2.1 Dosing Guidelines

Draw Lipiodol into a disposable syringe.
Use the smallest possible amount of Lipiodol according to the anatomical area to be visualized.

Hysterosalpingography

Using aseptic technique inject Lipiodol into the endometrial cavity with fluoroscopic control. Inject increments of 2 mL of Lipiodol until tubal patency is determined; stop the injection if patient develops excessive discomfort. The total volume to be injected depends on the
volume of the uterine cavity, usually not exceeding 15 mL. A 24-hour image can be obtained if, after slow peritoneal spillage, the evaluation of adhesions is needed.  Perform the procedure during the follicular phase of the menstrual cycle.

Before using Lipiodol exclude the presence of these conditions: pregnancy, uterine bleeding and endocervicitis, acute pelvic inflammatory disease, the immediate pre-or postmenstrual phase or within 30 days of curettage or conization. [see Contraindications (4) & Pregnancy (8.1)].

Lymphography

Inject Lipiodol into a lymphatic vessel under radiologic guidance to prevent inadvertent venous administration or intravasation.

Adults:

• unilateral lymphography of the upper extremities 2 to 4 mL
• unilateral lymphography of the lower extremities 6 to 8 mL
• penile lymphography 2 to 3 mL
• cervical lymphography 1 to 2 mL

Pediatric patients:

• Inject a minimum of 1 mL to a maximum of 6 mL according to the anatomical area to be visualized. Do not exceed 0.25 mL/kg.

The following method is recommended for lymphography of the upper or lower extremities. Start the injection of Lipiodol into a lymphatic channel at a rate not to exceed 0.2 mL per minute. Inject the total dose of Lipiodol in no less than 1.25 hours. Use frequent radiologic monitoring to determine the appropriate injection rate and to follow the progress of Lipiodol within the lymphatics. Interrupt the injection if the patient experiences pain. Terminate the injection if lymphatic blockage is present to minimize introduction of Lipiodol into the venous circulation via lymphovenous channels. Terminate the injection as soon as Lipiodol is radiographically evident in the thoracic duct to minimize entry of Lipiodol into the subclavian vein and pulmonary embolization. Obtain immediate post-injection images. Re-image at 24 or 48 hours to evaluate nodal architecture.

Selective Hepatic Intra-arterial Injection

Determine the dose depending on the tumor size, local blood flow in the liver and in the tumor(s).

• Inject from 1.5 to 15 mL slowly under continuous radiologic monitoring. Stop the injection when stagnation or reflux is evident. Limit the dose to only the quantity required for adequate visualization. The total dose of Lipiodol administered should not exceed 20 mL.

2.2 Drug Handling

Inspect Lipiodol visually for particulate matter and discoloration before administration. Do not use the solution if particulate matter is present or if the container appears damaged. Lipiodol is a clear, pale yellow to amber colored oil; do not use if the color has darkened.

Draw Lipiodol into a disposable syringe and use promptly. Discard any unused portion of Lipiodol.

5.1 Pulmonary and Cerebral Embolism

Pulmonary embolism may occur immediately or after a few hours to days from inadvertent systemic vascular injection or intravasation of Lipiodol and cause decreased pulmonary diffusing capacity and pulmonary blood flow, pulmonary infarction, acute respiratory distress syndrome and fatalities. Embolization of Lipiodol to brain and other major organs may occur. Avoid use of Lipiodol in patients with severely impaired lung function, cardiorespiratory failure, or right–sided cardiac overload. Perform radiological monitoring during the Lipiodol injection. Do not exceed the recommended maximum dose and rate of injection of Lipiodol. During lymphography to minimize the risk of pulmonary embolism obtain radiographic confirmation of intralymphatic (rather than venous) injection, and terminate the procedure when Lipiodol becomes visible in the thoracic duct or lymphatic obstruction is observed.

