Methotrexate

Class: Antineoplastic Agents
VA Class: AN300
Molecular Formula: C₂₀H₂₂N₈O₅
CAS Number: 59-05-2
Brands: Rheumatrex, Trexall

• Experience of Supervising Clinician


• 
  

  Administer only under supervision of qualified clinicians experienced in use of antimetabolite therapy.^{b c}

  
  

• Serious Toxic Reactions (Sometimes Fatal) Possible


• 
  

  Deaths reported with use in treatment of malignancy, psoriasis, and rheumatoid arthritis.^{b c}

  
  


• 
  

  Use only for treatment of life-threatening neoplastic diseases or severe, recalcitrant, disabling psoriasis or rheumatoid arthritis in patients who have not responded adequately to other forms of therapy.^{b c}

  
  


• 
  

  Closely monitor patients for bone marrow, hepatic, pulmonary, or renal toxicities.^{b c} (See Major Toxicities under Cautions.)

  
  


• 
  

  Inform patients of risks involved with therapy and importance of remaining under care of clinician throughout therapy.^{b c}

  
  

• High-Dose Regimens


• 
  

  Use of high-dose regimens recommended for treatment of osteosarcoma requires meticulous care.^b (See High-Dose Methotrexate Therapy with Leucovorin Rescue and also see Osteosarcoma, under Dosage and Administration.)

  
  


• 
  

  Use of high-dose regimens for other neoplastic diseases is investigational; therapeutic advantage not established.^b

  
  

• Formulations or Diluents Containing Preservatives


• 
  

  Do not use formulations or diluents containing preservatives for intrathecal administration or high-dose therapy.^b

  
  

• Fetal/Neonatal Morbidity and Mortality


• 
  

  Fetal death and/or congenital anomalies reported.^{b c} Not recommended for use in women of childbearing potential unless potential benefit clearly outweighs risks; do not use in pregnant women with psoriasis or rheumatoid arthritis.^{b c} (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

  
  

• Reduced Elimination


• 
  

  Elimination reduced in patients with renal impairment, ascites, or pleural effusions.^{b c} Carefully monitor for toxicity in such patients; dosage reduction or discontinuance may be required.^{b c}

  
  

• Concomitant Therapy with NSAIAs


• 
  

  Unexpectedly severe, sometimes fatal, myelosuppression, aplastic anemia, and GI toxicity reported with concomitant use of methotrexate (usually at high dosages) and some NSAIAs.^{b c} (See Specific Drugs under Interactions.)

  
  

• Hepatotoxicity


• 
  

  Possible hepatotoxicity, fibrosis, and cirrhosis, generally only after prolonged use.^{b c} (See Hepatic Effects under Cautions.)

  
  


• 
  

  Acute liver enzyme elevations frequently observed; usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease.^{b c}

  
  


• 
  

  Liver biopsy after sustained use often shows histologic changes.^{b c} Fibrosis and cirrhosis may not be preceded by symptoms or abnormal liver function tests in patients with psoriasis; periodic liver biopsies usually recommended in such patients undergoing long-term therapy.^{b c}

  
  


• 
  

  Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in patients with rheumatoid arthritis.^{b c}

  
  

• Pulmonary Toxicity


• 
  

  Potentially dangerous pulmonary lesions, not always reversible, may occur acutely at any time during therapy and have been reported at dosages as low as 7.5 mg weekly.^{b c} Pulmonary symptoms (especially dry, nonproductive cough) may require therapy interruption and careful evaluation.^{b c}

  
  

• GI Toxicity


• 
  

  Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.^{b c}

  
  

• Malignant Lymphomas


• 
  

  Malignant lymphomas (e.g., non-Hodgkin’s lymphoma) may occur in patients receiving low-dose oral therapy; such lymphomas may regress following methotrexate discontinuance and may not require cytotoxic therapy.^{a b c} If the lymphoma does not regress following discontinuance, institute appropriate therapy.^{b c}

  
  

• Tumor Lysis Syndrome


• 
  

  May induce tumor lysis syndrome in patients with rapidly growing tumors; appropriate pharmacologic and supportive treatment may prevent or alleviate syndrome.^{b c}

  
  

• Dermatologic Reactions


• 
  

  Severe, occasionally fatal skin reactions reported following single or multiple doses; reactions occurred within days of oral, IM, IV, or intrathecal administration.^{b c} Recovery reported with discontinuance of therapy.^{b c} (See Dermatologic and Sensitivity Reactions under Cautions.)

