METHOTREXATE, VIALS 4 Dosage And Administration

methotrexate, vials

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4.1 Dosing Considerations

  • Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
  • Women of childbearing potential should not be started on Methotrexate Injection USP until pregnancy is excluded. 

Neoplastic Diseases: 

  • Methotrexate Injection USP without preservative may be given by the intramuscular, intravenous (as a bolus), intra-arterial, intrathecal or intracerebroventricular (via Ommaya reservoir into the CNS) routes.
  • Methotrexate Injection USP formulations which contain benzyl alcohol as preservative are contraindicated in neonates and for intrathecal, intracerebroventricular, or high-dose therapy (see 2 CONTRAINDICATIONS).
  • Methotrexate Injection USP may only be administered by physicians experienced in the treatment of neoplasia. Typical dosages reported in the literature for the following malignancies are listed in the following section. 

Psoriasis and Rheumatoid Arthritis:

  • The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see 7 WARNINGS AND PRECAUTIONS).
  • All dosage schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see 8 Adverse Reactions). Maximal myelosuppression usually occurs in seven to ten days.
  • Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. 

4.2 Recommended Dose and Dosage Adjustment 

Breast Cancer: The initial doses of CMF will be cyclophosphamide 100 mg/m2 p.o. days 1 through 14, methotrexate 40 mg/m2 IV day 1, 8, and 5 - Fluorouracil 600 mg/m2 IV day 1, 8. Cycle length will be 28 days ("2 weeks-on, 2 weeks-off"). In patients over 60 years of age, the dosage of methotrexate will be 30 mg/m2 IV day 1, 8. If total bilirubin exceeds 1.5 mg/dL, decrease the dose of methotrexate only by 50%. 

Bladder Cancer: Typical dosage regimens for bladder cancer are the CMV Regimen and the “M-VAC Regimen" which are represented in the following tables. 

Table 1: CMV Regimen*
Drugs**Days
 128
Cisplatin‡-100-
Vinblastine4-4
Methotrexate***30-30

*

All doses in mg/m2 with cycles repeated on day 22.

**

Patients >70 years old receive 80% of all doses; if vomiting persists to day 8, no drug is given.

For each cycle, adjust cisplatin to 100% for Ccr >60 mL/min; 50% of dose for Ccr 50-60 mL/min; none for Ccr <50 mL/min.

***

No drug for a decrease on day 8 of >30 mL/min compared to day 1 or Ccr <50 mL/min or Cr >1.8 mg/dL.

Major dose modifications for both drugs depending on myelosuppression.

 

Table 2: M-VAC Regimen*
DrugsDays
 121522***
Methotrexate30-3030
Vinblastine-333
Doxorubicin-30**--
Cisplatin-70--

*

All doses in mg/m2 with cycles repeated every 28 - 32 days.

**

Patients having prior pelvic irradiation equivalent to >2500 rad in 5 days, reduce the dose of doxorubicin 15 mg/m2.

***

No doses given when the WBC <2500 cells/mm3, platelets >100,000 cells/mm3, or mucositis present.

Head and Neck Cancer: Methotrexate remains the standard of therapy for patients with recurrent or metastatic disease. It has been given in a wide variety of doses and schedules (a few of which are represented in the table below).

 

Table 3: Methotrexate Schedule**
0.8 mg/kg every 4 days IV
25 - 50 mg every 4 to 7 days
60 mg/m2 weekly IV or 40 mg/m2 biweekly IV
40 - 60 mg/m2 weekly IV
80 mg/m2 for 30 h every 2 wk with escalation to toxicity
40 mg/m2 weekly IV
40 - 200 mg/m2 IV on days 1, 4 weekly; leucovorin on days 2,5
60 mg/m2 IV weekly

**

excerpt from Devita, et al: CANCER 3rd Ed, p. 496

 

For palliation of patients with advanced, incurable disease and acceptable renal function, it is appropriate to begin intravenous methotrexate with weekly doses of 40-50 mg/m2 or biweekly doses of 15 to 20 mg/m2 and escalate the dose in weekly increments until either mild toxicity or therapeutic response is achieved. 

Gastric Cancer: A regimen used in a clinical trial in Belgium in patients with resectable gastric cancer follows: methotrexate (1.5 g/m2 IV day 1) + 5-Fluorouracil (1.5 g/m2 IV) + Leucovorin (15 mg/m2 orally or IV every 6 hours for 72 hours) + Adriamycin (30 mg/m2 IV, day 15).  The schedule is repeated on day 29 for 6 cycles. 

Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered intramuscularly in doses of 15 to 30 mg daily for a 5-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin hormone (beta-HCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of beta-HCG are usually recommended.  Before each course of the drug, careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumour drugs has been reported as being useful. 

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. 

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. 

Lymphomas: In Burkitt's tumour, Stages I-II, methotrexate has produced prolonged remissions in some cases. In Stage III, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. 

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

The treatment of choice for localized histologically aggressive lymphoma is primary combination chemotherapy with or without involved-field radiation therapy.  Frequently used regimens for intermediate, or high grade NHL that include methotrexate include groups: the ProMACE/MOPP, ProMACE-CytaBOM, Magrath Protocols. Represented in the table below for example, is the ProMACE-CytaBOM Regimen.

 

Table 4: ProMACE CytaBOM Regimen
ProMACE-CytaBOMDay 1Day 8Day 14Days 15-21
Cyclophosphamide 650 mg/m2 I.V.    x  No therapy
Doxorubicin 25 mg/m2 I.V.  x   
Etoposide 120 mg/m2 I.V. x   
Cytarabine 300 mg/m2 I.V.   
Bleomycin 5 mg/m2 I.V.   
Vincristine 1.4 mg/m2 I.V.                  x
Methotrexate 120 mg/m2 I.V.                   x with leucovorin rescue
Prednisone 60 mg/m2 PO    x---------------------------------------------- x
Co-trimoxazole 2 PO bid throughout 6 cycles of therapy

In early stage childhood non-Hodgkin's lymphoma, methotrexate is used effectively in combination chemotherapy regimens. 

 

Mycosis Fungoides (cutaneous T-cell lymphoma): Therapy with methotrexate appears to produce clinical responses in up to 50% of patients treated, but chemotherapy is not curative. Dose levels of drug and adjustment of dose regimen by reduction or cessation of drug are guided by patient response and hematologic monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg of methotrexate twice weekly 

Leukemia: Acute lymphoblastic leukemia (ALL) in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. 

Methotrexate alone or in combination with steroids was used initially for induction of remission in ALL. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug‑induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: methotrexate is administered twice weekly intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, re-induction of remission can again usually be obtained by repeating the initial induction regimen.  

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in ALL. 

Meningeal Leukemia: In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. 

For intrathecal administration, preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP. 

The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years. 

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in children and high concentrations and neurotoxicity in adults. 

The following dosage regimen is based on age instead of body surface area:

Table 5: Dosage regimen
Age (years)Dose (mg)

<1

1

2

3 or older

6

8

10

12

In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in children with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age. 

Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients. 

For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature. 

Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy. 

Leptomeningeal Carcinomatosis: Intrathecal administration of methotrexate as a single-drug or in combination regimens, is the most common therapy for carcinomatous leptomeningitis. 

Treatment is optimally administered through an Ommaya reservoir and is usually started with methotrexate (10 mg/m2) given twice weekly until the cerebrospinal fluid cytology becomes negative. The treatment regimen is gradually decreased, first to a weekly course, and eventually to a single administration every two months. 

Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose Methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

Table 6: Doses and schedule


 

Drug*

Dose*Treatment Week After Surgery

Methotrexate

 

 

Leucovorin

12 g/m2 IV as 4 hour infusion (starting dose)

 

15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

4,5,6,7,11,12,15,16,29,30,44,45
Doxorubicin** as a single drug30 mg/m2/day IV x 3 days8,17

Doxorubicin**

Cisplatin**

50 mg/m2  IV

100 mg/m2  IV

20,23,33,36

20,23,33,36

Bleomycin**

Cyclophosphamide**

Dactinomycin**

15 units/mIV x 2 days

600 mg/m 2 IV x 2 days

0.6 mg/m2 IV x 2 days

2,13,26,39,42

2,13,26,39,42

2,13,26,39,42

*

Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

**

See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

 

When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed. 

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 

Administration of Methotrexate Injection USP should be delayed until recovery if:

  • The WBC count is less than 1500/microliter
  • The neutrophil count is less than 200/microliter
  • The platelet count is less than 75,000/microliter
  • The serum bilirubin level is greater than 1.2 mg/dL
  • The SGPT level is greater than 450 U
  • Mucositis is present, until there is evidence of healing
  • Persistent pleural effusion is present; this should be drained dry prior to infusion. 