5.2 Hypersensitivity Reactions

Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Lipiodol administration. Avoid use in patients with a history of sensitivity to other iodinated contrast agents, bronchial asthma or allergic disorders because of an increased risk of a hypersensitivity reaction to Lipiodol. Administer Lipiodol only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation; ensure continuous medical monitoring and maintain an intravenous access line. Most hypersensitivity reactions to Lipiodol occur within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and for at least 30 minutes following Lipiodol administration.

5.3 Exacerbation of Chronic Liver Disease

Lipiodol hepatic intra-arterial administration can exacerbate the following conditions: portal hypertension and cause variceal bleeds due to obstruction of the intrahepatic portal channels by opening a pre sinusoidal anastomosis; hepatic ischemia and cause liver enzyme elevations, fever and abdominal pain; hepatic failure and cause ascites and encephalopathy. Hepatic vein thrombosis, irreversible liver insufficiency and fatalities have been reported. Procedural risks include vascular complications and infections.

5.4 Thyroid Dysfunction

Iodinated contrast media can affect thyroid function because of the iodide content and can cause hyperthyroidism or hypothyroidism. Ethiodized oil may remain in the body for several months, depending on dose administered and route of administration. Keep the dose of Lipiodol as low as possible and consider monitoring thyroid function closely for several months after administration of Lipiodol.

6.2 Postmarketing Experience

The following adverse reactions (Table 1) have been identified during post approval use of Lipiodol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions are described in more detail in other sections of the prescribing information:
Pulmonary and cerebral embolism [see Warnings and Precautions (5.1)]
Hypersensitivity reactions [see Warnings and Precautions (5.2)]
Exacerbation of chronic liver disease [see Warnings and Precautions (5.3)]

Thyroid dysfunction [see Warnings and Precautions (5.4)]. Thyroid dysfunction in the mother and the infant of a subsequent pregnancy
[See Use in Specific Populations (8.1)]

Hysterosalpingography

Abdominal pain, foreign body reactions, exacerbation of pelvic inflammatory disease, salpingitis or pelvic peritonitis have been reported
after the examination in case of latent infection.

Lymphography

Lymphangitis, thrombophlebitis, edema or exacerbation of preexisting lymphedema, dyspnea and cough, iodism (headache, soreness of mouth and pharynx, coryza and skin rash), allergic dermatitis, lipogranuloma, delayed healing at the site of incision.

Selective Hepatic Intra-arterial Injection

Abdominal pain, nausea, and vomiting are the most common reactions; other reactions include hepatic vein thrombosis, hepatic ischemia, liver enzymes abnormalities, transitory decrease in liver function, liver decompensation and renal insufficiency. Procedural risks include vascular complications and infections.

7.1 Interference with Iodine-Based Diagnostic Tests and Iodine-Based Radiotherapy

Following Lipiodol administration, ethiodized oil remains in the body for several months. Ethiodized oil interferes with radioactive iodine uptake by the thyroid for several weeks to months may impair visualization of thyroid scintigraphy and reduce effectiveness of iodine 131 treatment.

8.1 Pregnancy

Risk Summary

Hysterosalpingography is contraindicated in pregnant women due to the potential risk to the fetus from an intrauterine procedure [see
Contraindications (4)]. The use of Lipiodol before or during pregnancy may interfere with thyroid function in both the pregnant woman
and her fetus and may affect fetal development. There are maternal, fetal, and neonatal clinical considerations for women who are exposed to Lipiodol either before or during pregnancy (see Clinical Considerations). Rare pregnancy outcomes reported in the post marketing setting with Lipiodol use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects or miscarriage (see Data). Animal reproduction studies have not been conducted using the indicated routes of administration of Lipiodol, it was not embryotoxic or teratogenic in animal studies with oral administration.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a
background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of
major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal adverse reactions
The use of Lipiodol before or during pregnancy may interfere with the thyroid function of the pregnant woman. Untreated hypothyroidism in pregnancy is associated with adverse perinatal outcomes, such as spontaneous abortion, preeclampsia, preterm birth, abruptio placentae, and fetal death. Consider thyroid function testing during pregnancy if a woman was exposed to Lipiodol either before or during pregnancy or if clinically indicated [see Warnings and Precautions (5.4)].

