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THALIDOMIDE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Thalidomide, a glutamic acid derivative, is an immunomodulatory agent. It also has antiinflammatory and antiangiogenic properties. Long term effects may include neuropathy, often irreversible, as well as teratogenic effects. Pomalidomide, a thalidomide analogue, is also an immunomodulatory agent with antineoplastic activity.

Specific Substances

    1) 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione
    2) N-(2,6-dioxo-3-piperidyl)phthalimide
    3) alpha-(N-phthalimido)glutarimide
    4) K-17
    5) N-phthalylglutamic acid imide
    6) N-phthaloylglutamimide
    7) NSC-66847
    8) Molecular formula C13-H1O-N2-O4
    9) CAS 50-35-1
    10) Pomalidomide
    1.2.1) MOLECULAR FORMULA
    1) POMALIDOMIDE: C13H11N3O4
    2) THALIDOMIDE: C13H1ON2O4

Available Forms Sources

    A) FORMS
    1) Thalidomide is available as a 50 mg, 100 mg, 150 mg and 200 mg capsule (Prod Info THALOMID(R) oral capsules, 2012).
    2) Pomalidomide is available as a 1 mg, 2 mg, 3 mg and 4 mg capsule (Prod Info POMALYST(R) oral capsules, 2013).
    B) USES
    1) THALIDOMIDE: The FDA approved thalidomide for treatment of a Hansen's disease (leprosy) side effect, erythema nodosum leprosum (ENL) in July, 1998. Due to its potential for causing teratogenicity, thalidomide is a tightly restricted drug (Prod Info Thalomid(R), thalidomide, 1999; FDA, 1998). Thalidomide is also used as maintenance therapy for the prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum (Prod Info THALOMID(R) oral capsules, 2012).
    a) It is also indicated in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma (Prod Info THALOMID(R) oral capsules, 2012). It has also been used for multiple off-label indications (eg, graft versus host disease, cachexia in HIV and cancer, rheumatoid arthritis, discoid lupus erythematosus) (Prommer et al, 2011).
    2) POMALIDOMIDE: Pomalidomide, a thalidomide analogue, is indicated for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including lenalidomide and bortezomib and have disease progression on or within 60 days of completion of the last therapy. However, clinical benefit (ie improvement in survival or symptoms) has not been determined (Prod Info POMALYST(R) oral capsules, 2013).
    3) LENALIDOMIDE: Lenalidomide, a thalidomide analogue, is also used for the treatment of multiple myeloma. See LENALIDOMIDE management for further information.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Thalidomide in combination with dexamethasone is used for the treatment of patients with newly diagnosed multiple myeloma. It is also indicated for the acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum. Pomalidomide, a thalidomide analogue, is used to treat patients with multiple myeloma who have received prior therapies (ie, lenalidomide and bortezomib) with evidence of disease progression.
    B) PHARMACOLOGY: The precise mechanism of thalidomide is not fully understood. It has immunomodulatory, antiinflammatory, and antiangiogenic properties.
    C) EPIDEMIOLOGY: Exposure is uncommon due to restricted distribution; fatal overdoses have not been reported.
    D) TOXICOLOGY: Thalidomide should not be used by pregnant women, because it is a known teratogen that can cause severe birth defects or fetal death.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse events include: fatigue, hypocalcemia, edema, constipation, neuropathy (sensory and motor) , dyspnea, muscle weakness, leukopenia, neutropenia, rash, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, weight gain, dizziness, and dry skin. Hepatotoxicity is rare. Teratogenicity has occurred.
    2) CHRONIC USE: Peripheral neuropathy (may be irreversible) and bradycardia may occur.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdoses have been limited and have been followed by uneventful recoveries.
    2) MILD TO MODERATE TOXICITY: Acute toxicity is minimal, but may consist of hypotension, sedation, fatigue, dizziness, constipation, and dermatologic effects.
    3) SEVERE TOXICITY: Limited data. Sedation and peripheral neuropathy may occur. Severe hepatotoxicity may develop.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypotension and fever may occur following overdoses.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Edema of the extremities has been reported as an adverse effect. Bradycardia and thrombolic events have been reported following the long-term use of thalidomide for multiple myeloma.
    B) WITH POISONING/EXPOSURE
    1) Transient hypotension has been reported following an overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Adverse effects following therapeutic doses have included CNS depression with sedation, fatigue and dizziness.
    2) Peripheral neuropathy has been reported following long-term use of thalidomide.
    B) WITH POISONING/EXPOSURE
    1) CNS effects following overdoses have included sedation.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Constipation and nausea are frequently reported adverse effects of thalidomide.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Neutropenia has been reported as an adverse effect.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Skin rashes are a frequently reported adverse effect.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Hypersensitivity reactions have been reported following therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Thalidomide and pomalidomide are classified as FDA pregnancy category X. Thalidomide is a known human teratogen that causes life-threatening human birth defects. Because there is evidence that thalidomide is present in semen; it is recommended that males using thalidomide always use a barrier contraceptive method (even following a successful vasectomy) during sexual contact with women of childbearing age.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of thalidomide or pomalidomide.
    0.2.22) OTHER
    A) DRUG INTERACTION: Thalidomide may potentiate the action of sedative/hypnotics.