Adequate renal function must be documented.

   a) Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy.

   b) Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 

Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization.

   a) Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the Methotrexate Injection USP infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the Methotrexate Injection USP infusion, and for 2 days after the infusion has been completed.

   b) Alkalinize urine to maintain pH above 7.0 during Methotrexate Injection USP infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 

Repeat serum creatinine and serum methotrexate 24 hours after starting Methotrexate Injection USP and at least once daily until the methotrexate level is below 5x10-8 mol/L (0.05 micromolar). 

The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels (See table below). 

Patients who experience delayed early methotrexate elimination are likely to develop non-reversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. 

Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with Methotrexate Injection USP (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

 

Table 7: Leucovorin rescue schedules following treatment with higher doses of Methotrexate. 
Clinical SituationLaboratory FindingsLeucovorin Dosage and Duration
Normal Methotrexate EliminationSerum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate EliminationSerum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.Continue 15 mg PO, IM or IV q six hours, until Methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal InjurySerum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).150 mg IV q three hours, until methotrexate level is less than 1 micromolar; than 15 mg IV q three hours, until methotrexate level is less than 0.05 micromolar.

 

Psoriasis: 

Recommended starting dose schedule: 

  • Weekly single intramuscular or intravenous dose schedule: 10 to 25 mg per week until adequate response is achieved. 

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 25 mg/week should not ordinarily be exceeded. 

Once optimal clinical response has been achieved, the dosage schedule should be reduced to the lowest possible effective dose and to the longest possible rest period. 

Rheumatoid Arthritis: 

Recommended starting dosage schedule: 

Dosages may be gradually adjusted to achieve optimal clinical response, but not ordinarily to exceed a total weekly dose of 20 mg. 

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. Upon achieving the therapeutically desired result, dosage should be reduced gradually to the lowest possible effective maintenance dose. The optimal duration of therapy is unknown; limited data from long-term studies indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. 

Special Populations:

Hepatic impairment: Hepatic excretion of methotrexate is a minor route of elimination. However, the liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. 

Renal Impairment: Methotrexate is excreted to a significant extent by the kidneys, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide inter subject pK variability. Methotrexate Injection USP is contraindicated in patients with severe renal impairment (see 2 CONTRAINDICATIONS). 

Table 8: Dose Adjustments in Patients with Renal Insufficiency
Creatinine Clearance (mL/min)% Standard Dose to Administer
>80Full Dose
8075
6063
5056
<50Use alternative therapy

 

Pediatrics (< 18 years of age): Safety and effectiveness in pediatric patients have not been established, other than in cancer chemotherapy (see 7 WARNINGS AND PRECAUTIONS: Special Populations, and 7.1.3 Pediatrics). 

Geriatrics (≥ 65 years of age): Due to diminished hepatic and renal function as well as decreased folate stores in elderly population, relatively low doses (especially in rheumatoid arthritis and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity. See Table 1 for reduced doses in oncology patients with renal impairment. 

4.3 Reconstitution 

Parental products 

Methotrexate Injection USP may be diluted with any of the solutions for IV infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL.  

Solutions: 

0.9% Sodium Chloride Injection

5% Dextrose Injection

4% Dextrose and 0.18% Sodium Chloride Injection

Ringer's Injection

4.4 Administration

Dilution: 

Methotrexate Injection USP may be diluted with any of the solutions for IV infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL.  Dilutions should be used within 24 hours if kept at room temperature.  Unused solution should be discarded after this time in order to avoid risk of microbial contamination. 

Solutions: 

0.9% Sodium Chloride Injection

5% Dextrose Injection

4% Dextrose and 0.18% Sodium Chloride Injection

Ringer's Injection 

Since methotrexate is poorly soluble in acid media, use of potassium chloride solution is not advisable. 

If a preservative-free diluent is used, the solution should be used immediately because of the possibility of microbial growth. It is advisable to protect diluted solutions from light. 

Due to the number of brands available, stability data of methotrexate in plastic syringes and bags are not available.

Unused preservative-free products should be discarded due to the possibility of microbial growth. 

