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meth-oh-TREK-sate)
Folex, Folex PFS, Rheumatrex Dose Pack, Rheumatrex Tablets
Class: Antineoplastic/antimetabolite; antipsoriatic; antiarthritic
Action Competitively inhibits dihydrofolic acid reductase and thereby

inhibits DNA synthesis and cellular replication. In rheumatoid arthritis, believed


to reduce immune function.
Indications Antineoplastic chemotherapy for treatment of gestational

choriocarcinoma, chorioadenoma destruens, hydatidiform mole; treatment and


prophylaxis of acute meningeal) lymphocytic leukemia; treatment of breast
cancer, epidermoid cancers of head and neck, advanced mycosis fungoides and
lung cancer; in combination therapy in advanced-stage non-Hodgkin's lymphoma;
as adjunct in high doses followed by leucovorin rescue in nonmetastatic
osteosarcoma (postsurgically); ymptomatic control of severe psoriasis and severe
rheumatoid arthritis. Unlabeled use(s): Reduction of corticosteroid requirements
in patients with severe corticosteroid-dependent asthma.
Contraindications Use in nursing mothers. In patients with psoriasis or

rheumatoid arthritis, methotrexate is contraindicated in pregnancy, alcoholism,


alcoholic liver disease, chronic liver disease, overt or laboratory evidence of
immunodeficiency syndrome and preexisting blood dyscrasias (eg, leukopenia,
thrombocytopenia).
Route/Dosage

Choriocarcinoma and Thromboblastic Diseases


ADULTS: PO/IM 1530 mg for 5 days. Repeat courses 35 times as required,
with rest periods of > 1 wk between courses.
Leukemia

ADULTS & CHILDREN: INDUCTION: 3.3 mg/m2/day in combination with


prednisone 60 mg/m2/day usually for 4 to 6 wk. Postremission maintenance
therapy (usually in combination with other drugs): PO/IM 2 times weekly in total
weekly doses of 30 mg/m2 or IV 2.5 mg/kg q 14 days.
Meningeal Leukemia
ADULTS: Intrathecal 12 mg/m2 or empirical dose of 15 mg. Administer q 25
days until cell count of CSF returns to normal; then give one additional dose.
Dose reduction may be required in elderly patients because of differences in CSF
volume. CHILDREN 3 YR: 12 mg. Administer q 25 days until CSF cell count
returns to normal. CHILDREN 2 YR: 10 mg. CHILDREN 1 YR: 8 mg.
CHILDREN < 1 YR: 6 mg.
Lymphoma: Burkitt's Lymphoma, Stages 1 & 2
ADULTS: PO 1025 mg/day for 48 days. Provide 7-to 10-day rest period
between courses.
Stage 3 Lymphosarcoma as Part of Combination Therapy
ADULTS: PO 0.6252.5 mg/kg/day.
Mycosis Fungoides
ADULTS: PO 2.510 mg/day for weeks to months (based on clinical response or
hematologic function). IM 25 mg twice weekly or 50 mg weekly.
Osteosarcoma
Complex high dose with leucovorin rescue and other chemotherapeutic agents.
Starting dose for high-dose methotrexate is 12 gm/m2.
Rheumatoid Arthritis
ADULTS: INITIAL THERAPY: PO 7.5 mg/week in single dose or 2.5 mg q 12 hr
for 3 doses each wk. Gradually adjust dosage to maximal response; do not exceed
20 mg/wk.
Psoriasis
Individualize dosage. Administer 510 mg parenteral test dose 1 wk prior to
therapy. ADULTS: IM/IV 1025 mg/wk (maximum 50 mg/wk). ADULTS: PO
2.5 mg q 12 hr for 3 doses or at 8 hr intervals for 4 doses q wk (maximum 30
mg/wk). ALTERNATIVE SCHEDULE: PO 2.5 mg qd for 5 days followed by 2-

day rest period (maximum 6.25 mg qd). This schedule may pose increased risk of
liver toxicity.
Interactions

Charcoal, folic acid: May reduce methotrexate efficacy. Digoxin: May reduce
serum digoxin levels and actions. Hydantoins: May reduce plasma levels.
Etretinate, NSAIDs, penicillins, probenecid, salicylates, sulfonamides: May
increase methotrexate blood levels and toxicity.
Lab Test Interferences None well documented.

Adverse Reactions

CNS: Dizziness; fatigue; headache; aphasia; hemiparesis; paresis; convulsions;


eukoencephalopathy (IV after craniospinal irradiation); chemical arachnoiditis;
ransient paresis; neurotoxicity. DERM: Erythematous rashes; pruritus; urticaria;
photosensitivity; igmentary changes; alopecia; ecchymosis; telangiectasia; acne;
furunculosis; ggravation of psoriasis by ultraviolet light. EENT: Blurred vision;
ulcerative stomatitis; gingivitis; pharyngitis. GI: Nausea; abdominal distress
(common); anorexia; vomiting; diarrhea; hematemesis; elena; GI ulceration and
bleeding; enteritis. GU: Renal failure; azotemia; cystitis; hematuria; severe
nephropathy; reproductive disorders; infertility; abortion; fetal defects. HEMA:
Leukopenia; bone marrow depression; thrombocytopenia; anemia;
ypogammaglobulinemia; hemorrhage; septicemia. HEPA: Hepatotoxicity; hepatic
cirrhosis and fibrosis. RESP: Deaths from interstitial pneumonitis; chronic
interstitial obstructive pulmonary disease. OTHER: Malaise; chills; fever; lower
resistance to infections; arthralgia; yalgia; diabetes; osteoporosis; anaphylactoid
reaction; sudden death.
Precautions

Pregnancy: Category X (for rheumatoid arthritis and psoriasis); Category D (other


uses). Lactation: Contraindicated in nursing mothers. Children: Safety and
efficacy not established other than for cancer treatment. Elderly patients: Closely
monitor for early signs of toxicity. May require dose reduction. Infection: Severe

reactions may occur if live vaccines are administered. Intrathecal therapy: Large
doses may cause convulsions and systemic toxicity. Dosage regimens based on
age may be more effective and associated with fewer neurotoxic side effects. Do
not use formulations or diluents containing preservatives. Renal impairment: Use
drug with extreme caution. Determine renal status before and during therapy.
Severe effects: Use of high-dose methotrexate regimens (ie, to treat osteosarcoma)
require meticulous care. Deaths have occurred after use of methotrexate for any
condition. Potential toxicities include bone marrow depression; hepatotoxicity;
lung disease (suggested by symptoms of dry, nonproductive cough);
nephrotoxicity and GI toxicity.

PATIENT CARE
CONSIDERATIONS
Administration/Storage

Ensure that leucovorin is available from pharmacy before beginning highdose administration of methotrexate. Leucovorin diminishes methotrexate
toxicity.

Oral administration is often preferred. Give medication 12 hr before


meals.

Preservative-free methotrexate may be given IM, IV, intra-arterially or


intrathecally.

For intrathecal use, reconstitute immediately prior to use with


preservative-free medium such as 0.9% Sodium Chloride for Injection.

Follow procedures for proper handling and disposal of anticancer drugs.


Wear gloves and avoid skin exposure and inhalation of fumes.

Store medication in tightly closed, light-resistant container.


Assessment/Interventions

Obtain patient history, including drug history and any known allergies.

Before beginning therapy, check that serum creatinine is normal and


creatinine clearance is > 60 ml/min.

Assess for alcoholism, alcoholic liver disease or other chronic liver


disease.

Determine whether patient has any evidence of immunodeficiency


syndromes, active infection, preexisting blood dyscrasias (eg, bone
marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia).

Assess pulmonary function; note especially presence of any pulmonary


effusion. Establish baseline pulmonary function measurements.

Maintain adequate hydration and urine alkalinization during therapy.


Monitor I&O.

Avoid IM injections and taking temperatures rectally during methotrexate


therapy; apply pressure to venipuncture sites for at least 10 min.

Determine renal status before therapy and monitor during therapy.

During therapy monitor periodically for toxicity. Mandatory monitoring


includes CBC with differential and platelet counts and liver and renal
function tests. Periodic liver biopsies may be indicated in some situations.

Assess frequently for pulmonary symptoms, especially dry, nonproductive


cough or nonspecific pneumonitis.

Monitor closely for any symptoms of diarrhea and ulcerative stomatitis.

Inspect patient's mouth daily. Report any patchy necrotic areas, bleeding
and discomfort or black/furry tongue.

Inform physician if diarrhea or ulcerative stomatitis occur during


treatment; therapy must be interrupted.

Inform physician of development of pulmonary symptoms (dry,


nonproductive cough, fever, shortness of breath, hypoxemia or presence of
infiltrate on chest x-ray film) during therapy. Methotrexate must be
discontinued and symptoms investigated and treated.
OVERDOSAGE: SIGNS & SYMPTOMS
Hepatotoxicity, nephrotoxicity, GI toxicity,

bone marrow toxicity, pulmonary toxicity


Patient/Family Education

Advise patient to contact physician if vomiting occurs after medication is


taken.

Inform patient that pregnancy should be avoided during therapy if either


partner is receiving methotrexate and for minimum of 3 mo after therapy
for men and during and for at least one ovulatory cycle after therapy for
women.

Advise patient and parents that immunization with live virus vaccines is
generally not recommended during methotrexate therapy.

Instruct patient to avoid crowds and persons with known infections.

Emphasize importance of lab tests during therapy and encourage patient to


keep all scheduled appointments.

Stress importance of strict oral hygiene to prevent infection.

Inform patient of possibility of hair loss and reassure patient that hair will
regrow following discontinuation of therapy.

Instruct patient to report these symptoms to physician immediately: ny


symptoms of pulmonary infection (cough, shortness of breath, fever) or GI
complications (diarrhea, abdominal pain, black tarry stools) occur. Instruct
patient to report these symptoms to physician: presence of chills and fever,
unusual bleeding or bruising, jaundice, dark or bloody urine, swelling of
feet or legs and joint pain.

Advise patient to avoid intake of alcoholic beverages, salicylates and


NSAIDs.

Caution patient to avoid exposure to sunlight or sunlamps and to wear


protective clothing to avoid photosensitivity reaction.

Instruct patient not to take otc preparations (including vitamins) ithout


notifying physician. Folic acid, an ingredient in some otc products,
reduces methotrexate efficacy.
meth-oh-TREK-sate)
Folex, Folex PFS, Rheumatrex Dosis Pack, Rheumatrex Tablet
Kelas: antineoplastik / antimetabolit; antipsoriatik; antiartritik
Action bersaing menghambat reduktase asam dihydrofolic dan
dengan demikian menghambat sintesis DNA dan replikasi sel.
Dalam rheumatoid arthritis, diyakini mengurangi fungsi
kekebalan tubuh. Indikasi kemoterapi antineoplastik untuk
pengobatan koriokarsinoma gestasional, destruens
chorioadenoma, mola hidatidosa; pengobatan dan pencegahan
meningeal akut) leukemia limfositik; pengobatan kanker
payudara, kanker epidermoid dari kepala dan leher, mikosis
fungoides canggih dan kanker paru-paru; dalam terapi
kombinasi dalam limfoma stadium lanjut non-Hodgkin; sebagai
tambahan dalam dosis tinggi diikuti dengan penyelamatan
leucovorin di osteosarcoma nonmetastatic (postsurgically);
kontrol gejala psoriasis berat dan rheumatoid arthritis yang
parah. Penggunaan berlabel (s): Pengurangan persyaratan
kortikosteroid pada penderita asma kortikosteroid tergantung
parah. Kontraindikasi Gunakan pada ibu menyusui. Pada pasien
dengan psoriasis atau rheumatoid arthritis, methotrexate
merupakan kontraindikasi pada kehamilan, alkoholisme,
penyakit hati alkoholik, penyakit hati kronis, terang-terangan
atau laboratorium bukti immunodeficiency syndrome dan
diskrasia darah yang sudah ada sebelumnya (misalnya,
leukopenia, trombositopenia). Route / Dosis
Koriokarsinoma dan Penyakit Thromboblastic
DEWASA: PO / IM 15-30 mg selama 5 hari. Ulangi program 3-5
kali diperlukan, dengan waktu istirahat dari> 1 minggu antara
kursus.
Leukemia
DEWASA & ANAK: INDUKSI: 3,3 mg / m2 / hari dalam kombinasi
dengan prednison 60 mg / m2 / hari biasanya selama 4 sampai 6
minggu. Terapi Postremission pemeliharaan (biasanya dalam
kombinasi dengan obat lain): PO / IM 2 kali seminggu secara
total dosis mingguan dari 30 mg / m2 atau IV 2,5 mg / kg q 14
hari.
Leukemia meningeal
DEWASA: intratekal 12 mg / dosis m2 atau empiris dari 15 mg.
Mengelola q 2-5 hari sampai jumlah sel dari CSF kembali normal;
kemudian memberikan satu dosis tambahan. pengurangan dosis
mungkin diperlukan pada pasien usia lanjut karena perbedaan
dalam volume CSF. ANAK 3 YR: 12 mg. Mengelola q 2-5 hari
sampai jumlah sel CSF kembali normal. ANAK 2 YR: 10 mg. ANAK
1 YR: 8 mg. ANAK <1 YR: 6 mg.
Limfoma: Burkitt limfoma, Tahapan 1 & 2

DEWASA: PO 10-25 mg / hari selama 4-8 hari. Memberikan 7-10hari masa istirahat antara kursus.
Tahap 3 Lymphosarcoma sebagai Bagian dari Terapi Kombinasi
DEWASA: PO 0,625-2,5 mg / kg / hari.
mikosis fungoides
DEWASA: PO 2,5-10 mg / hari selama minggu ke bulan
(berdasarkan respon klinis atau fungsi hematologi). IM 25 mg
dua kali seminggu atau 50 mg mingguan.
osteosarcoma
Kompleks dosis tinggi dengan penyelamatan leucovorin dan
agen kemoterapi lainnya. Mulai dosis untuk metotreksat dosis
tinggi adalah 12 gm / m2.
Radang sendi
DEWASA: AWAL TERAPI: PO 7,5 mg / minggu di dosis tunggal
atau 2,5 mg tiap 12 jam selama 3 dosis setiap minggu. Secara
bertahap menyesuaikan dosis untuk respon maksimal; tidak
melebihi 20 mg / minggu.
Psorias
Individualize dosis. Mengelola 5-10 mg tes parenteral dosis 1
minggu sebelum terapi. DEWASA: IM / IV 10-25 mg / minggu
(maksimal 50 mg / minggu). DEWASA: PO 2,5 mg tiap 12 jam
selama 3 dosis atau 8 interval jam untuk 4 dosis q wk
(maksimum 30 mg / minggu). ALTERNATIF JADWAL: PO 2,5 mg
qd selama 5 hari diikuti oleh 2-hari masa istirahat (maksimum
6,25 mg qd). Jadwal ini dapat menimbulkan peningkatan risiko
toksisitas hati. interaksi
Arang, asam folat: Dapat mengurangi efikasi metotreksat.
Digoxin: Dapat mengurangi tingkat digoxin serum dan tindakan.
Hydantoins: Dapat mengurangi kadar plasma. Etretinate, NSAID,
penisilin, probenesid, salisilat, sulfonamid: Dapat meningkatkan
kadar metotreksat dan toksisitas. Lab Uji Gangguan Tidak
didokumentasikan dengan baik. Reaksi yang merugikan
SSP: Pusing; kelelahan; sakit kepala; aphasia; hemiparesis;
paresis; kejang; eukoencephalopathy (IV setelah iradiasi
craniospinal); arachnoiditis kimia; paresis ransient;
neurotoksisitas. Derm: ruam eritematosa; pruritus; urtikaria;
fotosensitifitas; Perubahan igmentary; alopecia; ecchymosis;
telangiectasia; jerawat; furunculosis; ggravation psoriasis oleh
sinar ultraviolet. EENT: Penglihatan kabur; ulseratif stomatitis;
radang gusi; faringitis. GI: Mual; distress abdominal (umum);
anoreksia; muntah; diare; hematemesis; elena; ulserasi GI dan
perdarahan; radang usus. GU: Gagal ginjal; azotemia; sistitis;
hematuria; nefropati parah; gangguan reproduksi; infertilitas;
abortus; cacat janin. HEMA: Leukopenia; sumsum depresi tulang;
trombositopenia; anemia; ypogammaglobulinemia; pendarahan;
keracunan darah. HEPA: Hepatotoksisitas; sirosis hati dan
fibrosis. RESP: Kematian akibat pneumonitis interstitial; penyakit
paru kronik interstitial obstruktif. LAIN: Malaise; panas dingin;
demam; resistensi rendah terhadap infeksi; arthralgia; yalgia;
diabetes; osteoporosis; Reaksi anafilaktoid; kematian mendadak.

kewaspadaan
Kehamilan: Kategori X (untuk rheumatoid arthritis dan psoriasis);
Kategori D (kegunaan lain). Laktasi: Kontraindikasi pada ibu
menyusui. Anak-anak: Keamanan dan kemanjuran tidak didirikan
selain untuk pengobatan kanker. pasien usia lanjut: Erat
memantau tanda-tanda awal keracunan. Mungkin memerlukan
pengurangan dosis. Infeksi: Reaksi parah dapat terjadi jika
vaksin hidup yang diberikan. Terapi intratekal: dosis besar dapat
menyebabkan kejang-kejang dan toksisitas sistemik. regimen
dosis berdasarkan usia mungkin lebih efektif dan dikaitkan
dengan lebih sedikit efek samping neurotoksik. Jangan
menggunakan formulasi atau pengencer yang mengandung
pengawet. gangguan ginjal: Gunakan obat dengan hati-hati.
Menentukan status ginjal sebelum dan selama terapi. Efek yang
parah: Penggunaan rejimen metotreksat dosis tinggi (yaitu,
untuk mengobati osteosarkoma) memerlukan perawatan teliti.
Kematian terjadi setelah penggunaan methotrexate untuk
kondisi apapun. Potensi toksisitas termasuk depresi sumsum
tulang; hepatotoksisitas; Penyakit paru-paru (disarankan oleh
gejala kering, batuk tidak produktif); nefrotoksisitas dan
toksisitas GI.
PASIEN PERAWATAN PERTIMBANGAN
________________________________________ Administrasi / Storage
Pastikan bahwa leucovorin tersedia dari apotek sebelum
memulai pemberian dosis tinggi metotreksat. Leucovorin
mengurangi toksisitas methotrexate.
Oral sering disukai. Berikan obat 1-2 jam sebelum makan.
methotrexate Pengawet bebas dapat diberikan IM, IV, intraarterially atau intratekal.
Untuk penggunaan intratekal, menyusun kembali segera
sebelum digunakan dengan media bebas pengawet seperti 0,9%
Natrium Klorida untuk Injeksi.
prosedur Ikuti untuk penanganan dan pembuangan obat
antikanker. Pakailah sarung tangan dan menghindari paparan
kulit dan menghirup asap.
obat Simpan dalam tertutup rapat, kontainer cahaya-tahan.
Penilaian / Intervensi
Mendapatkan riwayat pasien, termasuk riwayat obat dan alergi
dikenal.
Sebelum memulai terapi, periksa kreatinin serum normal dan
kreatinin> 60 ml / menit.
Kaji alkoholisme, penyakit hati alkoholik atau penyakit hati
kronis lainnya.
Tentukan apakah pasien memiliki bukti sindrom
imunodefisiensi, infeksi aktif, yang sudah ada sebelumnya
diskrasia darah (misalnya, hipoplasia sumsum tulang,
leukopenia, trombositopenia atau anemia yang signifikan).
Kaji fungsi paru; perhatikan terutama Adanya efusi paru.
Membangun pengukuran fungsi paru dasar.
Pertahankan hidrasi yang memadai dan alkalinization urin

selama terapi. Memantau I & O.


