thalidomide
Generic Name: thalidomide
(tha LID oh mide)
Brand Name: Thalomid
Pronunciation
(tha LI
doe mide)
Dosage Forms
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)]
Brand Names:U.S.
Thalomid
Pharmacologic Category
Angiogenesis InhibitorAntineoplastic AgentImmunomodulator, Systemic
Pharmacology
Thalidomide
exhibits immunomodulatory and antiangiogenic characteristics; immunologic
effects may vary based on conditions. Thalidomide may suppress excessive tumor
necrosis factor-alpha production in patients with erythema nodosum leprosum,
yet may increase plasma tumor necrosis factor-alpha levels in HIV-positive
patients. In multiple myeloma, thalidomide is associated with an increase in
natural killer cells and increased levels of interleukin-2 and interferon
gamma. Other proposed mechanisms of action include suppression of angiogenesis,
prevention of free-radical-mediated DNA damage, increased cell mediated
cytotoxic effects, and altered expression of cellular adhesion molecules.
Absorption
Slow,
good
Distribution
Vd:
1.1 L/kg
Metabolism
Minimal
(unchanged drug is the predominant circulating component)
Excretion
Urine (~92%;
<4% of the dose as unchanged drug); feces (<2%)
Time to Peak
Plasma:
~2 to 5 hours
Half-Life Elimination
5.5 to
7.3 hours
Protein Binding
55% to
66%
Special Populations Note
Hansen disease:
Based on data
from a small study, in relation to healthy subjects, patients with Hansen
disease may have increased thalidomide bioavailability, manifested as increased
area under the curve and peak plasma levels.
Use: Labeled Indications
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)
Off Label Uses
AIDS-related aphthous stomatitis
Data from a
double-blind, randomized, placebo-controlled trial in HIV-infected patients
with oral aphthous ulcers supports the use of thalidomide for this
condition [Jacobson 1997].
Chronic graft-versus-host disease,
refractory (adults)
Data from two
trials evaluating the use of thalidomide for the treatment of patients with
high-risk or refractory chronic graft-versus-host disease (GVHD) suggests that
thalidomide may be beneficial for the treatment of this condition [Parker 1995], [Vogelsang 1992]. Data from a prospective trial
evaluating patients with refractory acute or chronic GVHD supports the use of
thalidomide in the treatment of chronic GVHD; no activity was seen in patients
with acute GVHD [Kulkarni 2003]. Additional data may be necessary to further
define the role of thalidomide in this condition.
Based on the American
Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on
Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic
Graft-versus-Host Disease, thalidomide is an effective and
suitable second-line treatment for this condition.
Chronic graft-versus-host disease, refractory
(children)
Data from
a preliminary trial evaluating the use of thalidomide for the treatment of
patients with high-risk chronic graft-versus-host disease (GVHD) suggests that
thalidomide may be beneficial for the treatment of this condition [Vogelsang
1992]. Data from a limited number of pediatric patients with high-risk
and/or refractory chronic GVHD also suggest that thalidomide may be beneficial
for the treatment of this condition [Rovelli 1998]. Additional
data may be necessary to further define the role of thalidomide in this
condition.
Multiple myeloma, maintenance
Data from
a large randomized phase III trial and a retrospective analysis support the use
of thalidomide for maintenance therapy after autologous stem cell
transplantation [Brinker 2006], [Spencer 2009].
Multiple myeloma, salvage
Multiple
clinical studies have supported the use of thalidomide (alone or in combination
with dexamethasone or other cytotoxic chemotherapy) in the treatment of
relapsed/refractory multiple myeloma [Garderet 2012], [Lee
2003], [Palumbo 2001], [Singhal 1999].
Systemic light chain amyloidosis
Data from
a trial evaluating the use thalidomide in patients with advanced systemic light
chain amyloidosis suggests that thalidomide may be beneficial for the treatment
of this condition [Wechalekar 2007]. Additional data may be
necessary to further define the role of thalidomide in this condition.
Uremic pruritus, refractory
Data
regarding thalidomide, a recognized teratogen, in the treatment of pruritus are
limited. Despite apparent benefits observed in a small number of patients,
several other treatment modalities with more benign safety profiles are
available. Additional data may be necessary to further define the role of
thalidomide in this condition.
