Transcript Close monitoring

Methotrexate
Pharm D student: Noha Alaa El Dine
Alexandria University Hospitals
Supervised by: Prof. Nashaat Lotfy
Professor of Oncology Faculty of Medicine
Mechanism of action
MTX is an antifolate belonging to the antimetabolite class of antineoplastic agents.
MTX is a cell cycle specific chemotherapeutic agents that acts on S-phase &
thus inhibit DNA synthesis
Folic acid
Dihydrofolate reductase
Tetrahydrofolic
acid
THF included at two stages in the biosynthesis of purines (adenine and
guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine,
and uracil)
Indications
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All Labeled Uses:
 Acute Lymphoid Leukemia
 Breast Carcinoma
 Burkitt's Lymphoma
 Diffuse Large B-Cell Lymphoma
 Gestational Trophoblastic
Neoplasm
 Juvenile Rheumatoid Arthritis
 Locally Advanced Breast
Carcinoma
 Lung Carcinoma
 Malignant Tumor of Head and
Neck
 Metastatic Breast Carcinoma
 Mycosis Fungoides
 Psoriasis
 Rheumatoid Arthritis
 Small Cell Lung Carcinoma
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Unlabeled Uses:
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Acute Myeloid Leukemia
Acute Promyelocytic Leukemia
Colorectal Cancer
Ectopic Pregnancy
Malignant Tumor of Cervix
Malignant Tumor of Urinary
Bladder
Metastatic Colorectal Cancer
Polymyositis
Psoriatic Arthritis
Systemic Dermatomyositis
Systemic Lupus Erythematosus
Vasculitis
Wegener's Granulomatosis
Protocols
Trophoblastic Neoplasms
 The usual dosage of methotrexate is 15–30 mg daily, administered
orally or IM for 5 days.
 A repeat course may be given after a period of one or more weeks
provided all signs of residual toxicity have disappeared.
 Three to five courses of therapy are usually employed.
 Therapy is usually evaluated by 24-hour quantitative analysis of
urinary chorionic gonadotropin which should return to normal or less
than 50 IU/24 hours, usually after the third or fourth course.
 Complete resolution of measurable lesions usually occurs 4–6
weeks later.
 One or two courses of methotrexate therapy are usually given after
normalization of urinary chorionic gonadotropin hormone
concentrations is achieved.
 In the treatment of trophoblastic disease in women, regimens
alternating courses of methotrexate therapy and dactinomycin
therapy or combining administration of methotrexate and
mercaptopurine or methotrexate, dactinomycin, and chlorambucil
have also been used.
Protocols
Lymphomas
 The usual dosage of methotrexate for the treatment of stages I or II of
Burkitt’s lymphoma is 10–25 mg/day orally for 4–8 days.
 Methotrexate is commonly given concomitantly with other antineoplastic
agents in the treatment of stage III Burkitt’s lymphoma and lymphosarcomas.
 In all stages, several courses of drug therapy are usually administered
interposed with 7- to 10-day rest periods. Stage III lymphosarcomas may
respond to combined drug therapy with methotrexate given in doses of
0.625–2.5 mg/kg daily.
Mycosis Fungoides
 Clinical response occurs in up to 50% of patients receiving single-agent
therapy with methotrexate for mycosis fungoides (cutaneous T-cell
lymphoma).
 In early stages of the disease, the usual dosage is 5–50 mg orally once
weekly. The need for dosage reduction or discontinuance of therapy is
determined by response to therapy and hematologic monitoring.
 Methotrexate also has been administered twice weekly in doses of 15–37.5
mg in patients with disease that has responded poorly to once-weekly
dosing.
 In patients with advanced stages of mycosis fungoides, combination
chemotherapy regimens that include IV methotrexate in higher doses
followed by leucovorin rescue have been used.
Protocols
Breast Cancer
 One commonly employed regimen (CMF) for the treatment of
early breast cancer includes a methotrexate dosage of 40
mg/m2 (administered IV) on days 1 and 8 of each cycle
combined with cyclophosphamide 100 mg/m2 on days 1
through 14 of each cycle and fluorouracil 600 mg/m2 on days
1 and 8 of each cycle.
 Cycles generally were repeated monthly (i.e., allowing a 2week rest period between cycles) for a total of 6–12 cycles.
 Dosage was reduced In patients older than 60 years of age
& if myelosuppression developed.
 There is some evidence that the addition of doxorubicin to a
regimen of cyclophosphamide, methotrexate, and fluorouracil
can improve outcome further in patients with early breast
cancer and more than 3 positive axillary lymph nodes.
Administration
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Great care should be taken to prevent
inhaling particles of the chemical and
exposing the skin to it.
Methotrexate formulations or diluents
containing preservatives (benzyl alcohol)
must not be used for intrathecal
administration or high-dose methotrexate
therapy.
