Thalidomide

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to thalidomide.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Pregnancy: Based on the mechanism of action, human and animal data, thalidomide can cause embryo-fetal harm when administered to pregnant female; contraindicated during pregnancy

Lactation: There is no information regarding presence of thalidomide in human milk; effects of thalidomide on breastfed infant, or effects of thalidomide on milk production; because many drugs are excreted in human milk and because of potential for adverse reactions in breastfed infants from thalidomide advise women not to breastfeed during therapy

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Overdosages of up to 14.4 g have been reported in the literature. No fatalities have been reported and all overdosed patients recovered without sequelae. There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.

Mechanism Of Action

The mechanism of action of THALOMID is not fully understood. Cellular activities of thalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. THALOMID possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. 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 (T cell-derived cytokines associated with cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.

Pharmacokinetics

Absorption of THALOMID is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel thalidomide study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 5 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Table 5: Pharmacokinetic Parameter Values for THALOMID Mean (%CV)

Coadministration of THALOMID® (thalidomide) with a high-fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.

In human plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.

In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalidomide is not a substrate of the cytochrome P450 system. At therapeutic concentrations, thalidomide is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro. Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.

The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (< 2% of the dose). Unchanged thalidomide is not eliminated by the kidney to a notable degree (<3.5% of the dose).

There is a linear relationship between body weight and estimated thalidomide clearance. In MM patients with body weight from 47-133 kg, thalidomide clearance ranged from approximately 6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10 kg body weight increase.

Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.

While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.

Pharmacokinetic differences due to race have not been studied.

Pharmacokinetic Data In Special Populations

There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single-dose administration of THALOMID Capsules.

Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID. The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.

No pharmacokinetic data are available in subjects below the age of 18 years.

Clinical Studies

Multiple Myeloma (MM)

The efficacy and safety of THALOMID in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2). Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to THALOMID plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The THALOMID dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.

Study 2 randomized 470 newly diagnosed patients with MM to THALOMID plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the THALOMID/dexamethasone arm, a starting dose of thalidomide 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.

Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).

Table 6: Baseline Patient Demographics

Table 7: Baseline Disease Characteristics (Study 1)

Table 8: Baseline Disease Characteristics (Study 2)

In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of THALOMID plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).

Table 9: Summary of Efficacy (Study 2)

The Kaplan-Meier plot of the time to progression by treatment group is presented in Figure 1.

Figure 1: Kaplan-Meier Plot of Time to Disease Progression

KEY: Placebo/Dex=placebo/dexamethasone; Thal/Dex=THALOMID/dexamethasone

Erythema Nodosum Leprosum (ENL)

The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.

Table 10: Double-Blind, Controlled Clinical Trials of Thalidomide in Patients with ENL:
Cutaneous Response

Waters reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.

Table 11: Double-Blind, Controlled Trial of Thalidomide in Patients with ENL:
Reduction in Steroid Dosage

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.

Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.

Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.

Thalidomide can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medication at the time of conception or during pregnancy. Even one dose of thalidomide can cause major birth defects of the baby's arms and legs, bones, ears, eyes, face, and heart. Never use thalidomide if you are pregnant.

For Women: You will be required to use two reliable forms of birth control beginning 4 weeks before you start taking thalidomide and ending 4 weeks after you stop taking it. Any woman who has not had a hysterectomy or has not been in menopause for at least 24 months in a row must agree in writing to use birth control before, during, and after taking thalidomide. Even women with fertility problems are required to use birth control while taking this medication. You must also have a negative pregnancy test within 24 hours before you start thalidomide treatment. While you are taking thalidomide, you will need to have a pregnancy test weekly during the first month of treatment, and then every 4 weeks thereafter.

Stop using thalidomide and call your doctor at once if you quit using birth control, if your period is late, or if you think you might be pregnant.

For Men: You must not cause a woman to become pregnant while you are taking thalidomide because the medicine may affect your sperm and cause birth defects in the baby. You must agree in writing to always use latex condoms when having sex with a woman who is able to get pregnant, even if you have had a vasectomy. Avoid ejaculating without a condom because thalidomide can be passed in your sperm.

