methotrexate (Rx)

Brand and Other Names:Trexall, Otrexup, more...Rasuvo, Xatmep, RediTrex
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Dosing & Uses

AdultPediatricGeriatric

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)

SC prefilled syringe (RediTrex)

  • 7.5mg/0.3mL
  • 10mg/0.4mL
  • 12.5mg/0.5mL
  • 15mg/0.6mL
  • 17.5mg/0.7mL
  • 20mg/0.8mL
  • 22.5mg/0.9mL
  • 25mg/mL

tablet

  • 2.5mg
  • 5mg
  • 7.5mg
  • 10mg
  • 15mg

Acute Lymphoblastic Leukemia

Indicated for adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen

IV: Varies from 10-5,000 mg/m2; dose varies and depends disease state, patient risk category, concurrent drugs used, phase of treatment and response to treatment  

Use leucovorin rescue in accordance with high-dose methotrexate IV regimen guidelines

Meningeal Leukemia

Indicated for prophylaxis and treatment of meningeal leukemia in adult and pediatric patients

Use preservative-free methotrexate for intrathecal (IT) injection

Treatment: 12 mg IT; not to exceed 15 mg/dose every 2-7 days; administer 1 additional dose after cell count on CSF returns to normal

Prophylaxis: 12-15 mg IT no more than once weekly

Patients with Down syndrome: Administer leucovorin rescue with methotrexate IT

Non-Hodgkin Lymphoma

Indicated for treatment of adults and pediatric patients with Non-Hodgkin lymphoma (NHL)

Recommended dosage varies; refer to specific institutional protocol

See leucovorin rescue protocols for intermediate- and high-dose methotrexate regimens

Combination with other antineoplastics

  • Range 10-8,000 mg/m2 IV
  • Part of combination chemotherapy regimen: 1,000-3,000 mg/m2 IV infusion over 24 hr followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Single agent

  • Cutaneous forms of NHL: 5-75 mg IV

CNS-directed therapy

  • Single agent: 8,000 mg/m2 IV infusion over 4 hr
  • Combination with immunochemotherapy: 3,000-8,000 mg/m2 IV infusion followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Osteosarcoma

Indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen

12 g/m2 IV over 4 hr on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy  

If peak serum methotrexate <454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m2 in subsequent treatments

Not to exceed 20 g/dose

Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Breast Cancer

Indicated for breast cancer as part of a combination chemotherapy regimen

40 mg/m2 IV as a component of a cyclophosphamide- and fluorouracil-based multidrug regimen  

Squamous Cell Carcinoma of the Head and Neck

Indicated for squamous cell carcinoma of the head and neck as a single-agent

40-60 mg/m2 IV qWeek  

Gestational Trophoblastic Neoplasia

Indicated for adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen

30-200 mg/m2 or 0.4-1 mg/kg IV or IM  

High-risk GTN: 300 mg/m2 IV infused over 12 hr as a component of a multidrug regimen

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/IV/IM as a single weekly dose, OR

2.5 mg PO q12hr for 3 sequential doses per week

Increase 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 or RediTrex (SC), initial dose: 7.5 mg as a single SC dose once weekly; adjust autoinjector dose by 2.5 mg increments as clinically required

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

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 or RediTrex (SC): 10-25 mg SC once weekly

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

Dosage Modifications

Renal impairment

  • Methotrexate elimination reduced with CrCl <90 mL/min
  • Patients with renal impariemtn are at increased risk for adverse effects; carefully monitor for toxicity
  • Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens
  • Some patients may require dose reduction or, in some cases, discontinuation

Hepatic impairment

  • Safety in patients with hepatic impairment is unknown
  • Patients with hepatic impairment may be at increased risk for adverse reactions based on methotrexate elimination characteristics
  • Consider dose reduction or discontinuing with hepatic impairment as appropriate

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

Myasthenia Gravis (Orphan)

Orphan designation for treatment of myasthenia gravis

Orphan Sponsor

  • University of Kansas Medical Center; 3901 Rainbow Blvd, MSN 2012; Kansas City , KS 66160

Proliferative Vitreoretinopathy (Orphan)

Orphan designation for prevention of proliferative vitreoretinopathy (PVR)