Guidelines for parenteral administration of
intermediate- or high-dose methotrexate
(HDMTX)
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500mg/m2 over <4hrs or 1gm/m2 over >4hrs
Prior to MTX administration the following laboratory
parameters should be confirmed:
WBCs > 1500/mm3
Neutrophils > 200/mm3
s.bilirubin<1.2mg/dl
SGPT (ALT)<450 U
Platelets > 75,000/mm3
Normal s. Cr.
Creatinine clearance>60ml/min
Previous mucositis should be healed
& pleural effusions should be drained prior to MTX administration
Hydration, Urine alkalinization &
Leucoverin rescue
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Administer 1 L/m2 of IV fluids over 6 hrs prior to
initiation of MTX infusion. Continue hydration at
125ml/m2/hr (3 L/m2 daily) during the MTX infusion & for 2
days after the infusion has been completed.
Urine should be alkalinized using sodium bicarbonate.
Alkalinize urine to maintain the urine pH >7 during the
MTX infusion & leucoverin therapy. Alkalinization may be
either orally or by incorporating sodium bicarbonate in
the IV fluids
Leucovorin rescue required for MTX doses >500mg/m2,
& considered for MTX doses 100-500mg/m2 for ALL,
Breast CA, head/neck CA lung CA, osteosarcoma, non
hodgkin’s lymphoma, others
Leucoverin dose 15 mg/m2 every 6 hours for 12 doses
was begun at the end of the MTX infusion
IV Administration
Reconstitution. Reconstitute lyophilized powder for
injection immediately before use with a sterile,
preservative-free solution (e.g., 5% dextrose injection,
0.9% sodium chloride injection)
Reconstitute 20 mg vial to a concentration ≤25 mg/mL
Reconstitute 1 g vial with 19.4 mL of appropriate solution
to yield a concentration of 50 mg/mL.
Dilution. When high doses are administered by IV infusion,
dilute total dose of reconstituted solution in 5% dextrose
injection.
May further dilute commercially available solution for IV
injection containing preservatives with a compatible
solution (e.g., 0.9% sodium chloride injection).
Preservative-free solutions may be diluted immediately
prior to use with an appropriate sterile, preservative-free
solution (e.g., 5% dextrose injection, 0.9% sodium
chloride injection)
Stability
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Methotrexate sodium injection and powder for injection
should be protected from light and stored at 15–30°C.
Compatible with:
 Dextrose 5% in water
 Sodium chloride 0.9%
Maximum reported stability periods:
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In D5W- 10 days at room temperature and 30 days refrigerated
protected from light.
In NS- 7 days at room temperature and 105 days refrigerated
protected from light.
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Storage of solutions containing preservatives after
further dilution for 24 hours at 21–25°C results in a
product within 90% of label potency.
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Use preservative-free solution immediately after further
dilution
Intrathecal Administration
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Reconstitution. For intrathecal injection, reconstitute lyophilized
powder to a concentration of 1 mg/mL with an appropriate sterile
preservative-free diluent (e.g., 0.9% sodium chloride injection).
Dilution. For intrathecal injection, dilute methotrexate preservativefree solution for injection to a concentration of 1 mg/mL with an
appropriate sterile preservative-free diluent (e.g., 0.9% sodium
chloride injection).
Adverse drug reactions
Dermatologic and Sensitivity Reactions.
Severe, occasionally fatal cutaneous or sensitivity reactions e.g.,
 Toxic epidermal necrolysis
 Stevens-Johnson syndrome
 Exfoliative dermatitis
 Skin necrosis
 Erythema multiforme
reported in pediatric and adult patients within days of receiving drug at
various dosages, by various routes, and for various conditions.
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Erythematous rashes, pruritus, dermatitis, urticaria, folliculitis,
photosensitivity, depigmentation, hyperpigmentation, petechiae,
ecchymoses, telangiectasia, acne, furunculosis, and skin ulceration
also reported.
Hematologic
Effects
Suppressed hematopoiesis:
 Anemia
 Aplastic anemia
 Pancytopenia
 Leukopenia
 Neutropenia
 Thrombocytopenia.
Monitoring
Perform CBCs, including
differential and platelet
counts, at least weekly in
patients with neoplastic
disease
Management
If profound leukopenia and fever occur, observe patient closely and initiate
broad-spectrum antibiotic therapy if there are signs of infection.
Blood or platelet transfusions may be necessary in patients with severe
myelosuppression.
Nephrotoxicity
Prevention
•May cause renal
damage that may lead
to acute renal failure.
•Nephrotoxicity is due
principally to
precipitation of
methotrexate and 7hydroxymethotrexate in
the renal tubules.
Careful attention to
renal function
including:
 Adequate hydration
 Urine alkalinization
 Measurement of
methotrexate and Scr
concentrations is
essential.
Management
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Monitoring
Scr
must be normal
and Clcr >60 ml/min
before therapy
initiation.
 Repeat Scr and
serum methotrexate 24
hours after starting
methotrexate and at
least once daily until
the methotrexate
concentration is <0.023
mcg/mL (0.05 mcM).
