Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 25mg/mL
powder for injection
- 1g/vial (25mg/mL when reconstituted)
SC autoinjector (Otrexup)
- 7.5 mg/0.4mL
- 10mg/0.4mL
- 12.5mg/0.4mL
- 15mg/0.4mL
- 17.5mg/0.4mL
- 20mg/0.4mL
- 22.5mg/0.4mL
- 25mg/0.4mL
SC autoinjector (Rasuvo)
- 2.5mg/0.05mL (delivers doses between 7.5 mg and 30 mg in 2.5 mg increments)
tablet
- 2.5mg
- 5mg
- 7.5mg
- 10mg
- 15mg
Neoplasms
Antineoplastic dosage range: 30-40 mg/m²/week to 100-12,000 mg/m² with leucovorin rescue
Trophoblastic neoplasms: 15-30 mg/day PO/IM for 5 days; may be repeated
Burkitt lymphoma, stage I/II: 10-25 mg/day PO for 4-8 days
Dosing considerations
- Various dosing regimens exist; consult oncologist
Meningeal Leukemia
12 mg intrathecally; not to exceed 15 mg/dose every 2-7 days; administer 1 additional dose after cell count on CSF returns to normal;
Dosing considerations
- Administration at intervals less than 1 week may result in increased subacute toxicity
- Use preservative-free methotrexate only; dilute to 1 mg/mL in preservative-free NS
Osteosarcoma
12 g/m² IV over 4 hours on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy; leucovorin rescue
If peak serum methotrexate <454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m² in subsequent treatments
Dosing considerations
- High-dose therapy requires adequate hydration and urine alkalinization
- Delay methotrexate if severe myelosuppression, hepatotoxicity, mucositis, or pleural effusion present
Rheumatoid Arthritis
Indicated for management of severe, active rheumatoid arthritis (RA) in adults who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs
Initial: 7.5 mg PO as a single weekly dose, OR
2.5 mg PO q12hr for 3 sequential doses per week
Increase PO dose to optimum response; single dose not to exceed 20 mg/week PO (increased risk of bone marrow suppression); reduce to lowest possible effective dose
Otrexup (SC): If used as initial therapy, start at lowest available dose (ie, 10 mg SC qWeek)
Rasuvo (SC), initial dose: 7.5 mg as a single SC dose once weekly; adjust autoinjector dose by 2.5 mg increments as clinically required
Psoriasis
For symptomatic control of severe, recalcitrant, disabling psoriasis in adults not adequately responsive to other forms of therapy; use only with established diagnosis (by biopsy and/or after dermatologic consultation)
Initial: 10-25 mg weekly in single PO/SC/IM/IV dose; not to exceed 30 mg/wk
Gradually adjust dose to achieve to optimal clinical response; use lowest dose and longest rest period possible with return to conventional topical therapy encouraged
Trexall: May give weekly dose divided as 2.5 mg PO q12hr for 3 sequential doses
Otrexup (SC): If used as initial therapy, start a lowest available dose (ie, 10 mg SC qWeek)
Rasuvo (SC): 10-25 mg SC once weekly
Breast Cancer
40 mg/m² IV; days 1 and 8 every 4 weeks in combination with cyclophosphamide and fluoracil for 6-12 cycles
Head and Neck Cancer
40 mg/m² IV; once weekly until disease progression or unacceptable toxicity
Mycosis Fungoides (Cutaneous T-cell Lymphoma)
5-50 mg PO/IM once weekly or 15-37.5 mg twice weekly for who have responded poorly to weekly therapy
Dosage Modifications
Renal impairment
- Methotrexate elimination reduced with impaired renal function; carefully monitor for toxicity; some patients may require dose reduction or, in some cases, discontinuation
- CrCl 10-50 mL/min: 50% of dose at normal dosing interval
- CrCl <10 mL/min: Avoid use
- Intermittent hemodialysis: 50% of dose at normal dosing interval
- Continuous renal replacement therapy: 50% of dose at normal dosing interval
Hepatic impairment
- Bilirubin 3.1-5.0 mg/dL or AST > 3 times ULN: Give 75% of dose
- Bilirubin >5.0 mg/dL: Avoid use
Dosing Considerations
Otrexup and Rasuvo (SC injections) are not indicated for neoplastic disease
If switching from PO to SC (Otrexup, Rasuvo), consider higher bioavailability with SC compared with PO (see Pharmacology Absorption section)
Ectopic Pregnancy (Off-label)
50 mg/m² IM; measure serum hCG levels on days 4 and 7; may repeat dose on day 7 if necessary
If hCG levels decrease <15% between days 4 and 7, administer methotrexate 50 mg/m² IM; if hCG ≥15% between days 4 and 7, discontinue treatment and measure hCG weekly until reaching nonpregnant levels
Acute Lymphoblastic Leukemia (Orphan)
Orphan indication sponsor
- Only for Children Pharmaceuticals; 35 bis rue Gay; Lusac, France
Myasthenia Gravis (Orphan)
Orphan designation for treatment of myasthenia gravis
Sponsor
- Universtiy of Kanasa Medical Center; 3901 Rainbow Blvd, MSN 2012; Kanasa City , KS 66160
Proliferative Vitreoretinopathy (Orphan)
Orphan designation for prevention of proliferative vitreoretinopathy (PVR)
Sponsor
- Helio Vision, Inc; 1000 Winter Street, 4th Floor; Waltham, Massachusetts 02451
