Thalidomide (Thalomid) is a chemotherapeutic medicine used in the treatment of multiple myeloma and other plasma cell dyscrasias. In the mid 19th century, it was used to relieve nausea associated with pregnancy. However, it led to severe fetal malformations including absent limbs. Currently, it is recommended for only a few diseases because of its potent anti-angiogenic properties.

Indications of Thalidomide:

• Erythema nodosum leprosum:

  • It is used for the acute treatment of moderate to severe cutaneous manifestations of erythema nodosum leprosum.
  • It is also used for the maintenance treatment for suppression and prevention of recurrence of cutaneous manifestations of erythema nodosum leprosum.
  • Limitation of use: Thalidomide is not indicated as monotherapy for erythema nodosum leprosum treatment in the presence of moderate to severe neuritis.

• Multiple myeloma:

  • It is indicated for the treatment of newly diagnosed multiple myeloma (in combination with dexamethasone).

• Off Label Use of Thalidomide in Adults:

  • AIDS-related aphthous stomatitis;
  • refractory Chronic graft-versus-host disease;
  • Multiple myeloma, maintenance therapy;
  • Multiple myeloma, salvage therapy;
  • Systemic light chain amyloidosis;
  • refractory Uremic pruritus;
  • Waldenström macroglobulinemia

Thalidomide (Thalomid) dose in Adults

Thalidomide (Thalomid) dose in the treatment of acute cutaneous erythema nodosum leprosum:

Initial: 100 to 300 mg per oral once daily at bedtime, continue until signs and symptoms subside (usually 2 weeks), then tapering in 50 mg decrements every 2 to 4 weeks is recommended. For severe cases with moderate to severe neuritis, corticosteroids may be initiated with thalidomide (taper off and discontinue corticosteroids when neuritis improves).

• Patients weighing <50 kg:

  • It should be started at a lower end of the dosing range.

  • Severe cutaneous reaction or patients previously requiring high doses:

    • May be initiated at up to 400 mg once daily at bedtime or in divided doses.

Thalidomide (Thalomid) dose in the maintenance treatment of erythema nodosum leprosum (prevention and suppression, or with flares during tapering attempts):

•  Maintain on the minimum dosage necessary to control the reaction, tapering should be done every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.

Thalidomide (Thalomid) dose in the treatment of newly diagnosed multiple myeloma:

• 200 mg per oral once daily at bedtime (in combination with dexamethasone).

Thalidomide (Thalomid) dose in the treatment of multiple myeloma (off-label dosing or combinations):

• In combination with bortezomib and dexamethasone (off-label combination):

  • Induction therapy: 100 mg per oral once daily for the first 14 days, then 200 mg once daily for 3 (21-day) cycles or 100 mg once daily for up to 8 (21-day) cycles.

• In combination with melphalan and prednisone (off-label combination):

  • 200 to 400 mg per oral once daily or 100 mg once daily or 50 to 100 mg once daily, depending on patient tolerance.

Thalidomide (Thalomid) dose in the maintenance treatment of multiple myeloma (following autologous stem cell transplant; off-label):

• 200 mg per oral once daily starting 3 to 6 months after transplant.
• It should be continued until disease progression or unacceptable toxicity or 100 mg once daily starting 42 to 60 days following transplant.
• The dose should be increased to 200 mg once daily after 2 weeks if tolerated and continued for up to 12 months in addition to prednisolone.

Thalidomide (Thalomid) dose in the treatment of Multiple myeloma as salvage therapy:

• Initial: 200 mg per oral once daily at bedtime;
• The dose may be increased daily by 200 mg every 2 weeks for 6 weeks (if tolerated) to a maximum of 800 mg once daily at bedtime or
• 100 mg once daily (in combination with dexamethasone) or
• 200 mg once daily (in combination with bortezomib and dexamethasone) for 1 year or
• 400 mg once daily at bedtime (in combination with dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide).

Thalidomide (Thalomid) dose in the treatment of AIDS-related aphthous stomatitis (off-label):

• 200 mg per oral once daily at bedtime for up to 8 weeks, if no response, then 200 mg twice daily for 4 weeks.