Laboratory Monitoring

    A) Monitor patients for CNS depression and peripheral neuropathies.
    B) Monitor CBC, serum electrolytes and renal function after significant overdose.
    C) Monitor vital signs, especially blood pressure following overdose.
    D) Because a single dose of thalidomide or pomalidomide may be teratogenic, obtain a pregnancy test in all women of childbearing potential who ingest thalidomide or pomalidomide.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs and neuro status. Treat symptomatic hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor neuro status and vital signs; obtain a baseline CBC and electrolytes. Moderate to severe hypotension may require IV fluids, dopamine or norepinephrine. Treat symptomatic bradycardia with atropine. Obtain liver enzymes in a symptomatic patient.
    C) DECONTAMINATION
    1) PREHOSPITAL: Emesis is not recommended due to the risk of CNS depression. Activated charcoal may be indicated if the ingestion was recent and the patient is able to protect the airway.
    2) HOSPITAL: Activated charcoal may be indicated if the ingestion was recent, and the airway can be protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a mild to moderate exposure; airway support may be needed following a severe exposure (eg, CNS depression, severe hypersensitivity reaction).
    E) ANTIDOTE
    1) None.
    F) HYPOTENSION
    1) Monitor blood pressure. Administer IV 0.9% NaCl, dopamine, norepinephrine.
    G) PAIN
    1) Peripheral and circumoral neuropathies should be treated with pain management as needed.
    H) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be beneficial. These agents have a relatively high volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with a minor exposure (one tablet) can be monitored at home. An asymptomatic adult taking an inadvertent extra dose of thalidomide can be monitored at home. However, because a single dose of thalidomide may be teratogenic, all women of childbearing potential who ingest thalidomide should have a pregnancy test.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients who exhibit only mild CNS depression or other signs of mild intoxication should be observed, either in the emergency department or as an inpatient, until no longer intoxicated.
    3) ADMISSION CRITERIA: Patients with persistent or ongoing symptoms should be admitted for further monitoring and supportive measures.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist. Any woman of child bearing age exposed to these agents should have a pregnancy test done due to the risk of severe birth defects and fetal death. Contact the FDA via MedWatch program at 1-800-FDA-1088.
    J) PHARMACOKINETICS
    1) THALIDOMIDE: Oral absorption is relatively slow, with peak levels occurring in 2.9 to 5.7 hours. The extent of mean plasma protein binding is 55% and 66%, respectively for (+)-(R)- and (-)-(S)-thalidomide. Apparent volume of distribution is approximately 120 L. Thalidomide is a known teratogen. The manufacturer reports an elimination half-life of approximately 5 to 7 hours following a single oral dose, which is not altered upon multiple dosing.
    2) POMALIDOMIDE: Pomalidomide is a thalidomide analogue. Following a single oral dose, the Cmax occurs at 2 and 3 hours post dose. Protein binding ranges from 12% to 44%; not concentration dependent. Apparent volume of distribution is approximately 62 L, and 138 L at steady state. It is metabolized in the liver by CYP1A2 and CYP3A4. Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in a healthy individual and 7.5 hours in a patient with multiple myeloma.
    K) PITFALLS
    1) Discharging the patient before symptoms may develop due to the relatively slow absorption with thalidomide. Early discharge of the patient before the agent has been eliminated (approximately 6 to 10 hours). Omission of pregnancy status in all women of childbearing age that have been exposed.
    L) DIFFERENTIAL DIAGNOSIS
    1) Underlying disease process (multiple myeloma); fever or neutropenia due to other causes; sepsis

Range Of Toxicity

    A) THALIDOMIDE: TOXICITY: Overdose data are limited. Adults have developed mild, transient toxicity after doses as high as 14.4 g. Fatalities have not been reported following overdose in humans. THERAPEUTIC DOSE: ADULT: 100 to 300 mg/day; maximum daily dose not to exceed 400 mg.
    B) POMALIDOMIDE: TOXICITY: At the time of this review, there is no overdose information. THERAPEUTIC DOSE: RECOMMENDED DOSE: ADULT: 4 mg once daily orally on days 1 to 21 of repeated 28-day cycles until disease progression.

Clinical Effects

Summary Of Exposure

    A) USES: Thalidomide in combination with dexamethasone is used for the treatment of patients with newly diagnosed multiple myeloma. It is also indicated for the acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum. Pomalidomide, a thalidomide analogue, is used to treat patients with multiple myeloma who have received prior therapies (ie, lenalidomide and bortezomib) with evidence of disease progression.
    B) PHARMACOLOGY: The precise mechanism of thalidomide is not fully understood. It has immunomodulatory, antiinflammatory, and antiangiogenic properties.
    C) EPIDEMIOLOGY: Exposure is uncommon due to restricted distribution; fatal overdoses have not been reported.
    D) TOXICOLOGY: Thalidomide should not be used by pregnant women, because it is a known teratogen that can cause severe birth defects or fetal death.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The most common adverse events include: fatigue, hypocalcemia, edema, constipation, neuropathy (sensory and motor) , dyspnea, muscle weakness, leukopenia, neutropenia, rash, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, weight gain, dizziness, and dry skin. Hepatotoxicity is rare. Teratogenicity has occurred.
    2) CHRONIC USE: Peripheral neuropathy (may be irreversible) and bradycardia may occur.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdoses have been limited and have been followed by uneventful recoveries.
    2) MILD TO MODERATE TOXICITY: Acute toxicity is minimal, but may consist of hypotension, sedation, fatigue, dizziness, constipation, and dermatologic effects.
    3) SEVERE TOXICITY: Limited data. Sedation and peripheral neuropathy may occur. Severe hepatotoxicity may develop.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension and fever may occur following overdoses.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Febrile reactions are a common adverse event, and were reported in 20 HIV-infected patients (36%) following 14 to 21 days of thalidomide therapy in one study (Haslett et al, 1997).
    B) WITH POISONING/EXPOSURE
    1) Fever has been reported following a 14.4 gram thalidomide overdose combined with alcohol, but this may have been attributable to a concurrent influenza infection (Neuhaus & Ibe, 1960).