Orphan 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/vial (25mg/mL when reconstituted)

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)

SC prefilled syringe (RediTrex)

  • 7.5mg/0.3mL
  • 10mg/0.4mL
  • 12.5mg/0.5mL
  • 15mg/0.6mL
  • 17.5mg/0.7mL
  • 20mg/0.8mL
  • 22.5mg/0.9mL
  • 25mg/mL

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, RediTrex), 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
  • Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

Meningeal Leukemia

Indicated for prophylaxis and treatment of meningeal leukemia in adult and pediatric patients

Use preservative-free methotrexate for intrathecal (IT) injection

Treatment: Dose may be given at intervals of ≥2 days up to twice weekly; however, administration at intervals of <1 week may result in increased subacute toxicity

Prophylaxis: Administered no more than once weekly

Patients with Down syndrome: Administer leucovorin rescue with methotrexate IT

Age-based dosing

<1 year: 6 mg IT

1 to <2 years: 8 mg IT

2 to <3 years: 10 mg IT

3 to <9 years: 12 mg IT

≥9 years: 12-15 mg IT

Acute Lymphoblastic Leukemia

Indicated for treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy regimen

IV: Varies from 10-5,000 mg/m2; dose varies and depends disease state, patient risk category, concurrent drugs used, phase of treatment and response to treatment  

Oral solution (Xatmep): 20 mg/m2 PO qWeek

Use leucovorin rescue in accordance with high-dose methotrexate IV regimen guidelines

Non-Hodgkin Lymphoma

Indicated for treatment of adults and pediatric patients with Non-Hodgkin lymphoma (NHL)

Recommended dosage varies; refer to specific institutional protocol

See leucovorin rescue protocols for intermediate- and high-dose methotrexate regimens

Combination with other antineoplastics

  • Range 10-8,000 mg/m2 IV
  • Part of combination chemotherapy regimen: 1,000-3,000 mg/m2 IV infusion over 24 hr followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Single agent

  • Cutaneous forms of NHL: 5-75 mg IV

CNS-directed therapy

  • Single agent: 8,000 mg/m2 IV infusion over 4 hr
  • Combination with immunochemotherapy: 3,000-8,000 mg/m2 IV infusion followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Osteosarcoma

  • Indicated for adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen
  • 12 g/m2 IV over 4 hr on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy
  • Not to exceed 20 g/dose
  • Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines
  • If peak serum methotrexate <454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m2 in subsequent treatments

Dosage Modifications

Renal impairment

  • Methotrexate elimination reduced with CrCl <90 mL/min
  • Patients with renal impairment are at increased risk for adverse effects; carefully monitor for toxicity
  • Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens
  • Some patients may require dose reduction or, in some cases, discontinuation

Hepatic impairment

  • Safety in patients with hepatic impairment is unknown
  • Patients with hepatic impairment may be at increased risk for adverse reactions based on methotrexate elimination characteristics
  • Consider dose reduction or discontinuing with hepatic impairment as appropriate

Dosing Considerations

May impair fertility, cause oligospermia, and menstrual dysfunction; exclude pregnancy before initiating treatment

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)

Use only preservative-free methotrexate injection for treatment of neonates or low-birth weight infants and for intrathecal use; do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available

Leucovorin rescue

  • Administer leucovorin rescue doses ≥500 mg/m2 (ie, high-dose)
  • Consider leucovorin rescue for doses 100 to <500 mg/m2 (ie, intermediate-dose)

Supportive care

  • For high-dose regimens, the following are recommended; also consider for intermediate-dose regimens
  • Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy
  • Administer IV fluids starting before first dose and continue throughout treatment to maintain hydration and urine output
  • Alkalinize urine starting before first dose and continue throughout treatment to maintain urine pH ≥7
  • Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed
  • Glucarpidase: Administer in patients with toxic plasma methotrexate concentrations (>1 micromole/L) and delayed methotrexate clearance owing to impaired renal function

Monitor closely for early signs of bone marrow suppression, and renal or hepatic toxicity

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Interactions

Interaction Checker

and methotrexate

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            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

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            Warnings

            Black Box Warnings

            Severe hypersensitivity

            • Contraindicated with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis

            Embryofetal toxicity

            • Can cause embryofetal toxicity, including fetal death
            • Contraindicated in non-neoplastic diseases during pregnancy
            • Advise females and males of reproductive potential to use effective contraception during and after treatment