Hindari suntikan IM dan mengambil suhu rektal selama terapi
methotrexate; menerapkan tekanan ke situs venipuncture
selama setidaknya 10 menit.
Tentukan status ginjal sebelum terapi dan memantau selama
terapi.
Selama terapi memantau secara berkala untuk toksisitas.
pemantauan wajib meliputi CBC dengan diferensial dan
trombosit jumlah dan hati dan tes fungsi ginjal. Periodik biopsi
hati dapat diindikasikan dalam beberapa situasi.
Menilai sering untuk gejala paru, terutama kering, batuk
produktif atau pneumonitis spesifik.
Pantau erat untuk setiap gejala diare dan stomatitis ulseratif.
Periksa mulut pasien setiap hari. Melaporkan setiap daerah
nekrosis tambal sulam, perdarahan dan ketidaknyamanan atau
hitam / "berbulu" lidah.
Menginformasikan dokter jika diare atau stomatitis ulseratif
terjadi selama pengobatan; Terapi harus terganggu.
Menginformasikan dokter dari perkembangan gejala paru
(kering, batuk produktif, demam, sesak napas, hipoksemia atau
adanya infiltrat pada film rontgen dada) selama terapi.
Metotreksat harus dihentikan dan gejala diselidiki dan diobati.
Overdosis: TANDA & GEJALA Hepatotoksisitas, nefrotoksisitas,
toksisitas GI, toksisitas sumsum tulang, toksisitas paru Pasien /
Pendidikan Keluarga
Anjurkan pasien untuk menghubungi dokter jika muntah
terjadi setelah obat diambil.
Menginformasikan pasien yang hamil harus dihindari selama
terapi jika salah satu pasangan menerima metotreksat dan
untuk minimal 3 bulan setelah terapi untuk pria dan selama dan
untuk setidaknya satu siklus ovulasi setelah terapi bagi wanita.
Menyarankan pasien dan orang tua bahwa imunisasi dengan
vaksin virus hidup umumnya tidak dianjurkan selama terapi
methotrexate.
Anjurkan pasien untuk menghindari orang banyak dan orang
dengan infeksi dikenal.
Tekankan pentingnya tes laboratorium selama terapi dan
mendorong pasien untuk menjaga semua janji yang dijadwalkan.
Stres pentingnya kebersihan mulut yang ketat untuk
mencegah infeksi.
Menginformasikan pasien dari kemungkinan rambut rontok
dan meyakinkan pasien bahwa rambut akan tumbuh kembali
setelah penghentian terapi.
Anjurkan pasien untuk melaporkan gejala-gejala tersebut ke
dokter segera: ny gejala infeksi paru (batuk, sesak napas,
demam) atau komplikasi GI (diare, sakit perut, hitam tinja)
terjadi. Anjurkan pasien untuk melaporkan gejala-gejala tersebut
ke dokter: kehadiran menggigil dan demam, perdarahan yang
tidak biasa atau memar, sakit kuning, urin berwarna gelap atau
berdarah, pembengkakan kaki atau kaki dan nyeri sendi.

Anjurkan pasien untuk menghindari asupan minuman


beralkohol, salisilat dan NSAID.
Perhatian pasien untuk menghindari paparan sinar matahari
atau sunlamps dan memakai pakaian pelindung untuk
menghindari reaksi fotosensitifitas.
Anjurkan pasien untuk tidak mengambil persiapan otc
(termasuk vitamin) ithout memberitahukan dokter. Asam folat,
bahan dalam beberapa produk otc, mengurangi efikasi
metotreksat.
Ahfs

Methotrexate (Systemic)
Introductory Information
Antineoplastic agent and immunosuppressant; folic acid antagonist.a, b, c
Class: 10:00 Antineoplastic Agents; an300 (VA primary)
Brands*: Rheumatrex, Trexall
*

also available generically

Generic Name: Methotrexate


CAS Number: 59-05-2
Synonym: Amethopterin
Generic Name Abbreviation: MTX
Generic Name: Methotrexate Sodium
CAS Number: 15475-56-6
Molecular Formula: C20H22N8O5
Boxed Warning
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 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 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
Uses
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 druginduced 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-lined systemic chemotherapy for advanced cutaneous T-cell lymphoma (e.g.,
mycosis fungoides, Sezary 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 osteosarcomab, 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 therapyd for invasive and advanced bladder
cancer
.182, 205, 206, 207, 208, 209

Use of leucovorin rescue or deletion of methotrexate is advised if methotrexatecontaining 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

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
Scr must be normal and Clcr >60 mL/minute before therapy initiation.b 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).b
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).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 intraarterially.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 preservativefree 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
>Recommended Intrathecal Dose Based on Age107, 108, 127
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 10day 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-Qp: 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
>Leucovorin Rescue Schedules Based on Serum Methotrexate Concentrationsb
Leucovorin Dosage and
Clinical Situation Laboratory Findings
Duration
Serum methotrexate concentration
15 mg orally, IM, or IV
approximately 4.54 mcg/mL (10
Normal
every 6 hours for 60 hours
mcM) at 24 hours after
methotrexate
(10 doses starting at 24
administration, 0.454 mcg/mL (1
elimination
hours after start of
mcM) at 48 hours, and <0.091
methotrexate infusion)
mcg/mL (0.2 mcM) at 72 hours
Serum methotrexate concentration Continue 15 mg orally, IM,
Delayed late
remaining >0.091 mcg/mL (0.2
or IV every 6 hours, until
methotrexate
mcM) at 72 hours and >0.023
methotrexate concentration
elimination
mcg/mL (0.05 mcM) at 96 hours is <0.023 mcg/mL (0.05
after administration
mcM)

Serum methotrexate 22.7 mcg/mL


150 mg IV every 3 hours,
(50 mcM) at 24 hours or 2.27
until methotrexate
Delayed early
mcg/mL (5 mcM) at 48 hours after
concentration is <0.454
methotrexate
administration, or a 100%
mcg/mL (1 mcM), then 15
elimination and/or increase in Scr concentration at 24
mg IV every 3 hours until
evidence of acute hours after methotrexate
methotrexate concentration
renal injury
administration (e.g., an increase
is <0.023 mcg/mL (0.05
from 0.5 mg/dL to a concentration
mcM)
of 1 mg/dL)
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.b, c
Cautions
Contraindications
Pregnant women with psoriasis or rheumatoid arthritis; use in treatment of
neoplastic diseases only when potential benefit outweighs risk to fetus.b, c (See
Boxed Warning.)
Nursing women.127, b, c
Excessive alcohol consumption, alcoholic liver disease, or other chronic liver
disease in patients with psoriasis or rheumatoid arthritis.127, b, c
Overt or laboratory evidence of immunodeficiency syndromes in patients with
psoriasis or rheumatoid arthritis.127, b, c
Preexisting blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia,
thrombocytopenia, clinically important anemia) in patients with psoriasis or
rheumatoid arthritis.127, b, c
Known hypersensitivity to methotrexate.b, c
Warnings/Precautions
Warnings
Also see Boxed Warnings.
Fetal/Neonatal Morbidity and Mortality
Fetal death and/or congenital anomalies reported.b, c Exclude pregnancy before
initiating treatment.b, c Avoid pregnancy if either partner is receiving methotrexate;
avoid pregnancy during therapy and for 3 months after therapy in male patients
and for at least one ovulatory cycle after therapy in female patients.b, c If used
during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.b, c
Sensitivity Reactions
Dermatologic and Sensitivity Reactions
Severe, occasionally fatal cutaneous or sensitivity reactions (e.g., toxic epidermal
necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis,
erythema multiforme) reported in pediatric and adult patients within days of
receiving drug at various dosages, by various routes, and for various conditions.193,
b, c

Erythematous rashes, pruritus, dermatitis, urticaria, folliculitis, photosensitivity,


depigmentation, hyperpigmentation, petechiae, ecchymoses, telangiectasia, acne,
furunculosis, and skin ulceration also reported.a, b, c
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet
radiation; possible "recall" radiation dermatitis and sunburn with methotrexate
use.b, c
Major Toxicities
Hematologic Effects
Possible suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia,
leukopenia, neutropenia, and/or thrombocytopenia.b, c Use with caution in patients
with malignancy and preexisting hematopoietic impairment.b, c
Perform CBCs, including differential and platelet counts, at least weekly in
patients with neoplastic disease and at least monthly in patients with psoriasis or
rheumatoid arthritis.a, b, c
In patients with psoriasis or rheumatoid arthritis, discontinue if clinically
important decrease in blood counts occurs and institute appropriate alternative
therapy; in patients with neoplastic disease, continue only if potential benefit
warrants risk of severe myelosuppression.a, b, c
If profound granulocytopenia and fever occur, observe patient closely and initiate
broad-spectrum antibiotic therapy if there are signs of infection.a, b, c
Blood or platelet transfusions may be necessary in patients with severe
myelosuppression.a
GI Effects
Risk of vomiting, diarrhea, or stomatitis resulting in dehydration; discontinue
drug until recovery occurs.b, c (See GI Toxicity in Boxed Warning.)
Use with extreme caution in presence of peptic ulcer disease or ulcerative colitis.b,
c

Hepatic Effects
Possible hepatotoxicity; may be acute (increased serum aminotransferase
concentrations) or chronic (fibrosis and cirrhosis).127, 128, 131, 155, 164, b, c
Chronic hepatotoxicity, potentially fatal, generally occurs after prolonged use (2
years) and after a total dose of 1.5 g.127, 128, 131, 164, b, c
Risk of hepatotoxicity in patients with psoriasis appears to be related to
cumulative dose and may be enhanced by alcoholism, obesity, diabetes, and
advanced age.116, 127, 131, 141, 142, 150, 158, 160, b, c These risk factors also may apply to
patients with rheumatoid arthritis;127, 150 age at first use and duration of therapy
also reported as risk factors in rheumatoid arthritis patients.b, c

Use with particular caution in patients with preexisting liver damage or hepatic
impairment.b, c
Psoriasis: Perform liver function tests, including serum albumin, periodically prior
to dosing, although results may be normal despite developing fibrosis or
cirrhosis.116, 127, 131, 138, 141, 142, 147, 148, b, c Liver biopsy recommended before therapy
or shortly after therapy initiation (2-4 months), at cumulative dose of 1.5 g, and
after each additional 1-1.5 g.127, 163, b, c Usually discontinue drug if moderate
fibrosis or any cirrhosis; repeat biopsy in 6 months if mild fibrosis.b, c Continue
use with caution if milder changes (e.g., fatty changes, low-grade portal
inflammation).b, c
Rheumatoid arthritis: Prolonged, substantial abnormalities in liver function test
results may precede appearance of hepatic fibrosis or cirrhosis; 127, b, c perform
liver function tests at baseline and at 4- to 8-week intervals.b, c Pretreatment liver
biopsy recommended if history of excessive alcohol consumption, persistently
abnormal baseline liver function tests, or chronic hepatitis B or C infection.127
Perform liver biopsy during therapy if persistent liver function test abnormalities
or serum albumin concentrations fall below normal (in setting of well-controlled
rheumatoid arthritis).b, c If liver biopsy shows mild changes (Roenigk grade I, II,
or IIIa), continue therapy and monitoring; discontinue if persistently abnormal
liver function tests, if biopsy shows moderate to severe changes (Roenigk grade
IIIb or IV), or if patient refuses biopsy.b, c
Respiratory Effects
Potentially fatal119, 127, 154 pulmonary toxicity; can progress rapidly117, 118, 119, 127, 128,
129, 130
and may not be fully reversible.119, 127, 128 Adverse pulmonary effects (i.e.,
acute or chronic interstitial pneumonitis, pulmonary fibrosis) may occur at any
dosage at any time during therapy.117, 118, 119, 242, b, c
If manifestations (e.g., fever, cough [especially dry and nonproductive], dyspnea,
chest pain, hypoxemia [possibly severe], radiographic evidence of pulmonary
infiltrates [usually diffuse and/or alveolar])117, 118, 119, 127, 128, 129, 130, 159, 160, b, c occur,
discontinue and carefully evaluate, including exclusion of possible infectious
causes.119, 127, 128, 129, 130
Management is mainly supportive and may include mechanical ventilation.119, 128,
129, 130

Potentially fatal opportunistic infections (e.g., P. jiroveci pneumonia) reported;


consider possibility of P. jiroveci pneumonia in patients who develop pulmonary
symptoms.b, c
Renal Effects
May cause renal damage that may lead to acute renal failure.b, c

Nephrotoxicity is due principally to precipitation of methotrexate and 7hydroxymethotrexate in the renal tubules.b, c
Careful attention to renal function, including adequate hydration, urine
alkalinization, and measurement of methotrexate and Scr concentrations is
essential.c
Perform renal function tests prior to and periodically during therapy (at 1- to 2month intervals in patients with psoriasis or rheumatoid arthritis; more frequently
in patients with neoplastic disease).a, b, c
If renal impairment develops during therapy, reduce dosage or discontinue drug
until renal function is improved or restored.a, b, c
Immunosuppressive Effects
Consider immunosuppressive effects when evaluating use in patients in whom
immune response may be important or essential.a (See Vaccines under
Interactions.)
Usually contraindicated in patients with overt or laboratory evidence of
immunodeficiency syndromes.a, b, c (See Contraindications under Cautions.)
Use with extreme caution in presence of active infection.a, b, c
Hypogammaglobulinemia reported rarely.b, c
Neurologic Effects
Leukoencephalopathy reported following IV administration in patients who had
received craniospinal irradiation; chronic leukoencephalopathy also reported in
patients receiving repeated high-dose therapy with leucovorin rescue even without
cranial irradiation.b
Severe neurotoxic effects, manifested mainly by focal or generalized seizures,
reported with increased frequency in pediatric patients with ALL who received
intermediate-dose IV therapy (1 g/m2);193, b leukoencephalopathy and/or
microangiopathic calcifications usually were observed in diagnostic imaging
procedures of symptomatic patients.193
A transient acute neurologic syndrome observed in patients receiving high-dosage
regimens; exact cause unknown.b Manifestations of this stroke-like
encephalopathy may include confusion, hemiparesis, transient blindness, seizures,
and coma.b
Intrathecal Administration
Possible acute chemical arachnoiditis manifested by headache, back pain, nuchal
rigidity, and/or fever; subacute myelopathy manifested by paraparesis/paraplegia
involving one or more spinal nerve roots; chronic leukoencephalopathy (may be

progressive and fatal) manifested by confusion, irritability, somnolence, ataxia,


dementia, and occasionally seizures and coma; and increased CSF pressure.127
Systemic toxicity also may occur following intrathecal administration.a, b
Inadvertent intrathecal overdosage has occurred;101, 102, 103 symptoms generally
include CNS effects (i.e., headache, nausea, vomiting, seizure, acute toxic
encephalopathy),b although in some cases, no symptoms were reported.b Death
has occurred following intrathecal overdose; in these cases, cerebellar herniation
associated with increased intracranial pressure and acute toxic encephalopathy
also reported.b
Accidental intrathecal overdosage may require intensive systemic support, highdose systemic leucovorin (intrathecal leucovorin contraindicated), alkaline
diuresis, and rapid CSF drainage and ventriculolumbar perfusion.b
Focal leukemic involvement of the CNS may not respond to intrathecal
methotrexate and may best be treated with radiation therapy.a
General Precautions
Adequate Patient Evaluation and Monitoring
Therapeutic response is not likely without some evidence of toxicity.a Severity of
toxic reactions may be increased when used in combination with other
antineoplastic agents and/or radiation therapy.a
Closely monitor patients with complete hematologic studies, urinalysis, renal
function tests, liver function tests, and chest radiographs.a, b, c (See Major
Toxicities under Cautions.)
If serious toxicity occurs, reduce dosage or discontinue and institute appropriate
corrective measures (e.g., use of leucovorin calcium, acute intermittent
hemodialysis with a high-flux dialyzer).c
Third-Space Compartments
Exits slowly from third-space compartments (e.g., pleural effusions, ascites),
resulting in prolonged elimination and unexpected toxicity in patients with
substantial third-space accumulations.a, c Evacuation of fluid recommended before
treatment; monitor plasma methotrexate concentrations.c
Specific Populations
Pregnancy
Category X.b (See Fetal/Neonatal Morbidity and Mortality in Boxed Warning and
under Cautions.)
Lactation
Distributed into milk.b Contraindicated in nursing women because of risk to
nursing infant.127, b, c