Fetal / Neonatal adverse reactions
The use of Lipiodol before or during pregnancy causes iodide transfer across the placenta which may interfere with fetal thyroid function
and may affect fetal development. Untreated hypothyroidism is associated with increased fetal risk of low birth weight, fetal distress, and
impaired neuropsychological development. Consider thyroid function testing in infants whose mothers were exposed to Lipiodol before
and during pregnancy or if clinically indicated [see Warnings and Precautions (5.4)].

Data

Human Data
In a prospective study, twenty-two euthyroid women with infertility underwent hysterosalpingography, and thyroid stimulating hormone,
serum iodine concentration, and urinary iodide/creatine excretion were evaluated at 4, 8, 12, 24 weeks. Six patients were followed upto12 months. The median value of urinary iodide excretion peaked at four weeks post-procedure and remained elevated at 8, 12, 24 weeks post-procedure compared to pre-procedure. Three patients showed elevated TSH (5 uIU/L) with normal T4 at 4 or 8 weeks after
hysterosalpingography.

In addition, there are post marketing reports of goiters and hypothyroidism in fetuses and infants whose mothers were exposed to Lipiodol for hysterosalpingography prior to pregnancy.

Animal Data
Lipiodol was not embryotoxic or teratogenic in rats after oral administration of up to 250 mg Iodine/kg each day between gestation days 6 to 17, or in rabbits after 4-5 intermittent (once every three days) oral administrations of 12.5 mg Iodine/kg between gestation days 6 to 18. Maternal
toxicity was observed in rats at 250 mg Iodine/kg/day.

8.2 Lactation

Risk Summary

Ethiodized oil is present in human milk.

There are no data on the effects of ethiodized oil on the breastfed infant, or effects on milk production, however, the use of Lipiodol may
increase the concentration of iodide in human milk and may interfere with the thyroid function of the breastfed infant. Consider thyroid
function testing in a breastfed infant whose mother was exposed to Lipiodol or if clinically indicated. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical need for Lipiodol and any potential adverse effects on the
breastfed child from Lipiodol or from the underlying maternal condition.

8.3 Females and Males of Reproductive potential

Pregnancy Testing

Confirm that the patient has a negative pregnancy test within 24 hours before Lipiodol administration for hysterosalpingography [see
Dosage and Administration (2.1), Contraindications (4)].

8.4 Pediatric Use

For lymphography use a dose of minimum of 1 mL to a maximum of 6 mL according to the anatomical area to be visualized. Do not exceed 0.25 mL/kg. Administer the smallest possible amount of Lipiodol according to the anatomical area to be visualized.

8.5 Geriatric Use

There are no studies conducted in geriatric patients.

8.6 Renal Impairment

Prior to an intra-arterial administration of Lipiodol screen all patients for renal dysfunction by obtaining history and/or laboratory tests.
Consider follow-up renal function assessments for patients with a history of renal dysfunction.

12.1 Mechanism of Action

Lipiodol opacifies vessels and body structures in the path of the flow of the contrast medium, permitting visualization of the internal structures.

12.2 Pharmacodynamics

Following administration of Lipiodol, the degree of enhancement is directly related to the local iodine content in the body structures to be imaged.

12.3 Pharmacokinetics

Following intra-arterial administration of Lipiodol, ethiodized oil retained in normal hepatic parenchyma is phagocytized by the Kupffer cells of the liver and washed out via the hepatic lymphatic system in about 2 to 4 weeks. In HCC, retention in the liver tumor is prolonged, allowing re-imaging of the tumor for four weeks or longer.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Lipiodol did not demonstrate mutagenic potential in bacterial reverse mutation assays (in vitro), in a chromosomal aberration test in the mouse lymphoma assay (in vitro), and was negative in an in vivo micronucleus test in rats after intravenous injection of 479 mg I/kg.