            Benzyl alcohol-containing products

            • Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis; use only preservative-free methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use
            • Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available

            Serious adverse effects

            • Serious adverse reactions, including death, reported with methotrexate
            • Closely monitor for infections and adverse reactions of bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin
            • Withhold or discontinue methotrexate as appropriate

            Contraindications

            Pregnant women with nonmalignant disease

            Known hypersensitivity; severe reactions observed

            Cautions

            Based on published reports and its mechanism of action, can cause embryofetal toxicity, including fetal death; contraindicated in females with nonmalignant disease

            Hypersensitivity reactions, including anaphylaxis, reported; if hypersensitivity occurs, immediately discontinue and institute appropriate therapy

            Myelosuppression reported, including severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia; obtain blood counts at baseline and periodically; provide supportive care and withhold, reduce dose, or discontinue methotrexate if needed

            GI toxicity may occur, including diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation; patients with peptic ulcer disease or ulcerative colitis at greater risk; withhold or discontinued for severe GI toxicity and institute supportive care

            Pulmonary toxicity reported, including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels; pulmonary symptoms (especially a dry, non-productive cough) may require interruption of therapy and careful investigation

            Pulmonary toxicity reported, including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels

            Secondary malignancies can occur at all dose levels; in some cases, lymphoproliferative disease that occurred during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate; if lymphoproliferative disease occurs, discontinue and institute appropriate treatment if lymphoma does not regress

            Can induce tumor lysis syndrome with rapidly growing tumors; institute appropriate treatment for prevention and management

            Can cause impairment of fertility, oligospermia, and menstrual dysfunction; unknown if infertility is reversible; discuss reproduction risks with female and male patients of reproductive potential

            Methotrexate can exit slowly from third space accumulations resulting in prolonged terminal plasma half-life and toxicity; evacuate significant third-space accumulations prior injection Concomitant radiation therapy increases risk of soft tissue necrosis and osteonecrosis associated with methotrexate

            Serious adverse reactions, including death, have occurred due to medication errors; most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed; ensure that patients receive the recommended dosage

            Risk associated with benzyl alcohol preservative

            • Formulations with benzyl alcohol can cause severe CNS toxicity or metabolic acidosis, if used in neonates or low-birth weight infants, IT, or in high-dose regimens
            • Use only preservative-free injection for treatment of neonates or low-birth weight infants and for intrathecal use
            • Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available
            • Benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when injection required during pregnancy to treat neoplastic disease
            • Gasping syndrome
              • Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol
              • Gasping syndrome characterized by CNS depression, metabolic acidosis, and gasping respirations
              • When prescribing in infants (non-neonate, non-low-birth weight), if preservative-free formulation unavailable and use of a benzyl alcohol-containing formulation is necessary, consider combined daily metabolic load of benzyl alcohol from all sources

            Neurotoxicity

            • Serious neurotoxicity, including generalized and focal seizures, reported in pediatric patients
            • Leukoencephalopathy can occur with intermediate and high-dose IV regimens, IT administration, and low-dose methotrexate therapy; risk increased with prior cranial radiation
            • Transient acute stroke-like syndrome can occur with high-dose regimens; clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma
            • Intrathecal (IT) administration
              • IT administration can cause acute chemical arachnoiditis manifested by symptoms such as headache, back pain, nuchal rigidity, and fever
              • May also cause subacute myelopathy characterized by paraparesis or paraplegia Avoid IT use of methotrexate injection that contains the preservative benzyl alcohol because of risk of serious neurotoxicity

            Infections

            • Increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections (eg, Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, disseminated Herpes zoster and cytomegalovirus infections)
            • Closely monitor patients for development of signs and symptoms of infection during and after treatment; withhold or discontinue in patients who develop serious infections

            Renal Toxicity

            • Can cause renal toxicity including irreversible acute renal failure
            • Monitor renal function and withhold or discontinue as needed for severe renal toxicity
            • For high-dose regimens, follow recommendations to decrease renal injury and mitigate renal toxicity (eg, hydration, alkalinize urine, leucovorin rescue)
            • Patients with impaired renal function have increased risk for toxicity
            • Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed clearance due to impaired renal function