Not having sexual intercourse (abstinence) is the most effective method of preventing pregnancy.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Thalidomide may be found in some form under the following brand names:

• Thalomid

Thalidomide may cause serious effects, including:

• See "Thalidomide Precautions" and FDA Warning.
• Drowsiness and sleepiness. 
• Nerve damage. Nerve damage is common with thalidomide.  If the nerve damage is severe, it may not go away.  Stop taking Thalomid and call your healthcare provider right away if you have any of these early symptoms of nerve damage in your hands, legs, or feet:
  • numbness
  • tingling
  • pain
  • burning sensation
• Dizziness and decreased blood pressure when changing positions. Thalidomide may cause a decrease in your blood pressure, and you may feel dizzy when you go from a lying down or sitting position to standing up.  When changing positions, sit upright for a few minutes before standing to help prevent this.
• Decreased white blood cell count. Thalidomide can cause decreased white blood cell counts, including neutrophils.  Neutrophils are a type of white blood cell that is important in fighting bacterial infections.  Your healthcare provider should check your white blood count before and regularly while you take thalidomide.  If your neutrophils are too low you should not start thalidomide and if they are low during treatment, your dose of thalidomide may need to be changed.
• Increased HIV virus in the blood.  If you are HIV positive, your healthcare provider should check your viral load after one month and three months of treatment, then every 3 months after that.
• Slow heartbeat (bradycardia). Tell your healthcare provider if you have a slow heartbeat, fainting, dizziness or shortness of breath.
• Serious skin reactions. Serious skin reactions can happen with thalidomide and may cause death.  Call your healthcare provider right away if you have any skin reaction while taking thalidomide.
• Seizures. Tell your healthcare provider right away if you have a seizure while taking thalidomide.
• Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause a build up of potassium, phosphorus, uric acid, and low calcium levels in your blood. This can cause you to have serious kidney  problems, an abnormal heart beat and can cause death. Your healthcare provider will check your blood for these problems.
• Birth control. Certain birth control methods may pose a higher risk of serious side effects and should not be used in some women. These risks include severe decreased white blood cell count, low platelet counts, and blood clots. Use of an intrauterine device (IUD) or implantable birth control may also increase your risk of infection or bleeding during insertion, removal or during use of the device.
• Allergic reaction. Allergic reactions can happen with thalidomide and may be severe. Call your healthcare provider or get medical help right away if you have any of these symptoms of allergic reaction:
  • a red, itchy rash
  • fever
  • fast heartbeat
  • feel dizzy or faint

The most common side effects of thalidomide for treatment of multiple myeloma include:

• tiredness
• decreased calcium levels
• swelling of the hands and feet
• constipation
• numbness or tingling
• muscle weakness
• skin rash or peeling
• confusion
• decreased appetite
• nausea
• anxiety
• decreased energy or strength
• tremor
• fever
• weight loss
• muscle twitching and cramping
• weight gain
• dizziness
• dry skin

The most common side effects thalidomide for treatment of leprosy include:

• sleepiness
• rash
• headache
• dizziness
• impotence
• decreased energy or strength
• not feeling well
• pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of thalidomide. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Take thalidomide exactly as prescribed and follow all the instructions of the S.T.E.P.S. program.

• explain the S.T.E.P.S. program to you
• have you sign the Patient-Physician Agreement Form

Keep thalidomide in the blister pack until you take your daily dose.

• Swallow thalidomide capsules whole with water.
• Thalidomide is taken one time each day, at least 1 hour after your evening meal. Bedtime is the preferred time to take thalidomide.
• Do not open the thalidomide capsules or handle them any more than needed.  If you touch a broken thalidomide capsule or the medicine in the capsule, wash the area of your body with soap and water.
• If you miss a dose of thalidomide and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take 2 doses at the same time.
• If you take too much thalidomide or overdose, call your healthcare provider or poison control center right away.