Heent

    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) LONG-TERM EFFECTS: In a study conducted in Brazil, individuals affected by thalidomide embryopathy (TE) were studied to assess their current health status. Of the 23 adult subjects (between 19 and 55 years of age) with TE, progressive deafness after the age of 40 was reported in 6 individuals (Kowalski et al, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) There have been several reports of severe hepatotoxicity following therapeutic use of thalidomide (Dabak & Kuriakose, 2009; Hanje et al, 2006).
    b) CASE REPORTS: A 79-year-old woman recently diagnosed with IgA lambda multiple myeloma was treated with thalidomide (50 mg daily for one week than increased weekly to 200 mg daily) and dexamethasone daily and developed jaundice, fatigue, anorexia, a 9 to 10 pound weight loss and elevated liver enzymes approximately 7 weeks after starting therapy. Liver function tests had been normal one month prior to therapy. Serologic studies were negative. A liver biopsy showed cholestasis and bile duct injury. Thalidomide was stopped and over the course of several months the patient's liver enzymes remained elevated. She was placed in hospice for her ongoing liver failure and died 3 months later (Dabak & Kuriakose, 2009). The authors also reported liver injury in a 57-year-old woman with multiple myeloma after receiving one cycle of thalidomide therapy. Liver function studies gradually improved over 2 weeks after stopping treatment. The patient was restarted on bortezomib with no further adverse events reported.
    c) CASE REPORT: A 76-year-old woman recently diagnosed with multiple myeloma and receiving a combination of dexamethasone and daily thalidomide developed severe hepatotoxicity 6 weeks after the initiation of therapy. Routine laboratory tests obtained at 4 weeks revealed elevated liver enzymes with clinical evidence of jaundice one week later. Laboratory studies included: aspartate aminotransferase of 2376 U/L (normal 5-34 U/L), alanine aminotransferase of 2205 U/L (normal 8-35 U/L), and an international normalized ratio (INR) of greater than 15 (target range 2-3). Serologic and autoimmune studies were negative. Liver biopsy demonstrated drug-induced acute liver injury with hepatocyte necrosis and periportal inflammation. Liver function studies improved with the discontinuation of thalidomide, and normalized within 3 months (Hanje et al, 2006). Although hepatotoxicity is rare, the authors reported several other cases in the literature of moderate liver injury with thalidomide use.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) In clinical trial of multiple myeloma patients treated with pomalidomide, 16 of 107 patients (15%) developed renal failure (Prod Info POMALYST(R) oral capsules, 2013).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Neutropenia has been reported as an adverse effect.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been reported in association with the therapeutic use of thalidomide, particularly in patients with underlying disorders which may affect the hematologic system (Prod Info THALOMID(R) oral capsules, 2012; Parker et al, 1995; Jacobson et al, 1997; Peuckmann et al, 2000). In a clinical trial of thalidomide as therapy for graft-versus-host disease, neutropenia was reported in 18% of the patients (Parker et al, 1995).
    b) In clinical trial of multiple myeloma patients treated with pomalidomide, 56 of 107 patients (52%) developed neutropenia and 50 (47%) of them developed grade 3 or 4 neutropenia (Prod Info POMALYST(R) oral capsules, 2013).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In clinical trial of multiple myeloma patients treated with pomalidomide, 27 of 107 patients (25%) developed thrombocytopenia and 24 (22%) of them developed grade 3 or 4 thrombocytopenia (Prod Info POMALYST(R) oral capsules, 2013).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In clinical trial of multiple myeloma patients treated with pomalidomide, 41 of 107 patients (38%) developed anemia and 24 (22%) of them developed grade 3 or 4 anemia (Prod Info POMALYST(R) oral capsules, 2013).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Skin rashes are a frequently reported adverse effect.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Erythematous and papulovesicular eruptions have been reported as common adverse effects during thalidomide therapy (Naafs & Faber, 1985; Gutierrez-Rodriguez et al, 1989; Grosshans & Illy, 1984; Heney et al, 1990; Haslett et al, 1997; Clark et al, 2001). Generally the incidence is less than 10%, although higher incidences have been reported (Gutierrez-Rodriguez et al, 1989; Reyes-Teran et al, 1996; Haslett et al, 1997).
    b) Williams et al (1991) reports the occurrence of a hypersensitivity rash in 2 of 8 HIV-1 infected patients treated with thalidomide for oropharyngeal ulceration. Bielsa et al (1994) report two patients with a severe erythematous rash that progressed to erythroderma and was associated with peripheral eosinophilia following therapy with thalidomide.
    c) Sixteen percent of chronic graft-versus-host disease patients reported a rash following thalidomide therapy in one study (Parker et al, 1995).
    d) Toxic pustuloderma was reported secondary to thalidomide therapy (3 weeks) in a 34-year-old woman with severe nodular prurigo. A skin biopsy confirmed the diagnosis. Thalidomide was stopped, and the rash steadily improved over 4 weeks (Darvay et al, 1997).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epiderma necrolysis (TEN) has been reported with thalidomide therapy. Patients that develop any type of skin rash should be appropriately evaluated prior to continuing therapy (Prod Info THALOMID(R) oral capsules, 2012).
    b) CASE REPORT: A 64-year-old man was started on thalidomide and dexamethasone for previously untreated myeloma. Twenty-four days after starting therapy, a rash was noted and thalidomide was discontinued. The rash progressed to TEN over the next 3 days. The patient recovered following 2 weeks of intensive therapy. The authors have suggested the possibility of a drug interaction between dexamethasone and thalidomide as a cause (Rajkumar et al, 2000).
    c) CASE REPORT: A 62-year-old woman developed TEN approximately 5 weeks after starting thalidomide for treatment of glioblastoma. The patient was also taking phenobarbital, dexamethasone, valproic acid, nizatidine, diphenhydramine, and bisoprolol. Both thalidomide and phenobarbital were discontinued and the rash improved over 6 days. On rechallenge with thalidomide, the rash returned (Horowitz & Stirling, 1999).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens Johnson syndrome has been identified in postmarketing reporting for patients with malignancies treated with thalidomide (Prod Info THALOMID(R) oral capsules, 2012; Clark et al, 2001). Patients that develop any type of skin rash should be appropriately evaluated prior to continuing therapy (Prod Info THALOMID(R) oral capsules, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) DISORDER OF MUSCULOSKELETAL SYSTEM