Dispensing of Pharmacy Bulk Vials:

Pharmacy Bulk Vials contain 25 mg/mL methotrexate (as methotrexate sodium) in 20 mL, 40 mL or 100 mL of sterile, unpreserved, isotonic solution (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING: Composition). 

The availability of Pharmacy Bulk Vials is restricted to hospitals with a recognized intravenous admixture program. It is recommended that the vial remains in the carton until time of use. The Methotrexate Injection USP vial should be inspected for damage and visible signs of leaks. If there are signs of breakage or leakage from the vial, do not use. Incinerate the unopened package. 

Pharmacy Bulk Vials are intended for multiple dispensing FOR INTRAVENOUS USE ONLY, employing a single puncture (see 12 SPECIAL HANDLING INSTRUCTIONS). 

The Pharmacy Bulk Vial content should be dispensed within eight hours.  Any unused solution should be discarded.  The diluted solutions prepared from the Pharmacy Bulk vial should be used within 24 hours from the time of the initial puncture of the Pharmacy Bulk Vial, when kept at room temperature. 

Pharmacy Bulk Vials contain no preservatives.  Care must be taken to minimize the potential for inadvertent introduction of micro‑organisms during manipulation in the hospital environment. 

Incompatibilities: Other drugs should not be mixed with methotrexate in the same infusion bottle. Methotrexate has been reported to be incompatible with cytarabine, fluorouracil, and prednisolone sodium phosphate; however, its incompatibility with fluorouracil has been questioned and subsequent studies documented in the literature indicate that methotrexate and cytarabine are physically and chemically stable in intravenous admixtures over a range of concentrations and in a variety of typical vehicles. A mixture of methotrexate with cytarabine and hydrocortisone sodium succinate in various infusion fluids has been reported to be visually compatible for at least 8 hours at 25°C, although precipitation did not occur on storage for several days. In general, compatibility of any medicinal product admixed with Methotrexate Injection USP must be assured prior to patient administration. 

Contact with acidic solutions should be avoided since Methotrexate Injection USP is sparingly soluble in acid media and precipitation may occur (see 7 Warnings And Precautions for clinical incompatibilities).

4.5 Missed Dose 

If a scheduled dose is missed, contact your doctor for instructions.

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4 Dosage And Administration

4.1 Dosing Considerations

  • Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
  • Women of childbearing potential should not be started on Methotrexate Injection USP until pregnancy is excluded. 

Neoplastic Diseases: 

  • Methotrexate Injection USP without preservative may be given by the intramuscular, intravenous (as a bolus), intra-arterial, intrathecal or intracerebroventricular (via Ommaya reservoir into the CNS) routes.
  • Methotrexate Injection USP formulations which contain benzyl alcohol as preservative are contraindicated in neonates and for intrathecal, intracerebroventricular, or high-dose therapy (see 2 CONTRAINDICATIONS).
  • Methotrexate Injection USP may only be administered by physicians experienced in the treatment of neoplasia. Typical dosages reported in the literature for the following malignancies are listed in the following section. 

Psoriasis and Rheumatoid Arthritis:

  • The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see 7 WARNINGS AND PRECAUTIONS).
  • All dosage schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see 8 Adverse Reactions). Maximal myelosuppression usually occurs in seven to ten days.
  • Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. 

4.2 Recommended Dose and Dosage Adjustment 

Breast Cancer: The initial doses of CMF will be cyclophosphamide 100 mg/m2 p.o. days 1 through 14, methotrexate 40 mg/m2 IV day 1, 8, and 5 - Fluorouracil 600 mg/m2 IV day 1, 8. Cycle length will be 28 days ("2 weeks-on, 2 weeks-off"). In patients over 60 years of age, the dosage of methotrexate will be 30 mg/m2 IV day 1, 8. If total bilirubin exceeds 1.5 mg/dL, decrease the dose of methotrexate only by 50%. 

Bladder Cancer: Typical dosage regimens for bladder cancer are the CMV Regimen and the “M-VAC Regimen" which are represented in the following tables. 

Table 1: CMV Regimen*
Drugs**Days
 128
Cisplatin‡-100-
Vinblastine4-4
Methotrexate***30-30

*

All doses in mg/m2 with cycles repeated on day 22.

**

Patients >70 years old receive 80% of all doses; if vomiting persists to day 8, no drug is given.