The
European Dermatology Forum andEuropeanAcademyof Dermatology
and Venereology guidelines on the management of chronic pruritus state that
though there is evidence for antipruritic effect, thalidomide is not
recommended for the treatment of chronic pruritus due to its adverse effects.
Waldenström macroglobulinemia
Data from
a phase II study in patients with symptomatic Waldenström macroglobulinemia
suggests that thalidomide may be beneficial in the treatment of this
condition [Treon 2008]. Additional data may be necessary to
further define the role of thalidomide in this condition.
Contraindications
Hypersensitivity
to thalidomide or any component of the formulation; pregnancy
Canadian
labeling: Additional
contraindications (not in theUSlabeling): Hypersensitivity to lenalidomide or pomalidomide; females at risk of
becoming pregnant and male patients who are unable to follow or comply with
conditions for use (refer to manufacturer labeling); breastfeeding
Dosing: Adult
Erythema
nodosum leprosum, acute cutaneous: Oral:
Initial: 100 to 300 mg once daily at bedtime, continue until signs/symptoms
subside (usually ~2 weeks), then taper off in 50 mg decrements every 2 to 4
weeks. For severe cases with moderate to severe neuritis, corticosteroids may
be initiated with thalidomide (taper off and discontinue corticosteroids when
neuritis improves).
Patients
weighing <50 kg: Initiate at lower end of the dosing range
Severe
cutaneous reaction or patients previously requiring high doses: May be
initiated at up to 400 mg once daily at bedtime or in divided doses
Erythema
nodosum leprosum, maintenance (prevention/suppression, or with flares during
tapering attempts): Oral:
Maintain on the minimum dosage necessary to control the reaction; efforts to
taper off should be attempted every 3 to 6 months, in decrements of 50 mg every
2 to 4 weeks.
Multiple
myeloma, newly diagnosed: Oral:
200 mg once daily at bedtime (in combination with dexamethasone)
Multiple
myeloma (off-label dosing or combinations):
In
combination with bortezomib and dexamethasone (off-label combination):
Induction therapy: 100 mg once daily for the first 14 days, then 200 mg once
daily for 3 (21-day) cycles (Cavo 2010) or 100 mg once daily
for up to 8 (21-day) cycles (Kaufman 2010)
In
combination with melphalan and prednisone (off-label combination): 200 to 400
mg once daily (Facon 2007) or 100 mg once daily (Palumbo
2008) or 50 to 100 mg once daily, depending on patient
tolerance (Hulin 2009)
Multiple
myeloma, maintenance (following autologous stem cell transplant; off-label
use): Oral: 200 mg once daily
starting 3 to 6 months after transplant; continue until disease progression or
unacceptable toxicity (Brinker 2006) or 100 mg once daily starting 42 to 60
days following transplant; increase to 200 mg once daily after 2 weeks if
tolerated; continue for up to 12 months (in combination with prednisolone)
(Spencer 2009)
Multiple
myeloma, salvage therapy: Initial:
200 mg once daily at bedtime; may increase daily dose by 200 mg every 2 weeks
for 6 weeks (if tolerated) to a maximum of 800 mg once daily at bedtime
(Singhal, 1999) or 100 mg once daily (in combination with
dexamethasone) (Palumbo 2001) or 200 mg once daily (in
combination with bortezomib and dexamethasone) for 1 year (Garderet 2012) or 400
mg once daily at bedtime (in combination with dexamethasone, cisplatin,
doxorubicin, cyclophosphamide and etoposide) (Lee 2003)
AIDS-related
aphthous stomatitis (off-label use): Oral: 200 mg once daily at bedtime for up to 8 weeks, if
no response, then 200 mg twice daily for 4 weeks (Jacobson, 1997)
Chronic
graft-versus-host disease (refractory), treatment (off-label second-line use;
optimum dose not determined): Oral:
Initial: 100 mg once daily at bedtime, with dose escalation up to 400 mg daily
in 3 to 4 divided doses (Wolff 2010) or Initial: 50 to 100 mg
3 times daily; maximum dose: 600 to 1,200 mg daily (Kulkarni 2003) or 200
mg 4 times daily (dose adjusted to goal thalidomide concentration of ≥5 mcg/mL
2 hours postdose) (Vogelsang, 1992) or 100 to 300 mg 4 times
daily (Parker, 1995)
Systemic
light chain amyloidosis (off-label use): Oral: 200 mg once daily (starting dose 50 to 100 mg once
daily; titrate at 4-week intervals) in combination with cyclophosphamide and
dexamethasone (Wechalekar 2007)
Uremic
pruritus, refractory (off-label use): Oral: 100 mg once daily at bedtime (Silva 1994). Additional data
is necessary to further define the role of thalidomide in this condition;
several other treatment modalities with more benign safety profiles are
available.