    1) WITH POISONING/EXPOSURE
    a) LONG TERM EFFECTS: In a study conducted in Brazil, individuals affected by thalidomide embryopathy (TE) were studied to assess their current health status. Of the 23 adult subjects (between 19 and 55 years of age) with TE, musculoskeletal issues (including osteopenia, arthrosis) were a relatively frequent compliant (7/23, 30%) (Kowalski et al, 2015).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypersensitivity reactions have been reported following therapeutic use.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Hypersensitivity reactions have been associated with thalidomide therapy. Symptoms have included erythematous macular rash, along with fever, tachycardia, and hypotension. In some cases, therapy may need to be stopped (Prod Info THALOMID(R) oral capsules, 2012).
    b) Williams et al (1991) has reported 8 HIV-infected patients treated with thalidomide who experienced erythematous macular rashes. Two of these patients were rechallenged with thalidomide and experienced hypersensitivity reactions, including fever, tachycardia, and rash. One of these patients became hypotensive, requiring colloid infusion and hydrocortisone.
    1) HIV-infected patients who are rechallenged with thalidomide have been reported to have an accelerated hypersensitivity response (Haslett et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) Thalidomide and pomalidomide are classified as FDA pregnancy category X. Thalidomide is a known human teratogen that causes life-threatening human birth defects. Because there is evidence that thalidomide is present in semen; it is recommended that males using thalidomide always use a barrier contraceptive method (even following a successful vasectomy) during sexual contact with women of childbearing age.
    3.20.2) TERATOGENICITY
    A) THALIDOMIDE
    1) CONGENITAL ANOMALY
    a) Severe birth defects or death to the unborn baby have been reported with maternal thalidomide exposure. A single dose of one capsule containing 50 mg, 100 mg, or 200 mg of thalidomide taken by a pregnant woman has been shown to cause birth defects. Teratogenic effects have included: amelia, phocomelia, hypoplasia of the bones, as well as absence of bones, external ear abnormalities (anotia, microtia), facial palsy, eye abnormalities (anophthalmos, microphthalmos), congenital heart defects, gastrointestinal tract, urinary tract, and genital malformations. Neonatal mortality at or shortly after birth has been reported in about 40% of pregnancies with thalidomide exposure (Prod Info THALOMID(R) oral capsules, 2012).
    b) Up to 12,000 birth defects, primarily phocomelias, were associated with use of thalidomide during pregnancy in the late 1950's (Randall, 1990). Abnormalities observed following exposure to thalidomide during the critical period include facial hemangioma (strawberry birthmark) and the absence or blockage of the esophagus or duodenum (Beckman & Brent, 1984). Anomalies of the heart, kidney, external ears, central nervous system and genitourinary tract have also been reported (Brown et al, 1990; Beckman & Brent, 1984). In addition, thalidomide exposure resulted in eye disorders in 46 (54%) patients and included ocular mobility defects, facial palsy, and abnormal lacrimation (Stromland & Miller, 1993). Thalidomide is a known teratogene (Beckman & Brent, 1984; Grosshans & Illy, 1984).
    c) A review of thalidomide embryopathy is available (Lenz, 1988). The critical period for embryopathy is between days 34 and 50 after the last menstrual period (Pers Comm, 1998; Randall, 1990aa; Beckman & Brent, 1984). The mechanism involved in thalidomide-induced teratogenicity is not fully understood (Randall, 1990a; Beckman & Brent, 1984). One hypothesis has been proposed that thalidomide acts on the sensory nerves of the embryo (embryonic neuropathy) (McCredie, 1976). Another hypothesis is that thalidomide-induced early fetal thrombosis and severe limb hemorrhages could be responsible for circulatory blocks leading to necrosis (Petter, 1977).
    d) Congenital anomalies related to thalidomide may continue to pose problems throughout childhood and adult life. Children suffering from thalidomide embryopathy often have hidden defects of the spine and hip joints which are not detected by clinical examination. Early osteoarthritis is one consequence of these defects (Ruffing, 1980; Ruffing, 1977).
    e) Thalidomide does not appear to cause second generation birth defects (Smithells, 1998).
    2) SKELETAL MALFORMATION
    a) Skeletal anomalies related to thalidomide use during pregnancy include: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, and absence of bones (Prod Info THALOMID(R) oral capsules, 2006).
    3) PHOCOMELIA
    a) An estimated 5000 to 6000 infants were reported with characteristic thalidomide-induced phocomelia, often accompanied by deformities of internal organs during the 1950's and 1960's (D'Arcy & Griffin, 1994).
    b) In the early 1960's there was a large increase in the incidence of phocomelia (McBride, 1961; Randall, 1990a; Lenz, 1966). Reports indicate that there is a very clear relationship between the time of exposure to thalidomide and the type of congenital anomalies. Limb defects have been limited to exposure during a 2-week period (day 27 to 40 of gestation). Even one dose during this period can result in birth abnormalities (Randall, 1990a; Beckman & Brent, 1984). From day 27 to 30 of gestation abnormalities of the arms are most common. Leg and arm defects have occurred after exposure on days 30 to 33 (Beckman & Brent, 1984). These findings correlate with the appearance of the lower limb buds in the human embryo at about the 30th day (Iffy et al, 1967; Schumacher, 1975; Jonsson, 1972). .
    4) UROGENITAL ABNORMALITIES
    a) Perhaps the most common problems associated with thalidomide exposure are those involving genital malformations in females. These malformations may take the form of a rudimentary or absent uterus and abnormalities of the vagina (Muhlenstedt & Schwarz, 1984). In one case, a 14-year-old patient with abnormalities of both upper extremities experienced cyclic pain in the lower abdomen. Although the patients' ovaries and fallopian tubes were normally developed, the uterus and vagina were absent (Hoffmann et al, 1976).
    5) GROWTH RETARDED
    a) Studies which examined the growth patterns of children exposed to thalidomide found that the children were shorter than normal but grew at a normal rate once puberty had been reached (Brook et al, 1977).
