Thalidomide

Thalidomide is an antineoplastic agent belonging to the pharmacological class of immunomodulatory agents.

The FDA approved Thalidomide for treating newly diagnosed multiple myeloma and erythema nodosum leprosum.

With a high 90% bioavailability, Thalidomide absorbs slowly in the gastrointestinal System. It is widely distributed, crosses the placenta, and is found in semen. In the liver, non-enzymatic hydrolysis is the primary process of metabolism. Urine is responsible for the majority of elimination (92%).

The most common side effects of Thalidomide include headache, sleepiness, nausea, rash, weakness, and dizziness.

Thalidomide is available in oral capsules.

The molecule is available in India, the United States, Switzerland, Canada, countries within the European Union, Australia, Argentina, Japan and South Korea.

Thalidomide is an antineoplastic agent belonging to the pharmacological class of immunomodulatory agents.

The exact mechanism of action of Thalidomide is unknown. According to research conducted both in vitro and in vivo, it prevents monocytes from producing tumour necrosis factor-alpha. Reduced IgM production, altered CD4/CD8 T-cell ratios, increased overall numbers of CD8 and CD4 T-cells, and inhibition of angiogenesis are all possible side effects of Thalidomide. It can also cause the down-regulation of integrin receptors and other surface adhesion proteins. Reduced synthesis of oxygen-free radicals and other inflammatory response mediators has been linked to anti-inflammatory qualities. By directly promoting cytotoxic T-cells, Thalidomide has the potential to improve cell-mediated immunity.

Thalidomide reaches its peak plasma time in 3-6 hours.

The peak plasma concentration of Thalidomide ranges from 1.15 to 3.2 mcg/mL.

Thalidomide is available in oral capsules.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, preferably after meals.

Multiple myeloma(MM)

Erythema Nodosum Leprosum (ENL)

• Multiple myeloma (MM): The body breaks down bone faster than it replaces it when a patient has multiple myeloma. This weakens, hurts, and increases the likelihood that bones may shatter. Chemotherapy and other cancer therapies may be used in addition to Thalidomide. It boosts the chances of survival for those with multiple myeloma and is a crucial component of the treatment. This medication will destroy the malignant cells, which will also stop them from growing and spreading to other areas of the body. If the blood calcium levels are not high, the physician may prescribe calcium and vitamin D3 supplements, which are also beneficial.
• Erythema Nodosum Leprosum (ENL): For moderate-to-severe cutaneous symptoms of Erythema Nodosum Leprosum (ENL) associated with leprosy, Thalidomide is an effective acute and maintenance treatment. It inhibits cutaneous recurrence, lowers inflammation, and relieves symptoms, including fever, malaise, and nodules. Because of this, Thalidomide is a beneficial treatment choice for those with ENL, providing comfort and enhancing the general quality of life for those who suffer from this inflammatory skin condition.

Thalidomide is indicated in the following health conditions:

• For treating moderate-to-severe erythema nodosum leprosum (ENL) cutaneous manifestations, both acutely and as maintenance therapy to prevent and suppress recurrence.
• Also, in combination with dexamethasone for newly diagnosed multiple myeloma (MM).

Orally: Thalidomide is available in capsules and is administered orally. It is recommended to take it once a day at bedtime, ideally, one hour after dinner. It is essential to consume the capsules whole; do not chew, crush, or open them. Patients should continue their regular dosage schedule and forgo the missing dose in case of one. Those who are nursing or pregnant should exercise caution. Women who are or may become pregnant should not touch this medicine or breathe in the dust from broken capsules since it can be absorbed through the skin and lungs and damage an unborn child. After handling this medication, everyone should thoroughly wash their hands.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

• Erythema Nodosum Leprosum (ENL)

• Multiple myeloma

While undergoing Thalidomide treatment, patients can take charge of side effects by adjusting their diet. Incorporate iron-rich foods like lean red meat, raisins, bell peppers, Brussels sprouts, and broccoli. To prevent constipation, include fibre-rich foods such as whole grains, broccoli, dried fruits, nuts, beans, apples, oranges, and pears. Additionally, it is advisable to abstain from smoking and alcohol consumption.

The dietary restriction should be individualized as per patient requirements.

