2-(2,6-Dioxo-3-piperidinyl)-1H-isoindol-1,3(2H)-dion

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Commercially available thalidomide capsules should be stored at 15-30 °C and protected from light.

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs.

Since thalidomide has been shown to be present in the serum and semen of patients receiving thalidomide, healthcare providers or other care givers who have been exposed to body fluids from patients receiving thalidomide should take appropriate precautions (e.g., wearing gloves to prevent potential cutaneous exposure to thalidomide, washing the exposed area with soap and water).

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Skin protection: Handle with gloves.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Provide appropriate exhaust ventilation at places where dust is formed.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored. (L1721)

Thalidomide has been reported to enhance the sedative effects of some drugs, including barbiturates, chlorpromazine, and reserpine, and may potentiate the somnolence caused by alcohol.

Because of the potential for additive effects, drugs known to be associated with peripheral neuropathy (e.g., certain antiretroviral agents (e.g., didanosine), certain antineoplastic agents (e.g., paclitaxel; platinum-containing drugs such as cisplatin; vinca alkaloids such as vincristine)) should be used with caution in patients receiving thalidomide.

Use of these medications /carbamazepine or griseofulvin or human immunodeficiency virus (HIV)-protease inhibitors or rifabutin or rifampin/ with hormonal contraceptive agents may reduce the effectiveness of the contraception; women requiring treatment with one or more of these medications must abstain from heterosexual intercourse or use two other effective or highly effective methods of contraception.

Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving thalidomide with dexamethasone.

For more Interactions (Complete) data for THALIDOMIDE (17 total), please visit the HSDB record page.

The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy. Thalidomide can cause severe birth defects in humans.

Serum enzyme elevations occur in 8% to 15% of patients taking thalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, both thalidomide and its derivatives, lenalidomide and pomalidomide, have been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with thalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT). There appears to be cross reactivity to this complication among thalidomide and its two derivatives. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that thalidomide is expected to have very high mobility in soil(SRC). Volatilization of thalidomide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Thalidomide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Utilizing the Closed Bottle test and the Manometric respiratory test, thalidamide exhibited less than 35% degradation in 28 days(4), indicating that biodegradation is a slow environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that thalidomide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.3X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 0.33(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Utilizing the Closed Bottle test and the Manometric respiratory test, thalidamide exhibited less than 35% degradation in 28 days(7), indicating that biodegradation is a slow environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), thalidomide, which has an estimated vapor pressure of 2.1X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase thalidomide may be removed from the air by wet and dry deposition(SRC). Thalidomide absorbs UV light at wavelengths of 300 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Thalidomide treatment may be limited by its many adverse effects caused by numerous active metabolites derived from the degradation of its enantiomers. Common side effects include constipation, hypothyroidism, ACTH stimulation, hypoglycemia, xerostomia, fever, mood changes, headache, peripheral neuropathy, somnolence, sedation, rash, and deep vein thrombosis.

The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.