Waldenström
macroglobulinemia (off-label use): Oral:
≤200 mg once daily for up to 52 weeks (in combination with rituximab) (Treon
2008)
Dosing: Geriatric
Refer to
adult dosing. A reduced initial dose may be appropriate (depending on patient
tolerance) in patients ≥75 years (Hulin 2009).
Dosing: Pediatric
Erythema
nodosum leprosum, acute cutaneous: Children
≥12 years of age: Oral: Refer to adult dosing.
Erythema
nodosum leprosum, maintenance (prevention/suppression, or with flares during
tapering attempts): Children
≥12 years of age: Oral: Refer to adult dosing.
Chronic
graft-versus-host disease (refractory), treatment (off-label second-line use;
limited data):Children ≥3 years of
age: Oral: 3 mg/kg 4 times daily (dose adjusted to goal thalidomide
concentration of ≥5 mcg/mL 2 hours postdose) (Vogelsang 1992) or Initial:
3 to 6 mg/kg/day in 2 to 4 divided doses; target dose 12 mg/kg/day; Maximum
daily dose: 800 mg (Rovelli 1998)
Dosing: Renal Impairment
No dosage
adjustment necessary for patients with renal impairment and on dialysis (per manufacturer).
In a study of 6 patients with end-stage renal disease on dialysis, although
clearance was increased by dialysis, a supplemental dose was not needed
(Eriksson 2003).
Multiple
myeloma: An evaluation of 29 newly
diagnosed myeloma patients with renal failure (serum creatinine ≥2 mg/dL)
treated with thalidomide and dexamethasone (some also received
cyclophosphamide) found that toxicities and efficacy were similar to patients
with normal renal function (Seol 2010). A study evaluating induction therapy
with thalidomide and dexamethasone in 31 newly diagnosed myeloma patients with
renal failure (CrCl <50 mL/minute), including 16 patients with severe renal
impairment (CrCl <30 mL/minute) and 7 patients on chronic hemodialysis found
that toxicities were similar to patients without renal impairment and that
thalidomide and dexamethasone could be administered safely (Tosi 2009). The
International Myeloma Working Group (IMWG) suggests that thalidomide may be
safely administered to patients with renal impairment, including those on
dialysis (Dimopoulos 2016). The IMWG recommends the use of the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the
Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function
estimation in multiple myeloma patients with a stable serum creatinine.
Dosing: Hepatic Impairment
There are
no dosage adjustments provided in the manufacturer's labeling (has not been
studied). However, thalidomide does not appear to undergo significant hepatic
metabolism.
Dosing: Adjustment for Toxicity
ANC ≤750/mm3: Withhold treatment if clinically appropriate
Grade 3
or 4 adverse reactions: Consider
dose reduction, delay or discontinuation (based on clinical judgment).
Multiple
myeloma:
Constipation,
oversedation: Temporarily withhold or continue with a reduced dose
Peripheral
neuropathy:
The
manufacturer recommends to temporarily withhold or continue with a reduced
dose.
The
follow adjustments have also been recommended (Richardson 2012):
Grade 1:
Reduce dose by 50%
Grade 2:
Temporarily interrupt therapy; once resolved to ≤ grade 1, resume therapy with
a 50% dosage reduction (if clinically appropriate)
Grade 3
or higher: Discontinue therapy
Extemporaneously Prepared
A 20
mg/mL oral suspension may be prepared with capsules and a 1:1 mixture of
Ora-Sweet and Ora-Plus. Empty the contents of twelve 100 mg capsules into a
glass mortar. Add small portions of the vehicle and mix to a uniform paste; mix
while adding the vehicle in incremental proportions to almost 60 mL; transfer
to an amber calibrated bottle, rinse mortar with vehicle, and add quantity of
vehicle sufficient to make 60 mL. Label “shake well,” “protect from light,” and
“refrigerate”. Stable for 35 days refrigerated.
