Thalidomide {Thalomid] compiled by doctordee | Search LMS site |

Historical Perspective Restricted Distribution General Considerations Descriptive Information Prescribing Information Additional Information Clinical Trial Results
Historical Perspective
Thalidomide, The Story So Far... In the late 1950s, in several countries worldwide, thalidomide was marketed as a sedative, useful alone or in combination with other drugs for treating conditions like asthma, high blood pressure, migraine, and morning sickness of pregnancy. Thalidomide had a prompt onset of sedation without hangover, and a safe overdose profile. It was a good alternative to barbiturates [these were pre-Valium days], and it was promoted as a nontoxic drug without adverse effects, and safe to take for pregnant women. Thalidomide did not receive FDA approval at that time principally because of reports from Europe of possibly irreversible peripheral neuropathy as well as the possibility of potential adverse effects on fetuses. Then, use of thalidomide was linked to an epidemic appearing in 46 countries -- severe and often fatal fetal and neonatal malformations (most frequently phocomelia). At that time, 17 babies were born in the US with thalidomide-associated phocomelia. Their mothers had received the drug from overseas sources or as marketing samples. Thalidomide was withdrawn from the world market in 1961. After a few years, reports surfaced that leprosy patients with inflammatory lesions had experienced improvement in these lesions while using thalidomide as a sedative. This led to the discovery of thalidomide's anti-inflammatory and immunomodulatory properties. Studies evaluating thalidomide in various autoimmune and inflammatory conditions led to discovery of thalidomide's antiangiogenesis effects. The use of thalidomide is currently being evaluated in a variety of neoplastic diseases. Because thalidomide is a weak antiangiogenesis agent, derivatives of it have been made which will hopefully be stronger antiangiogenesis agents.
Restricted Distribution
[from www.medscape.com] "Because thalidomide is a known human teratogen and can cause severe, life-threatening birth defects or fetal death if given during pregnancy, the drug was approved by the FDA for marketing in the US in 1998 only under a special restricted distribution program, the System for Thalidomide Education and Prescribing Safety (STEPS), designed to help ensure the safe and effective prescribing, dispensing, and use of commercially available thalidomide." "In the US, the STEPS distribution program restricts access to commercially available thalidomide to prescribing clinicians, pharmacies, and patients who are registered in the program and mandates compliance with registration, education, and safety requirements of the program." "The STEPS program minimizes, but may not completely eliminate, the risk that thalidomide may inadvertently be given to a pregnant woman. Thalidomide also is available in the US for use in clinical trials under protocol conditions. The risks versus benefits of thalidomide must be addressed each time use of the drug is being considered." To receive commercially available thalidomide, a patient must be registered in the STEPS program and agree to comply with all requirements of the program, including mandatory contraceptive measures, and extensive and comprehensive educational counseling, and ongoing monitoring, including regular pregnancy tests if female and of childbearing potential, as outlined in the STEPS informed consent. Compliance is monitored through patient surveys that must be completed by doctors and patients when each prescription of thalidomide is written. A quality assurance committee composed of Celgene employees, agents, and consultants also monitors the STEPS program. In addition, all aspects of the STEPS program are subject to FDA audits. The FDA states that if there is even one fetal exposure to thalidomide, the entire distribution system will be reevaluated, and steps taken to correct deficiencies. The STEPS program is not designed to restrict prescribing and dispensing of commercially available thalidomide to only the FDA-labeled use of the drug. It is designed to try to keep the environment and water supply free of thalidomide, however. You MUST return any unused thalidomide to your doctor.