IDENTIFICATION AND USE: Thalidomide is a white to off-white crystalline powder. Thalidomide is an immunomodulatory agent with anti-inflammatory, antiangiogenic, and sedative and hypnotic activity. It is used for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). It is also used as maintenance therapy for prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum recurrence. It is used in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. HUMAN EXPOSURE AND TOXICITY: Overdosage of thalidomide may cause prolonged sleep as a result of the drug's sedative and hypnotic effects, but fatalities are unlikely since the drug does not cause respiratory depression. In 3 reported suicide attempts involving deliberate ingestion of up to 14.4 g of thalidomide, all individuals recovered without reported sequelae. Thalidomide is a known human teratogen. The severe malformation induced by thalidomide may involve defects of the limbs, axial skeleton, head and face, eyes, ears, tongue, teeth, central nervous, respiratory, cardiovascular, and genitourinary systems, and the gastrointestinal tract. The neurological complications may include severe mental retardation secondary to sensory deprivation. Thus, thalidomide is contraindicated during pregnancy. Thalidomide is also known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (> or =10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Seizures have been reported, including tonic-clonic (grand mal) seizures. Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have also been reported. The use of thalidomide in multiple myeloma patients causes an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. ANIMAL STUDIES: In an acute toxicity study, guinea pigs administered a 650 mg/kg oral dose became quiet and sedated. Two-year carcinogenicity studies were conducted in male and female mice, male and female rats. No compound-related tumorigenic effects were observed at the highest dose levels in male and female mice (9 to 14-fold human exposure), and male rats (12-fold human exposure). In female rats, a tumorigenic effect was not observed at 300 mg/kg/day (16-fold human exposure). In another carcinogenicity study, 56 adult beagle dogs were orally administered thalidomide for 53 weeks. There were no deaths during the study. There was no gross and histopathologic evidence of any tumors. A large number of reproductive studies have shown that thalidomide is a potent teratogen. Cynomolgus monkeys were orally administered thalidomide at 15 or 20 mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. The teratogenicity of thalidomide in rats was investigated after a single maternal intravenous injection during the organogenesis period. Thalidomide induced skeletal deformities of thoracic ribs and of the spinal column in fetuses upon maternal administration of the drug. Deformities of the eyeball in fetuses were induced by the maternal administration of the drug on day 10 and 12. A single dose (500 mg/kg) of thalidomide was administered orally to pregnant rabbits in various stages of organogenesis. Head anomalies in fetuses were induced at a high frequency by the maternal administration of thalidomide on day 7. Microphthalmia in fetuses was observed with a single administration from day 7 to 12 of gestation. Contracture of forearms and club foot in fetuses resulted from the maternal administration of thalidomide on day 8 or 9 of gestation, respectively. With a single administration on day 8 or 9 of gestation, kinky tail in fetuses resulted, and brachyury was observed with a high frequency from day 8 to 11 of gestation. Skeletal anomalies such as fusion or displacement of coccygeal vertebral bodies were observed at a high frequency with a single treatment from day 8 to 10 of gestation. Among the internal anomalies observed was abnormal lobation of the lung, and abnormal lobation of the liver, cardiovascular anomalies. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits. Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (Salmonella typhimurium and Escherichia coli) reverse mutation assay, a Chinese hamster ovary cell forward mutation assay, and an in vivo mouse micronucleus test.

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; Click on the "Chemical Explorer" button on the tool bar to see the data./[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2014: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of thalidomide can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that thalidomide is expected to have very high mobility in soil.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including thalidomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

U.S. Food & Drug Administration. ... Because of /its/ toxicity and in an effort to make the chance of fetal exposure to thalidomide as negligible as possible, thalidomide is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called the "System for thalidomide education and prescribing safety (S.T.E.P.S.)". Under this restricted distribution program, only prescribers and pharmacists registered with the program are allowed to prescribe and dispense the product. In addition, patients must be advised of, agree to, and comply with the requirements of the S.T.E.P.S. program in order to receive product.

If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking the drug. Even a single dose (1 capsule (regardless of strength)) taken by a pregnant woman during her pregnancy can cause severe birth defects. Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to Thalomid (thalidomide) as negligible as possible, Thalomid (thalidomide) is approved for marketing only through a special restricted distribution program: Thalomid REMS program, approved by the Food and Drug Administration. This program was formerly known as the "System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. program)".

Any suspected fetal exposure to thalidomide must be reported immediately to the FDA via the MedWATCH number at 1-800-FDA-1088 and also to Celgene Corporation (1-888-668-2528). The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

MEDICATION

Angiogenesis Inhibitors; Immunosuppressive Agents; Leprostatic Agents; Teratogens

For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. Used to treat multiple myeloma.

Thalidomide was first marketed in Germany 1957 under the name Contergan, in the UK in 1958 as Distaval, and finally at least under 35 further names worldwide.

Table: Thalidomide Preparations [Table#4648]