Pediatric Use
Safety and efficacy established only for cancer chemotherapy or polyarticularcourse juvenile rheumatoid arthritis.b, c
In clinical studies, safety in pediatric patients 2-16 years of age with juvenile
rheumatoid arthritis was similar to that observed in adults with rheumatoid
arthritis.b, c
Severe neurotoxic effects (e.g., focal or generalized seizures) reported in pediatric
patients with ALL who received intermediate-dose IV therapy (1 g/m2).193, b (See
Neurologic Effects under Cautions.)
Preparations containing benzyl alcohol preservative not recommended in neonates
because of toxicity.b
Geriatric Use
Insufficient experience in patients 65 years of age to determine whether geriatric
patients respond differently than younger adults; select dosage with caution due to
greater frequency of decreased hepatic and renal function and folate stores and of
concomitant disease and drug therapy (i.e., that interfere with renal function or
methotrexate or folate metabolism) observed in the elderly.b, c
Occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis
may increase with age.b, c
Closely monitor geriatric patients for early signs of hepatic, bone marrow, and
renal toxicity; certain toxicities may be reduced by folate supplementation.b, c Scr
may overestimate renal function in geriatric patients; consider more accurate
methods (i.e., Clcr). Serum methotrexate concentrations may be helpful.b, c
Hepatic Impairment
Contraindicated in patients with psoriasis or rheumatoid arthritis who have
alcoholic liver disease or other chronic liver disease.b c Use with extreme caution,
if at all, in patients with malignant disease who have preexisting liver damage or
impaired hepatic function.a
Renal Impairment
Usually contraindicated.a
Debilitated Patients
Use with extreme caution.c
Common Adverse Effects
Ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue
fatigue, chills, fever, dizziness, decreased resistance to infection.b, c
Interactions

Protein-bound Drugs
Possible increased methotrexate toxicity because of displacement from protein
binding sites.a (See Specific Drugs under Interactions.)
Weak Organic Acids
Potential to delay renal excretion and increase accumulation of methotrexate.a
(See Specific Drugs under Interactions.)
Hepatotoxic Agents
Increase in adverse hepatic effects expected.b, c
Nephrotoxic Drugs
Possible altered renal elimination of methotrexate. Exercise caution if high-dose
methotrexate administered in conjunction with nephrotoxic drugs in patients with
osteosarcoma.b
Specific Drugs
Drug
Adalimumab
Aminobenzoic acid

Amiodarone

Anakinra

Asparaginase

Interaction
Comments
Decreased adalimumab
Dosage adjustment not
clearance
needed
Possible increased
methotrexate toxicity because Use concomitantly with
of displacement from protein cautiona
binding sitesa, b, c
Possible inhibition of
methotrexate metabolism with
prolonged administration (2
weeks) of oral amiodarone
Administered concurrently in
clinical studies, but specific
drug interactions not
evaluated in humans
No effect on clearance or
toxicologic profile of either
drug when administered
concurrently in rats
Administration of
Decreased effectiveness of
methotrexate with or
methotrexate during period of shortly after
asparagine suppression
asparaginase not
recommended

Azathioprine

Chloramphenicol

Cisplatin

Co-trimoxazole

Cyclosporine

DMARDs (e.g., gold,


hydroxychloroquine,
penicillamine,
sulfasalazine)
Folic acid (e.g.,
multivitamins)

Possible increased risk of


hepatotoxicity127, b
Possible increased
methotrexate toxicity because
of displacement from protein
binding sitesa, b, c
Possible decreased intestinal
absorption of methotrexate or
interference with
enterohepatic circulationb, c

Possible altered renal


elimination of methotrexate

Closely monitor for


toxicity127, b

Use concomitantly with


cautiona

Possible synergistic
antineoplastic effects
Exercise caution if highdose methotrexate
administered in
conjunction with
cisplatin in patients with
osteosarcomab

Sulfonamides can displace


methotrexate from plasma
protein-binding sites resulting
in increased free methotrexate
concentrationsa
Use concomitantly with
Co-trimoxazole rarely
cautiona
increases myelosuppression in
patients receiving
methotrexate, probably by
additive antifolate effectb
Generally administer
Possible increased plasma
cyclosporine
concentrations of
formulations for
methotrexate and its active
emulsion (Neoral) at
metabolite; no apparent effect 3 mg/kg daily in
on blood concentrations of
patients receiving
cyclosporine
methotrexate 15 mg
weekly
Concomitant administration
not studied; possible
increased incidence of
adverse effectsb, c
Potential for decreased
methotrexate effectiveness;a, b
however, folate deficiency
may increase methotrexate
toxicityb

Infliximab

Possible decreased rate of


clearance of infliximab
Possible decrease in rate of
development of antibodies to
infliximab
Increased serum methotrexate
concentrations and deaths
from severe hematologic and
GI toxicity reported when
NSAIAs used concomitantly
with high-dose
methotrexate120, 121, 122, 123, 124,

Interaction not studied


specifically; used
concomitantly in clinical
studies

Avoid NSAIAs in
patients receiving
125, 126, 127, 128, b, c
relatively high dosages
NSAIAs (e.g.,
NSAIAs and salicylates may of methotrexate (e.g.,
indomethacin,
inhibit renal elimination of
those used in
ketoprofen,
methotrexate;120, 121, 122, 123, 124, osteosarcoma)127, 128, 155
phenylbutazone [not
125, 126, b, c
possibly increased Use caution if low-dose
commercially available in
and prolonged serum
methotrexate and
US], salicylates)
methotrexate
NSAIAs or salicylates
127, 128, 138, 139, a
concentrations
used concomitantly127,
128, b, c
Possible increased
methotrexate toxicity because
of displacement from protein
binding sites by
phenylbutazone or
salicylatesa, c
Possible decreased
methotrexate renal
clearance127, 188, 190
Increased serum methotrexate Carefully monitor
Penicillins (e.g.,
concentrations and GI or
patients during
amoxicillin, carbenicillin) hematologic toxicity reported concomitant use127, 188,
in patients receiving low- or 189, 190
high-dose methotrexate
therapy concomitantly with
penicillins127, 188, 189, 190
Possible increased
methotrexate toxicity because Use concomitantly with
Phenytoin
of displacement from protein cautiona
binding sitesa, c
Renal tubular transport of
Probenecid
Carefully monitorc
methotrexate diminishedb, c
Possible increased risk of
Do not administer
Pyrimethamine
myelosuppressionm
concomitantlya
Retinoids
Possible increased risk of
Closely monitor for

Sulfasalazine
Sulfonamides

Tetracyclines

hepatotoxicity127, b
Possible increased risk of
hepatotoxicity127, b
Possible increased
methotrexate toxicity because
of displacement from protein
binding sitesa, c
Possible increased
methotrexate toxicity because
of displacement from protein
binding sitesa, b, c
Possible decreased intestinal
absorption of methotrexate or
interference with
enterohepatic circulationb, c

toxicity127, b
Closely monitor for
toxicity127, b
Use concomitantly with
cautiona

Use concomitantly with


cautiona

Theophylline

Possible decreased
theophylline clearancec

Monitor serum
theophylline
concentrationsc

Vaccines

Disseminated vaccinia
infection reported following
smallpox vaccination in
patients receiving
methotrexate127, 128, 151
Although antibody response
to killed virus vaccines is not
normal, partial or complete
protection may still be
attained; however, may be
ineffectivea, b, c

Generally, do not use


live virus vaccines in
patients receiving
methotrexatea
Use killed virus
vaccines if necessarya

Pharmacokinetics
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.b, c
Duration
In patients with arthritis, limited data indicate that initial improvement is
maintained for at least 2 years with continued therapy.b, c Arthritis usually worsens
within 3-6 weeks after methotrexate discontinuance.b, c
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, b, c At high
doses, elimination half-life is about 8-15 hours.127, b, c
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, b, c
Stability
Storage
Oral
Tablets
Well-closed containers at 15-30C.c Protect from light.c
Parenteral
Injection
20-25C (may be exposed to 15-30C).b Protect from light.b
Storage of solutions containing preservatives after further dilution for 24 hours at
21-25C results in a product within 90% of label potency.b Use preservative-free
solution immediately after further dilution.b
Powder for Injection
20-25C (may be exposed to 15-30C).b Protect from light.b
Use immediately after reconstitution.b
Compatibility
For information on systemic interactions resulting from concomitant use, see
Interactions.
Parenteral
Solution Compatibilityb, HID
Compatible
Amino acids 4.25%, dextrose 25%
Dextrose 5% in water
Sodium bicarbonate 0.05 M
Sodium chloride 0.9%

>Drug Compatibility
>Admixture CompatibilityHID
Compatible
Cyclophosphamide
Cyclophosphamide with fluorouracil
Cytarabine
Fluorouracil
Hydroxyzine HCl
Mercaptopurine sodium
Ondansetron HCl
Sodium bicarbonate
Vincristine sulfate
Incompatible
Bleomycin sulfate
>Y-Site CompatibilityHID
Compatible
Allopurinol sodium
Amifostine
Amphotericin B cholesteryl sulfate complex
Asparaginase
Aztreonam
Bleomycin sulfate
Cefepime HCl
Ceftriaxone sodium
Cimetidine HCl
Cisplatin
Cyclophosphamide
Cytarabine
Daunorubicin HCl
Dexchlorpheniramine maleate
Diphenhydramine HCl
Doxorubicin HCl
Doxorubicin HCl liposome injection
Etoposide
Etoposide phosphate
Famotidine
Filgrastim
Fludarabine phosphate
Fluorouracil
Furosemide

Ganciclovir sodium
Gallium nitrate
Granisetron HCl
Heparin
Heparin sodium
Hydromorphone HCl
Imipenem-cilastatin sodium
Lansoprazole
Leucovorin calcium
Linezolid
Lorazepam
Melphalan HCl
Mesna
Methylprednisolone sodium succinate
Metoclopramide HCl
Mitomycin
Morphine sulfate
Ondansetron HCl
Oxacillin sodium
Oxaliplatin
Paclitaxel
Piperacillin sodium-tazobactam sodium
Prochlorperazine edisylate
Ranitidine HCl
Sargramostim
Teniposide
Thiotepa
Vinblastine sulfate
Vincristine sulfate
Vindesine sulfate
Vinorelbine tartrate
Incompatible
Chlorpromazine HCl
Gemcitabine HCl
Idarubicin HCl
Ifosfamide
Midazolam HCl
Nalbuphine HCl
Promethazine HCl
Propofol
Variable

Dexamethasone sodium phosphate


Droperidol
Vancomycin HCl
Actions
Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate
reductase (enzyme that reduces folic acid to tetrahydrofolic acid); inhibition of
tetrahydrofolate formation limits availability of one-carbon fragments necessary
for synthesis of purines and conversion of deoxyuridylate to thymidylate in DNA
synthesis and cell reproduction.a, b, c
Also causes an increase in intracellular deoxyadenosine triphosphate, which is
thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme
concerned in DNA synthesis and repair.a
Tissues with high rates of cellular proliferation (e.g., neoplasms, psoriatic
epidermis, bone marrow, lining of GI tract, hair matrix, fetal cells, urinary
bladder) are most sensitive.a
Also has immunosuppressive activity, possibly because of lymphocyte
multiplication inhibition.a
Mechanism(s) of action in rheumatoid arthritis not known; suggested mechanisms
have included immunosuppressive and/or anti-inflammatory effects.113, 116, 127, 128,
138, 141, 142, 144, 145, b, c

Advice to Patients
Necessity of informing patients of potential benefits and risks of therapy and
importance of remaining under care of clinician throughout therapy.b, c
Risk of hematologic, hepatic, pulmonary, and renal toxicities; importance of close
follow-up, including periodic laboratory tests to monitor toxicity.b, c
Importance of recognizing early manifestations of toxicity and informing clinician
promptly if such manifestations occur.b, c
Importance of emphasizing to patients that the recommended dose is taken weekly
in rheumatoid arthritis and psoriasis, and that mistaken daily use of recommended
dose has led to fatal toxicity.c Encourage patients to read patient instruction sheet
provided with mnemonic dispensing packages.c
Importance of informing clinicians of existing or contemplated concomitant
therapy, including prescription and OTC drugs, as well as any concomitant
illnesses.b
Importance of women informing clinicians if they are or plan to become pregnant
or plan to breast-feed.b Importance of informing both male and female patients of
risks to fetus if pregnancy occurs.b, c Advise patients to avoid pregnancy while
either partner is receiving methotrexate, and for a minimum of 3 months after
therapy in men and at least 1 ovulatory cycle after therapy in women.b, c
Importance of informing patients of other important precautionary information.b
(See Cautions.)

Preparations
Excipients in commercially available drug preparations may have clinically
important effects in some individuals; consult specific product labeling for
details.
Methotrexate Sodium
Dosage
Routes
Strengths
Brand Names
Manufacturer
Forms
2.5 mg (of
Rheumatrex Dose Pack
Oral
Tablets
Wyeth
methotrexate)*
(scored)
Tablets,
5 mg (of
Trexall (scored)
Barr
film-coated methotrexate)*
7.5 mg (of
Trexall (scored)
Barr
methotrexate)*
10 mg (of
Trexall (scored)
Barr
methotrexate)*
15 mg (of
Trexall (scored)
Barr
methotrexate)*
25 mg (of
Methotrexate Sodium
Abraxis,
Parenteral Injection methotrexate) per Injection Isotonic (with
Mayne
mL
benzyl alcohol 0.9%)
* available from one or more manufacturer, distributor, and/or repackager by
generic (nonproprietary) name
Methotrexate Sodium (Preservative-free)
Dosage
Routes
Strengths
Brand Names
Forms
Methotrexate
For
20 mg (of
Parenteral
Sodium for
injection methotrexate)
Injection
Methotrexate
1 g (of
Sodium for
methotrexate)
Injection
25 mg (of
Methotrexate
Injection methotrexate) per Sodium Injection
mL
Isotonic

Manufacturer
Mayne
Abraxis, Mayne
Abraxis, Bedford,
Mayne, Bedford

Comparative Pricing
This pricing information is subject to change at the sole discretion of DS
Pharmacy. This pricing information was updated 03/2011. For the most current
and up-to-date pricing information, please visit www.drugstore.com. Actual costs

to patients will vary depending on the use of specific retail or mail-order


locations and health insurance copays.
Methotrexate 2.5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$31.99 or
60/$51.98
Methotrexate Sodium 25MG/ML Solution (HOSPIRA): 2/$15.56 or 6/$33.33
Methotrexate Sodium 25MG/ML (PF) Solution (BEDFORD LABORATORIES):
10/$24.99 or 30/$61.97
Methotrexate Sodium 25MG/ML (PF) Solution (BEDFORD LABORATORIES):
2/$14.99 or 4/$19.97
Trexall 10MG Tablets (TEVA PHARMACEUTICALS USA): 30/$470.87 or
90/$1349.79
Use is not currently included in the labeling approved by the US Food
and Drug Administration.
Methotrexate (sistemik)
Informasi pengantar
agen antineoplastik dan imunosupresan; folat antagonist.a asam, b, c
Kelas: 10:00 Agen antineoplastik; an300 (VA primer)
Merek *: Rheumatrex, Trexall
* Juga tersedia dalam bentuk generik
Nama generik: Methotrexate
Nomor CAS: 59-05-2
Sinonim: Amethopterin
Generik Nama Singkatan: MTX
Nama generik: Sodium Methotrexate
Nomor CAS: 15475-56-6
Formula molekul: C20H22N8O5

kemas Peringatan
Pengalaman Pembimbing Clinician
Berikan hanya di bawah pengawasan dokter yang berkualitas
berpengalaman dalam penggunaan antimetabolit therapy.b, c
Serius Reaksi Beracun (Kadang-kadang Fatal) Kemungkinan
Kematian dilaporkan dengan penggunaan dalam pengobatan
keganasan, psoriasis, dan arthritis.b arthritis, c

Gunakan hanya untuk pengobatan mengancam jiwa penyakit


neoplastik atau berat, bandel, menonaktifkan psoriasis atau
rheumatoid arthritis pada pasien yang tidak merespon secara memadai
untuk bentuk lain dari therapy.b, c
Erat memantau pasien untuk sumsum tulang, hati, paru, atau
toxicities.b ginjal, c (Lihat Major toksisitas bawah Perhatian.)
Menginformasikan pasien dari risiko yang terlibat dengan terapi dan
pentingnya tersisa di bawah perawatan dokter di seluruh therapy.b, c
Tinggi Dosis Regimen
Penggunaan rejimen dosis tinggi direkomendasikan untuk
pengobatan osteosarcoma membutuhkan care.b teliti (Lihat Tinggi
Dosis Methotrexate Terapi dengan leucovorin Penyelamatan dan juga
Osteosarkoma, di bawah Dosis dan Administrasi.)
Penggunaan rejimen dosis tinggi untuk penyakit neoplastik lainnya
adalah diteliti; Keuntungan terapi tidak established.b
Formulasi atau Pengencer Mengandung Pengawet
Jangan menggunakan formulasi atau pengencer yang mengandung
pengawet untuk pemberian intratekal atau therapy.b dosis tinggi
Janin / neonatus Morbidity and Mortality
Kematian janin dan / atau anomali kongenital reported.b, c Tidak
direkomendasikan untuk digunakan pada wanita usia subur kecuali
potensi manfaat jelas melampaui risiko; tidak menggunakan pada
wanita hamil dengan psoriasis atau arthritis.b arthritis, c (Lihat
Kontraindikasi dan juga janin / neonatus Morbidity and Mortality, di
bawah Peringatan.)
mengurangi Penghapusan
Eliminasi dikurangi pada pasien dengan gangguan ginjal, asites, atau
effusions.b pleura, hati-hati c memantau toksisitas pada pasien
tersebut; pengurangan dosis atau penghentian dapat required.b, c
Terapi bersamaan dengan NSAIAs
Tanpa diduga parah, kadang-kadang fatal, myelosupresi, anemia
aplastik, dan toksisitas GI dilaporkan dengan penggunaan seiring
methotrexate (biasanya pada dosis tinggi) dan beberapa NSAIAs.b, c
(Lihat Obat Spesifik bawah Interaksi.)
hepatotoksisitas
Kemungkinan hepatotoksisitas, fibrosis, dan sirosis, umumnya hanya
setelah use.b berkepanjangan, c (Lihat hepatik Effects di bawah
Perhatian.)
liver akut peningkatan enzim sering diamati; biasanya bersifat
sementara dan tanpa gejala dan tidak muncul prediksi dari disease.b