General Considerations
From M about her use of thalidomide: I took thalidomide 18 months for GIST, 1 gram per day. I received 4 months of stable disease, which occurred between month 2 and month 6 of the treatment. Evidently, thalidomide requires a few weeks before its effect "kicks in." I continued with thalidomide though my tumors resumed growth. I have a general impression that they grew at a slower rate than they had at other times. Side effects were easy to tolerate, and included somnolence, fatigue, constipation, gradual hair loss, ...and later and serious--peripheral neuropathy [nerve damage in my feet.] 1 gram per day is a fairly high dose. It's addictive. I liked taking it. I know of one other individual with a GI tumor, who claimed some level of stable disease with thalidomide. I also remember two other individuals, one with a uterine primary and the other kidney primary, for whom thalidomide was not effective. M Thalidomide is used in the treatment of: Various symptoms of leprosy, TB, and other mycobacterial infections HIV wasting syndrome and other HIV conditions Recurrent aphthous stomatitis of the terminally immunocompromised Prevention and treatment of graft-versus-host disease [bone transplant pts] Crohn's disease Behcet's Syndrome A variety of inflammatory and skin disorders In cachectic patients with advanced cancer, thalidomide may provide benefits in terms of improvement in symptoms of insomnia, nausea, and poor appetite, and an increase in feelings of well being. Many of these have an outraged and overactive immune system as a common factor. Thalidomide evidently moderates the immune reactions in these conditions, and this has been called an "immunomodulatory" property. Thalidomide is also being used for treatment of primary brain tumors, multiple myeloma, and various other malignancies. It is thought that antiangiogenesis properties of thalidomide play a role here. That thalidomide can cross the blood brain barrier to have an effect on some primary brain tumors is also quite useful. Thalidomide in the Treatment of Neoplastic Diseases Thalidomide is being evaluated for the treatment of a variety of cancers, and is also being prescribed off-label for many others, as a single agent disease stabilizer. There are also ongoing trials with thalidomide as one in a combination of chemotherapy agents. There have been trial results published on thalidomide's efficacy in Kaposi's sarcoma, melanoma, multiple myeloma, ovarian cancer, primary brain tumors (recurrent high-grade astrocytomas and mixed gliomas), androgen-independent prostate cancer, various advanced solid tumor malignancies, and renal carcinoma. Further studies are necessary to establish safety, efficacy, and optimal dosages and combinations.
Descriptive Information
Chemistry Thalidomide is a synthetic glutamic acid derivative. The drug is structurally similar to glutethimide, and that similarity may be responsible for its sedative and hypnotic effects. Thalidomide occurs as a white to off-white, nearly odorless, crystalline powder. Commercially available thalidomide capsules should be stored at 15--30 C and protected from light. In vitro in whole blood, serum, or plasma, thalidomide undergoes spontaneous hydrolysis. The rate of hydrolysis of thalidomide increases with pH over the range of 7--7.5. Actions Thalidomide is an immunomodulatory agent with anti-inflammatory activity. The drug also has anti-angiogenic effects and sedative and hypnotic effects. Immunomodulatory Effects The mechanism(s) of action of the immunomodulatory and anti-inflammatory effects of thalidomide are complex and have not been fully determined. It is suggested that there are some interactions with tumor necrosis factor alpha (TNF-alpha) levels, T-cells, interleukin-2, interferon-Gamma, and/or leukocyte migration and chemotaxis. medscape The immunomodulatory and anti-inflammatory effects of thalidomide differ from those of other immunosuppressive agents, including corticosteroids, cyclosporin, macrolide immunosuppressants, pentoxifylline, immunosuppressive purine analogs and purine metabolism inhibitors, and also differ from those of nonsteroidal anti-inflammatory agents. Thalidomide does not appear to interfere with important host germ fighting mechanisms; and has no direct antibacterial activity in those bacterial diseases where it is effective. Effects on Angiogenesis Thalidomide inhibits angiogenesis, and it has been suggested that the prevention of growth on fetal limbs may be related to inhibition of blood vessel growth. Thalidomide's anti-angiogenic effects have been demonstrated in several animal angiogenesis models; however, there is evidence that the drug's antiangiogenic effects may be species specific and possibly may be related to a species-specific metabolite and/or metabolic activation. The mechanism of thalidomide's antiangiogenic effects is unknown. Sedative and Hypnotic Effects Thalidomide has CNS depressant effects and causes sedation. The drug has a prompt sedative effect, and does not cause a hangover. The glutarimide ring contained in thalidomide appears to be responsible for the sedative and hypnotic effects of the drug; the ring is structurally similar to ring moieties contained in some other sedative and hypnotic drugs. Thalidomide may activate a sleep center in the forebrain, a mechanism of action unlike that of barbiturates. Thalidomide has little acute CNS toxicity, and does not cause incoordination or respiratory depression even at large doses. While thalidomide initially was investigated for use as a sedative and hypnotic in the late 1950s, the drug is no longer promoted for use as a sedative and hypnotic because of the risk to developing fetuses. One does not want this drug to seep into the general water supply. Medscape Information