    B) ANIMAL STUDIES
    1) POMALIDOMIDE
    a) RATS, RABBITS: There are no adequate or well controlled studies of pomalidomide use during human pregnancy. In animal studies, administration of oral pomalidomide 25 to 1000 mg/kg/day in pregnant rats during organogenesis resulted in the absence of the urinary bladder and thyroid gland as well as fusion and misalignment of the lumbar and thoracic vertebral elements. Increased resorptions and decreased viable offspring was also observed. Similarly, administration of oral pomalidomide 10 to 250 mg/kg/day in pregnant rabbits during organogenesis resulted in increased cardiac malformations, limb anomalies, skeletal malformations, dilation of the lateral ventricle, abnormal subclavian artery placement, absence of the intermediate lobe of the lung, low set kidneys, liver morphology alterations, and an incomplete or nonossified pelvis. Increased resorptions were also reported in this group. Maternal toxicities were not observed in rats or rabbits (Prod Info POMALYST(R) oral capsules, 2013).
    2) THALIDOMIDE
    a) RABBITS: Drug-related increased abortion and elevated fetotoxicity were reported in a reproductive study of pregnant female rabbits at the lowest oral thalidomide dose of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon body surface area) and all higher doses (Prod Info THALOMID(R) oral capsules, 2012).
    b) RATS: In pregnant rats given oral thalidomide doses of 500 to 1200 mg/kg, structural abnormalities and fetal death were reported. Similar oral doses in the mouse produced musculoskeletal defects and fetal death. When pregnant rabbits were treated with oral thalidomide 450 mg/kg, craniofacial and musculoskeletal abnormalities were observed (RTECS, 1996).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturers have classified pomalidomide and thalidomide as FDA pregnancy category X (Prod Info POMALYST(R) oral capsules, 2013; Prod Info THALOMID(R) oral capsules, 2012).
    2) Limited data on reproductive effects in males after thalidomide exposure includes a brief reference to congenital defects in the offspring of thalidomide-treated males (Stellman, 1979); however, the manufacturer states that the risk to the fetus from the semen of thalidomide-treated males is unknown (Prod Info THALOMID(R) oral capsules, 2006). Because there is evidence that thalidomide is present in semen; it is recommended that males using thalidomide also use a barrier contraceptive, even following a successful vasectomy (Prod Info THALOMID(R) oral capsules, 2012; Teo et al, 2001).
    B) THALIDOMIDE
    1) PREGNANCY COMPLICATIONS
    1) Several studies have examined the course of pregnancy in thalidomide-affected women (Maouris & Hirsch, 1988; Brown et al, 1990). In one case, a 26-year-old woman with upper limb phocomelia developed renal failure during pregnancy which required dialysis. The pregnancy was complicated by uncontrollable hypertension and deteriorating renal function resulting in fetal loss at 26-weeks gestation. The patient developed end-stage renal failure and required a renal transplant (Brown et al, 1990).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) POMALIDOMIDE
    1) Lactation studies with pomalidomide have not yet been conducted, however, pomalidomide has been detected in the milk of lactating rats. It is not known whether pomalidomide is excreted into human breast milk; however, there is the potential for serious adverse effects in nursing infants from pomalidomide. Therefore, a decision should be made to discontinue nursing or discontinue pomalidomide treatment, taking into account the importance of the drug to the mother (Prod Info POMALYST(R) oral capsules, 2013).
    B) THALIDOMIDE
    1) It is not known whether thalidomide is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. However, given the known teratogenicity of thalidomide and the likelihood of transfer based on the pharmacokinetic properties of the drug, a decision should be made to either discontinue nursing or discontinue the drug considering the importance of the drug to the mother (Prod Info THALOMID(R) oral capsules, 2012).
    C) ANIMAL STUDIES
    1) Neonatal mortality occurred at a greater frequency in lactating rabbits when given oral thalidomide at doses of 150 mg/kg/day (approximately 7.5-fold the maximum human dose) and greater (Prod Info THALOMID(R) oral capsules, 2012).
    2) No delay in postnatal development, including cognitive function, was observed when lactating rabbits were given oral thalidomide doses of 150 mg/kg/day that yielded average thalidomide breast milk concentrations of 11 to 36 mcg/mL (Prod Info THALOMID(R) oral capsules, 2012).
    3.20.5) FERTILITY
    A) SEMEN
    1) Limited data on reproductive effects in males after thalidomide exposure demonstrates congenital defects in the offspring of thalidomide-treated males (Stellman, 1979); however, the manufacturer states that the risk to the fetus from the semen of thalidomide-treated males is unknown (Prod Info THALOMID(R) oral capsules, 2012). Because there is evidence that thalidomide is present in semen; it is recommended that males using thalidomide also use a barrier contraceptive method, even following a successful vasectomy (Prod Info THALOMID(R) oral capsules, 2012; Teo et al, 2001).
    B) ANIMAL STUDIES
    1) There were no drug-related effects on mating or fertility at any oral thalidomide dose given to female and male rabbits, including the maximum doses of 100 and 500 mg/kg/day (approximately 5-fold and 25-fold the maximum human dose), respectively.
    2) MALE: Slight testicular pathological and histopathological effects were observed in male rabbits at oral thalidomide doses of 30 mg/kg/day (approximately 1.5-fold the maximum human dose) and greater (Prod Info THALOMID(R) oral capsules, 2006).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS50-35-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of thalidomide or pomalidomide.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In 2-year carcinogenicity studies in male and female rats and mice, no compound-related tumorigenic effects were observed at the highest dose levels of 3000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily dose of 400 mg), 3000 mg/kg/day to female rats (75-fold the maximum human dose based on body surface area (BSA)), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA) (Prod Info THALOMID(R) oral capsules, 2012).
    B) ACUTE MYELOID LEUKEMIA
    1) MONKEYS: Administration of pomalidomide 1 mg/kg (approximately 15 times the recommended human dose) resulted in the development of acute myeloid leukemia in 1 out of 12 monkeys during a 9-month, repeat-dose toxicology study (Prod Info POMALYST(R) oral capsules, 2013).