  
  

• Opportunistic Infections


• 
  

  Potentially fatal opportunistic infections, especially Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia.^{b c}

  
  

• Concomitant Radiotherapy


• 
  

  Possible increased risk of soft tissue necrosis and osteonecrosis in patients receiving methotrexate concomitantly with radiotherapy.^{b c}

  
  

Introduction

Antineoplastic agent and immunosuppressant; folic acid antagonist.^{a b c}

Uses for Methotrexate

Breast Cancer

Treatment (alone or, more commonly, in combination chemotherapy) of breast cancer.^{a b c}

First-line adjuvant chemotherapy in combination with other drugs (i.e., cyclophosphamide and fluorouracil, with or without hormonal therapy).^{166 167 168 169 170 171 172 173 174 175 178 179 182 185 186 187 d} An anthracycline-containing regimen is preferred in patients with node-positive disease.^d

Some studies suggest a slight advantage for anthracycline-containing regimens in relapse-free and survival rates in both premenopausal and postmenopausal patients.^l

Also used in patients with metastatic disease.^{d l}

Head and Neck Cancer

Palliative treatment (alone and in combination therapy) of recurrent or metastatic head and neck carcinoma.^{182 210 211 212 b c d}

Frequently used in combination regimens with other antineoplastic agents (e.g., bleomycin, fluorouracil, vincristine).²¹⁰

Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for recurrent or metastatic squamous cell carcinoma of the head and neck.²¹²

Further study needed to establish comparative benefit of methotrexate-containing regimens.^{210 212}

Leukemias

Component of various chemotherapy regimens in palliative treatment of acute leukemias.^{a b c}

Intrathecally for prophylaxis and treatment of meningeal leukemia.^{a b d}

First-line therapy in combination with mercaptopurine for maintenance of drug-induced remissions of acute lymphoblastic leukemia (ALL).^{b c d}

Has been used in high doses as a component of some alternative combination chemotherapy regimens for remission induction in ALL, but not generally considered a drug of choice for remission induction.^d

Rarely effective alone for treatment of acute myeloblastic leukemia (AML);^a has been used as an additional component in some chemotherapy regimens for induction or post-induction therapy of AML.^{a d}

Lung Cancer

Has been used in second-line therapy of recurrent small cell lung cancer.^{235 b c n}

Although labeled for use in squamous cell type of non-small cell lung cancer,^{127 b c} other agents are preferred.^{182 d}

Lymphomas

Component of combination chemotherapeutic regimens as first-line palliative therapy for high-grade Burkitt’s lymphoma or maintenance therapy for high-grade lymphoblastic non-Hodgkin’s lymphoma.^{b c d}

Component of alternative combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas (diffuse large cell, diffuse small cell, diffuse mixed, follicular large cell).^d

Has been used intrathecally in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab for first-line therapy of intermediate-grade non-Hodgkin’s lymphomas.^d

Although radiation or topical therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in generalized stages of these diseases.^a

First-line^d systemic chemotherapy for advanced cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).^{b c o}

First-line line therapy of primary CNS lymphoma.^d

Hodgkin’s disease responds poorly to methotrexate.^a

Osteosarcoma

High-dose therapy, followed by leucovorin rescue, in combination chemotherapy regimens as adjunct to surgical resection or amputation of primary tumor in patients with nonmetastatic osteosarcoma^{b d h} (designated an orphan drug by FDA for this use).¹⁹²

Also has been used as a component of adjunctive combination chemotherapy regimens in patients with metastatic osteosarcoma.^h

Psoriasis

Symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy in carefully selected patients; not curative.^{a b c}

Use only after diagnosis definitely established (e.g., biopsy, after dermatologic consultation).^{b c}

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.^{111 112 113 114 115 116 127 128 138 139 140 141 142 143 144 145 146 147 148 149 152 153 154 b c}

Management of active polyarticular-course juvenile rheumatoid arthritis in children who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy (i.e., full-dose NSAIAs).^{b c} (See Pediatric Use under Cautions.)