Prescribing Information
Total body clearance of thalidomide is about 170-200 ml/min, but the unmetabolized drug is only cleared at a rate of 1 to1.5 ml/min by kidneys, and less than 1% of the drug is excreted unchanged in the urine. So probably thalidomide is hydrolyzed and metabolized to other substances. It is not known what the exact route of elimination is. Store at room temperature between 59 and 86 degrees F (15-30 degrees C) away from sunlight and moisture. NOT in the bathroom. In the container it came in, tightly closed. Do not share this medicine with others. Keep this medicine away from children. Talk to your pharmacist about the proper disposal of your medication. DO NOT FLUSH IT OR THROW IT IN THE TRASH. Administration Thalidomide is taken by mouth, either at bedtime or at least an hour after the evening meal, because fatty meals delay its absorption. If taken in divided doses, it can be given with water at least one hour after meals. Dosage Is usually between 100 and 400 mg daily, but will be individualized for you by your doctor. If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to catch up. In case of overdose, call your local poison control center at 1-800-222-1212. If the victim has collapsed or is not breathing, call local emergency services at 911. Overdosage of thalidomide may cause prolonged sleep as a result of the drug's sedative and hypnotic effects, but since the drug does not cause respiratory depression, fatalities are unlikely. Three cases of deliberate ingestion of up to 14 g of thalidomide resulted in recovery without reported sequelae. Precautions While Using Thalidomide: Thalidomide may only be used within the S.T.E.P.S. Program (System for Thalidomide Education and Prescribing Safety) guidelines, in order to avoid any possible fetal exposure to the drug. For women of childbearing age: If you are able to bear children, you must have a pregnancy test within 24 hours before starting thalidomide treatment, once a week during the first month of treatment, and every 2 to 4 weeks after that. Also, you must have effective contraception, or else refrain from sexual activity, for one month prior to thalidomide therapy, during the therapy, and for one month after therapy stops. For men taking thalidomide: If you have heterosexual sexual contact with women of childbearing potential you must always use a condom during sexual contact while taking thalidomide and for 4 weeks after you stop taking it, even if you have had a vasectomy. If you have a missed period or abnormal vaginal bleeding, tell your doctor immediately. Thalidomide must not be used during pregnancy. If you think you might be pregnant inform your doctor immediately. Even ONE dose of thalidomide taken during a pregnancy can cause severe birth defects. If pregnancy does occur during treatment, this drug must be discontinued immediately. Before Using This Medicine: Allergies-Tell your doctor if you have ever had any unusual or allergic reaction to thalidomide or to any other substances, including foods, preservatives, dyes. Pregnancy-Thalidomide must not be used by pregnant women Breast-feeding-It is not known if thalidomide passes into breast milk. It is probably NOT a good idea to breastfeed while on this treatment. Older adults- Thalidomide has been tested on some patients up to 90 years of age and there do not seem to be any different side effects or other problems in older as compared to younger adults. Other medical problems-- Make sure you tell your doctor if you have any other medical problems, especially: Decreased white blood cell counts or Epilepsy or risk of seizures or Peripheral neuropathy. Thalidomide may make these conditions worse. Tell your doctor every medicine you are taking, including herbals, vitamins, and other supplements. Drug Interactions with Oral Contraceptives Thalidomide doesn't interact with the contraceptive hormones, so is unlikely to interfere with them. However, OTHER drugs can affect the reliability of oral contraceptives. SOME of the drugs that interact with oral contraceptives: HIV protease inhibitors Griseofulvin Rifampicin Rifabutin Tetracycline Other Antibiotics Phenytoin Carbamazepine Other anticonvulsants Check ALL the medications you are taking from a contraceptive standpoint as well. Discuss with your doctor. If you are a woman who is capable of getting pregnant, it is