hati berikutnya, c
Biopsi hati setelah digunakan berkelanjutan sering menunjukkan
histologis changes.b, c Fibrosis dan sirosis mungkin tidak didahului oleh
gejala atau gangguan fungsi hati pada pasien dengan psoriasis;
periodik biopsi hati biasanya dianjurkan pada pasien tersebut
menjalani therapy.b jangka panjang, c
kelainan persisten pada tes fungsi hati dapat mendahului penampilan
fibrosis atau sirosis pada pasien dengan arthritis.b arthritis, c
Keracunan paru
Lesi paru berpotensi berbahaya, tidak selalu reversibel, dapat terjadi
secara akut pada setiap saat selama terapi dan telah dilaporkan pada
dosis serendah 7,5 mg weekly.b, c gejala paru (terutama kering, batuk
tidak produktif) mungkin memerlukan gangguan terapi dan evaluasi
hati-hati .b, c
GI Keracunan
Diare dan stomatitis ulseratif memerlukan penghentian terapi; jika
tidak, hemoragik enteritis dan kematian dari perforasi usus dapat
occur.b, c
Limfoma ganas
limfoma maligna (misalnya, non-Hodgkin lymphoma) dapat terjadi
pada pasien yang menerima terapi oral dosis rendah; limfoma tersebut
dapat mundur berikut methotrexate penghentian dan mungkin tidak
memerlukan therapy.a sitotoksik, b, c Jika limfoma tidak mundur
penghentian berikut, lembaga therapy.b tepat, c
Tumor Syndrome Lisis
Dapat menginduksi tumor sindrom lisis pada pasien dengan tumor
berkembang pesat; farmakologis yang tepat dan pengobatan suportif
dapat mencegah atau meringankan syndrome.b, c
Reaksi dermatologi
parah, reaksi kulit kadang-kadang fatal yang dilaporkan berikut dosis
tunggal atau ganda; Reaksi terjadi dalam beberapa hari oral, IM, IV,
atau administration.b intratekal, c Pemulihan dilaporkan dengan
penghentian therapy.b, c (Lihat Dermatologic dan Sensitivitas Reaksi
bawah Perhatian.)
Infeksi oportunistik
infeksi oportunistik Berpotensi fatal, terutama jiroveci pneumonia
(sebelumnya Pneumocystis carinii) pneumonia.b, c
Radioterapi bersamaan
peningkatan risiko Kemungkinan nekrosis jaringan lunak dan

osteonekrosis pada pasien yang menerima methotrexate bersamaan


dengan radiotherapy.b, c

penggunaan
Kanker payudara
Pengobatan (sendiri atau, lebih umum, dalam kombinasi kemoterapi)
dari cancer.a payudara, b, c
Pertama-line kemoterapi adjuvan dalam kombinasi dengan obat lain
(yaitu, siklofosfamid dan fluorouracil, dengan atau tanpa terapi
hormonal) 0,166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 178,
179, 182, 185, 186, 187, d An rejimen anthracycline mengandung lebih
disukai pada pasien dengan disease.d node-positif
Beberapa studi menunjukkan sedikit keuntungan untuk rejimen
anthracycline mengandung tingkat kambuh bebas dan kelangsungan
hidup di kedua patients.l premenopause dan menopause
Juga digunakan pada pasien dengan disease.d metastasis, l
Kanker Kepala dan Leher
perawatan paliatif (sendirian dan dalam terapi kombinasi) dari
berulang atau kepala metastasis dan leher carcinoma.182, 210, 211,
212, b, c, d
Sering digunakan dalam kombinasi rejimen dengan agen antineoplastik
lainnya (misalnya, bleomycin, fluorouracil, vincristine) 0,210
Terapi kombinasi dengan cisplatin, methotrexate, bleomycin, dan
vincristine telah digunakan untuk karsinoma sel skuamosa berulang
atau metastasis dari kepala dan neck.212
Penelitian lebih lanjut diperlukan untuk membangun keuntungan
komparatif regimens.210 methotrexate mengandung, 212
leukemia
Komponen berbagai rejimen kemoterapi dalam pengobatan paliatif
akut leukemias.a, b, c
Intrathecal untuk profilaksis dan pengobatan leukemia.a meningeal, b,
d
terapi lini pertama dalam kombinasi dengan merkaptopurin untuk
pemeliharaan remisi obat-induced leukemia limfoblastik akut (ALL) .b,
c, d
Telah digunakan dalam dosis tinggi sebagai komponen dari beberapa
rejimen kombinasi kemoterapi alternatif untuk induksi remisi pada
SEMUA, tetapi umumnya tidak dianggap sebagai obat pilihan untuk
remisi induction.d
Jarang efektif sendirian untuk pengobatan leukemia myeloblastic akut
(AML); telah digunakan sebagai komponen tambahan dalam beberapa
rejimen kemoterapi untuk induksi atau terapi pasca-induksi AML.a, d
Kanker paru-paru
Telah digunakan dalam terapi lini kedua berulang cancer.235 paru-paru
sel kecil, b, c, n

Meskipun label untuk digunakan dalam jenis sel skuamosa kanker


paru-paru bukan sel kecil, 127, b, c agen lain preferred.182, d
limfoma
Komponen rejimen kemoterapi kombinasi sebagai lini pertama terapi
paliatif untuk bermutu tinggi Burkitt lymphoma atau pemeliharaan
terapi untuk bermutu tinggi lymphoblastic non-Hodgkin lymphoma.b, c,
d
Komponen rejimen kombinasi kemoterapi alternatif untuk pengobatan
menengah-grade limfoma non-Hodgkin (difus sel besar, menyebar sel
kecil, difus campuran, sel besar folikel) .d
Telah digunakan intratekal dalam kombinasi dengan siklofosfamid,
doxorubicin, vincristine, dan prednison dengan atau tanpa rituximab
untuk terapi lini pertama dari menengah-kelas non-Hodgkin
lymphomas.d ini
Meskipun radiasi atau terapi topikal umumnya digunakan untuk
pengobatan lokal limfoma, lymphosarcoma, dan mikosis fungoides
histiocytic, kemoterapi mungkin berguna dalam tahap umum dari
diseases.a ini
Pertama-berbaris kemoterapi sistemik untuk limfoma maju-sel T kulit
(misalnya, mikosis fungoides, sindrom Sezary) .b, c, o
Lini pertama terapi lini primer CNS lymphoma.d
Penyakit Hodgkin merespon buruk untuk methotrexate.a
osteosarcoma
Terapi dosis tinggi, diikuti oleh leucovorin penyelamatan, dalam
rejimen kombinasi kemoterapi sebagai tambahan untuk reseksi bedah
atau amputasi tumor primer pada pasien dengan osteosarcomab
nonmetastatic, d, h (ditunjuk obat yatim piatu oleh FDA untuk
digunakan ini) 0,192
Juga telah digunakan sebagai komponen dari rejimen kombinasi
kemoterapi ajuvan pada pasien dengan osteosarcoma.h metastasis
Psorias
kontrol gejala yang parah, bandel, psoriasis menonaktifkan yang tidak
memadai responsif terhadap bentuk-bentuk lain dari terapi pada
pasien yang dipilih secara hati-hati; tidak curative.a, b, c
Gunakan hanya setelah diagnosis pasti didirikan (misalnya, biopsi,
setelah berkonsultasi dermatologis) .b, c
Radang sendi
Pengelolaan rheumatoid arthritis pada orang dewasa yang gejalanya
kemajuan meskipun rejimen yang memadai 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
Pengelolaan polyarticular-kursus aktif arthritis juvenile rheumatoid
pada anak-anak yang telah memiliki respon terapi cukup untuk, atau
tidak toleran terhadap, sidang yang memadai terapi lini pertama
(yaitu, NSAIAs dosis penuh) .b, c (Lihat Gunakan Pediatric bawah
memperingatkan.)

Salah satu dari beberapa obat antirematik penyakit-memodifikasi


(DMARDs) yang dapat digunakan ketika terapi DMARD adalah
appropriate.220, 224
efikasi jangka panjang secara substansial lebih besar dari DMARDs lain;
digunakan sebagai awal atau anchor DMARD pada banyak pasien
dengan arthritis.220 arthritis, 222, 224, 225, 226 juga telah digunakan
dalam kombinasi dengan lainnya DMARDs.220, 222, 225, 228, 229,
230, 231, 232, 233 , 234
Gunakan hanya sebagai bagian dari program perawatan yang
komprehensif, termasuk terapi nondrug (misalnya, istirahat, terapi
fisik) 0,127
Tidak ada bukti substansial bahwa methotrexate permanen
penangkapan atau membalikkan proses penyakit yang mendasarinya,
127, 128, 138, 140, 144, 147, 153 meskipun perkembangan penyakit
diperlambat dalam beberapa patients.138, 140, 143, 144, 160, 220
trofoblas Neoplasma
Pengobatan (dengan atau tanpa leucovorin) neoplasma trofoblas
(koriokarsinoma, destruens chorioadenoma, mola hidatidosa) pada
wanita (kecuali orang-orang dengan fungsi ginjal atau hati gangguan
atau yang telah gagal untuk menanggapi terapi methotrexate
sebelumnya, dalam hal dactinomycin digunakan) .a , b, c, e
Paling efektif pada pasien yang memiliki penyakit hanya untuk waktu
singkat sebelum memulai kemoterapi, yang memiliki konsentrasi
gonadotropin awal yang rendah, dan yang tidak memiliki metastases.a
terapi lini pertama dengan atau tanpa leucovorin pada pasien dengan
nonmetastatic atau baik-prognosis metastatik gestational neoplasms.d
trofoblas, e
Komponen rejimen kombinasi kemoterapi dengan dactinomycin dan
klorambusil pada pasien dengan baik-prognosis metastasis neoplasma
trofoblas gestasional dengan disease.e refraktori
Pada pasien dengan neoplasma trofoblas metastasis miskin-prognosis,
methotrexate dalam kombinasi dengan etoposid, dactinomycin,
vincristine, dan siklofosfamid (EMA-CO) adalah pengobatan standar
option.e A regimen dosis intensif, EMA-CE, di mana etoposid dan
cisplatin yang digantikan untuk vincristine dan siklofosfamid dari
rejimen EMA-CO, mungkin menawarkan benefits.e tambahan
Telah digunakan sebagai profilaksis terhadap penyakit trofoblas ganas
pada pasien dengan mola mole.a
koriokarsinoma testis biasanya tahan terhadap methotrexate saja;
telah digunakan sebagai bahan terapi kombinasi pada pasien dengan
tumor metastatik dari testes.a yang
Kanker kandung kemih
Digunakan dalam kombinasi rejimen dengan vinblastin dan cisplatin,
dengan atau tanpa doxorubicin, seperti pertama atau kedua-line
therapyd untuk invasif dan lanjutan kanker kandung kemih 0,182, 205,
206, 207, 208, 209

Penggunaan penyelamatan leucovorin atau penghapusan


methotrexate disarankan jika rejimen methotrexate yang mengandung
sedang dipertimbangkan untuk pengobatan kanker kandung kemih
metastatik atau pada pasien dengan disfungsi ginjal, edema, koleksi
cairan pleura, atau ascites.205
Penyakit Crohn
Manajemen kronis aktif Crohn penyakit 0,241, 242, 243, 244 245, 246,
247, 248, 249, 250, 251, 258, 259, 260
Kehamilan ektopik
Digunakan sebagai alternatif untuk manajemen bedah kehamilan
ektopik pada pasien tertentu dengan kecil, ruptur tuba pregnancies.i, j,
k
multiple Sclerosis
terapi oral dosis rendah telah digunakan pada pasien dengan kronis
progresif multiple sclerosis 0,201, 202, 203, 204
Arthritis psoriatik
Telah digunakan untuk imunosupresif dan / atau efek anti-inflamasi
dalam pengobatan arthritis psoriatik 0,109, 110
Dosis dan Administrasi
Umum
Konsultasikan referensi khusus untuk prosedur penanganan dan
pembuangan antineoplastics.b, c
Jangan meresepkan atau mengeluarkan sebagai dibutuhkan ( "prn")
basis.c
Jika toksisitas sebelumnya mengharuskan penghentian, reinstitute
dengan hati-hati; pertimbangkan lebih lanjut perlu untuk obat dan
risiko toksisitas recurrence.a, b, c
Dosis Tinggi-Methotrexate Terapi dengan leucovorin Penyelamatan
Penggunaan rejimen dosis tinggi digunakan dalam terapi tambahan
dari osteosarcoma memerlukan pemahaman menyeluruh tentang
risiko yang terkait dengan terapi dan leucovorin rescue.a, b
pasien Hydrate dengan 1 L / m2 cairan IV lebih dari 6 jam sebelum
memulai methotrexate infusion.b Lanjutkan hidrasi pada 125 mL / m2
per jam (3 L / m2 setiap hari) selama infus metotreksat dan selama 2
hari setelah selesai infus. b
membasakan urine dengan natrium bikarbonat untuk menjaga pH> 7
selama methotrexate infus dan leucovorin kalsium terapi; mengelola
natrium bikarbonat oral atau melalui solution.b IV terpisah
Scr harus normal dan ClCr> 60 mL / menit sebelum terapi initiation.b
Ulangi Scr dan serum methotrexate 24 jam setelah mulai metotreksat
dan setidaknya sekali setiap hari sampai konsentrasi metotreksat
adalah <0,023 mcg / mL (0,05 MCM) .b
Ukur Scr sebelum setiap kursus berikutnya terapi; jika Scr meningkat
50% dibandingkan dengan nilai sebelumnya, mengukur dan dokumen
yang ClCr> 60 mL / menit (bahkan jika Scr masih dalam kisaran

normal) .b
Juga berkonsultasi protokol pembuat label dan diterbitkan untuk
rekomendasi tertentu berdasarkan laboratorium dan findings.a klinis
Administrasi
Mengelola secara lisan atau dengan IM, IV, atau injeksi intratekal;
mungkin juga mengelola intra-arterially.b, c Telah dikelola oleh sub-Q
injection.c, p
Jangan menggunakan formulasi atau pengencer yang mengandung
pengawet (misalnya, benzyl alcohol) untuk administrasi intratekal atau
therapy.b dosis tinggi
Administrasi Oral
Mengelola secara lisan sebagai tablets.c
oral sering disukai ketika dosis rendah digunakan sejak penyerapan
konsentrasi serum yang cepat dan efektif adalah achieved.b, c
Produsen tidak membuat rekomendasi spesifik tentang administrasi
dengan makanan; penyerapan penundaan makanan dan mengurangi
puncak serum concentrations.214, b, c
Sengaja harian bukannya administrasi mingguan pada pasien dengan
psoriasis atau rheumatoid arthritis dapat menyebabkan keracunan
yang fatal; hati-hati menginstruksikan pasien mengenai rejimen dan
frekuensi administration.c (Lihat Nasihat untuk Pasien.)
dispensing paket mnemonic (misalnya, Rheumatrex Dosis Pack)
dapat digunakan untuk terapi awal dan pemeliharaan pada pasien
yang menerima dosis mingguan 5-15 mg tetapi tidak dianjurkan untuk
titrasi dosis mingguan> 15 mg.a, c
Administrasi IV
Untuk solusi dan informasi kompatibilitas obat, lihat Kompatibilitas
bawah Stabilitas.
Mengelola melalui suntikan IV atau infusion.b
rekonstitusi
Menyusun kembali bubuk lyophilized untuk injeksi langsung sebelum
digunakan dengan steril, bebas pengawet solusi (misalnya, 5%
dextrose injeksi, 0,9% natrium klorida injeksi) .b
Menyusun kembali 20 mg vial untuk konsentrasi 25 mg / mL.b
menyusun kembali 1 g vial dengan 19,4 mL solusi yang tepat untuk
menghasilkan konsentrasi dari 50 mg / mL.b
Pengenceran
Ketika dosis tinggi diberikan oleh IV infus, encer dosis total solusi
dilarutkan dalam 5% dekstrosa injection.b
Lebih lanjut dapat encer solusi yang tersedia secara komersial untuk
injeksi IV yang mengandung pengawet dengan solusi yang kompatibel
(misalnya, 0,9% natrium klorida injeksi) .b
solusi bebas pengawet dapat diencerkan segera sebelum digunakan
dengan tepat steril, bebas pengawet solusi (misalnya, 5% dextrose
injeksi, 0,9% natrium klorida injeksi) .b

Administrasi IM
Mengelola dengan injection.b IM
rekonstitusi
Menyusun kembali bubuk lyophilized untuk injeksi langsung sebelum
digunakan dengan steril, bebas pengawet solusi (misalnya, 5%
dextrose injeksi, 0,9% natrium klorida injeksi) .b
Administrasi intratekal
Bebas pengawet solusi (1 mg / mL) digunakan untuk injection.b
intratekal Jangan mengelola larutan yang mengandung pengawet
intrathecally.b
Harus mengelola intrathecal untuk pengobatan leukemia meningeal
sejak berlalunya obat dari darah ke CSF adalah minimal.a, b
Sebelum administrasi intratekal, volume CSF kurang lebih setara
dengan volume larutan harus disuntikkan (misalnya, 5-15 mL)
biasanya removed.a
Jika pungsi lumbal adalah traumatis, tidak mengelola intrathecal;
memungkinkan 2 hari untuk dilalui sebelum kembali mencoba
injection.a
Menyuntikkan intrathecal hanya jika ada aliran mudah fluid.a spinal
darah bebas
Beberapa dokter merekomendasikan bahwa seluruh volume injeksi
methotrexate disuntikkan intrathecal di 15-30 seconds.a Aspirasi tidak
harus performed.a
Muncul dalam sirkulasi sistemik setelah pemberian intratekal;
menyesuaikan, mengurangi, atau menghentikan setiap pemberian
sistemik bersamaan sebagai appropriate.a, b
administrasi sistemik kalsium leucovorin bersamaan dengan
methotrexate intratekal dapat mencegah toksisitas sistemik tanpa
menghapuskan aktivitas obat di CNS.a
rekonstitusi
Untuk injeksi intratekal, menyusun kembali bubuk lyophilized untuk
konsentrasi 1 mg / mL dengan steril bebas pengawet pengencer yang
sesuai (misalnya, 0,9% natrium klorida injeksi) .b
Pengenceran
Untuk injeksi intratekal, encer methotrexate solusi bebas pengawet
untuk injeksi untuk konsentrasi 1 mg / mL dengan tepat steril bebas
pengawet pengencer (misalnya, 0,9% natrium klorida injeksi) .b
Dosis
Tersedia sebagai methotrexate natrium; dosis dinyatakan dalam
methotrexate.b, c
Berbagai jadwal dosis telah digunakan; individualize dosis, rute
pemberian, dan durasi terapi sesuai dengan penyakit yang diobati,
terapi lain yang digunakan, dan kondisi, respon, dan toleransi patient.a
yang Consult diterbitkan protokol untuk informasi tambahan tentang
rejimen alternatif dan dosis.
Pasien Pediatric