Kraft S,
Johnson CE, and Tyler RP, "Stability of an Extemporaneously Prepared
Thalidomide Suspension," Am J Health Syst Pharm, 2011,
69(1):56-8.22180553
Administration
Administer
orally, preferably at bedtime once daily, at least 1 hour after the evening
meal. Doses >400 mg/day may be given in divided doses at least 1 hour after
meals. Swallow capsules whole with water. Capsules should not be opened or
crushed.
Capsules
should remain in blister pack until ingestion. If exposed to the powder content
from broken capsules or body fluids from patients receiving thalidomide, the
exposed area should be washed immediately and thoroughly with soap and water.
Missed
doses: For missed doses, if
<12 hours patient may receive dose; if >12 hours wait until next dose due.
Storage
Store at
20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C
(59°F and 86°F). Protect from light. Keep in original package.
Drug Interactions
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: Angiogenesis Inhibitors (Systemic) 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
Chloramphenicol
(Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents.Monitor
therapy
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
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
Estrogen
Derivatives (Contraceptive): 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
Pembrolizumab:
May enhance the adverse/toxic effect of Thalidomide Analogues. Specifically,
mortality may be increased when this combination is used for treatment of
refractory multiple myeloma. 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
Pidotimod:
Immunosuppressants may diminish the therapeutic effect of Pidotimod. 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
Progestins
(Contraceptive): May enhance the thrombogenic effect of Thalidomide. 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
Adverse Reactions
Incidences
of adverse reactions may include combination therapy.
>10%:
Central nervous system: Drowsiness (≤38%), headache (≤13%), peripheral
neuropathy (≥10%)
1% to
10%:
Cardiovascular:
Facial edema (≤4%), peripheral edema (≤4%)
Central
nervous system: Malaise (≤8%), pain (≤8%), vertigo (≤8%), dizziness (≤4%)
Dermatologic:
Pruritus (≤8%), fungal dermatitis (≤4%), maculopapular rash (≤4%), nail disease
(≤4%)
Gastrointestinal:
Constipation (≤4%), nausea (≤4%), oral candidiasis (≤4%), toothache (≤4%)
Genitourinary:
Impotence (≤8%)
Neuromuscular
& skeletal: Weakness (≤8%), back pain (≤4%), neck pain (≤4%), neck
stiffness (≤4%), tremor (≤4%)
Miscellaneous:
Accidental injury (≤4%)
<1%,
postmarketing, and/or case reports: Acute renal failure, amenorrhea, aphthous stomatitis,
auditory impairment, biliary obstruction, bradycardia, carpal tunnel syndrome,
cerebrovascular accident, change in prothrombin time, chronic myelocytic
leukemia, cytomegalovirus disease, diplopia, ECG abnormality, erythema
multiforme, erythema nodosum, erythroleukemia, febrile neutropenia, foot-drop,
galactorrhea, gastric ulcer, gynecomastia, hangover effect, Hodgkin lymphoma,
hypercalcemia, hypersensitivity reaction, hypomagnesemia, hyponatremia,
hypothyroidism, increased serum alkaline phosphatase, interstitial pulmonary
disease, intestinal perforation, lethargy, loss of consciousness, lymphedema,
lymphocytopenia, mental status changes, migraine, myocardial infarction,
myxedema, neutropenia, nystagmus, oliguria, orthostatic hypotension, pancytopenia,
Parkinson disease, petechia, pleural effusion, pulmonary embolism, pulmonary
hypertension, purpura, Raynaud phenomenon, reactivation of HBV, renal failure,
seizure, sepsis, septic shock, sexual disorder, sick sinus syndrome, status
epilepticus, Stevens-Johnson syndrome, stupor, suicidal tendencies, syncope,
thrombocytopenia, tonic-clonic seizures, toxic epidermal necrolysis, tumor
lysis syndrome, urinary incontinence, uterine hemorrhage, varicella zoster
infection
ALERT:U.S.Boxed Warning
Pregnancy:
If
thalidomide is taken during pregnancy, it may cause severe birth defects or
embryo-fetal death. Thalidomide should never be used by females who are
pregnant or who could become pregnant while taking thalidomide. Even a single
dose (1 capsule [regardless of strength]) taken by a pregnant woman during
pregnancy may cause severe birth defects.