• In individuals who have a history of excipient or active drug hypersensitivity (e.g., angioedema, anaphylaxis).
• Pregnancy; Even a single dose is highly teratogenic.

• Ischemic Heart Disease and Stroke: Myocardial infarction and stroke are potential side effects of taking Thalidomide and dexamethasone together. Patients should have routine cardiac monitoring.
• Drowsiness and Somnolence: Advise patients to avoid situations that call for alertness and to be cautious while taking drowsiness-inducing drugs simultaneously.
• Peripheral Neuropathy: During the first three months of treatment and then on occasion after that, regularly check patients for symptoms of peripheral neuropathy. To identify neuropathy without symptoms, take into consideration electrophysiological tests.
• Dizziness and Orthostatic Hypotension: To avoid dizziness and orthostatic hypotension, advise patients to rise slowly from a reclined posture.
• Neutropenia: Monitor for the presence of neutropenia and modify dosage as necessary.
• Increased HIV Viral Load: Following therapy, monitor the viral load at predetermined intervals.
• Bradycardia: Monitor for bradycardia and, if required, reduce your dosage or stop altogether.
• Restarting Thalidomide after stopping it owing to severe skin problems such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis is not advised.
• Seizures: Continue to watch for any triggers or alterations that can cause acute seizure activity in individuals who have a history of seizures.
• Tumor Lysis Syndrome: Exercise caution while dealing with high-risk individuals and monitor for symptoms.

The adverse reactions related to Thalidomide can be categorized as:

• Common Adverse Effects: Drowsiness, somnolence, peripheral neuropathy, dizziness, orthostatic hypotension, neutropenia, and increased HIV viral load.
• Less Common Adverse Effects: Bradycardia, Stevens-Johnson Syndrome, toxic epidermal necrolysis, seizures, and tumour lysis syndrome.
• Rare Adverse Effects: Severe hypersensitivity

Reports on Postmarketing

Reduced white blood cell counts, including febrile neutropenia, prothrombin time alterations, pancytopenia, chronic myelogenous leukaemia, nodular sclerosing Hodgkin disease, erythroleukemia, lymphedema, and lymphopenia are among the blood and lymphatic conditions that might be affected.

Whole body: hangover impact

Cardiovascular System: pulmonary hypertension, abnormal EKG readings, and sick sinus syndrome

Digestive System: Stomatitis, aphthous ulcer, stomach ulcer, bile duct blockage, intestinal perforation, and gastrointestinal perforations

Disorders of the ears and labyrinths: Impairment of hearing

Immune system disorders: Solid organ transplant rejection, hypersensitivity, including anaphylaxis

Severe infections (such as septic shock and deadly sepsis) and viral infections (such as cytomegalovirus, varicella-zoster virus, and hepatitis B virus reactivation) can result in progressive and multifocal leukoencephalopathy.

Endocrine and metabolic disorders: hypercalcemia, hyponatremia, hypomagnesemia, hypothyroidism, elevated alkaline phosphatase, tumour lysis syndrome, and myxedema; electrolyte imbalance.

Nervous System: changes in mood or mental state, such as suicidal thoughts; disruptions in consciousness, such as drowsiness, loss of consciousness, or stupor; seizures, such as status epilepticus and grand mal convulsions; Parkinson's disease; stroke; carpal tunnel syndrome; Raynaud syndrome; migraine; foot drop

Disorders of the kidneys and urine system: oliguria, enuresis, acute renal failure, and renal failure

Amenorrhea, galactorrhea, gynecomastia, metrorrhagia, and sexual dysfunction are indications of reproductive System and breast problems.

Pleural effusion and interstitial lung disease in the respiratory System

Skin and appendages: purpura, petechiae, toxic epidermal necrolysis (TEN), erythema multiforme, erythema nodosum, and drug response with eosinophilia and systemic symptoms (DRESS).

Particular senses: nystagmus and diplopia

The clinically relevant drug interactions of Thalidomide are briefly summarized here.