One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.^{220 224}

Substantially greater long-term efficacy than other DMARDs; used as the initial or anchor DMARD in many patients with rheumatoid arthritis.^{220 222 224 225 226} Also has been used in combination with other DMARDs.^{220 222 225 228 229 230 231 232 233 234}

Use only as part of a comprehensive treatment program, including nondrug therapies (e.g., rest, physical therapy).¹²⁷

No substantial evidence that methotrexate permanently arrests or reverses the underlying disease process,^{127 128 138 140 144 147 153} although disease progression is slowed in some patients.^{138 140 143 144 160 220}

Trophoblastic Neoplasms

Treatment (with or without leucovorin) of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, hydatidiform mole) in women (except those with impaired renal or hepatic function or who have failed to respond to previous methotrexate therapy, in which case dactinomycin is used).^{a b c e}

Most effective in patients who have had disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases.^a

First-line therapy with or without leucovorin in patients with nonmetastatic or good-prognosis metastatic gestational trophoblastic neoplasms.^{d e}

Component of combination chemotherapy regimen with dactinomycin and chlorambucil in patients with good-prognosis metastatic gestational trophoblastic neoplasms with refractory disease.^e

In patients with poor-prognosis metastatic trophoblastic neoplasms, methotrexate in combination with etoposide, dactinomycin, vincristine, and cyclophosphamide (EMA-CO) is a standard treatment option.^e A dose-intensive regimen, EMA-CE, in which etoposide and cisplatin are substituted for vincristine and cyclophosphamide of the EMA-CO regimen, may offer additional benefits.^e

Has been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.^a

Testicular choriocarcinomas are usually resistant to methotrexate alone; has been used as component of combination therapy in patients with metastatic tumors of the testes.^a

Bladder Cancer

Used in combination regimens with vinblastine and cisplatin, with or without doxorubicin, as first- or second-line therapy^d for invasive and advanced bladder cancer†.^{182 205 206 207 208 209}

Use of leucovorin rescue or deletion of methotrexate is advised if methotrexate-containing regimens are being considered for the treatment of advanced or metastatic bladder cancer in patients with renal dysfunction, edema, pleural fluid collections, or ascites.²⁰⁵

Crohn’s Disease

Management of chronically active Crohn’s disease†.^{241 242 243 244 245 246 247 248 249 250 251 258 259 260}

Ectopic Pregnancy

Used as an alternative to surgical management of ectopic pregnancy† in selected patients with small, unruptured tubal pregnancies.^{i j k}

Multiple Sclerosis

Low-dose oral therapy has been used in patients with chronic progressive multiple sclerosis†.^{201 202 203 204}

Psoriatic Arthritis

Has been used for its immunosuppressive and/or anti-inflammatory effects in treatment of psoriatic arthritis†.^{109 110}

Methotrexate Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{b c}

  
  


• 
  

  Do not prescribe or dispense on as-needed (“prn”) basis.^c

  
  


• 
  

  If toxicity previously necessitated discontinuance, reinstitute with caution; consider further need for drug and risk of toxicity recurrence.^{a b c}

  
  

High-Dose Methotrexate Therapy with Leucovorin Rescue

• 
  

  Use of high-dose regimens employed in adjunctive treatment of osteosarcoma requires meticulous understanding of risks associated with therapy and leucovorin rescue.^{a b}

  
  


• 
  

  Hydrate patients with 1 L/m² of IV fluid over 6 hours prior to initiation of methotrexate infusion.^b Continue hydration at 125 mL/m² per hour (3 L/m² daily) during methotrexate infusion and for 2 days after completion of infusion.^b

  
  


• 
  

  Alkalinize urine with sodium bicarbonate to maintain pH >7 during methotrexate infusion and leucovorin calcium therapy; administer sodium bicarbonate orally or via a separate IV solution.^b

  
  


• 
  

  S_cr must be normal and Cl_cr >60 mL/minute before therapy initiation.^b Repeat S_cr 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).^b

  
  


• 
  

  Measure S_cr prior to each subsequent course of therapy; if S_cr increases by ≥50% compared to prior value, measure and document that Cl_cr >60 mL/minute (even if S_cr is still within normal range).^b

  
  


• 
  

  Also consult manufacturer’s labeling and published protocols for specific recommendations based on laboratory and clinical findings.^a

  
  

Administration

Administer orally or by IM, IV, or intrathecal injection; may also administer intra-arterially.^{b c} Has been administered by sub-Q injection.^{c p}

Do not use formulations or diluents containing preservatives (e.g., benzyl alcohol) for intrathecal administration or high-dose therapy.^b

Oral Administration

Administer orally as tablets.^c

Oral administration is often preferred when low doses are used since absorption is rapid and effective serum concentrations are achieved.^{b c}

Manufacturer makes no specific recommendations regarding administration with meals; food delays absorption and reduces peak serum concentrations.^{214 b c}

Inadvertent daily instead of weekly administration in patients with psoriasis or rheumatoid arthritis may result in fatal toxicity; carefully instruct patient regarding regimen and frequency of administration.^c (See Advice to Patients.)

