Midothal Capsule

Multiple Myeloma (MM): Midothal in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM).

Erythema Nodosum Leprosum (ENL): Midothal is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). It is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

Cellular activities of thalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Thalidomide possesses immunomodulatory, anti-inflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. Other anti-inflammatory and immunomodulatory properties of Thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.

Multiple Myeloma: The recommended dose of thalidomide in combination with dexamethasone is 200 mg once daily (in 28-day treatment cycles) orally with water, preferably at bedtime and at least 1 hour after the evening meal.

Erythema Nodosum Leprosum: The recommended dose of thalidomide for an episode of cutaneous ENL is 100 to 300 mg/day once daily orally with water, preferably at bedtime and at least 1 hour after the evening meal.

Dosing for patients weighing less than 50 kilograms should be initiated at the low end of the dose range.

Higher dosage range should be considered for patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction (possibly up to 400 mg/day) once daily at bedtime or in divided doses with water, at least 1 hour after meals. Concomitant use of corticosteroids should be considered in patients with moderate to severe neuritis associated with a severe ENL reaction. Steroid usage can be tapered and discontinued when the neuritis has ameliorated.

Higher dosage of Thalidomide should be continued until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks.

Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol): The use of opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants concomitantly with Midothal may cause an additive sedative effect and should be avoided.

Drugs which Cause Bradycardia: The use of drugs which slow cardiac conduction concomitantly with Midothal may cause an additive bradycardic effect and should be used with caution.

Drugs that Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John’s Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception up to one month after discontinuation of these concomitant therapies. Therefore, females requiring treatment with one or more of these drugs must use two other effective or highly effective methods of contraception while taking Midothal.

Drugs which Cause Peripheral Neuropathy: The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution.

Concomitant Therapies that may Increase the Risk of Thromboembolism: Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving Midothal with dexamethasone.

Thalidomide is contraindicated in females who are pregnant. Thalidomide can cause fetal harm when administered to a pregnant female. Thalidomide is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components.

The most frequently reported adverse reactions are fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, tremor, fever, weight loss, thrombosis/ embolism, neuropathy-motor, weight gain, dizziness, and dry skin.

Pregnancy: Based on the mechanism of action, human and animal data, thalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued.

Lactation: There is no information regarding the presence of thalidomide in human milk, the effects of thalidomide on the breastfed child, or the effects of thalidomide on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from thalidomide, women should be advised not to breastfeed during treatment with thalidomide.

Females and Males of Reproductive Potential-

Pregnancy Testing: Females of reproductive potential must have 2 negative pregnancy tests before initiating Thalidomide. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Thalidomide. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks.

Contraception: Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. Contraception must begin 4 weeks prior to initiating treatment with Thalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Thalidomide therapy.

Males: Thalidomide is present in the semen of males who take Thalidomide. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Thalidomide, during dose interruptions and for up to 28 days after discontinuing Thalidomide.

Embryo-Fetal Toxicity: Midothal is a powerful human teratogen that induces a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. When there is no satisfactory alternative treatment, females of reproductive potential may be treated with Midothal provided adequate precautions are taken to avoid pregnancy. There are no specific data available regarding the reproductive risks of cutaneous absorption or inhalation of Midothal; however, females of reproductive potential should avoid contact with Midothal Capsules. If there is contact with non-intact Midothal capsules or the powder contents, the exposed area should be washed with soap and water. If healthcare providers or other care givers are exposed to body fluids from patients receiving Midothal, the exposed area should be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to Midothal.

Blood Donation: Patients must not donate blood during treatment with Midothal and for 4 weeks following discontinuation of the drug.

Venous and Arterial Thromboembolism: The use of Midothal in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when Midothal is used in combination with standard chemotherapeutic agents including dexamethasone. Thromboprophylaxis should be considered based on an assessment of individual patients' underlying risk factors. Patients and physicians should be observant for the signs and symptoms of thromboembolism.

Thrombocytopenia: Thrombocytopenia, including Grade 3 or 4 occurrences, has been reported in association with the clinical use of Midothal. Blood counts, including platelet counts should be monitored. Dose reduction, delay, or discontinuation may be required. Patient should be monitored for signs and symptoms of bleeding including petechiae, epistaxis, and gastrointestinal bleeding, especially if concomitant medication may increase the risk of bleeding.

Drowsiness and Somnolence: Midothal frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Dose reductions may be required.

Peripheral Neuropathy: Midothal is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (>10%) and potentially severe adverse reaction of treatment with Midothal that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, peripheral neuropathy following relatively short-term use has been reported. Medications known to be associated with neuropathy should be used with caution in patients receiving Midothal.

Dizziness and Orthostatic Hypotension: Patients should also be advised that Midothal may cause dizziness and orthostatic hypotension and that, therefore, they should sit upright for a few minutes prior to standing up from a recumbent position.

Neutropenia: Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of Midothal. Treatment should not be initiated with an absolute neutrophil count (ANC) of <750/mm3. White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia, such as patients who are HIVseropositive. If ANC decreases to below 750/mm3 while on treatment, the patient’s medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding Midothal if clinically appropriate.

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use: Patients >65 years of age shows higher incidences of atrial fibrillation, constipation, fatigue, nausea, hypokalemia, deep venous thrombosis, hyperglycemia, and pulmonary embolism compared to patients <65 years of age.

Anti-Leprotic drugs, Immunosuppressant

Store below 30°C in cool and dry place. Keep away from light. Keep out of the reach of children.