For each cycle, adjust cisplatin to 100% for Ccr >60 mL/min; 50% of dose for Ccr 50-60 mL/min; none for Ccr <50 mL/min.

***

No drug for a decrease on day 8 of >30 mL/min compared to day 1 or Ccr <50 mL/min or Cr >1.8 mg/dL.

Major dose modifications for both drugs depending on myelosuppression.

 

Table 2: M-VAC Regimen*
DrugsDays
 121522***
Methotrexate30-3030
Vinblastine-333
Doxorubicin-30**--
Cisplatin-70--

*

All doses in mg/m2 with cycles repeated every 28 - 32 days.

**

Patients having prior pelvic irradiation equivalent to >2500 rad in 5 days, reduce the dose of doxorubicin 15 mg/m2.

***

No doses given when the WBC <2500 cells/mm3, platelets >100,000 cells/mm3, or mucositis present.

Head and Neck Cancer: Methotrexate remains the standard of therapy for patients with recurrent or metastatic disease. It has been given in a wide variety of doses and schedules (a few of which are represented in the table below).

 

Table 3: Methotrexate Schedule**
0.8 mg/kg every 4 days IV
25 - 50 mg every 4 to 7 days
60 mg/m2 weekly IV or 40 mg/m2 biweekly IV
40 - 60 mg/m2 weekly IV
80 mg/m2 for 30 h every 2 wk with escalation to toxicity
40 mg/m2 weekly IV
40 - 200 mg/m2 IV on days 1, 4 weekly; leucovorin on days 2,5
60 mg/m2 IV weekly

**

excerpt from Devita, et al: CANCER 3rd Ed, p. 496

 

For palliation of patients with advanced, incurable disease and acceptable renal function, it is appropriate to begin intravenous methotrexate with weekly doses of 40-50 mg/m2 or biweekly doses of 15 to 20 mg/m2 and escalate the dose in weekly increments until either mild toxicity or therapeutic response is achieved. 

Gastric Cancer: A regimen used in a clinical trial in Belgium in patients with resectable gastric cancer follows: methotrexate (1.5 g/m2 IV day 1) + 5-Fluorouracil (1.5 g/m2 IV) + Leucovorin (15 mg/m2 orally or IV every 6 hours for 72 hours) + Adriamycin (30 mg/m2 IV, day 15).  The schedule is repeated on day 29 for 6 cycles. 

Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered intramuscularly in doses of 15 to 30 mg daily for a 5-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin hormone (beta-HCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of beta-HCG are usually recommended.  Before each course of the drug, careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumour drugs has been reported as being useful. 

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. 

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. 

Lymphomas: In Burkitt's tumour, Stages I-II, methotrexate has produced prolonged remissions in some cases. In Stage III, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. 

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

The treatment of choice for localized histologically aggressive lymphoma is primary combination chemotherapy with or without involved-field radiation therapy.  Frequently used regimens for intermediate, or high grade NHL that include methotrexate include groups: the ProMACE/MOPP, ProMACE-CytaBOM, Magrath Protocols. Represented in the table below for example, is the ProMACE-CytaBOM Regimen.

 

Table 4: ProMACE CytaBOM Regimen
ProMACE-CytaBOMDay 1Day 8Day 14Days 15-21
Cyclophosphamide 650 mg/m2 I.V.    x  No therapy
Doxorubicin 25 mg/m2 I.V.  x   
Etoposide 120 mg/m2 I.V. x   
Cytarabine 300 mg/m2 I.V.   
Bleomycin 5 mg/m2 I.V.   
Vincristine 1.4 mg/m2 I.V.                  x
Methotrexate 120 mg/m2 I.V.                   x with leucovorin rescue
Prednisone 60 mg/m2 PO    x---------------------------------------------- x
Co-trimoxazole 2 PO bid throughout 6 cycles of therapy

In early stage childhood non-Hodgkin's lymphoma, methotrexate is used effectively in combination chemotherapy regimens. 

 

Mycosis Fungoides (cutaneous T-cell lymphoma): Therapy with methotrexate appears to produce clinical responses in up to 50% of patients treated, but chemotherapy is not curative. Dose levels of drug and adjustment of dose regimen by reduction or cessation of drug are guided by patient response and hematologic monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg of methotrexate twice weekly 

Leukemia: Acute lymphoblastic leukemia (ALL) in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. 