Juvenile Rheumatoid Arthritis


Oral: Semoga mengelola tes dosis awal sebelum jadwal dosis biasa
untuk mendeteksi sensitivitas mungkin untuk efek buruk yang terkait
dengan drug.c yang
Awalnya, 10 mg / m2 sekali weekly.b, c Semoga menyesuaikan dosis
secara bertahap untuk mencapai response.b optimal, c
Dosis sampai 30 mg / m2 mingguan telah digunakan pada anak-anak,
tetapi data yang diterbitkan terlalu terbatas untuk menilai risiko
toksisitas yang serius pada dosis> 20 mg / m2 weekly.b, c
Anak-anak menerima 20-30 mg / m2 (0,65-1 mg / kg) mingguan
mungkin memiliki penyerapan yang lebih baik dan efek samping GI
lebih sedikit jika diberikan baik IM atau sub-Q.b, c
Durasi optimal terapi adalah unknown.b, c
> IM atau Sub-Q
Anak-anak menerima 20-30 mg / m2 (0,65-1 mg / kg) mingguan
mungkin memiliki penyerapan yang lebih baik dan efek samping GI
lebih sedikit jika diberikan baik IM atau sub-Q.b, c
leukemia
> Meningeal Leukemia
Intratekal: Apapun metode yang digunakan untuk menentukan dosis
intratekal, hati-hati memeriksa dosis sebelum pemberian untuk
meminimalkan risiko overdosage.106 intratekal yang tidak disengaja
Studi klinis menunjukkan bahwa rejimen dosis intratekal berdasarkan
usia mungkin lebih efektif dan kurang neurotoksik dari rejimen dosis
berdasarkan permukaan tubuh area.107, 108, 127, b
> Direkomendasikan intratekal Dosis Berdasarkan Age107, 108, 127
Umur Dosis
<1 tahun 6 mg
1 tahun 8 mg
2 tahun 10 mg
3 tahun 12 mg
dosis intratekal berdasarkan luas permukaan tubuh (yaitu, 12 mg / m2,
maksimal 15 mg) dilaporkan menghasilkan konsentrasi methotrexate
CSF rendah dan mengurangi efikasi di patients.b pediatrik
Pengobatan: dapat mengelola dengan interval 2-5 hari sampai jumlah
sel CSF kembali normal, di mana titik 1 dosis tambahan Administrasi
advisable.b pada interval <1 minggu dapat mengakibatkan
meningkatnya toxicity.b subakut
Profilaksis: dosis adalah sama seperti untuk pengobatan; interval
administrasi berbeda dari rejimen yang digunakan dalam treatment.a,
b Konsultasikan referensi khusus dan literatur medis untuk
recommendations.a tertentu, b
Dewasa
Kanker payudara
Berbagai regimen kombinasi kemoterapi telah digunakan dalam

pengobatan kanker payudara; berkonsultasi protokol diterbitkan untuk


dosis dan metode dan urutan administration.168, 169, 170, 171, 172,
173, 174, 176, 180, 181, 183, 185, 187
Dosis intensitas kombinasi kemoterapi adjuvan tampaknya menjadi
faktor penting yang mempengaruhi hasil klinis pada pasien dengan
kanker payudara nodus positif awal, dengan respon meningkat dengan
intensitas dosis meningkat; menghindari pengurangan sewenangwenang dalam intensity.166 dosis, 170, 187
> IV
Dosis 40 mg / m2 IV pada hari 1 dan 8 dari setiap siklus dalam
kombinasi dengan siklofosfamid 100 mg / m2 pada hari 1-14 dari
setiap siklus dan fluorouracil 600 mg / m2 pada hari 1 dan 8 dari setiap
siklus yang umum digunakan untuk pengobatan payudara cancer.168
awal, 169, 187
Pada pasien> 60 tahun, dosis awal dikurangi menjadi 30 mg / m2 dan
awal dosis fluorouracil berkurang menjadi 400 mg / m2; 169 dosis juga
berkurang jika mielosupresi develops.168, 169
Siklus umumnya diulang bulanan (yaitu, memungkinkan periode
istirahat 2 minggu antara siklus) untuk total 6-12 siklus (yaitu, 6-12
bulan terapi) 0,168, 169, 187
Dalam rejimen berurutan di mana beberapa kursus dari doxorubicin
diberikan sebelum rejimen siklofosfamid, metotreksat, dan fluorouracil
pada pasien dengan kanker payudara dini dan> 3 kelenjar getah
bening aksila yang positif, 171 4 dosis doxorubicin hydrochloride 75 mg
/ m2 diberikan awalnya pada interval 3 minggu diikuti oleh 8 siklus
methotrexate 40 mg / m2, siklofosfamid 600 mg / m2, dan fluorouracil
600 mg / m2 pada interval 3 minggu untuk total sekitar 9 bulan
therapy.171, 185 Jika mielosupresi dikembangkan dengan rejimen
berurutan ini, siklus berikutnya umumnya ditunda daripada dosis
reduced.171, 185
Leukemia
> ALL (Induction Therapy)
Oral: Tidak umumnya obat pilihan, tapi 3,3 mg / m2 setiap hari dalam
kombinasi dengan prednison 40-60 mg / m2 setiap hari selama 4-6
minggu telah used.a, b, c
> ALL (Maintenance Therapy)
Oral atau IM: Setelah remisi tercapai, 20-30 mg / m2 dosis total
mingguan, diberikan dalam dosis terbagi dua kali weekly.a, b, c
IV: Atau, 2,5 mg / kg telah diberikan IV setiap 14 setiap hari.A, b, c
> Meningeal Leukemia
Intratekal: Pengobatan: 12 mg diberikan dengan interval 2-5 hari
sampai jumlah sel CSF kembali normal, di mana titik 1 dosis tambahan
advisable.b Namun, administrasi pada interval <1 minggu dapat
mengakibatkan meningkatnya toxicity.b subakut
Profilaksis: 12 mg; interval administrasi berbeda dari rejimen yang
digunakan dalam treatment.a, b Konsultasikan referensi khusus dan

literatur medis untuk recommendations.a tertentu, b


dosis intratekal dari 12 mg / m2 (maksimal 15 mg) dilaporkan
menghasilkan konsentrasi CSF methotrexate tinggi dan neurotoksisitas
di adults.b
limfoma
Oral: Untuk limfoma Burkett ini (stadium I atau II), 10-25 mg sehari
selama 4-8 days.b, c Pada tahap III limfoma Burkitt, umumnya
diberikan dengan agents.b antineoplastik lainnya, c Dalam semua
tahap, beberapa kursus biasanya diberikan, sela dengan 7- 10 hari
periods.b istirahat, c
Tahap III lymphosarcomas mungkin menanggapi terapi obat
dikombinasikan dengan methotrexate diberikan dalam dosis 0,625-2,5
mg / kg daily.b, c
> Cutaneous T-sel Limfoma; mikosis fungoides
Oral, IM, atau Sub-Qp: Biasanya, 5-50 mg mingguan di stages.b awal,
c, pengurangan 241 Dosis atau penghentian ditentukan oleh
pemantauan hematologi dan response.c pasien, 241
Juga telah diberikan dua kali seminggu dalam dosis mulai 15-37,5 mg
pada pasien yang telah merespon buruk untuk mingguan therapy.b, c,
241
IV: rejimen Kombinasi kemoterapi yang mencakup metotreksat dosis
tinggi dengan leucovorin penyelamatan telah digunakan dalam
stages.b maju, c, 241 Consult diterbitkan protokol untuk dosis.
osteosarcoma
> Dosis Tinggi-Methotrexate Terapi dengan leucovorin Penyelamatan
IV: Awalnya, 12 g / m2 diinfuskan selama 4 jam pada minggu ke 4, 5, 6,
7, 11, 12, 15, 16, 29, 30, 44, dan 45 setelah operasi pada jadwal dalam
kombinasi dengan agen kemoterapi lain ( misalnya, doxorubicin,
cisplatin, kombinasi bleomycin, siklofosfamid, dan dactinomycin) .b Jika
dosis awal tidak cukup untuk menghasilkan konsentrasi serum
methotrexate puncak 454 mcg / mL (1000 MCM [10-3 mol / L]) pada
akhir infus IV, dapat meningkatkan dosis untuk 15 g / m2 di
treatments.b berikutnya
Memulai terapi penyelamatan leucovorin dengan dosis 15 mg per oral
setiap 6 jam selama 10 dosis dimulai 24 jam setelah dimulainya
infusion.b methotrexate IV Semoga memberikan leucovorin IV atau IM
jika pasien tidak bisa mentolerir therapy.b lisan Jika toksisitas
methotrexate klinis penting adalah diamati, memperpanjang terapi
leucovorin untuk tambahan 24 jam (total 14 dosis bukan 10) di
courses.b berikutnya
Menunda pemberian methotrexate berikutnya sampai pemulihan jika
efek samping berikut terjadi: jika jumlah WBC adalah <1500 / mm3;
jumlah neutrofil adalah <200 / mm3; jumlah trombosit <75.000 / mm3;
konsentrasi serum bilirubin adalah> 1,2 mg / dL; konsentrasi ALT> 450
unit; mucositis hadir (sampai ada bukti penyembuhan); atau efusi
pleura persisten hadir (menguras kering sebelum infus) .b

> Jadwal leucovorin Penyelamatan Berdasarkan Serum Methotrexate


Concentrationsb
Situasi klinis Temuan Laboratorium leucovorin Dosis dan Durasi
methotrexate penghapusan konsentrasi serum methotrexate yang
normal sekitar 4,54 mcg / ml (10 MCM) pada 24 jam setelah
pemberian, 0,454 mcg / mL (1 MCM) pada 48 jam, dan <0,091 mcg /
mL (0,2 MCM) pada 72 jam 15 mg secara oral, IM, atau IV setiap 6 jam
selama 60 jam (10 dosis mulai 24 jam setelah dimulainya infus
metotreksat)
Tertunda akhir methotrexate penghapusan Serum konsentrasi
methotrexate tersisa> 0,091 mcg / mL (0,2 MCM) pada 72 jam dan>
0,023 mcg / mL (0,05 MCM) pada 96 jam setelah pemberian Lanjutkan
15 mg secara oral, IM, atau IV setiap 6 jam, sampai methotrexate
konsentrasi <0,023 mcg / mL (0,05 MCM)
Tertunda eliminasi methotrexate awal dan / atau bukti methotrexate
cedera ginjal akut Serum 22.7 mcg / mL (50 MCM) pada 24 jam atau
2.27 mcg / mL (5 MCM) pada 48 jam setelah pemberian, atau
meningkat 100% di Scr konsentrasi pada 24 jam setelah pemberian
methotrexate (misalnya, meningkat dari 0,5 mg / dL untuk konsentrasi
1 mg / dL) 150 mg IV setiap 3 jam, sampai konsentrasi methotrexate
adalah <0,454 mcg / mL (1 MCM), maka 15 mg IV setiap 3 jam sampai
konsentrasi methotrexate adalah <0,023 mcg / mL (0,05 MCM)
Psorias
Oral: Administrasi tunggal 5 sampai 10 mg dosis 1 minggu sebelum
memulai terapi telah direkomendasikan untuk mendeteksi reactions.a
istimewa
Dibagi jadwal sediaan oral: 2.5 mg pada interval 12 jam untuk 3 dosis
masing-masing week.c Semoga bertahap menyesuaikan dosis 2,5 mg /
minggu untuk mencapai respon yang optimal; tidak melebihi 30 mg
ordinarily.a mingguan, c
Setelah respon yang optimal diperoleh, mengurangi jadwal dosis untuk
dosis serendah mungkin dan selama mungkin sisanya period.c
Gunakan mungkin mengizinkan kembali ke therapy.c topikal
konvensional
> Oral, IM, atau IV
Mingguan jadwal tunggal dosis: 10-25 mg sebagai dosis tunggal sekali
seminggu sampai achieved.c respon yang memadai Semoga bertahap
menyesuaikan dosis untuk mencapai respon yang optimal; tidak
melebihi 30 mg ordinarily.c mingguan respon Setelah optimal
diperoleh, mengurangi jadwal dosis untuk dosis serendah mungkin dan
selama mungkin period.c sisanya
Radang sendi
Oral: Semoga mengelola tes dosis awal sebelum jadwal dosis biasa
untuk mendeteksi sensitivitas mungkin untuk effects.c merugikan
Awalnya, 7,5 mg sekali seminggu atau kursus sekali seminggu dari 2,5

mg diberikan pada interval 12 jam selama 3 doses.c Semoga bertahap


menyesuaikan dosis untuk mencapai response.c optimal
Pada dosis> 20 mg mingguan, mungkin peningkatan insiden dan
keparahan reaksi toksik yang serius, terutama myelosuppression.c
Durasi optimal terapi tidak diketahui; Data yang terbatas menunjukkan
bahwa peningkatan awal dipertahankan selama minimal 2 tahun
dengan therapy.c lanjutan
trofoblas Neoplasma
> Oral atau IM
Biasanya, 15-30 mg sehari selama 5 days.b, c A saja berulang dapat
diberikan setelah periode 1 minggu, asalkan semua tanda-tanda
toksisitas residual telah menghilang; 3-5 kursus biasanya employed.a,
b, c penilaian klinis sebelum setiap kursus adalah essential.b, c
Terapi biasanya dievaluasi oleh 24 jam analisis kuantitatif kemih
chorionic gonadotropin (hCG), yang biasanya menormalkan setelah
kursus ketiga atau keempat; resolusi lengkap lesi terukur biasanya
terjadi 4-6 minggu kemudian.
1 atau 2 program terapi biasanya diberikan setelah normalisasi
konsentrasi hCG urin dicapai.
Penyakit Crohn
> Penyakit Refractory Kronis Aktif
IM: 25 mg sekali seminggu telah diberikan selama 16 weeks.241, 243,
244, 250, 251
Oral: 12,5-22,5 mg sekali seminggu telah diberikan hingga 1 year.252
> Terapi Pemeliharaan
IM: 15 mg sekali seminggu telah used.252
Kehamilan ektopik
> IM
50 mg / m2 sebagai dose.i tunggal Dapat memerlukan dosis kedua
atau intervensi bedah jika konsentrasi hCG gagal untuk mengurangi
oleh setidaknya 15% dari hari 4 sampai hari ke-7 setelah metotreksat
administration.i
Atau, 1 mg / kg (pada hari 0, 2, 4, dan 6) bergantian dengan 0,1 mg /
kg leucovorin IM (pada hari 1, 3, 5, dan 7) telah used.i, k
resep Batas
Pasien Pediatric
Juvenile Rheumatoid Arthritis
> Oral, IM, atau Sub-Q
Data meskipun ada pengalaman dengan dosis sampai 30 mg / m2
mingguan pada anak-anak, yang diterbitkan terlalu terbatas untuk
menilai bagaimana dosis> 20 mg / m2 mingguan mungkin
mempengaruhi risiko serius toxicity.b, c
Anak-anak menerima 20-30 mg / m2 (0,65-1 mg / kg) mingguan
mungkin memiliki penyerapan yang lebih baik dan efek GI lebih sedikit
jika diberikan baik IM atau sub-Q.b, c
Dewasa

Psorias
> Oral, IM, atau IV
Biasanya tidak melebihi 30 mg weekly.c
Radang sendi
> Oral, IM, atau IV
Biasanya tidak melebihi 20 mg weekly.c
pengalaman terbatas menunjukkan peningkatan yang substansial
dalam insiden dan keparahan dari reaksi toksik yang serius, terutama
penekanan sumsum tulang, pada dosis> 20 mg weekly.c
Populasi khusus
Gangguan ginjal
pengurangan dosis dan pemantauan ekstra hati-hati untuk toksisitas
required.b, c
Pasien geriatri
Pilih dosis dengan hati-hati karena hati dan fungsi ginjal dan folat toko
mungkin akan menurun; memonitor tanda-tanda awal dari toxicity.b, c
Pasien dengan Ascites atau pleura Efusi
pengurangan dosis dan pemantauan ekstra hati-hati untuk toksisitas
required.b, c
Perhatian
kontraindikasi
Wanita hamil dengan psoriasis atau arthritis rheumatoid; digunakan
dalam pengobatan penyakit neoplastik hanya ketika potensi
keuntungan melebihi risiko untuk fetus.b, c (Lihat kemas Peringatan.)
Perawatan women.127, b, c
Konsumsi berlebihan alkohol, penyakit hati alkoholik, atau penyakit
hati kronis lain pada pasien dengan psoriasis atau arthritis.127
arthritis, b, c
jelas baru atau laboratorium bukti immunodeficiency sindrom pada
pasien dengan psoriasis atau arthritis.127 arthritis, b, c
diskrasia darah yang sudah ada sebelumnya (misalnya, sumsum
tulang hipoplasia, leukopenia, trombositopenia, anemia klinis penting)
pada pasien dengan psoriasis atau arthritis.127 arthritis, b, c
Dikenal hipersensitivitas terhadap methotrexate.b, c
Peringatan / Kewaspadaan
peringatan
Juga lihat Peringatan kemas.
Janin / neonatus Morbidity and Mortality
kematian janin dan / atau reported.b anomali kongenital, c Kecualikan
kehamilan sebelum memulai treatment.b, c Hindari kehamilan jika
salah satu pasangan menerima metotreksat; menghindari kehamilan
selama terapi dan untuk 3 bulan setelah terapi pada pasien laki-laki
dan untuk setidaknya satu siklus ovulasi setelah terapi di patients.b
perempuan, c Jika digunakan selama kehamilan atau pasien menjadi
hamil, memberitahukan potensi hazard.b janin, c

Reaksi sensitivitas
Dermatologi dan Sensitivitas Reaksi

Efek hematologi

Efek GI

Efek hati

Efek pernapasan

Efek ginjal

Tindakan Pencegahan Umum

Populasi tertentu
kehamilan
Laktasi
Gunakan Pediatric

Gunakan Geriatric

hati Penurunan
Gangguan ginjal

Efek samping yang umum


interaksi
Obat protein-terikat

Obat tertentu
Interaksi Obat Komentar

farmakokinetik
Penyerapan
bioavailabilitas

Serangan
Lamanya
Makanan
Populasi khusus
Distribusi
Tingkat

Protein Plasma Binding


Populasi khusus
penyisihan
Metabolisme

penghapusan Route
Setengah hidup
Populasi khusus
Stabilitas
Penyimpanan
Lisan
tablet
parenteral
Injeksi

Bubuk untuk injeksi

Kesesuaian
Untuk informasi tentang interaksi sistemik yang disebabkan dari
penggunaan bersamaan, melihat Interaksi.
parenteral
Cocok
Dekstrosa 5% dalam air
Natrium klorida 0,9%

Cocok
siklofosfamid
sitarabin
fluorouracil
hydroxyzine HCl
ondansetron HCl
natrium bikarbonat
vincristine sulfat
tidak kompatibel
bleomycin sulfat

Cocok

amifostine

aztreonam
bleomycin sulfat
ceftriaxone sodium
cimetidine HCl
cisplatin
siklofosfamid
sitarabin
daunorubisin HCl
diphenhydramine HCl
doxorubicin HCl
Doxorubicin HCl liposom injeksi
etoposide
famotidine
fosfat fludarabine
fluorouracil
furosemide
gansiklovir natrium
granisetron HCl
heparin
heparin natrium
hidromorfon HCl
Imipenem-cilastatin natrium

lorazepam
mesna
Methylprednisolone sodium suksinat
metoclopramide HCl
morfin sulfat
ondansetron HCl
oxaliplatin
paclitaxel

proklorperazin edisylate
ranitidin HCl
Teniposide
thiotepa
sulfat vinblastin
vincristine sulfat
vinorelbine tartrate
tidak kompatibel
klorpromazin HCl
idarubicin HCl
ifosfamida
Nalbuphine HCl
prometazin HCl
propofol
Variabel
Deksametason sodium fosfat
droperidol
vankomisin HCl
tindakan

Saran untuk Pasien

persiapan
Eksipien dalam persiapan obat yang tersedia secara komersial
mungkin memiliki efek klinis penting pada beberapa individu;
berkonsultasi pelabelan produk tertentu untuk rincian.

