Methotrexate Sodium

Breast Cancer

Treatment (alone or, more commonly, in combination chemotherapy) of breast cancer.a 262 265

First-line adjuvant chemotherapy in combination with other drugs (i.e., cyclophosphamide and fluorouracil, with or without hormonal therapy).166 167 168 169 170 171 172 173 174 175 178 179 182 185 186 187 267 An anthracycline-containing regimen is preferred in patients with node-positive disease.267

Some studies suggest a slight advantage for anthracycline-containing regimens in relapse-free and survival rates in both premenopausal and postmenopausal patients.274

Also used in patients with metastatic disease.267 274

Head and Neck Cancer

Palliative treatment (alone and in combination therapy) of recurrent or metastatic head and neck carcinoma.182 210 211 212 262 265 267

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

Intrathecally for prophylaxis and treatment of meningeal leukemia.a 262 267

First-line therapy in combination with mercaptopurine for maintenance of drug-induced remissions of acute lymphoblastic leukemia (ALL).262 265 267

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.267

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 267

Lung Cancer

Has been used in second-line therapy of recurrent small cell lung cancer.235 262 265 276

Although labeled for use in squamous cell type of non-small cell lung cancer,127 262 265 other agents are preferred.182 267

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.262 265 267

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).267

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.267

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-line267 systemic chemotherapy for advanced cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).262 265 277

First-line therapy of primary CNS lymphoma.267

Hodgkin’s disease responds poorly to methotrexate.a

Osteosarcoma

High-dose therapy, followed by leucovorin or levoleucovorin rescue, in combination chemotherapy regimens as adjunct to surgical resection or amputation of primary tumor in patients with nonmetastatic osteosarcoma262 263 264 267 270 (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.270

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 262 265

Use only after diagnosis definitely established (e.g., biopsy, after dermatologic consultation).262 265

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.111 112 113 114 115 116 127 128 138 139 140 141 142 143 144 145 146 147 148 149 152 153 154 262 265

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).262 265 (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 262 265 268

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.267 268

Component of combination chemotherapy regimen with dactinomycin and chlorambucil in patients with good-prognosis metastatic gestational trophoblastic neoplasms with refractory disease.268

In patients with poor-prognosis metastatic trophoblastic neoplasms, methotrexate in combination with etoposide, dactinomycin, vincristine, and cyclophosphamide (EMA-CO) is a standard treatment option.268 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.268

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 therapy267 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.271 272 273

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

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.262 265

• Do not prescribe or dispense on as-needed (“prn”) basis.265

• If toxicity previously necessitated discontinuance, reinstitute with caution; consider further need for drug and risk of toxicity recurrence.a 262 265

High-Dose Methotrexate Therapy with Leucovorin or Levoleucovorin Rescue

• Use of high-dose regimens employed in adjunctive treatment of osteosarcoma requires meticulous understanding of risks associated with therapy and leucovorin or levoleucovorin rescue.a 262 264

• Hydrate patients with 1 L/m2 of IV fluid over 6 hours prior to initiation of methotrexate infusion.262 Continue hydration at 125 mL/m2 per hour (3 L/m2 daily) during methotrexate infusion and for 2 days after completion of infusion.262

• Alkalinize urine with sodium bicarbonate to maintain pH ≥7 during methotrexate infusion and rescue therapy with a folic acid antidote (e.g., leucovorin, levoleucovorin);262 264 administer sodium bicarbonate orally or via a separate IV solution.262

• Scr must be normal and Clcr >60 mL/minute before therapy initiation.262 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).262

• Measure Scr prior to each subsequent course of therapy; if Scr increases by ≥50% compared to prior value, measure and document that Clcr >60 mL/minute (even if Scr is still within normal range).262

• May consider adding glucarpidase to leucovorin or levoleucovorin rescue therapy to treat toxic plasma methotrexate concentrations (>0.454 mcg/mL or >1 mcM) in patients with delayed methotrexate clearance due to renal impairment.266 If glucarpidase is used, do not administer leucovorin or levoleucovorin within 2 hours before or after a dose of glucarpidase.266