Methotrexate alone or in combination with steroids was used initially for induction of remission in ALL. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug‑induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: methotrexate is administered twice weekly intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, re-induction of remission can again usually be obtained by repeating the initial induction regimen.  

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in ALL. 

Meningeal Leukemia: In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. 

For intrathecal administration, preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP. 

The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years. 

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in children and high concentrations and neurotoxicity in adults. 

The following dosage regimen is based on age instead of body surface area:

Table 5: Dosage regimen
Age (years)Dose (mg)

<1

1

2

3 or older

6

8

10

12

In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in children with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age. 

Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients. 

For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature. 

Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy. 

Leptomeningeal Carcinomatosis: Intrathecal administration of methotrexate as a single-drug or in combination regimens, is the most common therapy for carcinomatous leptomeningitis. 

Treatment is optimally administered through an Ommaya reservoir and is usually started with methotrexate (10 mg/m2) given twice weekly until the cerebrospinal fluid cytology becomes negative. The treatment regimen is gradually decreased, first to a weekly course, and eventually to a single administration every two months. 

Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose Methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

Table 6: Doses and schedule


 

Drug*

Dose*Treatment Week After Surgery

Methotrexate

 

 

Leucovorin

12 g/m2 IV as 4 hour infusion (starting dose)

 

15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

4,5,6,7,11,12,15,16,29,30,44,45
Doxorubicin** as a single drug30 mg/m2/day IV x 3 days8,17

Doxorubicin**

Cisplatin**

50 mg/m2  IV

100 mg/m2  IV

20,23,33,36

20,23,33,36

Bleomycin**

Cyclophosphamide**

Dactinomycin**

15 units/mIV x 2 days

600 mg/m 2 IV x 2 days

0.6 mg/m2 IV x 2 days

2,13,26,39,42

2,13,26,39,42

2,13,26,39,42

*

Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

**

See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

 

When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed. 

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 

Administration of Methotrexate Injection USP should be delayed until recovery if:

  • The WBC count is less than 1500/microliter
  • The neutrophil count is less than 200/microliter
  • The platelet count is less than 75,000/microliter
  • The serum bilirubin level is greater than 1.2 mg/dL
  • The SGPT level is greater than 450 U
  • Mucositis is present, until there is evidence of healing
  • Persistent pleural effusion is present; this should be drained dry prior to infusion. 

Adequate renal function must be documented.

   a) Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy.

   b) Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 

Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization.

   a) Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the Methotrexate Injection USP infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the Methotrexate Injection USP infusion, and for 2 days after the infusion has been completed.

   b) Alkalinize urine to maintain pH above 7.0 during Methotrexate Injection USP infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 

Repeat serum creatinine and serum methotrexate 24 hours after starting Methotrexate Injection USP and at least once daily until the methotrexate level is below 5x10-8 mol/L (0.05 micromolar). 

The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels (See table below). 

Patients who experience delayed early methotrexate elimination are likely to develop non-reversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. 

Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with Methotrexate Injection USP (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

 

Table 7: Leucovorin rescue schedules following treatment with higher doses of Methotrexate. 
Clinical SituationLaboratory FindingsLeucovorin Dosage and Duration
Normal Methotrexate EliminationSerum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate EliminationSerum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.Continue 15 mg PO, IM or IV q six hours, until Methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal InjurySerum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).150 mg IV q three hours, until methotrexate level is less than 1 micromolar; than 15 mg IV q three hours, until methotrexate level is less than 0.05 micromolar.

 

Psoriasis: 

Recommended starting dose schedule: 

  • Weekly single intramuscular or intravenous dose schedule: 10 to 25 mg per week until adequate response is achieved. 

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 25 mg/week should not ordinarily be exceeded. 

Once optimal clinical response has been achieved, the dosage schedule should be reduced to the lowest possible effective dose and to the longest possible rest period. 

Rheumatoid Arthritis: 

Recommended starting dosage schedule: 

Dosages may be gradually adjusted to achieve optimal clinical response, but not ordinarily to exceed a total weekly dose of 20 mg. 

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. Upon achieving the therapeutically desired result, dosage should be reduced gradually to the lowest possible effective maintenance dose. The optimal duration of therapy is unknown; limited data from long-term studies indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. 

Special Populations:

Hepatic impairment: Hepatic excretion of methotrexate is a minor route of elimination. However, the liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. 