If renal impairment develops during methotrexate therapy, dosage should be
reduced or the drug discontinued until renal function is improved or restored.
Institute appropriate corrective measures (e.g., use of leucovorin calcium,
acute intermittent hemodialysis with a high-flux dialyzer).
In addition, tumor lysis syndrome associated with other cytotoxic drugs (e.g.,
fludarabine, cladribine) also has been reported in patients with rapidly
growing tumors who were receiving methotrexate.
Dose adjustment in renal
impairment
Cr Cl 60-80 ml/min Decrease dose 25%
Cr Cl 50-60 ml/min Decrease dose 33%
Cr Cl 10-50 ml/min Decrease dose 50-70%
Cr Cl < 10 ml/min
Avoid use
HD
Give 50% dose as supplement
CAPD
No supplement
Monitoring
Hepatotoxicity
Possible hepatotoxicity;
may be acute (increased
serum aminotransferase
concentrations) or
chronic (fibrosis and
cirrhosis).
Liver function tests at baseline.
 Abnormal liver function test results frequently
occur 1–2 days following a dose of methotrexate,
and it is recommended that liver function tests be
performed at least 1 week after the last dose of
the drug. Because these tests generally return to
normal within a few days.
 Liver biopsy is currently the only reliable
measure of hepatotoxicity.
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Management
If substantial abnormal liver function test results develop and persist,
methotrexate therapy should be withheld for 1–2 weeks and liver function
tests repeated. However, if substantial abnormal liver function test results
persist, a liver biopsy is recommended.
Dose adjustment in hepatic
impairment
s.bilirubin 4-5mg/dl Decrease dose 25%
s.bilirubin >5mg/dl Omit
ALT <180
Decrease dose 25%
ALT>450 U/L
Omit
Pulmonary
toxicity
Potentially
fatal pulmonary
toxicity; can progress rapidly
and may not be fully
reversible.
Adverse pulmonary effects
(i.e., acute or chronic
interstitial pneumonitis,
pulmonary fibrosis) may occur
at any dosage at any time
during therapy.
Monitoring
 Frequently Chest radiographs should
be performed
 If manifestations (e.g., fever, cough
[especially dry and nonproductive),
dyspnea, chest pain, hypoxemia
[possibly severe], radiographic
evidence of pulmonary infiltrates
[usually diffuse and/or alveolar]) occur,
discontinue and carefully evaluate,
including exclusion of possible
infectious causes.
Management
Management
is mainly supportive and may
include mechanical ventilation.
GI Effects.
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Vomiting
Diarrhea
Ulcerative Stomatitis
Management
Discontinue drug until recovery otherwise
intestinal perforation may lead to hemorrhagic
enteritis & death.
Previous mucositis should be healed
Use with extreme caution in presence of
peptic ulcer disease or ulcerative colitis.
Additive Adverse Drug effect:
Hepatotoxic Agents (retinoids, azathioprine,
sulfasalazine)
Increase in adverse hepatic effects expected.
Nephrotoxic Drugs
Possible altered renal elimination of methotrexate.
Action required:
Close monitoring of
LFTs & renal function
MTX cause
damage of GIT
Reduce
absorption of
Verapamil &
Phenytoin by 2035% and so loss
of therapeutic
effect.
MTX is also displaced from protein
binding sites by:
 Salicylates
 Co-trimoxazole(sulfonamides)
 Sulfonylureas, phenytoin,
phenylbutazone, tetracyclines,
chloramphenicol, and aminobenzoic
acid resulting in increased free
methotrexate concentrations.
MTX may
decrease
clearance of
theophylline
Salicylates & NSAIDs can cause
severe, possibly fatal MTX toxicity
including hematologic and GI toxicity ( HDMTX) either by competition with MTX
for active tubular secretion & delay of
elimination or by decreasing renal
perfusion (due to inhibition of PG
synthesis (PD interaction).
Action required:
NSAIDs should be avoided in
patients receiving HD -MTX
Monitor
theophyllin
e
level
Concomitant use of penicillins
(e.g., amoxicillin, carbenicillin)
may decrease renal clearance
of methotrexate, presumably
by inhibiting renal tubular
secretion of the drug & thus
increase serum concentrations
of methotrexate, resulting in GI
or hematologic toxicity
Action required:
Close monitoring
Resistance to methotrexate
Due to:
 Decreased cellular uptake of the drug
 Increased dihydrofolate reductase activity
(associated
with increased synthesis of the enzyme)
 Decreased binding of methotrexate to dihydrofolate
reductase (because of mutated dihydrofolate
reductase protein)
 Decreased intracellular concentrations of
polyglutamylated metabolites of methotrexate
However, the precise mechanism of this resistance
development has not been established.
References
AHFS detailed monograph 2009
 AHFS drug information, Dosing
Companion 2004
 Epocrates 2008
 Clinical pharmacology 2001
 Trissel’s™ 2 Clinical Pharmaceutics
Database 2009
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