumatoid arthritis

Contraindications

Diflunisal tablets are contraindicated in patients with known hypersensitivity to Diflunisal or the excipients (see DESCRIPTION).

Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic/Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma).

Diflunisal tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Warnings

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS).

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Diflunisal tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Diflunisal tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation

NSAIDs, including Diflunisal tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Diflunisal tablets in patients with advanced renal disease. Therefore, treatment with Diflunisal tablets is not recommended in these patients with advanced renal disease. If Diflunisal tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactic/Anaphylactoid Reactions

As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to Diflunisal tablets. Diflunisal tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/ anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Diflunisal tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity Syndrome

A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see ADVERSE REACTIONS, Dermatologic). It may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with Diflunisal tablets should be discontinued.

Pregnancy

In late pregnancy, as with other NSAIDs, Diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.

Precautions

General

Diflunisal tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Diflunisal tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Diflunisal tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Diflunisal tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Diflunisal tablets should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Diflunisal tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Diflunisal tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Diflunisal tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Diflunisal tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Ocular Effects

Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with Diflunisal tablets have ophthalmologic studies.

Reye’s Syndrome

Acetylsalicylic acid has been associated with Reye’s syndrome. Because Diflunisal is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Diflunisal tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).


2. Diflunisal tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).


3. Diflunisal tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.


4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.


5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.


6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).


7. In late pregnancy, as with other NSAIDs, Diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Diflunisal tablets should be discontinued.

Drug Interactions

ACE-inhibitors and Angiotensin II Anagonists

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the coadministration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.

Acetaminophen

In normal volunteers, concomitant administration of Diflunisal and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of Diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of Diflunisal tablets and acetaminophen should be used cautiously, with careful monitoring of patients.

Concomitant administration of Diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of Diflunisal/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established.

Antacids

Concomitant administration of antacids may reduce plasma levels of Diflunisal. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.

Aspirin

When Diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free Diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects.

In normal volunteers, a small decrease in Diflunisal levels was observed when multiple doses of Diflunisal and aspirin were administered concomitantly.

Cyclosporine

Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that Diflunisal can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

In normal volunteers, concomitant administration of Diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

NSAIDs

The administration of Diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and Diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and Diflunisal tablets should not be used concomitantly.

The concomitant use of Diflunisal tablets and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers.

Sulindac

The concomitant administration of Diflunisal and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.

Naproxen

The concomitant administration of Diflunisal and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of Diflunisal.

Oral Anticoagulants

In some normal volunteers, the concomitant administration of Diflunisal and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because Diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when Diflunisal tablets are administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Tolbutamide

In diabetic patients receiving Diflunisal and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

Drug/Laboratory Test Interactions

Serum Salicylate Assays

Caution should be used in interpreting the results of serum salicylate assays when Diflunisal is present. Salicylate levels have been found to be falsely elevated with some assay methods.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Diflunisal did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given Diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for Diflunisal.

Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.

No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.

Pregnancy

Teratogenic Effects

Pregnancy category C

A dose of 60 mg/kg/day of Diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to Diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times the human dose). Animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies with Diflunisal in pregnant women. Diflunisal tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.

In rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Diflunisal tablets on labor and delivery in pregnant women are unknown.

Nursing Mothers

Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants from Diflunisal, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Diflunisal in pediatric patients below the age of 12 have not been established. Use of Diflunisal tablets in pediatric patients below the age of 12 is not recommended.

The adverse effects observed following Diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and Diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of Diflunisal to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of Diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).

This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see WARNINGS, Renal Effects).

Adverse Reactions

The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.

Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain.

Incidence Greater Than 1%

Gastrointestinal

The most frequent types of adverse reactions occurring with Diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence.

Psychiatric

Somnolence, insomnia.

Central Nervous System

Dizziness.

Special Senses

Tinnitus.

Dermatologic

Rash*.

Miscellaneous

Headache*, fatigue/tiredness.

* Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.

Incidence Less Than 1 in 100

The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. The probability exists of a causal relationship between Diflunisal and these adverse reactions.

Dermatologic

Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.

Gastrointestinal

Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.