Because
of this toxicity and in an effort to make the chance of embryo-fetal exposure
to thalidomide as negligible as possible, thalidomide is approved for marketing
only through a special restricted distribution program: Thalomid REMS program,
approved by the Food and Drug Administration. Information about Thalomid and
the Thalomid REMS program is available at https://www.celgeneriskmanagement.com or by calling the manufacturer's toll-free
number 1-888-423-5436.
Thromboembolic
events:
The use
of thalidomide in multiple myeloma results in an increased risk of venous
thromboembolism, 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 1 controlled
trial, the rate of venous thromboembolism was 22.5% in patients receiving
thalidomide in combination with dexamethasone compared with 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.
Warnings/Precautions
Concerns
related to adverse effects:
• Bone
marrow suppression: May cause leukopenia and neutropenia; avoid initiating
therapy if ANC <750/mm3. Persistent neutropenia may require
treatment interruption. Thrombocytopenia (including grades 3 and 4) has been
reported; may require dose reduction, treatment delay, or discontinuation.
Monitor for signs and symptoms of bleeding (including petechiae, epistaxis, and
GI bleeding), especially if concomitant medication may increase the risk of
bleeding. Monitor CBC with differential and platelets. Anemia has also been
observed.
•
Bradycardia: May cause bradycardia; use with caution when administering
concomitantly with medications that may also decrease heart rate. May require
thalidomide dose reduction or discontinuation.
• CNS
effects: May cause dizziness, drowsiness, and/or somnolence; caution patients
about performing tasks which require mental alertness (eg, operating machinery
or driving). Avoid ethanol and concomitant medications that may exacerbate
these symptoms; dose reductions may be necessary for excessive drowsiness or
somnolence.
•
Constipation: Constipation may commonly occur. May require treatment
interruption or dosage reduction.
•
Dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) have been reported (may be fatal); withhold therapy and
evaluate if skin rash occurs; permanently discontinue if rash is exfoliative,
purpuric, bullous, or if SJS or TEN is suspected.
•
Hepatotoxicity: Abnormal liver function tests, hepatitis, and cholestatic jaundice
have been reported. Hepatotoxicity (including hepatocellular and cholestatic
injury) has been observed rarely (case reports), with a mean time to
development of 46 days; most events resolved after discontinuing thalidomide
(Vilas-Boas 2012).
• Hypersensitivity:
Hypersensitivity, including erythematous macular rash, possibly associated with
fever, tachycardia, and hypotension has been reported. May require treatment
interruption for severe reactions; discontinue if recurs with rechallenge.
•
Orthostatic hypotension: May cause orthostatic hypotension; use with caution in
patients who would not tolerate transient hypotensive episodes. When arising
from a recumbent position, advise patients to sit upright for a few minutes
prior to standing.
•
Peripheral neuropathy: Thalidomide is commonly associated with peripheral
neuropathy; may be irreversible. Neuropathy generally occurs following chronic
use (over months), but may occur with short-term use; onset may be delayed. Use
caution with other medications that may also cause peripheral neuropathy.
Monitor for signs/symptoms of neuropathy monthly for the first 3 months of
therapy and regularly thereafter. Electrophysiological testing may be
considered at baseline and every 6 months to detect asymptomatic neuropathy. To
limit further damage, immediately discontinue (if clinically appropriate) in
patients who develop neuropathy. Reinitiate therapy only if neuropathy returns
to baseline; may require dosage reduction or permanent discontinuation.
•
Secondary malignancy: Increased incidence of second primary malignancies
(SPMs), including acute myeloid leukemia (AML) and myelodysplastic syndrome
(MDS), has been observed in previously untreated multiple myeloma patients
receiving thalidomide in combination with melphalan, and prednisone. In
addition to AML and MDS, solid tumors have been reported with thalidomide
maintenance treatment for multiple myeloma (Usmani 2012). Carefully evaluate
patients for SPMs prior to and during treatment and manage as clinically
indicated.
•
Seizures: Seizures (including grand mal convulsions) have been reported in
postmarketing data; monitor closely for clinical changes indicating potential
seizure activity in patients with a history of seizures, concurrent therapy
with drugs that alter seizure threshold, or conditions that predispose to
seizures.