-Rute Dosis Bentuk Kekuatan Merek Produsen

* Tersedia dari satu atau lebih produsen, distributor, dan / atau


repackager oleh generik nama (hak milik)
-Rute Dosis Bentuk Kekuatan Merek Produsen

Harga komparatif
informasi harga ini dapat berubah kebijaksanaan DS Farmasi subjek.
informasi harga ini diperbarui 03/2011. Untuk yang terbaru dan up-todate informasi harga, silahkan kunjungi www.drugstore.com. biaya
yang sebenarnya kepada pasien akan bervariasi tergantung pada
penggunaan lokasi ritel atau mail-order khusus dan copays asuransi
kesehatan.
DIH

Methotrexate
Lexi-Drugs Online
English

English

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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions


section for a concise summary of this information. For verbatim wording of the
boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues

Sound-alike/look-alike issues:
Methotrexate may be confused with metolazone, mitoxantrone

MTX is an error-prone abbreviation (mistaken as mitoxantrone)


High alert medication: The Institute for Safe Medication Practices (ISMP)
includes this medication among its list of drugs which have a heightened risk
of causing significant patient harm when used in error.
Errors have occurred (resulting in death) when methotrexate was administered as
daily dose instead of the recommended weekly dose.
International issues:
Trexall may be confused with Truxal which is a brand name for
chlorprothixene in Belgium
Trexall may be confused with Trexol which is a brand name for
tramadol in Mexico
Pronunciation

(meth oh TREKS ate)

U.S. Brand Names

Rheumatrex Dose Pack; Trexall


Canadian Brand Names

Apo-Methotrexate; ratio-Methotrexate
Pharmacologic Category

Antineoplastic Agent, Antimetabolite (Antifolate); Antirheumatic, Disease


Modifying
Use: Labeled Indications

Treatment of trophoblastic neoplasms; leukemias; psoriasis; rheumatoid arthritis


(RA), including polyarticular-course juvenile rheumatoid arthritis (JRA); breast,
head and neck, and lung carcinomas; osteosarcoma; soft-tissue sarcomas;
carcinoma of gastrointestinal tract, esophagus, testes; lymphomas
Use: Unlabeled/Investigational

Treatment and maintenance of remission in Crohns disease; ectopic


pregnancy
Dosing: Adults

Refer to individual protocols.


Note: Doses between 100-500 mg/m2may require leucovorin rescue. Doses >500
mg/m2require leucovorin rescue: I.V., I.M., Oral: Leucovorin 10-15 mg/m2
every 6 hours for 8 or 10 doses, starting 24 hours after the start of
methotrexate infusion. Continue until the methotrexate level is 0.1
micromolar (10-7 M). Some clinicians continue leucovorin until the
methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8
M).
If the 48-hour methotrexate level is >1 micromolar (10-6 M) or the 72-hour
methotrexate level is >0.2 micromolar (2 x 10-7 M): I.V., I.M, Oral:
Leucovorin 100 mg/m2 every 6 hours until the methotrexate level is 0.1
micromolar (10-7 M). Some clinicians continue leucovorin until the
methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8
M).
Antineoplastic dosage range: I.V.: Range is wide from 30-40 mg/m2/week to
100-12,000 mg/m2 with leucovorin rescue
Trophoblastic neoplasms:
Oral, I.M.: 15-30 mg/day for 5 days; repeat in 7 days for 3-5 courses
I.V.: 11 mg/m2 days 1 through 5 every 3 weeks
Head and neck cancer: Oral, I.M., I.V.: 25-50 mg/m2 once weekly
Mycosis fungoides (cutaneous T-cell lymphoma): Oral, I.M.: Initial (early
stages):

5-50 mg once weekly or


15-37.5 mg twice weekly
Bladder cancer: I.V.:
30 mg/m2 day 1 and 8 every 3 weeks or
30 mg/m2 day 1, 15, and 22 every 4 weeks
Breast cancer: I.V.: 30-60 mg/m2 Day 1 and 8 every 3-4 weeks
Gastric cancer: I.V.: 1500 mg/m2 every 4 weeks
Lymphoma, non-Hodgkin's: I.V.:
30 mg/m2 days 3 and 10 every 3 weeks or
120 mg/m2 day 8 and 15 every 3-4 weeks or
200 mg/m2 day 8 and 15 every 3 weeks or
400 mg/m2 every 4 weeks for 3 cycles or
1 g/m2 every 3 weeks or
1.5 g/m2 every 4 weeks
Sarcoma: I.V.: 8-12 g/m2 weekly for 2-4 weeks
Rheumatoid arthritis: Oral: 7.5 mg once weekly or 2.5 mg every 12 hours for 3
doses/week, not to exceed 20 mg/week
Psoriasis: Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or Oral,
I.M.: 10-25 mg/dose given once weekly
Ectopic pregnancy (unlabeled use): I.M.: 50 mg/m2 single-dose
Active Crohns disease (unlabeled use): Induction of remission: I.M., SubQ:
15-25 mg once weekly; remission maintenance: 15 mg once weekly
Note: Oral dosing has been reported as effective but oral absorption is highly
variable. If patient relapses after a switch to oral, may consider
returning to injectable.

Dosing: Elderly

Refer to individual protocols; adjust for renal impairment.


Rheumatoid arthritis/psoriasis: Oral: Initial: 5-7.5 mg/week, not to exceed 20
mg/week
Dosing: Pediatric

Refer to individual protocols.


Note: Doses between 100-500 mg/m2may require leucovorin rescue. Doses >500
mg/m2require leucovorin rescue: I.V., I.M., Oral: Leucovorin 10-15 mg/m2
every 6 hours for 8 or 10 doses, starting 24 hours after the start of
methotrexate infusion. Continue until the methotrexate level is 0.1
micromolar (10-7 M). Some clinicians continue leucovorin until the
methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8
M).
If the 48-hour methotrexate level is >1 micromolar (10-6 M) or the 72-hour
methotrexate level is >0.2 micromolar (2 x 10-7 M): I.V., I.M, Oral:
Leucovorin 100 mg/m2 every 6 hours until the methotrexate level is 0.1
micromolar (10-7 M). Some clinicians continue leucovorin until the
methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8
M).
Dermatomyositis: Oral: 15-20 mg/m2/week as a single dose once weekly or 0.31 mg/kg/dose once weekly
Juvenile rheumatoid arthritis: Oral, I.M.:10 mg/m2 once weekly, then 5-15
mg/m2/week as a single dose or as 3 divided doses given 12 hours apart
Antineoplastic dosage range:
Oral, I.M.: 7.5-30 mg/m2/week or every 2 weeks
I.V.: 10-18,000 mg/m2 bolus dosing or continuous infusion over 6-42 hours
Pediatric solid tumors (high-dose): I.V.:
<12 years: 12-25 g/m2

12 years: 8 g/m2
Acute lymphocytic leukemia (intermediate-dose): I.V.: Loading: 100 mg/m2
bolus dose, followed by 900 mg/m2/day infusion over 23-41 hours.
Meningeal leukemia: I.T.: 10-15 mg/m2 (maximum dose: 15 mg) or an agebased dosing regimen; one possible system is:
3 months: 3 mg/dose
4-11 months: 6 mg/dose
1 year: 8 mg/dose
2 years: 10 mg/dose
3 years: 12 mg/dose
Dosing: Renal Impairment

The FDA-approved labeling does not contain dosage adjustment guidelines.


The following guidelines have been used by some clinicians:
Clcr 61-80 mL/minute: Administer 75% of dose
Clcr 51-60 mL/minute: Administer 70% of dose
Clcr 10-50 mL/minute: Administer 30% to 50% of dose
Clcr <10 mL/minute: Avoid use
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not
necessary
Peritoneal dialysis effects: Supplemental dose is not necessary
CAVH effects: Unknown
Aronoff, 2007:
Children:
Clcr 10-50 mL/minute: Administer 50% of dose

Clcr <10 mL/minute: Administer 30% of dose


Hemodialysis: Administer 30% of dose
Continuous ambulatory peritoneal dialysis (CAPD): Administer
30% of dose
Continuous renal replacement therapy (CRRT): Administer 50% of
dose
Adults:
Clcr 10-50 mL/minute: Administer 50% of dose
Clcr <10 mL/minute: Avoid use
Hemodialysis: Administer 50% of dose
Continuous renal replacement therapy (CRRT): Administer 50% of
dose
Kintzel, 1995:
Clcr 46-60 mL/minute: Administer 65% of normal dose
Clcr 31-45 mL/minute: Administer 50% of normal dose
Clcr <30 mL/minute: Avoid use
Dosing: Hepatic Impairment

The FDA-approved labeling does not contain dosage adjustment guidelines. The
following guidelines have been used by some clinicians (Floyd, 2006):
Bilirubin 3.1-5 mg/dL or transaminases >3 times ULN: Administer 75% of dose
Bilirubin >5 mg/dL: Avoid use
Dosing: Combination Regimens

Bladder cancer:

CMV
M-VAC (Bladder Cancer)
Breast cancer:
CMF
CMF-IV
CMFP
CMFVP (Cooper Regimen, VPCMF)
Dox-CMF (Sequential)
MF
M-VAC (Breast Cancer)
Cervical cancer: M-VAC (Cervical Cancer)
Endometrial cancer: MVAC (Endometrial Cancer)
Gastric cancer: FAMTX
Gestational trophoblastic tumor:
CHAMOCA (Modified Bagshawe Regimen)
CHAMOMA (Bagshawe Regimen)
EMA/CO
EP/EMA
Head and neck cancer:
CABO
MVAC (Head and Neck)
Leukemia, acute lymphocytic:
Hyper-CVAD + Imatinib

Hyper-CVAD (Leukemia, Acute Lymphocytic)


Linker Protocol
MTX/6-MP/VP (Maintenance)
POMP
PVA (POG 8602)
Leukemia, acute promyelocytic:Tretinoin-Idarubicin
Lymphoma, Hodgkin's disease: COMP
Lymphoma, non-Hodgkin's:
COMLA
Hyper-CVAD (Lymphoma, non-Hodgkin's)
IMVP-16
MACOP-B
m-BACOD
Pro-MACE-CytaBOM
Lymphoma, non-Hodgkin's (Burkitt's): CODOX-M/IVAC
Lymphoma, non-Hodgkin's: (Mantle Cell): Hyper-CVAD + Rituximab
Osteosarcoma:
HDMTX
MTX-CDDPAdr
POG-8651
Soft tissue sarcoma: Methotrexate-Vinblastine (Desmoid Tumor)
Calculations

Body Surface Area: Adults

Body Surface Area: Pediatrics

Creatinine Clearance: Adults

Creatinine Clearance: Pediatrics


Administration: I.M.

May be administered I.M.


Administration: I.V.

May be administered I.V.; I.V. administration may be as slow push, short bolus
infusion, or 24- to 42-hour continuous infusion
Specific dosing schemes vary, but high dose should be followed by leucovorin
calcium to prevent toxicity; refer to Leucovorin monograph
Administration: Other

May be administered I.T or SubQ.


Dietary Considerations

Sodium content of 100 mg injection: 20 mg (0.86 mEq)


Sodium content of 100 mg (low sodium) injection: 15 mg (0.65 mEq)
Storage

Store tablets and intact vials at room temperature (15C to 25C). Protect from
light. Solution diluted in D5W or NS is stable for 24 hours at room temperature
(21C to 25C). Reconstituted solutions with a preservative may be stored
under refrigeration for up to 3 months, and up to 4 weeks at room temperature.

Intrathecal dilutions are stable at room temperature for 7 days, but it is generally
recommended that they be used within 4-8 hours.
Reconstitution

Dilute powder with D5W or NS to a concentration 25 mg/mL (20 mg and 50


mg vials) and 50 mg/mL (1 g vial). Intrathecal solutions may be reconstituted to
2.5-5 mg/mL with NS, D5W, lactated Ringer's, or Elliott's B solution. Use
preservative free preparations for intrathecal or high-dose administration.
Compatibility

Stable in D5NS, D5W, NS.


Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B
cholesteryl sulfate complex, asparaginase, aztreonam, bleomycin, cefepime,
ceftriaxone, cimetidine, cisplatin, cyclophosphamide, cytarabine,
daunorubicin, dexchlorpheniramine, diphenhydramine, doxorubicin,
doxorubicin liposome, etoposide, etoposide phosphate, famotidine,
filgrastim, fludarabine, fluorouracil, furosemide, ganciclovir, gatifloxacin,
granisetron, heparin, hydromorphone, imipenem/cilastatin, leucovorin,
linezolid, lorazepam, melphalan, mesna, methylprednisolone sodium
succinate, metoclopramide, mitomycin, morphine, ondansetron, oxacillin,
paclitaxel, piperacillin/tazobactam, prochlorperazine edisylate, ranitidine,
sargramostim, teniposide, thiotepa, vinblastine, vincristine, vindesine,
vinorelbine. Incompatible: Chlorpromazine, gemcitabine, idarubicin,
ifosfamide, midazolam, nalbuphine, promethazine, propofol. Variable
(consult detailed reference): Dexamethasone sodium phosphate, droperidol,
vancomycin.
Compatibility in syringe: Compatible: Bleomycin, cisplatin,
cyclophosphamide, doxapram, doxorubicin, fluorouracil, furosemide,
heparin, leucovorin, mitomycin, vinblastine, vincristine. Incompatible:
Droperidol. Variable (consult detailed reference): Metoclopramide.
Compatibility when admixed: Compatible: Cyclophosphamide,
cyclophosphamide with fluorouracil, cytarabine, dacarbazine, fluorouracil,
hydrocortisone, hydroxyzine, mercaptopurine, ondansetron, sodium
bicarbonate, vincristine. Incompatible: Bleomycin.
Contraindications

Hypersensitivity to methotrexate or any component of the formulation; severe


renal or hepatic impairment; pre-existing profound bone marrow suppression in
patients with psoriasis or rheumatoid arthritis, alcoholic liver disease, AIDS, preexisting blood dyscrasias; pregnancy (in patients with psoriasis or rheumatoid
arthritis); breast-feeding
Allergy Considerations

Methotrexate/Trimetrexate Allergy
Warnings/Precautions

Boxed Warnings:
Acute renal failure: See Concerns related to adverse effects
below.
Ascites/pleural effusion: See Disease-related concerns below.
Bone marrow suppression: See Concerns related to adverse
effects below.
Dermatologic reactions: See Concerns related to adverse effects
below.
Diarrhea/stomatitis: See Concerns related to adverse effects
below.
Experienced physician: See Other warnings/precautions below.
Hepatotoxicity: See Concerns related to adverse effects below.
Lymphomas: See Concerns related to adverse effects below.
NSAID's: See Concurrent drug therapy issues below.
Opportunistic infections: See Concerns related to adverse effects
below.
Pneumonitis: See Concerns related to adverse effects below.
Pregnancy: See Special populations below.

Preservative containing formulations/diluents: See Dosage form


specific issues below.
Radiotherapy recipients: See Special populations below..
Renal impairment: See Disease-related concerns below.
Tumor lysis syndrome: See Concerns related to adverse effects
below.
Special handling:
Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
Acute renal failure: [U.S. Boxed Warning]: May cause renal damage
leading to acute renal failure, especially with high-dose
methotrexate; monitor renal function and methotrexate levels closely,
maintain adequate hydration and urinary alkalinization. Use caution in
osteosarcoma patients treated with high-dose methotrexate in
combination with nephrotoxic chemotherapy (eg, cisplatin).
Bone marrow suppression: [U.S. Boxed Warning]: Bone marrow
suppression may occur, resulting in anemia, aplastic anemia,
pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Use
caution in patients with pre-existing bone marrow suppression.
Discontinue therapy in RA or psoriasis if a significant decrease in
hematologic components is noted.
Dermatologic reactions: [U.S. Boxed Warning]: Any dose level or
route of administration may cause severe and potentially fatal
dermatologic reactions, including toxic epidermal necrolysis, StevensJohnson syndrome, exfoliative dermatitis, skin necrosis, and erythema
multiforme. Radiation dermatitis and sunburn may be precipitated by
methotrexate administration. Psoriatic lesions may be worsened by
concomitant exposure to ultraviolet radiation.
Diarrhea/stomatitis: [U.S. Boxed Warning]: Diarrhea and ulcerative
stomatitis may require interruption of therapy; death from
hemorrhagic enteritis or intestinal perforation has been reported. Use
with caution in patients with peptic ulcer disease, ulcerative colitis.
Fertility: May cause impairment of fertility, oligospermia, and menstrual
dysfunction.