Genotoxicity

    A) There was no evidence of mutagenicity or clastogenicity in the following tests: bacteria reverse mutation assay (Ames Test), in vitro assay using human peripheral blood lymphocytes, and the micronucleus test conducted in orally treated rats (Prod Info POMALYST(R) oral capsules, 2013).
    B) A number of short term studies for in vitro mutagenicity of thalidomide have been conducted. The US EPA Genetox Program (1988) reported negative results for thalidomide in D. melanogaster (whole and partial sex chromosome loss); D. melanogaster non-dysjunction and in a host mediated way. Negative results were also reported for the sperm morphology test in mouse (RTECS, 1996).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Edema of the extremities has been reported as an adverse effect. Bradycardia and thrombolic events have been reported following the long-term use of thalidomide for multiple myeloma.
    B) WITH POISONING/EXPOSURE
    1) Transient hypotension has been reported following an overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension was reported in a 21-year-old man following an overdose of 14.4 g thalidomide and alcohol. He recovered from the hypotension within a few hours (Neuhaus & Ibe, 1960).
    B) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema, primarily of the extremities, and controlled by diuretic therapy, has been reported as an adverse effect of thalidomide (Cazort & Song, 1966; Revuz et al, 1990; Gutierrez-Rodriguez et al, 1989; Grosshans & Illy, 1984; Iyer et al, 1971). Edema occurred in 50% of rheumatoid arthritis patients in one study (Gutierrez-Rodriguez et al, 1989).
    C) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thalidomide use in multiple myeloma patients may increase the risk of thromboembolic events including deep venous thrombosis and pulmonary embolus (Prod Info THALOMID(R) oral capsules, 2012).
    1) INCIDENCE: In one study, the rate of venous thromboembolic events was 22.5% in patients receiving thalidomide compared to 4.9% of patients receiving dexamethasone alone (Prod Info THALOMID(R) oral capsules, 2012).
    D) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia has been reported with therapeutic thalidomide use. In some cases, supportive care was necessary (Prod Info THALOMID(R) oral capsules, 2012).
    b) In a phase III study of newly diagnosed patients (n=200) with multiple myeloma, 96 patients were randomized to receive oral thalidomide (400 mg/day during induction phase and 200 mg every other day for the first year of maintenance and 100 mg/day orally) and 104 patients received placebo. Following the use of thalidomide for at least 3 months, 52 patients (53%) developed bradycardia (HR 30 to 60 bpm); 8 patients developed a heart rate as low as 30 bpm. Severe bradycardia was noted in 5 patients, requiring permanent pacemaker implantations. The authors proposed that thalidomide-related bradycardia may be due to reversible changes in autonomic balance. Since thalidomide inhibits TNF-alpha expression and activity, overactivity of the parasympathetic system may occur (Fahdi et al, 2004).
    E) CARDIOVASCULAR FUNCTION
    1) WITH POISONING/EXPOSURE
    a) LONG-TERM EFFECTS: In a study conducted in Brazil, individuals affected by thalidomide embryopathy (TE) were studied to assess their current health status. Of the 23 adult subjects (between 19 and 55 years of age) with TE, 6 (26%) adults had an early onset of cardiovascular disease (p = 0.009) (Kowalski et al, 2015).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Adverse effects following therapeutic doses have included CNS depression with sedation, fatigue and dizziness.
    2) Peripheral neuropathy has been reported following long-term use of thalidomide.
    B) WITH POISONING/EXPOSURE
    1) CNS effects following overdoses have included sedation.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Dizziness, headache, fatigue and mood changes have been observed as adverse effects in thalidomide treated patients (Prod Info THALOMID(R) oral capsules, 2012; Steins et al, 2002; Iyer et al, 1971; Revuz et al, 1990; Cazort & Song, 1966; Grosshans & Illy, 1984; Sheskin & Convit, 1969; Heney et al, 1990).
    B) SEIZURE DISORDER
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported in postmarketing experience with thalidomide, the exact frequency of these events is not known (Prod Info THALOMID(R) oral capsules, 2012). The manufacturer suggests careful monitoring in patients with a history of seizure activity.
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness is the most frequently observed adverse effect of thalidomide (Prod Info THALOMID(R) oral capsules, 2012; Clark et al, 2001; Williams et al, 1991; Revuz et al, 1990; Gunzler, 1992; Parker et al, 1995; Jacobson et al, 1997; Haslett et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Increased sedation has been reported following overdoses.
    b) CASE REPORT: A 21-year-old man was found unconscious 3 hours following the ingestion of 14.4 g thalidomide and alcohol. He eventually recovered (Neuhaus & Ibe, 1960).
    c) CASE REPORT: A 70-year-old man experienced drowsiness for 36 hours following an accidental ingestion of 2.1 grams thalidomide (DeSouza, 1959).
    D) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Thalidomide can produce permanent nerve damage. Peripheral neuropathy has been reported in 10% or more of patients receiving thalidomide. It usually occurs following chronic use, but has developed following short-term use (Prod Info THALOMID(R) oral capsules, 2012).
    b) One of the most serious adverse effects of long term thalidomide therapy is peripheral neuropathy, with incidences of 15% up to 50% reported in AIDS patients (Gunzler, 1992). Sensory neuropathies were reported to occur 2 to 12 months after thalidomide treatment in 3 of 4 patients with prurigo nodularis (Aronson et al, 1984). Symptoms may improve with the discontinuation of therapy, but may not completely resolve (Lagueny et al, 1986; Crawford, 1992; Peuckmann et al, 2000). In electrophysiology studies, thalidomide neuropathy has been shown to be characterized by axonal degeneration without demyelination, affecting mainly sensory fibers in the distal lower limbs with progression proximally (Clark et al, 2001; Lagueny et al, 1986; Wulff et al, 1985).
    c) In one study, seven patients with graft-vs-host disease, pyoderma gangrenosum, and discoid lupus received thalidomide with doses ranging from 100 to 1200 mg/day for 5 to 16 months (cumulative dosages of 24 to 384 grams). All seven patients experienced dose-dependent sensorimotor length-dependent axonal polyneuropathy with painful paresthesias or numbness. In 3 patients, sural nerve biopsies revealed evidence of Wallerian degeneration and loss of myelinated fibers (Chaudhry et al, 2002).
    d) In one study, neurotoxicity (eg; paresthesias, tremor and dizziness) was reported following the long-term (greater than 1 year) use of thalidomide in patients (n=40) with multiple myeloma. These patients received salvage therapy with thalidomide (200 to 400 mg/day) with (n=20) or without (n=20) dexamethasone (40 mg/day) for longer than 12 months. Various degrees of neurotoxicity were experienced by 30 patients (75%), from mild paresthesias (grade 1; n=6) to intolerable paresthesias (grade 3; n=11) that prompted drug withdrawal. Patients experienced symmetrical paresthesias and sensory loss, initially involving distal extremities and subsequently progressing to hands and arms. Electromyographic study of patients with grade 2 or higher showed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neurotoxicity was not related to cumulative or daily thalidomide dose, but only to the duration of the disease prior to thalidomide treatment (Tosi et al, 2005).
    e) In a phase I/II dose-escalating study, patients were given 200 mg/day of thalidomide, increasing by 200 mg/day every 2 weeks until a total dose of 800 mg/day was reached. Peripheral neuropathy (grade 1 to 2) was reported in 4 of the 20 patients with acute myeloid leukemia. Patients recovered following dose reduction or discontinuation (Steins et al, 2002).
    f) Harland et al (1993) found no correlation between occurrence of peripheral neuropathy and any genetically-determined variable route of metabolism. The cumulative dose of thalidomide appeared to be unrelated to the risk of neuropathy (Harland et al, 1993; Ochonisky et al, 1994).
    g) In clinical trial of multiple myeloma patients treated with pomalidomide, 11of 107 patients (10%) developed peripheral neuropathy (Prod Info POMALYST(R) oral capsules, 2013).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Constipation and nausea are frequently reported adverse effects of thalidomide.
    3.8.2) CLINICAL EFFECTS
    A) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation and nausea have been reported as frequent adverse effects of thalidomide therapy (Prod Info THALOMID(R) oral capsules, 2012; Steins et al, 2002; Haslett et al, 1997; Parker et al, 1995). Constipation appears to be the most frequent gastrointestinal adverse effect, with an incidence as high as 50% to 100% in some studies (Prod Info THALOMID(R) oral capsules, 2012; Vogelsang et al, 1992; Revuz et al, 1990; Gutierrez-Rodriguez et al, 1989).
    b) In clinical trial of multiple myeloma patients treated with pomalidomide, 38 of 107 patients (36%) developed constipation (Prod Info POMALYST(R) oral capsules, 2013).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In clinical trial of multiple myeloma patients treated with pomalidomide, 38 of 107 patients (36%) reported nausea and 15 (14%) of them developed vomiting (Prod Info POMALYST(R) oral capsules, 2013).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In clinical trial of multiple myeloma patients treated with pomalidomide, 36 of 107 patients (34%) developed diarrhea (Prod Info POMALYST(R) oral capsules, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor patients for CNS depression and peripheral neuropathies.
    B) Monitor CBC, serum electrolytes and renal function after significant overdose.
    C) Monitor vital signs, especially blood pressure following overdose.
    D) Because a single dose of thalidomide or pomalidomide may be teratogenic, obtain a pregnancy test in all women of childbearing potential who ingest thalidomide or pomalidomide.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function and CBC after significant overdose
    4.1.4) OTHER
    A) OTHER
    1) ELECTROPHYSIOLOGICAL TESTING
    a) It has been recommended to test peripheral sensory nerve action potential (SNAP) amplitudes and somatosensory evoked potential (SEP) latencies by sural nerve stimulation, and SNAP amplitudes on the median nerve at the wrist. Reductions in the SNAP amplitudes and increases in SEP latencies are sensitive indicators of neuropathy (Lagueny et al, 1986).