Ectopic Pregnancy (Orphan)
Orphan designation for treatment of ectopic pregnancy
Orphan sponsor
- Antares Pharma, Inc; Princeton Crossroads Corporate Center; 100 Princeton South Suite 300; Ewing, New Jersey 08628
Dosage Forms & Strengths
injectable solution
- 25mg/mL
powder for injection
- 1g
SC autoinjector (Otrexup)
- 7.5mg/0.4mL
- 10mg/0.4mL
- 12.5mg/0.4mL
- 15mg/0.4mL
- 17.5mg/0.4mL
- 20mg/0.4mL
- 22.5mg/0.4mL
- 25mg/0.4mL
SC autoinjector (Rasuvo)
- 2.5mg/0.05mL (delivers doses between 7.5 mg and 30 mg in 2.5 mg increments)
tablet
- 2.5mg
- 5mg
- 7.5mg
- 10mg
- 15mg
oral solution, ready-to-use (Xatmep)
- 2.5mg/mL
Polyarticular Juvenile Idiopathic Arthritis
Management of active polyarticular juvenile idiopathic arthritis (pJIA) in children who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs
Initial: 10 mg/m² PO/IM/SC qWeek
If switching from PO to SC (Otrexup, Rasuvo), consider higher bioavailability with SC compared with PO (see Pharmacology Absorption section)
Dosing Considerations (PJIA)
- Data with doses up to 30 mg/m²/wk in children exist, although there are too few published studies to assess how doses >20 mg/m²/wk might affect the risk of serious toxicity in children, especially bone marrow suppression
- Experience does suggest, however, that children receiving 20 to 30 mg/m²/wk (0.65-1 mg/kg/wk) may have better absorption and fewer GI side effects if methotrexate is administered either IM or SC
Meningeal Leukemia
<1 year: 6 mg intrathecally (IT) every 2-5 days
1-2 years: 8 mg IT every 2-5 days
2-3 years: 10 mg IT every 2-5 days
≥3 years: 12 mg IT every 2-5 days
Dosing considerations
- Use preservative-free methotrexate for injection only
- Dilute to 1 mg/mL in preservative-free 0.9% NaCl
Acute Lymphoblastic Leukemia
Xatmep (oral solution): Indicated for treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy regimen
20 mg/m² PO qWeek
Dosing considerations (ALL)
- Continuation of appropriate dosing requires periodic monitoring of ANC and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity
Dosage Modifications
Methotrexate elimination reduced with impaired renal function; carefully monitor for toxicity; some patients may require dose reduction or, in some cases, discontinuation
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Arachnoiditis with intrathecal administration
Subacute toxicity with intrathecal administration (paralysis of extremities, cranial nerve palsy, seizure or coma)
Demyelinating encephalopathy with cranial irradiation or other systemic chemotherapy
Reddening of skin
Hyperuricemia
Ulcerative stomatitis
Glossitis
Gingivitis
Nausea and vomiting
Diarrhea
Anorexia
Intestinal perforation
Mucositis (dose-dependent)
Leukopenia
Thrombocytopenia
Renal failure
Azotemia
Nephropathy
Pharyngitis
1-10%
Alopecia
Photosensitivity
Rash
Abdominal distress
Malaise
Fatigue
Chills, fever
Decreased resistance to infection
Gastrointestinal hemorrhage
Myelosuppression
Disorders of lung, interstitial pneumonia (acute, chronic)
Atrophy of liver, cirrhosis, hepatic fibrosis or necrosis, elevated liver function tests, hepatic failure
Warnings
Black Box Warnings
For use in life threatening neoplastic disease or patients with psoriasis or rheumatoid arthritis with severe recalcitrant disabling disease, not adequately responsive to other forms of therapy
Deaths reported with use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis
Monitor patients closely for bone marrow, liver, lung and kidney toxicities
Inform patients of risks involved; patient should be under a physician’s care throughout therapy
High dose regimens recommended for osteosarcoma requires meticulous care; high dose regimens are investigational; therapeutic advantage not established
Not recommended for women of childbearing potential, due to teratogenic activity, unless benefit-risk ratio is acceptable
May cause fetal death or congenital abnormalities; use is contraindicated in pregnant women
Methotrexate formulations or diluents containing preservatives should not be used for intrathecal or high-dose therapy
May cause renal damage leading to acute renal failure, especially in high doses
Elimination is reduced in impaired renal function, ascites, or pleural effusions; reduce dose and monitor carefully for toxicity
Bone marrow suppression, aplastic anemia, and GI toxicity reported with high doses and concurrent administration of NSAIDs
Any dose level or route of administration may cause severe and potentially fatal dermatologic reactions
Tumor lysis syndrome may occur in patients with high tumor burden
Administer therapy under supervision of physician experienced in use of antimetabolite therapy
Diarrhea and ulcerative stomatitis may necessitate interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur
Methotrexate has been associated with acute and potentially fatal chronic hepatotoxicity; acutely, liver enzyme elevations are common but are usually transient and asymptomatic and not predictive of subsequent hepatic disease; periodic liver biopsies are recommended for psoriatic patients receiving long-term therapy
Low-dose methotrexate has been associated with development of malignant lymphomas
Immune suppression may lead to potentially fatal opportunistic infections
May cause potentially fatal pneumonitis at any time during therapy even at low doses and is not fully reversible; pulmonary symptoms (especially a dry, non-productive cough) may require interruption of therapy and careful investigation
Concomitant use with radiotherapy may increase risk of soft tissue necrosis and osteonecrosis
Contraindications
Pregnancy: Do not use due to potential for fetal death and teratogenic effects
Nursing: Do not use due to potential for serious adverse effects in infants
Alcoholism, alcoholic liver disease, or other chronic liver disease
Immunodeficiency syndromes
Preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
Hypersensitivity: Do not use with known hypersensitivity; severe reactions have been observed with use
Cautions
Only for use by physicians experienced in antimetabolite therapy
For intrathecal and high-dose methotrexate therapy, use preservative-free formulation; preserved formulation of methotrexate is not for intrathecal or high dose therapy; contains benzyl alcohol
Elderly patients: monitor closely for early signs of hepatic, bone marrow, and renal toxicity
Response in 3-6 weeks; patient may continue to improve for another 12 weeks or more
Elimination reduced with renal impairment, ascites, or pleural effusions; monitor closely for renal, bone marrow, lung, or liver toxicity
Taking with folic acid 1 mg/day PO may significantly reduce liver toxicity
Dermatologic toxicity: severe, potentially fatal skin reactions have been reported; psoriatic lesions may also be aggravated by UV radiation and sunburns may be recalled or worsened
Good oral care recommended (risk of mucositis)
Use extreme caution with active infection, peptic ulceration, and ulcerative colitis
Immunizations: May be ineffective during therapy and live virus vaccines are not recommended due to risk of infection
Ectopic pregnancy: Ideally, human chorionic gonadotropin should be <5000 International Units/L and sonogram normal
Acute and chronic hepatoxicity: Acutely, liver enzyme elevations are common but are usually transient and asymptomatic and not predictive of subsequent hepatic disease; periodic liver biopsies are recommended for psoriatic patients receiving long-term therapy; should not be used in patient with alcoholism, alcoholic liver disease, or other chronic liver disease
Pulmonary toxicity: Pulmonary fibrosis, pulmonary interstitial infiltrates, and lung disease may occur acutely at any time during therapy (weekly doses >7.5 mg) but are fully reversible; symptoms (especially dry cough) may necessitate interruption of treatment and investigation
Methotrexate clearance rates vary widely and are generally decreased at higher doses
Glucarpidase is indicated for treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information); if glucarpidase used, do not administer leucovorin within two hours before or after dose of glucarpidase because leucovorin is a substrate for glucarpidase; there are published case reports of intravenous and intrathecal glucarpidase treatment to hasten clearance of methotrexate in cases of overdose
GI toxicity: Diarrhea or ulcerative stomatitis warrants discontinuance of therapy (risk of hemorrhagic enteritis or intestinal perforation)
Bone marrow suppression: May cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia; use caution in patients with preexisting hematopoietic impairment and with concomitant use of NSAIDs; a significant drop in blood counts warrants discontinuation of therapy
May impair fertility, cause oligospermia, and menstrual dysfunction; exclude pregnancy before initiating treatment
Neurotoxicity: May cause neurotoxicity, including strokelike encephalopathy, seizures, leukoencephalopathy, and myelopathy
Nephrotoxicity: Risk of acute renal failure especially at high doses
Caution should be used while driving or operating machinery due to risk of dizziness and fatigue
Use of nitrous oxide anesthesia potentiates effect on folate-dependent metabolic pathways, resulting in potential for increased toxicity such as stomatitis, myelosuppression, and neurotoxicity; avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate; use caution when administering methotrexate after a recent history of nitrous oxide administration
Pregnancy & Lactation
Pregnancy category: X
Lactation: Drug excreted in breast milk; do not nurse
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.