Females who can become pregnant:

• will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is regular, or every 2 weeks if your menstrual cycle is irregular. If you miss your period or have unusual bleeding, you will need to have a pregnancy test and receive counseling.

• must agree to use 2 different forms of effective birth control at the same time, for at least 4 weeks before, while taking, and for at least 4 weeks after stopping thalidomide.

Males who take thalidomide, even those who have had a vasectomy, must agree to use a latex or synthetic condom during sexual contact with a pregnant female or a female who can become pregnant.

• Females: Do not get pregnant and do not breastfeed while taking thalidomide.
• Males: Do not donate sperm. 
• Do not share thalidomide with other people. It may cause birth defects and other serious problems.
• Do not donate blood while you take thalidomide, and for 4 weeks after stopping thalidomide. If someone who is pregnant gets your donated blood, her baby may be exposed to thalidomide and may be born with birth defects.
• Thalidomide can cause dizziness and drowsiness.  Avoid drinking alcohol, operating machinery, and driving a car when taking thalidomide. Avoid taking other medicines that may cause drowsiness without talking to your healthcare provider first.

• Store thalidomide at 77°F (25°C).
• Protect from light.
• Keep thalidomide and all medicines out of the reach of children.

WARNING: FETAL RISK AND VENOUS THROMBOEMBOLIC EVENTS

FETAL RISK

If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn baby. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects.

Because of this toxicity and in an effort to make the chance of fetal exposure to Thalidomide as negligible as possible, Thalidomide is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called the “System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®)”.

You can get the information about Thalidomide and the S.T.E.P.S.® program on the Internet at www.thalomid.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

VENOUS THROMBOEMBOLIC EVENTS

The use of Thalidomide in multiple myeloma results in an increased risk of venous thromboembolic events, such as deep venous thrombosis and pulmonary embolism.  This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolic events was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Erythema Nodosum Leprosum

Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) reactions (lepra type 2 reactions);1 9 10 13 34 35 39 44 76 86 89 111 113 114 218 220 232 233 234 235 237 238 (designated an orphan drug by FDA for this use).28

Suggested by some clinicians as drug of choice for treatment of moderate to severe ENL reactions, especially severe, recurrent reactions.10 86 89 111

Maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence.1 9 10

Designated an orphan drug by FDA for treatment and maintenance of reactional lepromatous leprosy.28

Used in conjunction with corticosteroid therapy for acute treatment of ENL reactions complicated by moderate to severe neuritis.9 Should not be used as monotherapy in such patients.1 9 53 54

Undertake therapy for leprosy in consultation with an expert.10 74

Multiple Myeloma

Induction therapy (in combination with dexamethasone) in patients with newly diagnosed multiple myeloma1 9 100 161 162 163 198 199 200 201 242 (designated an orphan drug by FDA for this use).28

Combination therapy with dexamethasone more effective than dexamethasone monotherapy in achieving partial response (decreased concentrations of monoclonal immunoglobulins [e.g., myeloma or Bence-Jones proteins] in serum or urine) in patients with newly diagnosed multiple myeloma.1 242 243 Effect of combination therapy on survival in such patients not established.1

Other Neoplastic Diseases

Has also been used for treatment of melanoma†,9 175 232 237 ovarian cancer†,9 myelodysplastic syndrome (MDS)†,229 advanced pancreatic cancer†,229 primary brain tumors† (designated an orphan drug by FDA for this use),9 28 29 169 174 175 229 androgen-independent prostate cancer†,9 168 and renal carcinoma†.9 175

Inflammatory and/or Dermatologic Disorders

Has been used for treatment of a variety of severe, refractory (e.g., unresponsive to other appropriate agents [e.g., corticosteroids]),9 93 156 186 inflammatory and/or dermatologic disorders (e.g., erosive lichen planus†,9 104 127 215 219 232 erythema multiforme†,181 182 215 218 219 232 237 lupus erythematosus†,3 4 9 53 59 104 110 121 122 123 124 196 215 218 219 220 229 237 prurigo nodularis†,9 59 60 94 104 117 118 215 219 229 232 actinic prurigo†,104 119 cutaneous Langerhans cell histiocytosis†,4 104 183 184 232 uremic pruritus†,104 180 215 237 237 porphyria cutanea tarda†,195 215 and pyoderma gangrenosum†).4 5 9 53 104 125 126 219 232 237