Methods

    A) CHROMATOGRAPHY
    1) A high-performance liquid chromatography assay method has been developed for the quantitative determination of thalidomide and its major metabolites from human serum. Reversed-phase chromatography may be used to separate the parent compound and the metabolites (Czejka & Koch, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent or ongoing symptoms should be admitted for further monitoring and supportive measures.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with a minor exposure (one tablet) can be monitored at home. An asymptomatic adult taking an extra dose of thalidomide can be monitored at home. However, because a single dose of thalidomide may be teratogenic, all women of childbearing potential who ingest thalidomide should have a pregnancy test.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist. Any woman of childbearing age exposed to these agents should have a pregnancy test done due to the risk of severe birth defects and fetal death. Contact the FDA via the MedWatch program at 1-800-FDA-1088.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients who exhibit only mild CNS depression or other signs of mild intoxication should be observed, either in the emergency department or as an inpatient, until no longer intoxicated.

Monitoring

    A) Monitor patients for CNS depression and peripheral neuropathies.
    B) Monitor CBC, serum electrolytes and renal function after significant overdose.
    C) Monitor vital signs, especially blood pressure following overdose.
    D) Because a single dose of thalidomide or pomalidomide may be teratogenic, obtain a pregnancy test in all women of childbearing potential who ingest thalidomide or pomalidomide.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Emesis is not recommended due to the risk of CNS depression.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most patients may be safely managed with conservative, supportive care.
    2) Peripheral and circumoral neuropathies, which may not be reversible, particularly following long term use of thalidomide, should be treated with pain management as needed.
    B) MONITORING OF PATIENT
    1) Monitor patients for CNS depression and peripheral neuropathies.
    2) Monitor vital signs. Monitor CBC, serum electrolytes and renal function after significant overdoses.
    3) Because a single dose may be teratogenic, obtain a pregnancy test in all women of childbearing potential.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    E) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) SUMMARY
    1) It is unknown if hemodialysis would be beneficial. These agents have a relatively high volume of distribution.

Range Of Toxicity

Summary

    A) THALIDOMIDE: TOXICITY: Overdose data are limited. Adults have developed mild, transient toxicity after doses as high as 14.4 g. Fatalities have not been reported following overdose in humans. THERAPEUTIC DOSE: ADULT: 100 to 300 mg/day; maximum daily dose not to exceed 400 mg.
    B) POMALIDOMIDE: TOXICITY: At the time of this review, there is no overdose information. THERAPEUTIC DOSE: RECOMMENDED DOSE: ADULT: 4 mg once daily orally on days 1 to 21 of repeated 28-day cycles until disease progression.

Therapeutic Dose

    7.2.1) ADULT
    A) POMALIDOMIDE
    1) MULTIPLE MYELOMA
    a) The recommended dose is 4 mg/day orally on days 1 through 21 of a 28 day cycle. Cycles should continue until disease progression occurs (Prod Info POMALYST(R) oral capsules, 2013)
    B) THALIDOMIDE
    1) SUMMARY
    a) Thalidomide use can cause severe birth defects; therefore, drug administration must be in compliance with the terms described in the THALOMID REMS(TM) program formerly known as the System for Thalidomide Education and Prescribing Safety (STEPS). Thalidomide may only be prescribed and dispensed by those healthcare professionals registered with the THALOMID REMS(TM) program (Prod Info THALOMID(R) oral capsules, 2013).
    2) MULTIPLE MYELOMA
    a) Thalidomide is combined with dexamethasone (40 mg orally) in 28-day treatment cycles. Administer 200 mg thalidomide orally at bedtime and at least 1 hour after eating, with dexamethasone 40 mg orally daily on days 1 to 4, 9 to 12, and 17 to 20 every 28 days (Prod Info THALOMID(R) oral capsules, 2013).
    3) ERYTHEMA NODOSUM LEPROSUM
    a) Treat an episode of cutaneous erythema nodosum leprosum (ENL) with an initial 100 to 300 mg/day thalidomide; preferably at bedtime and at least 1 hour after the evening meal. For patients less than 50 kg, treatment should be started a the lowest dose range (Prod Info THALOMID(R) oral capsules, 2013).
    b) Severe cutaneous ENL may be started at 400 mg thalidomide daily at bedtime or in divided doses with water at least 1 hour after meals (Prod Info THALOMID(R) oral capsules, 2013).
    c) Treatment should continue until clinical improvement occurs which may take up to 2 weeks. Patients should be tapered off the medication in 50 mg decrements every 2 to 4 weeks. For those patients that require prolonged therapy, thalidomide should be maintained at the lowest dose to control reactions. An effort to taper the patient should occur every 3 to 6 months in decrements of 50 mg every 2 to 4 weeks (Prod Info THALOMID(R) oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) POMALIDOMIDE
    1) The safety and efficacy of pomalidomide has not been established in pediatric patients (Prod Info POMALYST(R) oral capsules, 2013).
    B) THALIDOMIDE
    1) The safety and efficacy of thalidomide use in patients below the age of 12 have not been established (Prod Info THALOMID(R) oral capsules, 2013).