Hepatotoxicity: [U.S. Boxed Warning]: Methotrexate has been


associated with acute (elevated transaminases) and potentially fatal
chronic (fibrosis, cirrhosis) hepatotoxicity. Risk is related to
cumulative dose and prolonged exposure. Monitor closely (with liver
function tests, including serum albumin) for liver toxicities. Liver
enzyme elevations may be noted, but may not be predictive of hepatic
disease in long term treatment for psoriasis (but generally is predictive
in rheumatoid arthritis [RA] treatment). With long-term use, liver
biopsy may show histologic changes, fibrosis or cirrhosis; periodic liver
biopsy is recommended with long-term use for psoriasis and for
persistent abnormal liver function tests with RA; discontinue
methotrexate with moderate-to-severe change in liver biopsy. Ethanol
abuse, obesity, advanced age, and diabetes may increase the risk of
hepatotoxic reactions. Use caution with preexisting liver impairment;
may require dosage reduction. Use caution when used with other
hepatotoxic agents (azathioprine, retinoids, sulfasalazine).
Lymphomas: [U.S. Boxed Warning]: Use of low dose methotrexate
has been associated with the development of malignant lymphomas;
may regress upon discontinuation of therapy; treat lymphoma
appropriately if regression is not induced by cessation of methotrexate.
Neurotoxicity: May cause neurotoxicity including seizures (usually in
pediatric ALL patients), leukoencephalopathy (usually with concurrent
cranial irradiation) and stroke-like encephalopathy (usually with highdose regimens). Chemical arachnoiditis (headache, back pain, nuchal
rigidity, fever), myelopathy and chronic leukoencephalopathy may
result from intrathecal administration.
Opportunistic infections: [U.S. Boxed Warning]: Immune suppression
may lead to potentially fatal opportunistic infections.
Pneumonitis: [U.S. Boxed Warning]: May cause potentially lifethreatening pneumonitis (may occur at any time during therapy and at
any dosage); monitor closely for pulmonary symptoms, particularly dry,
nonproductive cough. Other potential symptoms include fever, dyspnea,
hypoxemia, or pulmonary infiltrate.
Tumor lysis syndrome: [U.S. Boxed Warning]: Tumor lysis syndrome
may occur in patients with high tumor burden; use appropriate
prevention and treatment.
Disease-related concerns:

Ascites/pleural effusions: [U.S. Boxed Warning]: Elimination is


reduced in patients with ascites and/or pleural fluid; may require
dose reduction or discontinuation. Monitor closely for toxicity.
Hepatic impairment: Use with caution in patients with pre-existing liver
impairment.
Peptic ulcer disease: Use with caution in patients with peptic ulcer
disease; diarrhea and stomatitis may occur.
Renal impairment: [U.S. Boxed Warning]: Methotrexate elimination
is reduced in patients with renal impairment; may require dose
reduction or discontinuation; monitor closely for toxicity.
Ulcerative colitis: Use with caution in patients with ulcerative colitis;
diarrhea and stomatitis may occur.
Concurrent drug therapy issues:
Hepatotoxic agents: Use caution when used with other hepatotoxic
agents (azathioprine, retinoids, sulfasalazine).
Nephrotoxic chemotherapy: Use caution in osteosarcoma patients treated
with high-dose methotrexate in combination with nephrotoxic
chemotherapy (eg, cisplatin).
NSAID's: [U.S. Boxed Warning]: Concurrent administration with
NSAIDs may cause severe bone marrow suppression, aplastic
anemia, and GI toxicity. Do not administer NSAIDs prior to or during
high dose methotrexate therapy; may increase and prolong serum
methotrexate levels. Doses used for psoriasis may still lead to
unexpected toxicities; use caution when administering NSAIDs or
salicylates with lower doses of methotrexate for RA. Methotrexate may
increase the levels and effects of mercaptopurine; may require dosage
adjustments. Vitamins containing folate may decrease response to
systemic methotrexate; folate deficiency may increase methotrexate
toxicity.
Special populations:
Elderly: Use caution in the elderly; increased risk of toxicity.
Pregnancy: [U.S. Boxed Warning]: May cause fetal death or
congenital abnormalities; do not use for psoriasis or RA treatment
in pregnant women.

Radiotherapy recipients: [U.S. Boxed Warning]: Concomitant


methotrexate administration with radiotherapy may increase the
risk of soft tissue necrosis and osteonecrosis.
Dosage form specific issues:
Benzyl alcohol: Injection may contain benzyl alcohol which has been
associated with "gasping syndrome" in neonates.
Preservative containing formulations/diluents: [U.S. Boxed Warnings]:
Methotrexate formulations and/or diluents containing preservatives
should not be used for intrathecal or high-dose therapy.
Other warnings/precautions:
Experienced physician: [U.S. Boxed Warnings]: Should be
administered under the supervision of a physician experienced in
the use of antimetabolite therapy; serious and fatal toxicities have
occurred at all dose levels. For rheumatoid arthritis and psoriasis,
immunosuppressive therapy should only be used when disease is active
and less toxic, traditional therapy is ineffective.
Geriatric Considerations

Toxicity to methotrexate or any immunosuppressive is increased in the elderly.


Must monitor carefully. For rheumatoid arthritis and psoriasis,
immunosuppressive therapy should only be used when disease is active and less
toxic, traditional therapy is ineffective. Recommended doses should be reduced
when initiating therapy in the elderly due to possible decreased metabolism,
reduced renal function, and presence of interacting diseases and drugs. Adjust
dose as needed for renal function (Clcr).
Pregnancy Risk Factor

X (psoriasis, rheumatoid arthritis)


Pregnancy Considerations

[U.S. Boxed Warning]: May cause fetal death or congenital abnormalities; do


not use for psoriasis or RA treatment in pregnant women. Use for the
treatment of neoplastic diseases only when the potential benefit to the mother

outweighs the possible risk to the fetus. Pregnancy should be excluded prior to
therapy in women of childbearing potential. Pregnancy should be avoided for
3 months following treatment in male patients and 1 ovulatory cycle in
female patients.
Lactation

Enters breast milk/contraindicated


Adverse Reactions

Note: Adverse reactions vary by route and dosage. Hematologic and/or


gastrointestinal toxicities may be common at dosages used in chemotherapy; these
reactions are much less frequent when used at typical dosages for rheumatic
diseases.
>10%:
Central nervous system (with I.T. administration or very high-dose therapy):
Arachnoiditis: Acute reaction manifested as severe headache, nuchal
rigidity, vomiting, and fever; may be alleviated by reducing the
dose
Subacute toxicity: 10% of patients treated with 12-15 mg/m2 of I.T.
methotrexate may develop this in the second or third week of
therapy; consists of motor paralysis of extremities, cranial nerve
palsy, seizure, or coma. This has also been seen in pediatric cases
receiving very high-dose I.V. methotrexate.
Demyelinating encephalopathy: Seen months or years after receiving
methotrexate; usually in association with cranial irradiation or
other systemic chemotherapy
Dermatologic: Reddening of skin
Endocrine & metabolic: Hyperuricemia, defective oogenesis or
spermatogenesis
Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting,
diarrhea, anorexia, intestinal perforation, mucositis (dose dependent;
appears in 3-7 days after therapy, resolving within 2 weeks)

Hematologic: Leukopenia, thrombocytopenia


Renal: Renal failure, azotemia, nephropathy
Respiratory: Pharyngitis
1% to 10%:
Cardiovascular: Vasculitis
Central nervous system: Dizziness, malaise, encephalopathy, seizure, fever,
chills
Dermatologic: Alopecia, rash, photosensitivity, depigmentation or
hyperpigmentation of skin
Endocrine & metabolic: Diabetes
Genitourinary: Cystitis
Hematologic: Hemorrhage
Myelosuppressive: This is the primary dose-limiting factor (along with
mucositis) of methotrexate; occurs about 5-7 days after methotrexate
therapy, and should resolve within 2 weeks
WBC: Mild
Platelets: Moderate
Onset: 7 days
Nadir: 10 days
Recovery: 21 days
Hepatic: Cirrhosis and portal fibrosis have been associated with chronic
methotrexate therapy; acute elevation of liver enzymes are common
after high-dose methotrexate, and usually resolve within 10 days.
Neuromuscular & skeletal: Arthralgia
Ocular: Blurred vision

Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine


and BUN and a fall in urine output; more common with high-dose
methotrexate, and may be due to precipitation of the drug.
Respiratory: Pneumonitis: Associated with fever, cough, and interstitial
pulmonary infiltrates; treatment is to withhold methotrexate during the
acute reaction; interstitial pneumonitis has been reported to occur with
an incidence of 1% in patients with RA (dose 7.5-15 mg/week)
<1% (Limited to important or life-threatening): Acute neurologic syndrome (at
high dosages - symptoms include confusion, hemiparesis, transient blindness,
and coma); anaphylaxis, alveolitis, cognitive dysfunction (has been reported
at low dosage), decreased resistance to infection, erythema multiforme,
hepatic failure, leukoencephalopathy (especially following craniospinal
irradiation or repeated high-dose therapy), lymphoproliferative disorders,
osteonecrosis and soft tissue necrosis (with radiotherapy), pericarditis,
plaque erosions (psoriasis), seizure (more frequent in pediatric patients with
ALL), Stevens-Johnson syndrome, thromboembolism
Oncology: Vesicant

No
Oncology: Emetic Potential

Low (10% to 30%): <250 mg/m2


Moderate (30% to 90%): 250 mg/m2
Methotrexate (oral): Very low (<10%)
Drug Interactions

Acitretin: May enhance the hepatotoxic effect of Methotrexate. Risk X: Avoid


combination
Bile Acid Sequestrants: May decrease the absorption of Methotrexate. Risk C:
Monitor therapy

Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of


Cardiac Glycosides. This may only affect digoxin tablets. Exceptions:
Digitoxin. Risk C: Monitor therapy
Ciprofloxacin: May increase the serum concentration of Methotrexate. Risk C:
Monitor therapy
CycloSPORINE: Methotrexate may increase the serum concentration of
CycloSPORINE. This may result in nephrotoxicity. CycloSPORINE may
increase the serum concentration of Methotrexate. This may result in nausea,
vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Risk D: Consider
therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D:
Consider therapy modification
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1
Substrates. Management: According to eltrombopag prescribing information,
consideration of a preventative dose reduction may be warranted. Risk D:
Consider therapy modification
Leflunomide: Methotrexate may enhance the myelosuppressive effect of
Leflunomide. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of
Natalizumab. Specifically, the risk of concurrent infection may be increased.
Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May decrease the excretion of
Methotrexate. Risk D: Consider therapy modification
Penicillins: May decrease the excretion of Methotrexate. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of PGlycoprotein Substrates. P-glycoprotein inducers may also further limit the
distribution of p-glycoprotein substrates to specific cells/tissues/organs
where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes,
testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of PGlycoprotein Substrates. P-glycoprotein inhibitors may also enhance the
distribution of p-glycoprotein substrates to specific cells/tissues/organs
where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes,
testes, etc.). Risk C: Monitor therapy

Proton Pump Inhibitors: May decrease the excretion of Methotrexate.


Antirheumatic doses of methotrexate probably hold minimal risk. Risk C:
Monitor therapy
Salicylates: May increase the serum concentration of Methotrexate. Salicylate
doses used for prophylaxis of cardiovascular events are not likely to be of
concern. Risk D: Consider therapy modification
Sapropterin: Methotrexate may decrease the serum concentration of Sapropterin.
Specifically, methotrexate may decrease tissue concentrations of
tetrahydrobiopterin. Risk C: Monitor therapy
Sulfonamide Derivatives: May enhance the adverse/toxic effect of Methotrexate.
Risk D: Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk
C: Monitor therapy
Trimethoprim: May enhance the adverse/toxic effect of Methotrexate. Risk D:
Consider therapy modification
Uricosuric Agents: May decrease the excretion of Methotrexate. Risk D: Consider
therapy modification
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect
of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of
Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may
also decrease therapeutic response to vaccines. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the
anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may
diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may be associated with increased liver injury).


Food: Methotrexate peak serum levels may be decreased if taken with food. Milkrich foods may decrease methotrexate absorption. Folate may decrease drug
response.

Herb/Nutraceutical: Avoid echinacea (has immunostimulant properties).


Monitoring Parameters

For prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver


biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed;
WBC and platelet counts every 4 weeks; CBC and creatinine, LFTs every 3-4
months; chest x-ray
Reference Range

Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is


dependent upon therapeutic approach.
High-dose regimens produce drug levels that are between 0.1-1 micromole/L 2472 hours after drug infusion
Toxic: Low-dose therapy: >0.2 micromole/L; high-dose therapy: >1
micromole/L
Nursing: Physical Assessment/Monitoring

Monitor closely if used in presence of preexisting conditions that increase


potential for toxicity (eg, renal impairment, peptic ulcer disease, ulcerative colitis,
hepatic impairment, bone marrow suppression). Assess potential for interactions
with other pharmacological agents and herbal products patient may be using (eg,
NSAIDs and salicylates or other hepatotoxic agents, or drugs that may effect the
levels/effects of methotrexate). Evaluate results of laboratory tests prior to therapy
and at frequent intervals during therapy. Patient should be monitored closely for
adverse reactions (eg, hyper- or hypothyroidism, pneumonitis [dry, nonproductive
cough], gastrointestinal disturbance [ulcerative stomatitis, pain, intestinal
perforation], renal failure [decreased urine output]). Assess effectiveness at
regular intervals (according to purpose for use). Teach patient proper use, possible
side effects/appropriate interventions, and adverse symptoms to report.
Pregnancy risk factor X: Determine that patient is not pregnant before beginning
treatment. Instruct patient of childbearing age (or males who may have
intercourse with women of childbearing age) in appropriate use of contraceptive
measures during therapy and for 3 months following treatment of males or 1
ovulatory cycle in females.

Monitoring: Lab Tests

For prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver


biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed;
WBC and platelet counts every 4 weeks; CBC and creatinine, LFTs every 3-4
months; chest x-ray
Patient Education

Do not take any new medication during therapy unless approved by prescriber.
Infusion/injection: Report immediately any redness, swelling, pain, or burning at
infusion/injection site. It is very important to maintain adequate hydration (2-3
L/day of fluids) unless instructed to restrict fluid intake and nutrition (small
frequent meals may help). Avoid alcohol to prevent serious side effects. You will
be more susceptible to infection (avoid crowds and exposure to infection and do
not have any vaccinations without consulting prescriber). May cause sensitivity to
sunlight (use sunscreen, wear protective clothing, and eyewear); nausea or
vomiting (small frequent meals, frequent mouth care, sucking lozenges, or
chewing gum may help; if unresolved, contact prescriber); drowsiness, dizziness,
numbness, or blurred vision (use caution when driving or engaging in tasks that
require alertness until response to drug is known); loss of hair (may be reversible);
color change of skin; permanent sterility; or mouth sores (frequent mouth care
with soft toothbrush or cotton swabs and frequent rinses may help). Report
immediately any rash, excessive or unusual fatigue, or respiratory difficulty.
Report rapid heartbeat or palpitations, black or tarry stools, fever, chills, unusual
bleeding or bruising, shortness of breath, persistent GI disturbances, diarrhea,
constipation, pain on urination or change in urinary patterns, or any other
persistent adverse effects. Pregnancy/breast-feeding precautions: Do not get
pregnant while taking this medication. This drug should not be used in the 2nd or
3rd trimester of pregnancy. Consult prescriber for appropriate contraceptive
measures if necessary or if you suspect you might be pregnant. This drug may
cause birth defects. Do not breast-feed.
Dosage Forms

Excipient information presented when available (limited, particularly for


generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]: 20 mg, 1 g
Injection, solution: 25 mg/mL (2 mL, 10 mL) [contains benzyl alcohol]

Injection, solution [preservative free]: 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL, 40


mL)
Tablet: 2.5 mg
Trexall: 5 mg, 7.5 mg, 10 mg, 15 mg
Tablet, as sodium [dose pack] (Rheumatrex Dose Pack): 2.5 mg (4 cards with
2, 3, 4, 5, or 6 tablets each)
Generic Available

Yes
Pricing: U.S. (www.drugstore.com)

Solution (Methotrexate Sodium)


25 mg/mL (2): $8.99
25 mg/mL (2): $14.99
25 mg/mL (10): $24.99
25 mg/mL (40): $58.99
Solution (Methotrexate Sodium LPF)
25 mg/mL (2): $7.99
Tablets (Rheumatrex)
2.5 mg (8): $49.99
Tablets (Trexall)
10 mg (30): $426.29
Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate


irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced
folates, and thymidylate synthetase, resulting in inhibition of purine and
thymidylic acid synthesis. Methotrexate is cell cycle specific for the S phase of
the cycle.
The MOA in the treatment of rheumatoid arthritis is unknown, but may affect
immune function. In psoriasis, methotrexate is thought to target rapidly
proliferating epithelial cells in the skin.
In Crohns disease, it may have immune modulator and anti-inflammatory
activity.
Pharmacodynamics/Kinetics

Onset of action: Antirheumatic: 3-6 weeks; additional improvement may continue


longer than 12 weeks
Absorption: Oral: Rapid; well absorbed at low doses (<30 mg/m2), incomplete
after large doses; I.M.: Complete
Distribution: Penetrates slowly into 3rd space fluids (eg, pleural effusions,
ascites), exits slowly from these compartments (slower than from plasma);
crosses placenta; small amounts enter breast milk; sustained concentrations
retained in kidney and liver
Protein binding: 50%
Metabolism: <10%; degraded by intestinal flora to DAMPA by carboxypeptidase;
hepatic aldehyde oxidase converts methotrexate to 7-OH methotrexate;
polyglutamates are produced intracellularly and are just as potent as
methotrexate; their production is dose- and duration-dependent and they are
slowly eliminated by the cell once formed
Half-life elimination: Low dose: 3-10 hours; High dose: 8-12 hours
Time to peak, serum: Oral: 1-2 hours; I.M.: 30-60 minutes
Excretion: Urine (44% to 100%); feces (small amounts)
Related Information