Mnemonic dispensing packages (e.g., Rheumatrex Dose Pack) may be used for initial and maintenance therapy in patients receiving weekly doses of 5–15 mg but are not recommended for titration to weekly doses >15 mg.^{a c}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection or infusion.^b

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).^b

Reconstitute 20 mg vial to a concentration ≤25 mg/mL.^b Reconstitute 1 g vial with 19.4 mL of appropriate solution to yield a concentration of 50 mg/mL.^b

Dilution

When high doses are administered by IV infusion, dilute total dose of reconstituted solution in 5% dextrose injection.^b

May further dilute commercially available solution for IV injection containing preservatives with a compatible solution (e.g., 0.9% sodium chloride injection).^b

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).^b

IM Administration

Administer by IM injection.^b

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).^b

Intrathecal Administration

Preservative-free solutions (1 mg/mL) are used for intrathecal injection.^b Do not administer solutions containing preservatives intrathecally.^b

Must administer intrathecally for treatment of meningeal leukemia since passage of drug from blood to CSF is minimal.^{a b}

Prior to intrathecal administration, a volume of CSF approximately equivalent to volume of solution to be injected (e.g., 5–15 mL) is usually removed.^a

If lumbar puncture is traumatic, do not administer intrathecally; allow 2 days to elapse before again attempting injection.^a

Inject intrathecally only if there is easy flow of blood-free spinal fluid.^a

Some clinicians recommend that entire volume of methotrexate injection be injected intrathecally in 15–30 seconds.^a Aspiration should not be performed.^a

Appears in systemic circulation following intrathecal administration; adjust, reduce, or discontinue any concomitant systemic administration as appropriate.^{a b}

Systemic administration of leucovorin calcium simultaneously with intrathecal methotrexate may prevent systemic toxicity without abolishing drug’s activity in CNS.^a

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).^b

Dilution

For intrathecal injection, dilute methotrexate preservative-free solution for injection to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).^b

Dosage

Available as methotrexate sodium; dosage is expressed in terms of methotrexate.^{b c}

Various dosage schedules have been used; individualize dosage, route of administration, and duration of therapy according to disease being treated, other therapy employed, and condition, response, and tolerance of the patient.^a Consult published protocols for additional information on alternative regimens and dosages.

Pediatric Patients

Juvenile Rheumatoid Arthritis

Oral

May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects associated with the drug.^c

Initially, 10 mg/m² once weekly.^{b c} May adjust dosage gradually to achieve optimal response.^{b c}

Dosages up to 30 mg/m² weekly have been used in children, but published data are too limited to assess risk of serious toxicity at dosages >20 mg/m² weekly.^{b c}

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.^{b c}

Optimum duration of therapy is unknown.^{b c}

IM or Sub-Q

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.^{b c}

Leukemias

Meningeal Leukemia

Intrathecal

Regardless of method used to determine intrathecal dosage, carefully check dose prior to administration to minimize risk of inadvertent intrathecal overdosage.¹⁰⁶

Clinical studies indicate that intrathecal dosage regimens based on age may be more effective and less neurotoxic than dosage regimens based on body surface area.^{107 108 127 b}

Table 1. Recommended Intrathecal Dose Based on Age107108127

Age	Dose
<1 year	6 mg
1 year	8 mg
2 years	10 mg
≥3 years	12 mg

Intrathecal doses based on body surface area (i.e., 12 mg/m², maximum 15 mg) reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients.^b

Treatment: may administer at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable.^b Administration at intervals of <1 week may result in increased subacute toxicity.^b

Prophylaxis: dosage is the same as for treatment; administration intervals differ from regimen used in treatment.^{a b} Consult specialized references and medical literature for specific recommendations.^{a b}

Adults

Breast Cancer

Various combination chemotherapy regimens have been used in the treatment of breast cancer; consult published protocols for dosages and method and sequence of administration.^{168 169 170 171 172 173 174 176 180 181 183 185 187}

Dose intensity of adjuvant combination chemotherapy appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; avoid arbitrary reductions in dose intensity.^{166 170 187}

IV

Dosage of 40 mg/m² IV on days 1 and 8 of each cycle in combination with cyclophosphamide 100 mg/m² on days 1–14 of each cycle and fluorouracil 600 mg/m² on days 1 and 8 of each cycle is commonly employed for treatment of early breast cancer.^{168 169 187}