Minimum Lethal Exposure

    A) There have been no reports of fatalities with these agents (Prod Info POMALYST(R) oral capsules, 2013; Prod Info THALOMID(R) oral capsules, 2012).

Maximum Tolerated Exposure

    A) THALIDOMIDE
    1) CASE REPORT: A 21-year-old man tolerated an intentional overdose of 14.4 g of thalidomide with alcohol with transient effects of sedation, hypotension, and fever, all of which resolved within several hours (Neuhaus & Ibe, 1960).
    2) CASE REPORTS: Three cases of overdose (suicide attempts) have been reported, with doses up to 14.4 g; all patients recovered with no reported sequelae (Prod Info Thalomid(R), thalidomide, 1999).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) THALIDOMIDE
    a) ADULT: Peak plasma levels of 0.8 to 1.4 mcg/mL were achieved in a mean of 4.4 hours (range, 1.9 to 6.2 hours) following a single 200 mg oral dose in healthy male subjects. The authors calculated that steady-state peak serum levels of 3.6 mcg/mL would be achieved at steady-state with administration of thalidomide 200 mg every 6 hours (Chen et al, 1989; Gunzler, 1992).
    b) Time to peak plasma concentration: 2 to 6 hours; it may be delayed by food (Prommer et al, 2011).
    2) POMALIDOMIDE
    a) Following a single oral dose, the Cmax occurs at 2 and 3 hours post dose (Prod Info POMALYST(R) oral capsules, 2013)

Workplace Standards

    A) ACGIH TLV Values for CAS50-35-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS50-35-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS50-35-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS50-35-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 2 gm/kg (RTECS, 2001)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) >5 gm/kg (RTECS, 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) >6 gm/kg (RTECS, 2001)
    4) LD50- (ORAL)RAT:
    a) 113 mg/kg (RTECS, 2001)
    5) LD50- (SKIN)RAT:
    a) 1550 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) THALIDOMIDE
    1) Thalidomide, an immunomodulator, has anticytokine, anti-integrin, and anti-angiogenic properties. It inhibits the synthesis of the proinflammatory cytokine tumor necrosis factor alpha (TNF-a) by monocytes and stimulates interleukin-2 and interferon-gamma production (which stimulates human T lymphocytes). Thalidomide can also inhibit chemotaxis of neutrophils and monocytes. It also has antiproliferative and pro-apoptiotic activity in tumor cells (Prommer et al, 2011).
    2) In addition, it antagonizes PGE2 , PGF2, histamine, serotonin, and acetylcholine. By having properties to affect inflammation and immunomodulation it may have role in preventing irinotecan-induced diarrhea and for the treatment of paraneoplastic sweating and paraneoplastic pruritus (Prommer et al, 2011).
    3) Thalidomide has also been reported to reduce the generation of oxygen intermediates (superoxide and hydroxyl radicals) (Miyachi, 1985) and alter the T-cell ratio as evidenced by a reduction in helper T-cells and an increase in suppressor T-cells (Randall, 1990a). A decrease in IgM levels has been reported in erythema nodosum leprosum patients following thalidomide treatment (Shannon et al, 1981), and reduced antibody production in response to antigenic stimuli has been reported.
    4) SEDATIVE EFFECT is most likely mediated at the glutarimide ring of thalidomide. It acts differently than barbiturates, possibly involving activation of a sleep center in the forebrain (Tseng et al, 1996).
    5) TUMOR NECROSIS FACTOR: Thalidomide has been reported to selectively inhibit the production of tumor necrosis factor alpha (TNF-a) at a distinct point of the cytokine biosynthetic pathway. It was shown to enhance the degradation of TNF-a mRNA, thus making this drug a candidate for treatment of inflammatory conditions where TNF-a toxicities are observed and immunity must remain intact (Moreira et al, 1993; Sampaio et al, 1991).
    B) POMALIDOMIDE
    1) Pomalidomide, a thalidomide analogue, is an immunomodulatory agent with antineoplastic activity. In in vitro cellular assays, it inhibited proliferation and induced apoptosis of hematopoietic tumor cells. It also inhibited proliferation of lenalidomide-resistant multiple myeloma cell lines. Pomalidomide along with dexamethasone has also been shown to induce tumor cell apoptosis in both lenalidomide-sensitive and lenalidomide-resistant cell lines (Prod Info POMALYST(R) oral capsules, 2013).

Toxicologic Mechanism

    A) THALIDOMIDE
    1) TERATOGENIC MECHANISMS are still unresolved, but the phthalimide moiety has been implicated (Grosshans & Illy, 1984). Structural changes in the thalidomide molecule have been attempted in order to create derivatives with antiinflammatory/immunosuppressive actions but lacking teratogenic potential (Barnhill et al, 1984; Grosshans & Illy, 1984).
    B) POMALIDOMIDE
    1) Pomalidomide, a thalidomide analogue, can produce teratogenic effects and cause severe birth defects (Prod Info POMALYST(R) oral capsules, 2013).

Physicochemical

Physical Characteristics

    A) POMALIDOMIDE is a solid yellow powder that has a low solubility in pH solutions (about 0.01 mg/mL) and limited to low solubility in organic solvents (Prod Info POMALYST(R) oral capsules, 2013).
    B) THALIDOMIDE is a white to off-white, odorless, crystalline powder. It is soluble at 25 degrees C in dimethyl sulfoxide and sparingly soluble in water and ethanol (Prod Info THALOMID(R) oral capsules, 2014).

Molecular Weight

    A) POMALIDOMIDE: 273.24 (Prod Info POMALYST(R) oral capsules, 2013)
    B) THALIDOMIDE: 258.2 (Prod Info THALOMID(R) oral capsules, 2014)

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