Has been used to treat dermatologic, mucocutaneous, and arthritic manifestations of Behcet’s syndrome†.9 49 77 93 104 125 126 128 129 130 131 132 133 134 135 136 137 215 218 219 232 237

HIV-associated Aphthous Ulcers

Has been used for treatment of HIV-associated aphthous ulcers†.9 48 112 142 143 144 146 147 221 223 237 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)

May be effective in patients with recurrent ulcers refractory to other therapies (e.g., corticosteroids).55 142 143 144 147 221 Recommended as alternative therapy; not a drug of first choice.55 102 186

HIV-associated Wasting Syndrome

Has been used for treatment of HIV-associated wasting syndrome†9 11 41 48 50 112 140 141 224 (designated an orphan drug by FDA for this use).28 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)

HIV-associated Diarrhea

Has been used for treatment of HIV-associated diarrhea†.9 56 112 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)

AIDS-related Kaposi’s Sarcoma

Has been used for treatment of AIDS-related Kaposi’s sarcoma†9 30 48 115 170 227 (designated an orphan drug by FDA for this use).28 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)

Mycobacterium Infections

Has been used as an adjunct to anti-infective agents in treatment of mycobacterial infections†, including Mycobacterium tuberculosis† and M. avium complex† (MAC) infections, in HIV-infected patients.40 42 53 However, increases in HIV viral load reported.1 12 53 54 (See Effects on HIV Viral Load under Cautions.)

Graft-versus-host Disease

Has been used for treatment of graft-versus-host disease† (GVHD) in bone marrow transplant recipients (designated an orphan drug by FDA for this use).28 75 101 109 151 152 153 155 218 219 232 237

Should not be used for prophylaxis of chronic GVHD.153 189

Also has been used with some success in the treatment of GVHD† in adult peripheral blood stem cell transplant recipients.236 239

Recurrent Aphthous Stomatitis

Has been used for treatment of severe aphthous oral ulcers†.9 138 139 148 149

Crohn’s Disease

Has been used for treatment of refractory Crohn’s disease† (designated an orphan drug by FDA for this use).4 28 53 133 136 157 158 159 202 206

Rheumatic Diseases

Has been used for treatment of refractory ankylosing spondylitis†98 and refractory rheumatoid arthritis†.3 4 53 112 178 179

Sarcoidosis

Has been used for treatment of sarcoidosis†.4 99 237

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For thalidomide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to thalidomide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of thalidomide in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of thalidomide in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking thalidomide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using thalidomide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Dexamethasone
• Docetaxel

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of thalidomide. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clots or
• Bradycardia (slow heartbeat) or
• HIV infection or
• Neutropenia (low white blood cells) or
• Peripheral neuropathy (nerve problem) or
• Seizures, history of or
• Thrombocytopenia (low platelets in the blood)—Use with caution. May make these conditions worse.

• Deep vein thrombosis (blood clot in leg), history of or
• Heart attack, history of or
• Pulmonary embolism (blood clot in lung), history of or
• Stroke, history of—Use with caution. May cause side effects to become worse.

Take thalidomide exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

The Thalomid® product is only available under a restricted distribution program. You will have to read and sign papers that explain how the medicine is used when you pick up your prescription.

The medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

Take thalidomide with water, preferably at bedtime, and at least 1 hour after the evening meal.

Do not open the blister pack with the capsule until you are ready to take it. If you touch a broken capsule or the medicine in the capsule, wash your skin with soap and water right away.