•
Thromboembolic events: [US Boxed Warning]: Thalidomide use for the
treatment of multiple myeloma is associated with an increased risk for venous
thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary
embolism (PE); the risk is increased when used in combination with standard
chemotherapy agents, including dexamethasone. In one controlled study, the
incidence of VTE was 22.5% in patients receiving thalidomide in combination with
dexamethasone, compared to 4.9% for dexamethasone alone. Monitor for signs and
symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg
swelling) and instruct patients to seek prompt medical attention with
development of these symptoms. Consider thromboprophylaxis based on risk
factors. Ischemic heart disease, including MI and stroke, also
occurred at a higher rate (compared to placebo) in myeloma patients receiving
thalidomide plus dexamethasone who had not received prior treatment. Assess
individual risk factors for thromboembolism and consider thromboprophylaxis.
The American Society of Clinical Oncology guidelines for VTE prophylaxis and
treatment recommend thromboprophylaxis for patients receiving thalidomide in
combination with chemotherapy and/or dexamethasone; either aspirin or low
molecular weight heparin (LMWH) is recommended for lower risk patient and LMWH
is recommended for higher-risk patients (Lyman 2013; Lyman 2015). Anticoagulant
prophylaxis should be individualized and selected based on the venous
thromboembolism risk of the combination treatment regimen, using the safest and
easiest to administer (Palumbo 2008). Monitor for signs/symptoms of
thromboembolism and advise patients to seek immediate care if symptoms
(shortness of breath, chest pain, arm/leg swelling) develop. Other medications
that are also associated with thromboembolism should be used with caution.
• Tumor
lysis syndrome: Patients with a high tumor burden may be at risk for tumor
lysis syndrome; monitor closely; institute appropriate management for
hyperuricemia.
Disease-related
concerns:
• Heart
failure: In a scientific statement from the American Heart Association,
thalidomide has been determined to be an agent that may exacerbate underlying
myocardial dysfunction (magnitude: minor) (AHA [Page 2016]).
•
Multiple myeloma: An increase in mortality was noted in 2 clinical studies in
patients with multiple myeloma who received pembrolizumab in combination with a
thalidomide analogue and dexamethasone. Causes of death in the experimental arm
(containing pembrolizumab, dexamethasone, and a thalidomide analogue
[pomalidomide or lenalidomide]) included myocarditis, SJS, MI, pericardial
hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis,
sepsis, multiple organ dysfunction, respiratory failure, intestinal ischemia,
cardiopulmonary arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia,
sudden death, and large intestine perforation. Multiple myeloma is not an
approved indication for PD-1 or PD-L1 blocking antibodies; pembrolizumab should
not be used to treat multiple myeloma in combination with a thalidomide
analogue and dexamethasone unless as part of a clinical trial.
Concurrent
drug therapy issues:
•
Drug-drug interactions: Potentially significant interactions may exist,
requiring dose or frequency adjustment, additional monitoring, and/or selection
of alternative therapy. Consult drug interactions database for more detailed
information.
Special
populations:
•
Elderly: Certain adverse reactions (constipation, fatigue, weakness, nausea,
hypokalemia, hyperglycemia, DVT, pulmonary embolism, atrial fibrillation) are
more likely in elderly patients.
•
HIV-infected patients: Thalidomide is associated with increased viral loads in
studies conducted prior to the use of antiretroviral therapy. Monitor viral
load after the first and third months of therapy, and every 3 months
thereafter.
•
Pregnancy: [US Boxed Warning]: Thalidomide is contraindicated in
pregnant women. Thalidomide may cause severe birth defects or embryo-fetal
death if taken during pregnancy. Thalidomide cannot be used in women who are
pregnant or may become pregnant during therapy as even a single dose may cause
severe birth defects. In order to decrease the risk of fetal exposure,
thalidomide is available only through a special restricted distribution program
(Thalomid REMS). Use is also contraindicated in women who may become
pregnant. Pregnancy must be excluded prior to therapy initiation with 2
negative pregnancy tests. Women of reproductive potential must avoid pregnancy
beginning 4 weeks prior to therapy, during therapy, during therapy
interruptions, and for ≥4 weeks after therapy is discontinued; two reliable
methods of birth control, or abstinence from heterosexual intercourse, must be
used. Males taking thalidomide (even those vasectomized) must use a latex or
synthetic condom during any sexual contact with women of childbearing potential
and for up to 28 days following discontinuation of therapy. Males taking
thalidomide must not donate sperm. Some forms of contraception may not be
appropriate in certain patients. An intrauterine device (IUD) or implantable
contraceptive may increase the risk of infection or bleeding; estrogen
containing products may increase the risk of thromboembolism.