Thalidomide (Thalomid) dose in the treatment of refractory chronic graft-versus-host disease (as off-label second-line treatment; optimum dose not determined):

• Initial: 100 mg per oral once daily at bedtime, with dose escalation up to 400 mg daily in 3 to 4 divided doses or
• Initial: 50 to 100 mg three times a day
• The maximum dose: 600 to 1,200 mg daily or 200 mg four times a day (dose adjusted to goal thalidomide concentration of ≥5 mcg/mL 2 hours post-dose) or 100 to 300 mg four times a day.

Thalidomide (Thalomid) dose in the treatment of systemic light-chain amyloidosis (off-label):

• 200 mg per oral once daily (starting dose 50 to 100 mg once daily;
• Titrate at 4-week intervals) in combination with cyclophosphamide and dexamethasone.

Thalidomide (Thalomid) dose in the treatment of refractory uremic pruritus (off-label):

• 100 mg per oral once daily at bedtime.
• Additional data is necessary to further define the role of thalidomide in this condition;
• several other treatment modalities with more benign safety profiles are available.

Thalidomide (Thalomid) dose in the treatment of Waldenström macroglobulinemia (off-label):

• ≤200 mg per oral once daily for up to 52 weeks (in combination with rituximab).

Thalidomide (Thalomid) dose in Childrens

Thalidomide (Thaled) dose in the treatment of AIDS-related aphthous stomatitis:

• Adolescents ≥13 years:

  • 200 mg per oral once daily at bedtime for 4 weeks or sooner if resolution.
  • The dose may be increased to 200 mg twice daily if no improvement after 4 weeks.
  • Dosing is based on a double-blind, placebo-controlled trial by AIDS Clinical Trials Group (n=57, age: ≥13 years) which showed 55% healing in the treatment group vs 7% in placebo.

Thalidomide (Thalomid) dose in the treatment of refractory chronic graft-versus-host disease:

• Children ≥2 years and Adolescents:

  • Initial: 3 to 6 mg/kg/day per oral
  • The maximum initial daily dose: 100 mg/day at bedtime or in 2 to 4 divided doses before meals;
  • The dose may be adjusted at ≥2-week intervals based on patient response up to 12 mg/kg/day in 3 to 4 divided doses (maximum daily dose: 800 mg/day).
  • One trial using initial doses of 3 mg/kg/dose every 6 hours (dose adjusted to attain goal thalidomide concentration of ≥5 mcg/mL 2 hours post-dose).

Thalidomide (Thalomid) dose in the treatment of refractory Crohn's disease and ulcerative colitis:

• Children ≥1 year and Adolescents:

  • 0.5 to 3 mg/kg/day per oral (maximum daily dose: 300 mg/day), usually dosed once daily in the evening, after remission the drug should be titrated to the lowest effective dose.

Thalidomide (Thalomid) dose in the treatment of erythema nodosum leprosum (ENL):

• Children ≥12 years and Adolescents: 

  • Acute:

    • Initial: 100 to 300 mg per oral once daily at bedtime;
    • Continue until signs and symptoms subside (usually 2 weeks), then taper off in 50 mg decrements every 2 to 4 weeks.
    • For severe cases with moderate to severe neuritis, corticosteroids may be initiated with thalidomide (taper off and discontinue corticosteroids when neuritis improves).
    • Patients weighing <50 kg: Initiate at lower end of dosage range

  • Severe cutaneous reaction or patients previously requiring high doses:

    • May be initiated or increased to 400 mg/day at bedtime or in divided doses
    • Maintenance (prevention/suppression, or with flares during tapering attempts):
    • Maintain on the minimum dosage necessary to control the reaction, tapering should be done every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.

Thalidomide (Thalomid) dose in the treatment of Systemic juvenile idiopathic arthritis (SJIA):

• Children ≥3 years and Adolescents:

  • Initial 2 mg/kg/day per oral, if necessary may increase at 2-week intervals to 3 to 5 mg/kg/day.

• Dosing adjustment for toxicity:

  • Children and Adolescents:

    • ANC ≤750/mm³:

      • Withhold treatment if clinically appropriate
    • For other observed toxicities, the following have been used in adult patients with multiple myeloma:
    • Constipation and oversedation:
      • Dose reduction or temporarily withholding therapy.
    • Peripheral neuropathy:
      • The manufacturer recommends to dose reduction or temporary discontinuation. The following adjustments have also been recommended:
      • Grade 1: Dose reduction by 50%.
      • Grade 2: Temporarily interrupt therapy; once resolved to ≤ grade 1, resume therapy with a 50% dosage reduction (if clinically appropriate)
      • Grade 3 or higher: Therapy should be withdrawn.