In patients >60 years of age, initial dosage is reduced to 30 mg/m² and initial fluorouracil dosage is reduced to 400 mg/m²; ¹⁶⁹ dosage also reduced if myelosuppression develops.^{168 169}

Cycles are generally repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6–12 cycles (i.e., 6–12 months of therapy).^{168 169 187}

In a sequential regimen in which several courses of doxorubicin are administered prior to a regimen of cyclophosphamide, methotrexate, and fluorouracil in patients with early breast cancer and >3 positive axillary lymph nodes,¹⁷¹ 4 doses of doxorubicin hydrochloride 75 mg/m² were administered initially at 3-week intervals followed by 8 cycles of methotrexate 40 mg/m², cyclophosphamide 600 mg/m², and fluorouracil 600 mg/m² at 3-week intervals for a total of approximately 9 months of therapy.^{171 185} If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than dosage reduced.^{171 185}

Leukemia

ALL (Induction Therapy)

Oral

Not generally a drug of choice, but 3.3 mg/m² daily in combination with prednisone 40–60 mg/m² daily for 4–6 weeks has been used.^{a b c}

ALL (Maintenance Therapy)

Oral or IM

After remission attained, 20–30 mg/m² total weekly dose, administered in divided doses twice weekly.^{a b c}

IV

Alternatively, 2.5 mg/kg has been administered IV every 14 days.^{a b c}

Meningeal Leukemia

Intrathecal

Treatment: 12 mg administered at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable.^b However, administration at intervals of <1 week may result in increased subacute toxicity.^b

Prophylaxis: 12 mg; administration intervals differ from regimen used in treatment.^{a b} Consult specialized references and medical literature for specific recommendations.^{a b}

Intrathecal doses of 12 mg/m² (maximum 15 mg) reported to result in high CSF methotrexate concentrations and neurotoxicity in adults.^b

Lymphomas

Oral

For Burkett’s lymphoma (stage I or II), 10–25 mg daily for 4–8 days.^{b c} In stage III Burkitt’s lymphoma, commonly given with other antineoplastic agents.^{b c} In all stages, several courses are usually administered, interposed with 7- to 10-day rest periods.^{b c}

Stage III lymphosarcomas may respond to combined drug therapy with methotrexate given in doses of 0.625–2.5 mg/kg daily.^{b c}

Cutaneous T-cell Lymphoma; Mycosis Fungoides

Oral, IM, or Sub-Q^p

Usually, 5–50 mg weekly in early stages.^{b c 241} Dose reduction or discontinuance is determined by hematologic monitoring and patient response.^{c 241}

Also has been administered twice weekly in doses ranging from 15–37.5 mg in patients who have responded poorly to weekly therapy.^{b c 241}

IV

Combination chemotherapy regimens that include higher-dose methotrexate with leucovorin rescue have been used in advanced stages.^{b c 241} Consult published protocols for dosages.

Osteosarcoma

High-Dose Methotrexate Therapy with Leucovorin Rescue

IV

Initially, 12 g/m² infused over 4 hours on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery on a schedule in combination with other chemotherapy agents (e.g., doxorubicin; cisplatin; combination of bleomycin, cyclophosphamide, and dactinomycin).^b If initial dosage is not sufficient to produce peak serum methotrexate concentrations of 454 mcg/mL (1000 mcM [10^-3 mol/L]) at the end of IV infusion, may increase dose to 15 g/m² in subsequent treatments.^b

Initiate leucovorin rescue therapy at a dosage of 15 mg orally every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion.^b May give leucovorin IV or IM if patient cannot tolerate oral therapy.^b If clinically important methotrexate toxicity is observed, extend leucovorin therapy for an additional 24 hours (total of 14 doses instead of 10) in subsequent courses.^b

Delay subsequent methotrexate administration until recovery if the following adverse effects occur: if WBC count is <1500/mm³; neutrophil count is <200/mm³; platelet count is <75,000/mm³; serum bilirubin concentration is >1.2 mg/dL; ALT concentration is >450 units; mucositis is present (until there is evidence of healing); or persistent pleural effusion is present (drain dry prior to infusion).^b