Other
warnings/precautions:
• Blood
donation: Patients should not donate blood during thalidomide treatment and for
4 weeks after therapy discontinuation.
• REMS
program: Due to the embryo-fetal risk, thalidomide is only available through a
restricted program under the Thalomid REMS program. Prescribers and pharmacies
must be certified with the program to prescribe or dispense thalidomide.
Patients must sign an agreement and comply with the REMS program requirements.
Monitoring Parameters
CBC with
differential, platelets; thyroid function tests (TSH at baseline then every 2
to 3 months during thalidomide treatment [Hamnvik 2011]). Hepatic function
tests (periodic; particularly with preexisting hepatic dysfunction or
concomitant use of drugs associated with hepatotoxicity). In HIV-seropositive
patients: viral load after 1 and 3 months, then every 3 months. Pregnancy
testing (sensitivity of at least 50 milliunits/mL) is required 10 to 14 days
prior to therapy, within 24 hours prior to initiation of therapy, weekly during
the first 4 weeks, then every 4 weeks in women with regular menstrual cycles or
every 2 weeks in women with irregular menstrual cycles. Signs of neuropathy
monthly for the first 3 months, then periodically during treatment; consider
monitoring of sensory nerve application potential amplitudes (at baseline and
every 6 months) to detect asymptomatic neuropathy. Monitor for signs and
symptoms of thromboembolism (shortness of breath, chest pain, arm/leg
swelling), tumor lysis syndrome, bradycardia and syncope; monitor for clinical
changes indicating potential seizure activity (in patients with a history of
seizure). Monitor adherence.
Pregnancy Considerations
[US Boxed
Warning]: Thalidomide is contraindicated in pregnant women. Thalidomide may
cause severe birth defects or embryo-fetal death if taken during pregnancy.
Thalidomide cannot be used in women who are pregnant or may become pregnant
during therapy as even a single dose may cause severe birth defects. In order
to decrease the risk of fetal exposure, thalidomide is available only through a
special restricted distribution program (Thalomid REMS). Reproduction studies in animals and data from
pregnant women have shown evidence of fetal abnormalities; use is
contraindicated in women who are or may become pregnant. Anomalies observed in
humans include amelia, phocomelia, bone defects, ear and eye abnormalities,
facial palsy, congenital heart defects, urinary and genital tract
malformations; mortality in ~40% of infants at or shortly after birth has also
been reported.
Women of
reproductive potential must avoid pregnancy beginning 4 weeks prior to therapy,
during therapy, during therapy interruptions, and for at least 4 weeks after
therapy is discontinued. Two forms of effective/reliable contraception or total
abstinence from heterosexual intercourse must be used by females who are not
infertile or who have not had a hysterectomy. A negative pregnancy test
(sensitivity of at least 50 milliunits/mL) 10 to 14 days prior to therapy,
within 24 hours prior to beginning therapy, weekly during the first 4 weeks,
and every 4 weeks (every 2 weeks for women with irregular menstrual cycles)
thereafter is required for women of childbearing potential. Thalidomide must be
immediately discontinued for a missed period, abnormal pregnancy test or
abnormal menstrual bleeding; refer patient to a reproductive toxicity
specialist if pregnancy occurs during treatment.
Females
of reproductive potential (including health care workers and caregivers) must
also avoid contact with thalidomide capsules.
Thalidomide
is also present in the semen of males. Males (even those vasectomized) must use
a latex or synthetic condom during any sexual contact with women of
childbearing potential and for up to 28 days following discontinuation of
therapy. Males taking thalidomide must not donate sperm.
The
parent or legal guardian for patients between 12 to 18 years of age must agree
to ensure compliance with the required guidelines.
A
pregnancy exposure registry has been created to monitor outcomes in females
exposed to thalidomide during pregnancy and female partners of male patients
and to understand the root cause for the pregnancy. The pregnancy exposure
registry may be contacted at 1-888-423-5436. If pregnancy occurs during
treatment, thalidomide must be immediately discontinued and the patient
referred to a reproductive toxicity specialist. Any suspected fetal exposure to
thalidomide must be reported to the FDA via the MedWatch program
(1-800-FDA-1088) and to Celgene Corporation (1-888-423-5436).
Patient Education
• 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.