Dosing

The dose of thalidomide will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of thalidomide. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For erythema nodosum leprosum:
    • Adults and children 12 years and older—At first, 100 to 300 milligrams (mg) once a day. Your doctor may adjust your dose as needed.
    • Children younger than 12 years—Use and dose must be determined by your doctor.
  • For multiple myeloma:
    • Adults and children 12 years and older—200 milligrams (mg) once a day together with dexamethasone. The dose is repeated every 28 days.
    • Children younger than 12 years—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of thalidomide, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose and it has been more than 12 hours since your scheduled dose, skip the missed dose and take your next dose at the regular time.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Return unused capsules to your doctor or pharmacist.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about thalidomide, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about thalidomide. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using thalidomide.

Review Date: October 4, 2017

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Thalomid: 50 mg, 100 mg

Thalomid: 150 mg, 200 mg [contains fd&c blue #2 (indigotine)]

Erythema nodosum leprosum: Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum; maintenance treatment for prevention and suppression of cutaneous manifestations of erythema nodosum leprosum recurrence

Limitation of use: Thalidomide is not indicated as monotherapy for erythema nodosum leprosum treatment in the presence of moderate to severe neuritis.

Multiple myeloma: Treatment of newly diagnosed multiple myeloma (in combination with dexamethasone)

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Thalidomide. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Contraceptives (Estrogens): May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Contraceptives (Progestins): May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May enhance the dermatologic adverse effect of Thalidomide. Dexamethasone (Systemic) may enhance the thrombogenic effect of Thalidomide. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erythropoiesis-Stimulating Agents: May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Estrogen Derivatives: May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Pamidronate: Thalidomide may enhance the nephrotoxic effect of Pamidronate. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Zoledronic Acid: Thalidomide may enhance the adverse/toxic effect of Zoledronic Acid. Monitor therapy

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, headache, lack of appetite, nausea, edema, dry skin, fatigue, anxiety, tremors, weight gain or loss, or sexual dysfunction. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), burning or numbness feeling, seizures, dizziness, passing out, tachycardia, bradycardia, loss of strength and energy, signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; severe nausea; or vomiting), or signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

This drug 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. Animals studies revealed no effects in mating and fertility indices in males or females; however, testicular degeneration occurred in males. In the US, any suspected fetal exposure to this drug should be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and to Celgene Corporation at 1-888-423-5436. Consult the manufacturer product information for details about the Thalidomide Celgene Pregnancy Prevention Programme (UK) and the i-access(R) risk management program (AU). AU TGA pregnancy category X: Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

Comments: -Instruct patients to immediately discontinue this drug if pregnancy occurs or if pregnancy is suspected during treatment, if a menstrual period is missed, or if unusual menstrual bleeding is experienced; refer them to a physician experienced in reproductive toxicity/teratology for evaluation and consultation. -Counsel patients monthly about the risks associated with this drug, and provide appropriate information to patients' sexual partners. -Advise patients not to donate blood during treatment and for 1 to 4 weeks after treatment completion to prevent their blood from being given to a pregnant female. FEMALES OF REPRODUCTIVE POTENTIAL: -In some cases, this drug is contraindicated in this patient population; consult the manufacturer product information. -Perform pregnancy tests prior to and during treatment, and after treatment discontinuation; consult the manufacturer product information for specific pregnancy testing requirements and timelines. -Instruct these patients (even if they have amenorrhea) to avoid pregnancy through continuous abstinence from heterosexual sexual intercourse or by using 1 to 2 forms of effective contraception 4 weeks before initiating therapy, during therapy, during dose interruptions, and for 4 weeks after completing therapy. -Educate these patients on suitable methods of effective contraception, and advise against the use of hormonal contraceptives (due to the increased thromboembolism risk), and intrauterine devices (IUDs)/implantable contraception (due to the increased risk for infection and bleeding at the time of insertion/use/removal as some patients may develop sudden, severe neutropenia and/or thrombocytopenia during treatment). MALES: -Due to the presence of this drug in semen, instruct these patients (even if they have undergone a successful vasectomy) not to donate any sperm and to always use a latex or synthetic/polyurethane condom during treatment, during dose interruptions, and for 1 to 4 weeks after treatment discontinuation if they engage in any sexual contact with pregnant women or females of reproductive potential