• Also consult manufacturers’ labelings and published protocols for specific recommendations based on laboratory and clinical findings.a 262

Administration

Administer orally or by IM, IV, or intrathecal injection; may also administer intra-arterially.262 265 Has been administered by sub-Q injection.265 278

Do not use formulations or diluents containing preservatives (e.g., benzyl alcohol) for intrathecal administration or high-dose therapy.262

Oral Administration

Administer orally as tablets.265

Oral administration is often preferred when low doses are used since absorption is rapid and effective serum concentrations are achieved.262 265

Manufacturer makes no specific recommendations regarding administration with meals; food delays absorption and reduces peak serum concentrations.214 262 265

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.265 (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 5–20 mg but are not recommended for titration to weekly doses >20 mg.a 265

IV Administration

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

Administer by IV injection or infusion.262

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).262

Reconstitute 1 g vial with 19.4 mL of appropriate solution to yield a concentration of 50 mg/mL.262

Dilution

When high doses are administered by IV infusion, dilute total dose of reconstituted solution in 5% dextrose injection.262

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).262

IM Administration

Administer by IM injection.262

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).262

Intrathecal Administration

Preservative-free solutions (1 mg/mL) are used for intrathecal injection.262 Do not administer solutions containing preservatives intrathecally.262

Must administer intrathecally for treatment of meningeal leukemia since passage of drug from blood to CSF is minimal.a 262

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 262

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).262

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).262

Dosage

Available as methotrexate sodium; dosage is expressed in terms of methotrexate.262 265

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.265

Initially, 10 mg/m2 once weekly.262 265 May adjust dosage gradually to achieve optimal response.262 265

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.262 265

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.262 265

Optimum duration of therapy is unknown.262 265

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.262 265

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.107 108 127 262

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.262

Treatment: may administer at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable.262 Administration at intervals of <1 week may result in increased subacute toxicity.262

Prophylaxis: dosage is the same as for treatment; administration intervals differ from regimen used in treatment.a 262 Consult specialized references and medical literature for specific recommendations.a 262

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 60 mg/m2 daily for 4–6 weeks has been used.127 262 265

ALL (Maintenance Therapy) Oral or IM

After remission attained, 30 mg/m2 total weekly dose, administered in divided doses twice weekly.127 262 265

IV

Alternatively, 2.5 mg/kg has been administered IV every 14 days.127 262 265

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.262 However, administration at intervals of <1 week may result in increased subacute toxicity.262

Prophylaxis: 12 mg; administration intervals differ from regimen used in treatment.a 262 Consult specialized references and medical literature for specific recommendations.a 262

Intrathecal doses of 12 mg/m2 (maximum 15 mg) reported to result in high CSF methotrexate concentrations and neurotoxicity in adults.262

Lymphomas Oral

For Burkitt’s lymphoma (stage I or II), 10–25 mg daily for 4–8 days.262 265 In stage III Burkitt’s lymphoma, commonly given with other antineoplastic agents.262 265 In all stages, several courses are usually administered, interposed with 7- to 10-day rest periods.262 265

Stage III lymphosarcomas may respond to combined drug therapy with methotrexate given in doses of 0.625–2.5 mg/kg daily.262 265

Cutaneous T-cell Lymphoma; Mycosis Fungoides Oral, IM, or Sub-Q278

Usually, 5–50 mg weekly in early stages.241 262 265 Dose reduction or discontinuance is determined by hematologic monitoring and patient response.241 265

Also has been administered twice weekly in doses ranging from 15–37.5 mg in patients who have responded poorly to weekly therapy.241 262 265

IV

Combination chemotherapy regimens that include higher-dose methotrexate with leucovorin rescue have been used in advanced stages.262 265 241 Consult published protocols for dosages.