Pregnancy Risk Category: X

• [US Boxed Warning]
• Data from pregnant females and animal reproduction studies have shown evidence of fetal abnormalities such as amelia, phocomelia and bone defects.
• There has also been evidence of facial palsy, congenital heart defects and urinary tract malformations.
• Thalidomide should not be used during pregnancy because it can cause severe birth defects and even death of the embryos.
• Even one dose of this medication can cause birth defects. It is not recommended for pregnant women or those who plan to conceive.
• Thalidomide can only be obtained through a restricted distribution program (Thalomid REM) to reduce the risk of exposure to fetal.
• Avoid pregnancy for at least one month prior to starting therapy and during interruptions. Continued therapy should continue for at least one month after completion.
• Females who aren't infertile or have had a hysterectomy or aren't infertile must use two forms of effective/reliable contraception.
• Women of childbearing years must have a negative pregnancy test (sensitivity >=50 mg/mL) within two weeks of therapy.
• This should be done weekly for the first four weeks and then every 4 weeks thereafter (every 2 week for those with irregular menstrual periods).
• If thalidomide is used to treat missed periods, abnormal pregnancy tests, or abnormal menstrual flow, it should be discontinued immediately.
• Female caregivers and health workers must avoid contact with thalidomide capsules.
• The semen of males also contains thalidomide.
• Even those who have been vasectomized, males must use a latex condom or synthetic condom for any sexual contact with women having childbearing potential.
• This is also valid up to 28 days after the therapy has ended.
• Males who have taken thalidomide must not donate sperm.
• For patients aged 12-18 years, the legal guardian or parent must ensure compliance with these guidelines.
• To monitor the outcomes of females who have been exposed to thalidomide during pregnancy, and the female partners of male patients, a pregnancy exposure registry was established.
• This registry will help to identify the root cause.
• All suspected fetal exposures to thalidomide should be reported to FDA via MedWatch and Celgene Corporation.

Use of thalidomide during lactation

• It is unknown if breast milk secretes Thalidomide.
• The manufacturer does not recommend breastfeeding due to the risk of serious adverse reactions in breastfed babies.

Thalidomide (Thalomid) Dose adjustment in renal disease:

Patients with dialysis or renal impairment do not require dosage adjustments (per manufacturer). A study of six patients with end-stage renal disease was done. Although clearance was higher by dialysis it was not necessary to add a supplement.

• Multiple myeloma

  • Patients with normal renal function had similar toxicities and efficacy to those with 29 newly diagnosed myeloma patients suffering from renal failure (serum creatinine >=2mg/dL). They were treated with dexamethasone and thalidomide, while some also received cyclophosphamide.
  • Another study showed that patients with normal renal function had equal levels of toxicities to patients with severe kidney impairment who were dependent on dialysis with induction treatment with thalidomide or dexamethasone.
  • According to the International Myeloma Working Group, thalidomide can be safely administered to patients with kidney impairment and dialysis.
  • The IMWG recommends that you use the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), or the Modification Of Diet In Renal Disease formula (MDRD) to assess renal function estimation in multiple myeloma patient with stable serum creatinine.

Thalidomide (Thalomid) Dose adjustment in liver disease:

• There are no dosage adjustments provided in the manufacturer's labeling.
• However, thalidomide does not appear to undergo significant hepatic metabolism.