Table 2. Leucovorin Rescue Schedules Based on Serum Methotrexate Concentrationsb

Clinical Situation	Laboratory Findings	Leucovorin Dosage and Duration
Normal methotrexate elimination	Serum methotrexate concentration approximately 4.54 mcg/mL (10 mcM) at 24 hours after administration, 0.454 mcg/mL (1 mcM) at 48 hours, and <0.091 mcg/mL (0.2 mcM) at 72 hours	15 mg orally, IM, or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion)
Delayed late methotrexate elimination	Serum methotrexate concentration remaining >0.091 mcg/mL (0.2 mcM) at 72 hours and >0.023 mcg/mL (0.05 mcM) at 96 hours after administration	Continue 15 mg orally, IM, or IV every 6 hours, until methotrexate concentration is <0.023 mcg/mL (0.05 mcM)
Delayed early methotrexate elimination and/or evidence of acute renal injury	Serum methotrexate ≥22.7 mcg/mL (50 mcM) at 24 hours or ≥2.27 mcg/mL (5 mcM) at 48 hours after administration, or a ≥100% increase in Scr concentration at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a concentration of ≥1 mg/dL)	150 mg IV every 3 hours, until methotrexate concentration is <0.454 mcg/mL (1 mcM), then 15 mg IV every 3 hours until methotrexate concentration is <0.023 mcg/mL (0.05 mcM)

Psoriasis

Oral

Administration of a single 5- to 10-mg dose 1 week prior to initiation of therapy has been recommended to detect idiosyncratic reactions.^a

Divided oral dosage schedule: 2.5 mg at 12-hour intervals for 3 doses each week.^c May gradually adjust dosage by 2.5 mg/week to achieve optimal response; do not exceed 30 mg weekly ordinarily.^{a c}

Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.^c Use may permit return to conventional topical therapy.^c

Oral, IM, or IV

Weekly single-dosage schedule: 10–25 mg as a single dose once weekly until adequate response achieved.^c May gradually adjust dosage to achieve optimal response; do not exceed 30 mg weekly ordinarily.^c Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.^c

Rheumatoid Arthritis

Oral

May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects.^c

Initially, 7.5 mg once weekly or a course once weekly of 2.5 mg administered at 12-hour intervals for 3 doses.^c May gradually adjust dosage to achieve an optimal response.^c

At dosages >20 mg weekly, possible increased incidence and severity of serious toxic reactions, especially myelosuppression.^c

Optimal duration of therapy is not known; limited data indicate that initial improvement is maintained for at least 2 years with continued therapy.^c

Trophoblastic Neoplasms

Oral or IM

Usually, 15–30 mg daily for 5 days.^{b c} A repeat course may be given after a period of ≥1 week, provided all signs of residual toxicity have disappeared; 3–5 courses are usually employed.^{a b c} Clinical assessment before each course is essential.^{b c}

Therapy is usually evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which usually normalizes after third or fourth course; complete resolution of measurable lesions usually occurs 4–6 weeks later.

1 or 2 courses of therapy are usually given after normalization of urinary hCG concentrations is achieved.

Crohn’s Disease†

Chronically Active Refractory Disease

IM

25 mg once weekly has been administered for 16 weeks.^{241 243 244 250 251}

Oral

12.5–22.5 mg once weekly has been administered for up to 1 year.²⁵²

Maintenance Therapy

IM

15 mg once weekly has been used.²⁵²

Ectopic Pregnancy†

IM

50 mg/m² as a single dose.ⁱ May require second dose or surgical intervention if hCG concentration fails to decrease by at least 15% from day 4 to day 7 after methotrexate administration.ⁱ

Alternatively, 1 mg/kg (on days 0, 2, 4, and 6) alternating with 0.1 mg/kg of leucovorin IM (on days 1, 3, 5, and 7) has been used.^{i k}

Prescribing Limits

Pediatric Patients

Juvenile Rheumatoid Arthritis

Oral, IM, or Sub-Q

Although there is experience with dosages up to 30 mg/m² weekly in children, published data are too limited to assess how dosages >20 mg/m² weekly might affect risk of serious toxicity.^{b c}

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer GI effects if administered either IM or sub-Q.^{b c}

Adults

Psoriasis

Oral, IM, or IV

Do not ordinarily exceed 30 mg weekly.^c

Rheumatoid Arthritis

Oral, IM, or IV

Do not ordinarily exceed 20 mg weekly.^c

Limited experience suggests substantial increase in incidence and severity of serious toxic reactions, especially bone marrow suppression, at dosages >20 mg weekly.^c

Special Populations

Renal Impairment

Dose reduction and especially careful monitoring for toxicity required.^{b c}

Geriatric Patients

Select dosage with caution since hepatic and renal function and folate stores may be decreased; closely monitor for early signs of toxicity.^{b c}

Patients with Ascites or Pleural Effusions

Dose reduction and especially careful monitoring for toxicity required.