Osteosarcoma High-Dose Methotrexate Therapy with Leucovorin or Levoleucovorin 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).262 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.262

Initiate rescue therapy with leucovorin or levoleucovorin to prevent acute toxicity.262 263 264 If leucovorin is used, administer at a dosage of 15 mg orally every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion;262 may give leucovorin IV or IM if patient experiences GI toxicity (e.g., nausea, vomiting) or cannot tolerate oral therapy.262 263 If levoleucovorin is used, administer at a dosage of 7.5 mg IV every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion.264 If clinically important methotrexate toxicity is observed, extend leucovorin or levoleucovorin therapy for an additional 24 hours (total of 14 doses instead of 10) in subsequent courses.262 264 Adjustment of rescue schedule may be required (see Table 2).263 264

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).262

Table 2. Leucovorin and Levoleucovorin Rescue Schedules Based on Serum Methotrexate Concentrations262264

Clinical Situation	Laboratory Findings	Leucovorin Dosage and Duration262	Levoleucovorin Dosage and Duration264
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)	7.5 mg 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)	Continue 7.5 mg 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)	75 mg IV every 3 hours until methotrexate concentration is <0.454 mcg/mL (1 mcM), then 7.5 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.265 May gradually adjust dosage by 2.5 mg/week to achieve optimal response; do not exceed 30 mg weekly ordinarily.a 265

Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.265 Use may permit return to conventional topical therapy.265

Oral, IM, or IV

Weekly single-dosage schedule: 10–25 mg as a single dose once weekly until adequate response achieved.265 May gradually adjust dosage to achieve optimal response; do not exceed 30 mg weekly ordinarily.265 Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.265

Rheumatoid Arthritis Oral

May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects.265

Initially, 7.5 mg once weekly or a course once weekly of 2.5 mg administered at 12-hour intervals for 3 doses.265 May gradually adjust dosage to achieve an optimal response.265

At dosages >20 mg weekly, possible increased incidence and severity of serious toxic reactions, especially myelosuppression.265

Optimal duration of therapy is not known; limited data indicate that initial improvement is maintained for at least 2 years with continued therapy.265

Trophoblastic Neoplasms Oral or IM

Usually, 15–30 mg daily for 5 days.262 265 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 262 265 Clinical assessment before each course is essential.262 265

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.262

1 or 2 courses of therapy are usually given after normalization of urinary hCG concentrations is achieved.262

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.271 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.271

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.271 273

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.262 265

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.262 265

Adults

Psoriasis Oral, IM, or IV

Do not ordinarily exceed 30 mg weekly.262 265

Rheumatoid Arthritis Oral, IM, or IV

Do not ordinarily exceed 20 mg weekly.262 265

Limited experience suggests substantial increase in incidence and severity of serious toxic reactions, especially bone marrow suppression, at dosages >20 mg weekly.262 265

Special Populations

Renal Impairment

Dose reduction and especially careful monitoring for toxicity required.262 265

Geriatric Patients

Select dosage with caution since hepatic and renal function and folate stores may be decreased; closely monitor for early signs of toxicity.262 265

Patients with Ascites or Pleural Effusions

Dose reduction and especially careful monitoring for toxicity required.262 265

Absorption

Bioavailability

Oral absorption appears to be highly variable and dose dependent;127 214 215 oral bioavailability may be <50%.215 Bioavailability decreases with increasing oral doses; absorption may be substantially reduced at doses >80 mg/m2.127 214 215 Following oral administration, peak serum concentrations are attained in 1–2 hours.127

Appears to be completely absorbed following IM administration at doses ≤100 mg;127 215 peak serum concentrations are attained within 30–60 minutes.127

Onset

In patients with rheumatoid arthritis, effects on articular swelling and tenderness may be observed after 3–6 weeks of treatment; improvement may continue for another 12 weeks or more.262 265

Duration

In patients with arthritis, limited data indicate that initial improvement is maintained for at least 2 years with continued therapy.262 265 Arthritis usually worsens within 3–6 weeks after methotrexate discontinuance.262 265

Food

Food delays absorption and decreases peak serum concentrations following oral administration.127 214

Special Populations

Absorbed through the ileum; placement of a Foley catheter or frequent emptying of the reservoir is advised in patients with long ileal loops or internal reservoirs during administration of methotrexate-containing regimens for the treatment of advanced or metastatic bladder cancer.205 206