mandatory that you use effective contraceptive measures for at least 1 month prior to, throughout, and for at least 1 month after completion of thalidomide therapy. Women of childbearing potential receiving thalidomide at the same time with another drug that can reduce the reliability of oral contraceptives must use 2 other effective methods of contraception or abstain from heterosexual intercourse. CNS Agents Thalidomide has sedative properties. It will add to the effects of alcohol and other CNS depressants (medicines that may make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Caution is advised when performing tasks requiring alertness. Dependence or Addiction: Physical and/or psychological dependence have NOT been reported in individuals receiving thalidomide. However, the manufacturer states that like other anxiolytic, sedative, and hypnotic drugs, it is possible that habituation to the sedative and hypnotic effects of thalidomide could occur. Check with your doctor before taking any of these while you are using thalidomide: alcohol Some allergy or hay fever medicines anesthetics antihistamines barbiturates chlorpromazine cold and flu remedies muscle relaxants reserpine sleeping medicines tranquilizers Tricyclic antidepressants [amitriptyline & others[ Drugs Associated with Peripheral Neuropathy The central nervous system is the brain and spinal cord. All the nerves outside the central nervous system are peripheral nerves. Neuropathy means that nerves are being damaged. Peripheral neuropathy can start with tingling, burning, numbness, or pain, often in hands or feet, which can progress to inability to use the extremities well. Peripheral neuropathies can be temporary or permanent. If you get symptoms of peripheral neuropathy, tell your doctor promptly. Ongoing use of thalidomide may result in severe peripheral neuropathy, which can be irreversible. To ensure early detection of neuropathy, patients should be examined regularly. (Probably monthly for the first 3 months of thalidomide therapy, and periodically thereafter). Consideration should be given to using electrophysiologic testing [sensory nerve action potential (SNAP) amplitude measurement] at baseline and every 6 months thereafter. Because of the potential for additive effects, drugs known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. These drugs include: Some antiretroviral agents used for treating HIV infections Some chemotherapy agents [for example, paclitaxel; platinum-containing drugs such as cisplatin; vinca alkaloids such as vincristine]) Chloramphenicol Dapsone (Avlosulfon) Ethambutol (Myambutol) Ethionamide (Trecator-SC) Hydralazine (Apresoline) Isoniazid (Nydrazid) Lithium (Eskalith, Lithobid) Metronidazole (Flagyl) Nitrofurantoin (Furadantin, Macrodantin) Nitrous oxide Phenytoin (Dilantin) Side Effects The "A" group. If these occur, check with your doctor immediately: Allergic reaction -- seek immediate medical attention. Symptoms include rash, itching, swelling, dizziness or trouble breathing.. Peripheral neuropathy: tingling, burning, numbness, or pain in the hands, arms, feet or legs. Call your doctor right away. Continuing use of thalidomide may result in severe peripheral neuropathy, possibly irreversible. Regular examinations will pick it up earlier. Muscle weakness: whether associated with tingling or not. Urine: blood or decreased urination Fever: alone or with chills and sore throat Heart: irregular heartbeat Low Blood Pressure Skin: rash or blistering or itching or peeling and loosening of skin Mouth: sores, ulcers, or white spots Eyes: red or irritated Convulsions, or Faints, or Muscular jerking of arms and legs. In addition to these problems, thalidomide can cause low white cell counts. Thalidomide has been associated with thyroid problems. Thalidomide has also been associated with too high or too low blood sugar levels. The "B" Group. Other side effects that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. If they continue or are bothersome, however, check with your doctor. If you notice any effects not listed, check with your doctor. Gastrointestinal: Constipation, diarrhea, nausea, stomach pain Dizziness or drowsiness: Caution is advised when performing tasks requiring alertness. Thalidomide may cause dizziness and decreases in blood pressure that could result in falls. After lying down, you should sit upright for a few minutes before standing up. Sun Sensitivity: Avoid unnecessary or prolonged exposure to sunlight and sun lamps and wear protective clothing, sunglasses, and sunscreen. Thalidomide may make your skin sensitive to sunlight. DO NOT DONATE: You should not give blood or donate sperm during treatment with thalidomide. Dry mouth Dry skin Mood changes Increased appetite Swelling of legs Dependence or Addiction: Physical and/or psychological dependence have not been reported in individuals receiving thalidomide. However, the manufacturer states that like other anxiolytic, sedative, and hypnotic drugs, it is possible that habituation to the sedative and hypnotic effects of thalidomide could occur.