Drug-Drug Interactions: Avoid using anxiolytics, hypnotics, H1 antihistamines, antipsychotics, opioids, and barbiturates concurrently since they may intensify their sedative effects. β-blockers, Ca channel blockers, digoxin, lithium, TCAs, H2 blockers (such as famotidine, cimetidine), or neuromuscular blockers (such as succinylcholine) may have an added bradycardic impact. Medication known to induce peripheral neuropathy (e.g., vincristine, bortezomib, amiodarone, cisplatin, phenytoin, disulfiram, metronidazole) increases the risk of peripheral neuropathy. It may raise the risk of venous thromboembolic illness when used with other medications, such as estrogen-containing contraceptives.

Meal Interaction: Alcohol can increase its sedative effects; avoid using it concurrently.

The common side effects of Thalidomide include:

Constipation

Dizziness

Sleepiness

Dry skin

Weakness

Fatigue

Dysaesthesia, or unusual sensation

Drowsiness

Tremor

Low blood cell count

Swelling of hands and feet

Nausea

Vomiting

Indigestion

• Pregnancy

Pregnancy Category(FDA) X: When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

When given to a pregnant woman, Thalidomide can damage the developing fetus and should not be used during pregnancy.

Human teratogen thalidomide causes a high incidence of severe and potentially fatal congenital disabilities, including phocomelia (short limbs), amelia (absence of limbs), hypoplasticity of the bones, absence of bones, facial palsy, abnormalities of the external ears (anotia, micropinna, small or absent external auditory canals), and congenital heart defects. In addition to genital, urinary, and alimentary system anomalies, over 40% of newborns have been recorded to die at or soon after birth. If a pregnant woman takes even one dosage, it might result in birth abnormalities.

Patients should be informed of the possible risk to a baby if they use this medication while pregnant or if they get pregnant while taking it.

• Nursing Mothers

It is unknown if human milk contains thalidomide excretion. Rabbits that are nursing excrete Thalidomide in their milk. Given the likelihood of severe adverse effects in nursing babies from THALOMID and the fact that many medications are excreted in human milk, a decision should be made, considering the significance of the medication to the mother, whether to stop breastfeeding or to stop taking it.

• Pediatric Use

As per FDA, the safety and effectiveness have not been established in pediatric patients.

Dose Adjustment in Kidney Impairment Patients:

No clinical studies have been conducted in patients with Kidney impairment.

Dose Adjustment in Hepatic Impairment Patients:

No clinical studies have been conducted in patients with hepatic impairment.

The literature has reports of overdosages up to 14.4 g. Headache, irritability, and drowsiness are the signs and symptoms of thalidomide overdose. No fatalities from overdoses have been documented, and every patient who overdosed recovered without any side effects.

There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient's vital signs should be carefully checked, and suitable supportive care should be provided to maintain the respiration and blood pressure stable.

• Pharmacodynamics

The immunomodulatory and anti-inflammatory drug thalidomide was initially developed as a sedative and had an undetermined range of effects. But Thalidomide is thought to work by reducing and controlling the amount of several inflammatory mediators, namely IL-6 and tumour necrosis factor-alpha (TNF-a). A possible anti-angiogenic use of Thalidomide in cancer patients is suggested because it has also been demonstrated to suppress vascular endothelial growth factor (VEGF) and essential fibroblast growth factor (bFGF).

Racialidomide is a medication that has equal proportions of left- and right-handed isomers; the (+)R enantiomer is helpful in treating morning sickness, whereas the (−)S enantiomer has teratogenic side effects. Giving a patient only one enantiomer won't stop the teratogenic impact in people since the enantiomers are interconnected in vivo.

Pharmacokinetics

• Absorption: In the gastrointestinal System, Thalidomide is absorbed gradually. With a high bioavailability of 90%, the body can effectively absorb and utilize it.
• Distribution: The medication is extensively dispersed and is significantly found in semen, which may have consequences for reproductive health. The distribution volume, which indicates how widely the medicine is distributed throughout the body, is 1.1 L/kg. A substantial amount of plasma protein binding occurs between 55% and 66%.
• Metabolism: In the liver, Thalidomide is metabolized primarily via non-enzymatic hydrolysis.
• Excretion: The renal route processes the majority of drug elimination, with urine accounting for around 92% of the drug's excretion, while less than 4% of the medication remains unaltered. The faecal route eliminates less than 2% of total excretion.

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• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Thalomid® (thalidomide)
• https://www.ncbi.nlm.nih.gov/books/NBK557706/
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