Distribution

Extent

Widely distributed into body tissues, with highest concentrations in the kidneys, gallbladder, spleen, liver, and skin.a Distributes into third-space fluids.215 216

High-dose systemic therapy can result in peak CSF concentrations above the therapeutic threshold.216 219 Intrathecal administration may result in potentially cytotoxic serum concentrations that can persist for 24–48 hours.215

Crosses the placentaa and is distributed into milk.127 161 162

Plasma Protein Binding

About 50% (mainly albumin).127 215

Special Populations

Presence of pleural effusions or ascites can substantially alter drug disposition.215 216

Elimination

Metabolism

Undergoes hepatic and intracellular metabolism to polyglutamate metabolites;127 partially metabolized by intestinal flora after oral administration.127

Polyglutamate metabolites may be converted back to methotrexate by hydrolysis,127 and metabolites may remain in tissues for extended periods of time.127

Elimination Route

Excreted principally by the kidneys and to a lesser extent via feces.a

Half-life

At low-doses (<30 mg/m2), terminal half-life is about 3–10 hours.127 262 265 At high doses, elimination half-life is about 8–15 hours.127 262 265

Special Populations

Excretion is impaired and accumulation occurs more rapidly in patients with impaired renal function, pleural effusion, or other substantial third-space accumulations (e.g., ascites).a 262 265

Neoplastic Diseases

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorio-adenoma destruens and hydatidiform mole.

Methotrexate is used in maintenance therapy in combination with other chemotherapeutic agents.

Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma) and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.

Psoriasis

Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

Rheumatoid Arthritis Including Polyarticular-Course Juvenile Rheumatoid Arthritis

Methotrexate is indicated in the management of selected adults with severe, active, rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. (See PRECAUTIONS: Drug Interactions). Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-5 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

1. Controlling occupational exposure to hazardous drugs (OSHA Work-Practice Guidelines). Am J Health SystPharm 1996; 53:1669-1685. 2. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston Massachusetts 02115. 3. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426-428. 4. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. Ca - A Cancer Journal for Clinicians Sept/Oct 1983; 258-263. 5. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1049.

Distr. by: West-Ward

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10004494/08

Revised May 2016

NDC 0054-4550-15: Bottle of 36 Tablets

Rx only

NDC 0054-8550-25: 10x10 Unit-Dose

Rx only

Methotrexate Sodium  Methotrexate Sodium tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0054-4550 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Methotrexate Sodium (METHOTREXATE) METHOTREXATE 2.5 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   MAGNESIUM STEARATE   STARCH, CORN   SODIUM HYDROXIDE   SODIUM STARCH GLYCOLATE TYPE A POTATO

Product Characteristics Color YELLOW Score 2 pieces Shape ROUND Size 6mm Flavor Imprint Code 54323 Contains

Packaging # Item Code Package Description 1 NDC:0054-4550-25 100 TABLET in 1 BOTTLE, PLASTIC 2 NDC:0054-4550-15 36 TABLET in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040054 08/01/1994

Methotrexate Sodium  Methotrexate Sodium tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0054-8550 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Methotrexate Sodium (METHOTREXATE) METHOTREXATE 2.5 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   MAGNESIUM STEARATE   STARCH, CORN   SODIUM HYDROXIDE   SODIUM STARCH GLYCOLATE TYPE A POTATO

Product Characteristics Color YELLOW Score 2 pieces Shape ROUND Size 6mm Flavor Imprint Code 54323 Contains

Packaging # Item Code Package Description 1 NDC:0054-8550-25 10 BLISTER PACK in 1 CARTON 1 10 TABLET in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040054 08/01/1994

Labeler - West-Ward Pharmaceuticals Corp. (080189610)

Establishment
Name	Address	ID/FEI	Operations
West-Ward Columbus Inc.		058839929	MANUFACTURE(0054-4550, 0054-8550)

Revised: 09/2017   West-Ward Pharmaceuticals Corp.