Common Side Effects of Thalidomide (Thalomid):

• Central nervous system:

  • Drowsiness
  • Headache
  • Peripheral neuropathy

Rare Side Effects of Thalidomide (Thalomid):

• Cardiovascular:

  • Facial Edema
  • Peripheral Edema

• Central Nervous System:

  • Malaise
  • Pain
  • Vertigo
  • Dizziness

• Dermatologic:

  • Pruritus
  • Fungal Dermatitis
  • Maculopapular Rash
  • Nail Disease

• Gastrointestinal:

  • Constipation
  • Nausea
  • Oral Candidiasis
  • Toothache

• Genitourinary:

  • Impotence

• Neuromuscular & Skeletal:

  • Weakness
  • Back Pain
  • Neck Pain
  • Neck Stiffness
  • Tremor

• Miscellaneous:

  • Accidental Injury

Contraindications to Thalidomide (Thalomid):

• Hypersensitivity to thalidomide and any component of the formulation
• Pregnancy

• Canadian labeling: Additional contraindications not in the US labeling

  • Hypersensitivity to pomalidomide and lenalidomide
  • Females in childbearing years who wish to conceive and male patients who cannot follow or comply to the conditions of use (refer manufacturer labeling).
  • Breastfeeding

Thalomid Precautions and Warnings

• Suppression of bone marrow

  • Thalidomide is well-known for anemia, neutropenia and leukopenia. Therapy should be stopped if the ANC is less than 750/mm3.
  • With persistent neutropenia, treatment withdrawal is necessary.
  • In the case of thrombocytopenia (including grades 3, 4 and 5), it is necessary to reduce doses or withdraw from therapy.
  • You should monitor any bleeding symptoms, including epistaxis, petechiae and GI hemorhage.
  • It is necessary to monitor the CBC regularly.

• Bradycardia

  • Bradycardia can occur if it is combined with other medications that could lower your heart rate.
  • You have the option to reduce or stop thalidomide treatment.

• CNS effects

  • Patients should not drive or operate machinery that causes dizziness, drowsiness, or somnolence.
  • These symptoms may be exacerbated by concurrent ethanol consumption, so it is important to avoid them.
  • For excessive drowsiness and somnolence, dose reductions may be required.

• Constipation

  • It is possible to experience constipation, which may require a dose reduction or withdrawal.

• Dermatologic reactions

  • There are many fatal reactions, including Stevens-Johnson Syndrome, toxic epidermal Necrolysis and drug reaction with Eosinophilia (DRESS), which can lead to severe symptoms.
  • For grade 2 or 3, therapy should be stopped if it causes severe rash, exfoliation, bullous or severe.

• Hepatotoxicity

  • A variety of conditions can lead to abnormal liver function tests, hepatitis and cholestatic jaundice.
  • Hepatotoxicity is rare and can develop in 46 days. It usually disappears once therapy has been stopped.

• Hypersensitivity

  • Hypersensitivity can include angioedema and anaphylactic reactions, as well as erythematous and macular rash. This may present with fever, hypotension, and tachycardia.

• Orthostatic hypotension

  • Orthostatic hypotension can be caused by Thalidomide so it is important to use it with caution.
  • It is important that patients sit straight for at least a few minutes before getting up from a recumbent.

• Peripheral neuropathy

  • The irreversible side effects of long-term thalidomide therapy are known as peripheral neuropathy.
  • Be careful with any other medication that could also cause peripheral neuropathy.
  • For the first three months of therapy, it is important to monitor your symptoms and signs for neuropathy. Then, you should continue to check them monthly.
  • Electrophysiological testing can detect neuropathy symptoms at baseline and every six months.
  • Patients with neuropathy should stop receiving therapy immediately.
  • It may be necessary to reduce doses or withdraw completely.
  • The neuropathy should be resolved before therapy can begin.

• Secondary malignancy

  • Patients with multiple myeloma who have not been treated previously are at higher risk of developing malignancies.
  • Prednisone and thalidomide, in combination, with melphalan and melphalan, increase the likelihood of solid tumors, acute meeloid leukemia (AML), and myelodysplastic disorder (MDS).

• Seizures

  • Patients with a history or predisposition to seizures are at greater risk.

• Thromboembolic Events: [US Boxed Warning]

  • Combining thalidomide with dexamethasone increases the risk of venous embolism (VTE), which includes deep vein thrombosis and pulmonary embolism.
  • Thromboembolism can present with dyspnoea or chest pains, as well as arm or leg swelling. It should be closely monitored.
  • One controlled study found that VTE incidence was 22.5% among patients who received thalidomide with dexamethasone in combination, as opposed to 4.9% in patients who received dexamethasone only.
  • These risk factors include stroke, MI, and myeloma patients who have received thalidomide plus thalamethasone but not prior treatment.
  • According to the American Society of Clinical Oncology,
  • VTE treatment and prophylaxis should be performed for patients who are receiving thalidomide with chemotherapy or dexamethasone. Patients who receive thalidomide together with chemotherapy or dexamethasone ( or low-molecular-weight heparin [LMWH]) are recommended for lower-risk patients. LMWH is recommended in higher-risk patients.
  • It is important to determine the type of anticoagulant prophylaxis that you need, based on the risks involved.