Renal Impairment: Methotrexate is excreted to a significant extent by the kidneys, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide inter subject pK variability. Methotrexate Injection USP is contraindicated in patients with severe renal impairment (see 2 CONTRAINDICATIONS). 

Table 8: Dose Adjustments in Patients with Renal Insufficiency
Creatinine Clearance (mL/min)% Standard Dose to Administer
>80Full Dose
8075
6063
5056
<50Use alternative therapy

 

Pediatrics (< 18 years of age): Safety and effectiveness in pediatric patients have not been established, other than in cancer chemotherapy (see 7 WARNINGS AND PRECAUTIONS: Special Populations, and 7.1.3 Pediatrics). 

Geriatrics (≥ 65 years of age): Due to diminished hepatic and renal function as well as decreased folate stores in elderly population, relatively low doses (especially in rheumatoid arthritis and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity. See Table 1 for reduced doses in oncology patients with renal impairment. 

4.3 Reconstitution 

Parental products 

Methotrexate Injection USP may be diluted with any of the solutions for IV infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL.  

Solutions: 

0.9% Sodium Chloride Injection

5% Dextrose Injection

4% Dextrose and 0.18% Sodium Chloride Injection

Ringer's Injection

4.4 Administration

Dilution: 

Methotrexate Injection USP may be diluted with any of the solutions for IV infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL.  Dilutions should be used within 24 hours if kept at room temperature.  Unused solution should be discarded after this time in order to avoid risk of microbial contamination. 

Solutions: 

0.9% Sodium Chloride Injection

5% Dextrose Injection

4% Dextrose and 0.18% Sodium Chloride Injection

Ringer's Injection 

Since methotrexate is poorly soluble in acid media, use of potassium chloride solution is not advisable. 

If a preservative-free diluent is used, the solution should be used immediately because of the possibility of microbial growth. It is advisable to protect diluted solutions from light. 

Due to the number of brands available, stability data of methotrexate in plastic syringes and bags are not available.

Unused preservative-free products should be discarded due to the possibility of microbial growth. 

Dispensing of Pharmacy Bulk Vials:

Pharmacy Bulk Vials contain 25 mg/mL methotrexate (as methotrexate sodium) in 20 mL, 40 mL or 100 mL of sterile, unpreserved, isotonic solution (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING: Composition). 

The availability of Pharmacy Bulk Vials is restricted to hospitals with a recognized intravenous admixture program. It is recommended that the vial remains in the carton until time of use. The Methotrexate Injection USP vial should be inspected for damage and visible signs of leaks. If there are signs of breakage or leakage from the vial, do not use. Incinerate the unopened package. 

Pharmacy Bulk Vials are intended for multiple dispensing FOR INTRAVENOUS USE ONLY, employing a single puncture (see 12 SPECIAL HANDLING INSTRUCTIONS). 

The Pharmacy Bulk Vial content should be dispensed within eight hours.  Any unused solution should be discarded.  The diluted solutions prepared from the Pharmacy Bulk vial should be used within 24 hours from the time of the initial puncture of the Pharmacy Bulk Vial, when kept at room temperature. 

Pharmacy Bulk Vials contain no preservatives.  Care must be taken to minimize the potential for inadvertent introduction of micro‑organisms during manipulation in the hospital environment. 

Incompatibilities: Other drugs should not be mixed with methotrexate in the same infusion bottle. Methotrexate has been reported to be incompatible with cytarabine, fluorouracil, and prednisolone sodium phosphate; however, its incompatibility with fluorouracil has been questioned and subsequent studies documented in the literature indicate that methotrexate and cytarabine are physically and chemically stable in intravenous admixtures over a range of concentrations and in a variety of typical vehicles. A mixture of methotrexate with cytarabine and hydrocortisone sodium succinate in various infusion fluids has been reported to be visually compatible for at least 8 hours at 25°C, although precipitation did not occur on storage for several days. In general, compatibility of any medicinal product admixed with Methotrexate Injection USP must be assured prior to patient administration. 

Contact with acidic solutions should be avoided since Methotrexate Injection USP is sparingly soluble in acid media and precipitation may occur (see 7 Warnings And Precautions for clinical incompatibilities).

4.5 Missed Dose 

If a scheduled dose is missed, contact your doctor for instructions.

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