Additional Information
Thalidomide itself is already showing promise, in combination with chemotherapy, for treating some forms of cancer. Since it is not the Thalidomide molecule itself that is doing this, but metabolites of thalidomide, new drugs were created similar to the supposed active metabolites. New drugs based on Thalidomide are showing great promise as potent anti-cancer medications. The researchers looked at two different versions of the drug called IMiDs and SelCIDs and found that they were at least 10 times as potent as Thalidomide in preventing the growth of blood vessels. The research, carried out at St George's Hospital Medical School in London by Dr Keith Dredge also shows that these drugs can stimulate the immune system, enhancing the body's natural anti-cancer defenses or help reduce cancer-causing inflammation. Two forms of ImiD are already being used in early clinical trials for treating advanced cancer, one at St George's and another at Guy's Hospital, also in London. [British Journal of Cancer, 2002] Another doctor wrote in to say: Thalidomide is a very complex drug. While it does act as an angiogenesis inhibitor, in many settings Thalidomide has molecular and clinical effects on the immune, nervous and cutaneous systems and pathways we are not even near understanding. In my experience with Thalidomide mainly in renal cell cancer it can produce major shrinkage of tumors in as many as 10% of patients with perhaps another 30-40% having stabilization of disease for a variable period of time, sometimes for a long time. Those who do not respond may grow rapidly or slowly but whether Thalidomide contributes to growth rate in any way is unclear. The major problem with Thalidomide is its side effect profile especially peripheral neuropathy and central nervous effects like visual hallucinations, extreme sleepiness and mood disturbance. I have treated one patient with Adrenocortical Carcinoma with Thalidomide. She responded well initially and then was stable for many months before we stopped therapy because of side effects. She has intermittently taken Thalidomide for intervals of about 3 months since then, starting when here disease appears to be growing on chest Xray. Many groups are working on thalidomide analogues as potential new drugs as well as other antiangiogenic agents. BJC article ASCO abstract Thalidomide shows promise in treating myelodysplastic syndrome
Clinical Trial Results
The Clinical Trials results are the experiments done in the past to see if the drug works, and how well, and for how long. PubMed Searches Directions for use: When you click on the search link, it will connect you to Pubmed and display the first 20 citations [which they will call Summaries]. What you WANT is the complete listing of all the summaries [which they will call Abstracts.] Go to the second toolbar, and use the drop down menu to change summaries to Abstracts, and 20 to 200, and sort by DATE, and then click on DISPLAY on that same toolbar. You may have to wait while the page loads. NOW you can save this search to a folder on your hard drive as "Thalidomide Clinical Trials" as an HTML file - or as a text file. The entire file, or just those parts which you wish to discuss, can be printed out and taken to talk over with your doctor. Search Pubmed for thalidomide clinical trials and cancer Search Pubmed for thalidomide and cancer ASCO Searches You will have to go to the site and search for thalidomide. ASCO abstracts search page compiled by doctordee March 2003

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