• Tumor lysis syndrome

  • Patients with high tumor burdens may be at higher risk of developing tumor lysis syndrome.
  • It is essential to manage hyperuricemia properly and keep it under close supervision.

• Heart Failure:

  • The American Heart Association has released a scientific statement stating that thalidomide can exacerbate myocardial dysfunction.

• Multiple myeloma

  • Pembrolizumab was given to multiple myeloma patients in combination with thalidomide analogs and dexamethasone. Two clinical trials showed an increase in mortality.
  • Treatment trial with dexamethasone, pembrolizumab and a thalidomide analogue [pomalidomide and lenalidomide] caused the death of myocarditis and SJS.
  • Multiple myeloma does not qualify for PD-1 and PD-L1 blocking antibody approval.
  • Pembrolizumab in combination with dexamethasone and thalidomide analogs is not recommended unless it was part of a clinical trial.

Thalidomide: Drug Interaction

Thalidomide: Drug Interaction

Monitoring parameters:

• CBC with platelets and differential counts
• Two weeks prior to starting therapy, pregnancy testing (sensitivity of at minimum 50 milliunits/mL is required) weekly for the first four weeks.
• Then every 4 weeks thereafter in women with regular periods or every 2 weeks for those with irregular periods.
• Periodic monitoring of liver function (especially in the case of preexisting hepatic dysfunction and concomitant use drugs that are associated with hepatotoxicity).
• Thyroid function tests (TSH at baseline, then every 2 to 3-months during thalidomide therapy.

HIV-positive patients:

• After 1 to 3 months, viral load is reassessed every 3 months.
• Neuropathy symptoms may be noticed monthly for the first three months and then more frequently during treatment.
• To detect neuropathy, it is worth monitoring the sensory nerve application potential ampltudes at baseline and every six months to determine if there are any.
• Signs and symptoms for thromboembolism include shortness of breath and chest pain, arm/leg swelling, arm/leg swelling, tumor lysis syndrome and bradycardia.
• Patients with a history seizure are subject to monitoring for possible seizure activity.
• Monitoring compliance.

How to administer Thalidomide (Thalomid)?

• You should take one dose of the medication at bedtime, at least 1 hour after your evening meal.
• You can take 400 mg daily in divided doses, at least one hour after eating. 
• Capsules must be swallowed whole with water, without cracking or opening.
• The blister pack should contain the capsules until they are consumed. 
• The powdered content of broken capsules and body fluids from patients who have received thalidomide should not be inhaled.

Dosage missed

• If missed doses are not received within 12 hours, the patient will be given a dose.
• Patients who wait more than 12 hours can receive their next dose.

Mechanism of action of Thalidomide (Thalomid):

• Thalidomide is both antiangiogenic and immunomodulatory.
• The underlying condition may influence the immunologic effects.
• It reduces the production of tumor necrosis factors-alpha in patients with erythema, while HIV patients have higher plasma levels.
• Patients with multiple myeloma may experience an increase in their natural killer cells, as well as higher levels of interleukin-2 (interferon-gamma) and thalidomide.
• Other mechanisms include angiogenesis suppression and prevention of free-radical-mediated DNA damage. Cell-mediated cytotoxicity is also increased.

Absorption:

• Slow, good

Protein binding:

• 55% to 66%

Metabolism:

• Minimal (the unchanged drug is the predominant circulating component).

Half-life elimination:

• 5.5 to 7.3 hours

Time to peak plasma concentration:

• 2 to 5 hours.

Excretion:

• Urine (92%; <4% of the dose as unchanged drug).
• feces (<2%).

International Brands of Thalidomide:

• Bescamin
• Inmunoprin
• Midothal
• Myrin
• Talidex
• Talizer
• Thado
• Thaled
• Thalix
• Thaloma
• Thalomid

Thalidomide Brand Names in Pakistan: