Thalidomide

Extra appendage on the foot of an infant whose mother used thalidomide. Source:NCI

Other Names

• Thalomid
• Synovir
• Contergan
• Distaval
• Kevadon
• Neurosedyn
• Pantosediv
• Sedoval K-17
• Softenon
• Talimol

Uses

Thalomide is specifically indicated for the treatment of:

• Newly diagnosed multiple myeloma
• Acute treatment of the skin manifestations of moderate to severe erythema nodosum leprosum (ENL).

How Thalidomide is Taken

Thalidomide is available in oral capsules. Available strengths are 50 mg (white and opaque), 100 mg (tan), 150 mg (tan and blue) and 200 mg (blue).

Treatment is generally started at 100-200 mg/day. The dose can be increased by 50-100 mg/day every 1-2 weeks to a target therapeutic dose of 200 mg/day by 2 weeks.

Lower starting doses may be used in elderly patients and those with other conditions.

Multiple Myeloma

Thalidomide is administered in combination with dexamethasone in 28-day treatment cycles or with melphalan and prednisone in 28- to 42-day cycles. The dose of thalidomide is 100 to 200 mg administered orally once daily with water, preferably at bedtime and at least one hour after the evening meal.

ENL

For an episode of cutaneous ENL, thalidomide dosing should be initiated at 100-300 mg/day, administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal.

In patients with a severe cutaneous ENL reaction, dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals.

How Thalidomide Works

The mechanism of action of thalidomide is not fully understood. The drug appears to have multiple actions, including the ability to inhibit the growth and survival of myeloma cells in various ways and to inhibit the growth of new blood vessels.

How the body affects thalidomide

Thalidomide is slowly absorbed with peak circulating levels are reached 2.9 to 5.7 hours.

The metabolism is unknown but the drug is excreted through the urine.

Benefits

Thalidomide is shown to be effective in treating multiple myeloma and skin manifestations of ENL. A 2007 study from India showed complete response or near complete response to treatment for multiple myeloma in 50% of patients, partial response in 17% and minimal response (SD) in 34% patients. ^[1].

Side Effects

Drowsiness is the most common side effect. Other side effects include:

• Fatigue
• Constipation
• Dizziness
• Dry skin or rash
• Low white blood cell counts
• Peripheral neuropathy (a disorder of the nerves that can result in abnormal or decreased sensation, or burning/tingling in the hands and feet).

Drowsiness and neuropathy are the most common reasons for discontinuation of the drug.

Side effects are generally dose-related and most often disappear when the dose is reduced or the drug is discontinued.

Risks

Complications

Thalidomide can cause decreased thyroid activity, leading to hypothyroidism. Thyroid function may need to be monitored during treatment and thyroid hormone replaced if activity is low.

Thalidomide may cause slowing of the heart rate (bradycardia).

When taken in combination with dexamethasone, thalidomide may cause a skin condition known as toxic epidermal necrosis. Treatment may need to be stopped if this condition occurs.

Thalidomide, especially when prescribed in combination with dexamethasone, increases the risk of deep vein thrombosis (DVT). ^[2] However, this risk may be reduced by pharmacological prophylaxis with low-molecular-weight heparin.

Interactions

Thalidomide enhances the sedative activity of:

• Barbiturates
• Alcohol
• Chlorpromazine
• Reserpine

Medications associated with peripheral neuropathy are to be used with caution in patients receiving thalidomide.

Precautions

If thalidomide is taken during pregnancy, it can cause severe birth defects or death to the unborn baby. Therefore, routine pregnancy testing is required, as well as participation in the System for Thalidomide Education and Prescribing Safety (STEPS) program. In addition, a consent form must be signed before treatment with thalidomide can begin. ^[3]

The drug is likely to cause drowsiness. Patients taking thalidomide may be warned to exercise caution when conducting potentially dangerous activities, such as driving a car.

History

The German pharmaceutical firm Chemie Grüenthal discovered thalidomide in the 1950s in the course of searching for new antibiotics. Preliminary investigations led to the observation that thalidomide had calming effects on animals and, without much in the way of safety testing, the company gave out free samples across Germany beginning in 1954. Again without the benefit of safety or effectiveness testing, the drug was marketed as an over-the-counter sedative beginning in 1957. In 1958 the drug was introduced into England by the pharmaceutical firm Distillers Company. Within a few years the drug became the best-selling sedative in Germany. At its height, it was being sold in 46 countries around the world. A well-described disaster ensued.^[4]

Mothers who took thalidomide during pregnancy, when their babies' arms and legs were beginning to form, delivered babies with a variety of limb defects. The most well-known defect, a severe shortening of the arms or legs with flipper-like hands or feet, is called phocomelia. Affected babies almost always had defects on both sides and often had both the arms and legs malformed. In especially severe cases, the babies had complete absence of limbs, a condition known as amelia. The drug also caused malformations of the eyes and ears, heart, genitals, kidneys and digestive tract. ^[5]

For a time, thalidomide was not available for any indication, but a concerted effort led to its reintroduction, with strict guidelines to prevent further cases of birth defects. Thalidomide is currently marketed in the United States by Celgene Corporation under the name Thalomid. FDA approval for use in ENL was granted on July 16, 1998 and approval for use in multiple myeloma was granted on May 26, 2006.

Research

• Thalidomide may also have benefits in conditions such as aphthous (oral) and genital ulcers, cancer cachexia (wasting), HIV/AIDS, tuberculosis and chronic graft versus host disease, and is being investigated for treatment of renal cell carcinoma, and liver and thyroid cancers. ^[6].

Clinical Trials

There are many ongoing clinical trials involving thalidomide. A list is available from ClinicalTrials.gov: thalidomide trials.

Interesting Facts

Frances Kelsey receiving an award from President John F. Kennedy in 1962. Source: FDA

• All thalidomide tablets are imprinted with a "do not get pregnant" logo.
• British actor Matt Fraser wrote and starred in Thalidomide!! A Musical which was performed in Great Britain in late 2005. The musical focuses on the history of thaliomide as well as on Fraser's experiences growing with birth defects resulting from thalidomide taken during pregnancy. ^[7]
• News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market, arouse public support for stronger drug regulation. Dr. Kelsey received the President's Award for Distinguished Federal Civilian Service, the highest honor given to a civilian in the United States. The thaldomide controversy helped reform FDA regulations, requiring that drugs be shown to be both safe and effective, that informed consent be obtained from patients when used in clinical trials, and that adverse reactions be reported to the FDA.

References

1. ↑ Sharma A, Raina V, Uppal G, Kumar R, Grover J. Long term use of thalidomide: safe and effective. Indian J Cancer. 2007 Jul-Sep;44(3):108-10. Abstract
2. ↑ Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR, Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Abstract | Full Text
3. ↑ Multiple Myeloma Research Foundation. Thalomid (thalidomide)
4. ↑ Stephens T, Brynner R. Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine. Cambridge, MA: Perseus, 2001
5. ↑ March of Dimes web site. Thalidomide
6. ↑ Joglekar S, Levin M. The promise of thalidomide: evolving indications. Drugs Today (Barc). 2004 Mar;40(3):197-204. Abstract
7. ↑ Geoff Adams-Spink. Thalidomide gets musical treatment. BBC News.Tuesday, 18 October 2005.

External Links

Multiple Myeloma Research Foundation: Thalomid (thalidomide)

Medline Plus: Thalidomide