            Hepatotoxicity

            • Can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver
            • Avoid use in patients with chronic liver disease, unless benefits clearly outweigh risks; risk increased with heavy alcohol consumption
            • In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver function tests; risk of hepatotoxicity appears to increase with total cumulative dose ≥1.5 g
            • Assess liver function before initiating and monitor liver function tests during treatment; withhold or discontinue methotrexate Injection as appropriate

            Dermatologic reactions

            • Severe, including fatal, dermatologic reactions reported (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme)
            • Psoriasis may be aggravated by concomitant exposure to UV radiation
            • Can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation
            • Monitor for signs of dermatologic toxicity and withhold or permanently discontinue for severe dermatologic adverse reactions
            • Counsel patients to avoid excessive sun exposure and use sun protection measures

            Folic acid supplementation

            • Neoplastic diseases: Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate; avoid products containing folic acid or folinic acid unless clinically indicated
            • Non-neoplastic diseases: Folate deficiency may increase methotrexate adverse reactions; administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis

            Drug interaction overview

            • Drugs that increase methotrexate systemic exposure or adverse effects
              • If unable to avoid coadministration, monitor closely for methotrexate adverse effects
              • Penicillin or sulfonamide antibiotics
              • Highly protein-bound drugs (eg, oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, tetracyclines)
              • Proton pump inhibitors
              • Probenecid
              • Antifolate drugs (eg, dapsone, pemetrexed, pyrimethamine, sulfonamides)
              • Aspirin and other NSAIDs; unexpectedly severe and fatal GI toxicity can occur with concomitant administration of methotrexate (primarily at high dose)
              • Mercaptopurine
              • Hepatotoxic products
              • Weak acids (eg, salicylates)
              • Nephrotoxic products
            • Nitrous oxide
              • Avoid nitrous oxide anesthesia; consider alternative therapies in patients who have received prior nitrous oxide anesthesia
              • Coadministration with nitrous oxide anesthesia potentiates methotrexate’s effect on folate-dependent metabolic pathways, which may increase risk of severe methotrexate adverse reactions
              • Folic acid H5Avoid coadministration of folic/folinic acid supplements unless specifically prescribed (eg, for use with rheumatoid arthritis, psoriasis, or pJIA)
              • Coadministration with folic acid or its derivatives decreases clinical effectiveness of methotrexate in patients with neoplastic diseases
              • Methotrexate competes with reduced folates for active transport across cell membranes
            • Theophylline
              • Monitor theophylline levels and adjust theophylline dosage accordingly
              • Methotrexate may increase theophylline plasma concentrations
            • Immunizations
              • Update immunization per guidelines before initiating methotrexate if possible
              • May be ineffective during therapy and live virus vaccines are not recommended due to risk of infection
              • Disseminated infections following administration of live vaccines reported
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            Pregnancy & Lactation

            Pregnancy

            Based on published reports and mechanism of action, can cause embryo-fetal toxicity and fetal death when administered to pregnant women

            Advise pregnant women with neoplastic diseases of potential risk to fetus; preservative benzyl alcohol can cross placenta; when possible, use preservative-free formulation when methotrexate Injection needed during pregnancy to treat a neoplastic disease

            Verify pregnancy status of females of reproductive potential before initiating

            Contraindicated in pregnant women with nonmalignant disease

            Contraception

            • Females
              • Can cause fetal harm when administered to pregnant women;
              • Use effective contraception during and for 6 months after final dose
            • Males
              • Can cause chromosomal damage to sperm cells
              • Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after final dose

            Infertility

            • Females: Can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy; unknown if infertility may be reversed in all affected females
            • Males: Can cause oligospermia or infertility during and after cessation of therapy; unknown if infertility may be reversed in all affected males

            Lactation

            Limited published literature report the presence of methotrexate in human milk in low amounts; no information is available on the effects on breastfed infants or milk production

            Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during therapy and for 1 week after final dose

            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.

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            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)

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            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

            Use only preservative-free product

            May dilute further with preservative-free 0.9% NaCl

            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

            RediTrex is a single-dose prefilled syringe available in doses between 7.5 and 25 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

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.