Pharmacology
Mechanism of Action
Inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair, and cellular replication; cell cycle specific for S phase of cycle
May inhibit rapid proliferation of epithelial cells in skin
Absorption
Bioavailability (PO): 60% at PO doses <30 mg/m², bioavailability is significantly less at doses >80 mg/m²
Bioavailability (SC, Otrexup): 17, 13, 31, and 36% greater than PO methotrexate at doses of 10, 15, 20, and 25 mg respectively
AUC (SC, Rasuvo): 35%, 49%, 51%, and 68% greater than PO methotrexate at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg respectively
Peak plasma time: PO, 1-2 hr; IM, 30-60 min
Distribution
Protein bound: 50%
Vd: Initial, 0.18 L/kg; steady-state, 0.4-0.8 L/kg
Metabolism
Metabolized by liver and intracellularly
Metabolites: Polyglutamated forms
Elimination
Half-life: Psoriasis, rheumatoid arthritis, and low-dose cancer treatment, 3-10 hr; high-dose treatment, 8-15 hr
Excretion: Urine (80-100% within 24 hr), feces (small amounts)
Administration
IV Incompatibilities
Additive: Bleomycin
Syringe: Droperidol, metoclopramide (may be compatible at low concentrations of metoclopramide)
Y-site: Chlorpromazine, dexamethasone sodium phosphate(?), droperidol(?), gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol
IV/IM Preparation
Reconstitute with D5W or NS: 20-mg vial, up to 25 mg/mL; 1-g vial, up to 50 mg/mL
May dilute further for IV infusion
IV/IM Administration
Administer by IM, IV push, or IV infusion
Regular IV given with no more than 25 mg/mL
IV push: Administered at 10 mg/min
IV infusion (usually >100 mg): Administered over 30 minutes to 4 hours, or according to institutional protocol
High-dose therapy (uses 1-g vial): Administered over 4 hours
Specific dosing schemes vary, but high doses should be followed by leucovorin 24 hours after initiation of therapy to prevent toxicity
IT Administration
Do not use preservative-containing drug
For meningeal leukemia, intrathecal administration is mandatory because CSF penetration is poor
Before administration, equal volume of CSF is usually withdrawn; administer drug only if easy flow of blood-free CSF is noted
SC Administration
Otrexup is a single-dose auto-injector available in doses between 10 to 25 mg (in 5-mg increments) for once-weekly SC use only
Rasuvo is a single-dose auto-injector available in doses between 7.5 and 30 mg (in 2.5-mg increments) for once-weekly SC use only
Use another formulation in patients who require PO, IM, IV, intra-arterial, or IT dosing
Visually inspect for particulate matter and discoloration prior to administration; do not use if seal is broken
Administer SC in abdomen or thigh
May self-inject if determined appropriate by a physician and have received proper training on preparation and administration; a trainer device is available
Handling and disposal consistent with recommendation for cytotoxic drugs
Oral Administration
Oral solution (Xatmep)
- Intended for oral use only
- Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity
- Measure dose with an accurate measuring device to provide the correct dose, such as an oral syringe provided by the pharmacist (do NOT use a household teaspoon)
- May take with or without food; food does not affect AUC, but decreased maximum concentration levels by 50% and delayed the absorption
Storage
Store intact vials at room temperature
Protect from light
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Formulary
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