Label yang disetujui FDA termasuk peringatan kotak. Lihat bagian


Peringatan / Kehati-hatian dalam ringkasan singkat dari informasi ini.
Untuk kata-kata verbatim dari peringatan kotak, berkonsultasi dengan
label produk atau www.fda.gov.
Isu Obat Keselamatan
Suara-sama / mirip masalah:
Methotrexate mungkin bingung dengan metolazone, mitoxantrone
MTX adalah singkatan rawan kesalahan (keliru sebagai mitoxantrone)
obat siaga tinggi: The Institute for Praktek Obat Aman (ISMP) termasuk
obat ini antara daftar obat yang memiliki risiko tinggi menyebabkan
kerugian pasien yang signifikan bila digunakan dalam kesalahan.
Kesalahan telah terjadi (yang mengakibatkan kematian) ketika
methotrexate diberikan sebagai daily ?? dosis bukannya
direkomendasikan weekly ?? dosis.
isu-isu internasional:
Trexall " mungkin bingung dengan Truxal yang merupakan nama
merek untuk chlorprothixene di Belgia
Trexall " mungkin bingung dengan Trexol yang merupakan nama
merek untuk tramadol di Meksiko
Pengucapan
(Met oh TREKS makan)
AS Nama Merek
Rheumatrex Dosis Pack; Trexall "
Nama Merek Kanada
Apo-Methotrexate; Rasio-Methotrexate
farmakologis Kategori
Antineoplastik Agen, antimetabolit (antifolat); Antirematik, Penyakit
Memodifikasi
Gunakan: Indikasi Berlabel
Pengobatan neoplasma trofoblas; leukemia; psorias; rheumatoid
arthritis (RA), termasuk polyarticular-kursus juvenile rheumatoid
arthritis (JRA); payudara, kepala dan leher, dan paru-paru karsinoma;
osteosarcoma; sarkoma jaringan lunak; karsinoma saluran pencernaan,
kerongkongan, testis; limfoma
Gunakan: berlabel / Investigational
Pengobatan dan pemeliharaan remisi pada penyakit Crohn s;
kehamilan ektopik
Dosis: Dewasa
Mengacu pada protokol individual.
Catatan: Dosis antara 100-500 mg / m2may membutuhkan leucovorin
penyelamatan. Dosis> 500 mg / m2require leucovorin penyelamatan:
I.V., I.M., Oral: leucovorin 10-15 mg / m2 setiap 6 jam selama 8 atau 10
dosis, mulai 24 jam setelah dimulainya infus metotreksat. Lanjutkan
sampai tingkat metotreksat adalah 0.1 micromolar (10-7 M).
Beberapa dokter terus leucovorin sampai tingkat metotreksat adalah

<0,05 micromolar (5 x 10-8 M) atau 0,01 micromolar (10-8 M).


Jika tingkat methotrexate 48 jam adalah> 1 micromolar (10-6 M) atau
tingkat metotreksat 72 jam adalah> 0,2 micromolar (2 x 10-7 M): IV,
IM, Oral: leucovorin 100 mg / m2 setiap 6 jam sampai tingkat
metotreksat adalah 0.1 micromolar (10-7 M). Beberapa dokter
terus leucovorin sampai tingkat metotreksat adalah <0,05 micromolar
(5 x 10-8 M) atau 0,01 micromolar (10-8 M).
Antineoplastik rentang dosis: I.V .: Rentang lebar 30-40 mg / m2 /
minggu untuk 100-12,000 mg / m2 dengan leucovorin rescue
neoplasma trofoblas:
Oral, I.M .: 15-30 mg / hari selama 5 hari; ulangi dalam 7 hari selama 35 kursus
I.V .: 11 mg / hari m2 1 sampai 5 setiap 3 minggu
Kanker kepala dan leher: Oral, I.M., I.V .: 25-50 mg / m2 sekali
seminggu
mikosis fungoides (limfoma sel-T kulit): Oral, I.M .: awal (tahap awal):
5-50 mg sekali seminggu atau
15-37,5 mg dua kali seminggu
kanker kandung kemih: I.V .:
30 mg / m2 hari 1 dan 8 setiap 3 minggu atau
30 mg / m2 hari 1, 15, dan 22 setiap 4 minggu
Kanker payudara: I.V .: 30-60 mg / m2 hari 1 dan 8 setiap 3-4 minggu
Lambung kanker: I.V .: 1500 mg / m2 setiap 4 minggu
Limfoma, non-Hodgkin: I.V .:
30 mg / hari m2 3 dan 10 setiap 3 minggu atau
120 mg / m2 hari 8 dan 15 setiap 3-4 minggu atau
200 mg / m2 hari 8 dan 15 setiap 3 minggu atau
400 mg / m2 setiap 4 minggu selama 3 siklus atau
1 g / m2 setiap 3 minggu atau
1,5 g / m2 setiap 4 minggu
Sarkoma: I.V .: 8-12 g / m2 mingguan selama 2-4 minggu
rheumatoid arthritis: Oral: 7,5 mg sekali seminggu atau 2,5 mg setiap
12 jam selama 3 dosis / minggu, tidak melebihi 20 mg / minggu
Psoriasis: Oral: 2,5-5 mg / dosis setiap 12 jam selama 3 dosis yang
diberikan mingguan atau Oral, I.M .: 10-25 mg / dosis diberikan sekali
seminggu
kehamilan ektopik (penggunaan berlabel): I.M .: 50 mg / m2 dosis
tunggal
Active Crohn s penyakit (penggunaan berlabel): Induksi remisi:
I.M., SubQ: 15-25 mg sekali seminggu; remisi pemeliharaan: 15 mg
sekali seminggu
Catatan: dosis oral telah dilaporkan sebagai penyerapan efektif tetapi
mulut sangat bervariasi. Jika kambuh pasien setelah beralih ke mulut,
dapat mempertimbangkan kembali ke injeksi.
Dosis: Lansia
Mengacu pada protokol individual; menyesuaikan gangguan ginjal.

Rheumatoid arthritis / psoriasis: Oral: Awal: 5-7,5 mg / minggu, tidak


melebihi 20 mg / minggu
Dosis: Pediatric
Mengacu pada protokol individual.
Catatan: Dosis antara 100-500 mg / m2may membutuhkan leucovorin
penyelamatan. Dosis> 500 mg / m2require leucovorin penyelamatan:
I.V., I.M., Oral: leucovorin 10-15 mg / m2 setiap 6 jam selama 8 atau 10
dosis, mulai 24 jam setelah dimulainya infus metotreksat. Lanjutkan
sampai tingkat metotreksat adalah 0.1 micromolar (10-7 M).
Beberapa dokter terus leucovorin sampai tingkat metotreksat adalah
<0,05 micromolar (5 x 10-8 M) atau 0,01 micromolar (10-8 M).
Jika tingkat methotrexate 48 jam adalah> 1 micromolar (10-6 M) atau
tingkat metotreksat 72 jam adalah> 0,2 micromolar (2 x 10-7 M): IV,
IM, Oral: leucovorin 100 mg / m2 setiap 6 jam sampai tingkat
metotreksat adalah 0.1 micromolar (10-7 M). Beberapa dokter
terus leucovorin sampai tingkat metotreksat adalah <0,05 micromolar
(5 x 10-8 M) atau 0,01 micromolar (10-8 M).
Dermatomiositis: Oral: 15-20 mg / m2 / minggu sebagai dosis tunggal
sekali seminggu atau 0,3-1 mg / kg / dosis sekali seminggu
rheumatoid arthritis: Oral, I.M.:10 mg / m2 sekali seminggu, kemudian
5-15 mg / m2 / minggu sebagai dosis tunggal atau sebagai 3 dosis
terbagi diberikan 12 jam terpisah
Antineoplastik rentang dosis:
Oral, I.M .: 7,5-30 mg / m2 / minggu atau setiap 2 minggu
I.V .: 10-18,000 mg / m2 bolus dosis atau infus kontinu selama 6-42
jam
tumor Pediatric padat (dosis tinggi): I.V .:
<12 tahun: 12-25 g / m2
12 tahun: 8 g / m2
leukemia akut limfositik (intermediate-dosis): I.V .: Loading: 100 mg /
m2 dosis bolus, diikuti oleh 900 mg / m2 / hari infus selama 23-41 jam.
leukemia meningeal: I.T .: 10-15 mg / m2 (dosis maksimum: 15 mg)
atau rejimen dosis berdasarkan usia; satu sistem yang mungkin
adalah:
3 bulan: 3 mg / dosis
4-11 bulan: 6 mg / dosis
1 tahun: 8 mg / dosis
2 tahun: 10 mg / dosis
3 tahun: 12 mg / dosis
Dosis: Penurunan ginjal
Label yang disetujui FDA tidak mengandung pedoman penyesuaian
dosis.
Pedoman berikut telah digunakan oleh beberapa dokter:
ClCr 61-80 mL / menit: dosis 75% dari dosis
ClCr 51-60 mL / menit: dosis 70% dari dosis
ClCr 10-50 mL / menit: dosis 30% sampai 50% dari dosis

ClCr <10 mL / menit: Hindari penggunaan


Hemodialisis: Tidak dialyzable (0% sampai 5%); dosis tambahan tidak
diperlukan
Efek dialisis peritoneal: dosis tambahan tidak diperlukan
Efek CAVH: Unknown
Aronoff, 2007:
anak-anak:
ClCr 10-50 mL / menit: dosis 50% dari dosis
ClCr <10 mL / menit: dosis 30% dari dosis
Hemodialisis: dosis 30% dari dosis
Terus menerus ambulatory peritoneal dialisis (CAPD): dosis 30% dari
dosis
Terus menerus terapi penggantian ginjal (CRRT): dosis 50% dari dosis
Dewasa:
ClCr 10-50 mL / menit: dosis 50% dari dosis
ClCr <10 mL / menit: Hindari penggunaan
Hemodialisis: dosis 50% dari dosis
Terus menerus terapi penggantian ginjal (CRRT): dosis 50% dari dosis
Kintzel, 1995:
ClCr 46-60 mL / menit: dosis 65% dari dosis normal
ClCr 31-45 mL / menit: dosis 50% dari dosis normal
ClCr <30 mL / menit: Hindari penggunaan
Dosis: Penurunan Hati
Label yang disetujui FDA tidak mengandung pedoman penyesuaian
dosis. Pedoman berikut telah digunakan oleh beberapa dokter (Floyd,
2006):
Bilirubin 3,1-5 mg / dL atau transaminase> 3 kali ULN: dosis 75% dari
dosis
Bilirubin> 5 mg / dL: Hindari penggunaan
Regimen Kombinasi: Dosis
Kanker kandung kemih:
CMV
M-VAC (Kanker Kandung Kemih)
Kanker payudara:
CMF
CMF-IV
CMFP
CMFVP (Cooper Regimen, VPCMF)
Dox-CMF (Sequential)
MF
M-VAC (Kanker Payudara)
Kanker serviks: M-VAC (Kanker Serviks)
kanker endometrium: MVAC (Kanker endometrium)
kanker lambung: FAMTX
Gestational tumor trofoblas:
CHAMOCA (Modified Bagshawe Regimen)

CHAMOMA (Bagshawe Regimen)


EMA / CO
EP / EMA
Kanker kepala dan leher:
CABO
MVAC (Kepala dan Leher)
Leukemia, limfositik akut:
Hyper-CVAD + Imatinib
Hyper-CVAD (Leukemia, akut limfositik)
linker Protocol
MTX / 6-MP / VP (Maintenance)
KEMEGAHAN
PVA (POG 8602)
Leukemia, promyelocytic akut: Tretinoin-idarubicin
Limfoma, penyakit Hodgkin: COMP
Limfoma, non-Hodgkin:
COMLA
Hyper-CVAD (Limfoma, non-Hodgkin)
IMVP-16
MACOP-B
m-BACOD
Pro-MACE-CytaBOM
Limfoma, non-Hodgkin (Burkitt): CODOX-M / IVAC
Limfoma, non-Hodgkin: (Mantle Sel): Hyper-CVAD + Rituximab
osteosarcoma:
HDMTX
MTX-CDDPAdr
POG-8651
Lembut sarcoma jaringan: Methotrexate-Vinblastine (Desmoid Tumor)
perhitungan
Tubuh Permukaan Area: Dewasa
Tubuh Permukaan Area: Pediatrics
Kreatinin Jarak: Dewasa
Kreatinin Jarak: Pediatrics
Administrasi: I.M.
Dapat diberikan I.M.
Administrasi: I.V.
Dapat diberikan I.V .; I.V. pemberian dapat mendorong lambat, infus
bolus pendek, atau 24 untuk infus kontinu 42 jam
skema dosis tertentu bervariasi, tetapi dosis tinggi harus diikuti dengan
leukovorin kalsium untuk mencegah toksisitas; lihat leucovorin
monografi
Administrasi: Lainnya
Dapat diberikan I.T atau SubQ.
Pertimbangan diet
konten natrium injeksi 100 mg: 20 mg (0.86 mEq)

kandungan sodium dari 100 mg (sodium rendah) injeksi: 15 mg (0,65


mEq)
Penyimpanan
tablet toko dan botol utuh pada suhu kamar (15A C untuk 25 C).
Lindungi dari cahaya. Solusi diencerkan dalam D5W atau NS stabil
selama 24 jam pada suhu kamar (21 C ke 25 C). Dilarutkan solusi
dengan pengawet dapat disimpan dalam lemari pendingin hingga 3
bulan, dan sampai 4 minggu pada suhu kamar. pengenceran intratekal
stabil pada suhu kamar selama 7 hari, tetapi umumnya
direkomendasikan bahwa mereka digunakan dalam 4-8 jam.
rekonstitusi
Encerkan bubuk dengan D5W atau NS untuk konsentrasi 25 mg /
mL (20 mg dan 50 mg vial) dan 50 mg / mL (1 g vial). solusi intratekal
dapat dilarutkan ke 2,5-5 mg / mL dengan NS, D5W, Ringer laktat, atau
solusi B Elliott. Gunakan persiapan gratis pengawet untuk pemberian
intratekal atau dosis tinggi.
Kesesuaian
Stabil di D5NS, D5W, NS.
administrasi Y-situs: Kompatibel: Allopurinol, amifostine, amfoterisin B
kolesterol sulfat kompleks, asparaginase, aztreonam, bleomycin,
cefepime, ceftriaxone, cimetidine, cisplatin, siklofosfamid, sitarabin,
daunorubisin, deksklorfeniramin, diphenhydramine, doxorubicin,
doxorubicin liposom, etoposid, fosfat etoposid , famotidine, filgrastim,
fludarabine, fluorouracil, furosemide, gansiklovir, gatifloxacin,
granisetron, heparin, hidromorfon, imipenem / cilastatin, leucovorin,
linezolid, lorazepam, melphalan, mesna, methylprednisolone sodium
suksinat, metoclopramide, mitomycin, morfin, ondansetron, oksasilin,
paclitaxel , piperacillin / Tazobactam, proklorperazin edisylate,
ranitidine, sargramostim, teniposide, thiotepa, vinblastine, vincristine,
vindesine, vinorelbine. Kompatibel: Klorpromazin, gemcitabine,
idarubicin, ifosfamide, midazolam, nalbuphine, prometazin, propofol.
Variabel (konsultasikan referensi rinci): Deksametason natrium fosfat,
droperidol, vankomisin.
Kompatibilitas dalam jarum suntik: Kompatibel: Bleomycin, cisplatin,
siklofosfamid, doxapram, doxorubicin, fluorouracil, furosemide,
heparin, leucovorin, mitomycin, vinblastine, vincristine. Kompatibel:
Droperidol. Variabel (konsultasikan referensi rinci): Metoclopramide.
Kompatibilitas ketika dicampur: Kompatibel: Cyclophosphamide,
siklofosfamid dengan fluorouracil, sitarabin, dacarbazine, fluorouracil,
hidrokortison, hidroksizin, merkaptopurin, ondansetron, natrium
bikarbonat, vincristine. Kompatibel: Bleomycin.
kontraindikasi
Hipersensitivitas terhadap methotrexate atau komponen lain dalam
formulasi; ginjal berat atau gangguan hati; sudah ada penekanan
sumsum tulang yang mendalam pada pasien dengan psoriasis atau
rheumatoid arthritis, penyakit hati alkoholik, AIDS, sudah ada diskrasia

darah; kehamilan (pada pasien dengan psoriasis atau radang sendi);


menyusui
Pertimbangan alergi
Methotrexate / trimetreksat Alergi
Peringatan / Kewaspadaan
Peringatan kemas:
Gagal ginjal akut: Lihat Concerns terkait dengan merugikan
effects ?? di bawah.
Asites / efusi pleura: Lihat Disease terkait concerns ?? di
bawah.
penekanan sumsum tulang: Lihat Concerns terkait dengan
merugikan effects ?? di bawah.
reaksi Dermatologic: Lihat Concerns terkait dengan
merugikan effects ?? di bawah.
Diare / stomatitis: Lihat Concerns terkait dengan merugikan
effects ?? di bawah.
dokter berpengalaman: Lihat peringatan Other /
precautions ?? di bawah.
Hepatotoksisitas: Lihat Concerns terkait dengan merugikan
effects ?? di bawah.
Limfoma: Lihat Concerns terkait dengan merugikan effects
?? di bawah.
NSAID: Lihat Concurrent terapi obat issues ?? di bawah.
Infeksi oportunistik: Lihat Concerns terkait dengan
merugikan effects ?? di bawah.
Pneumonitis: Lihat Concerns terkait dengan merugikan
effects ?? di bawah.
Kehamilan: Lihat Special populations ?? di bawah.
Pengawet mengandung formulasi / Pengencer: Lihat Dosage
membentuk issues tertentu ?? di bawah.
penerima Radioterapi: Lihat Special populations ?? di
bawah..
Gangguan ginjal: Lihat Disease terkait concerns ?? di
bawah.
sindrom lisis Tumor: Lihat Concerns terkait dengan
merugikan effects ?? di bawah.
Penanganan spesial:
agen berbahaya: Gunakan tindakan pencegahan yang tepat
untuk penanganan dan pembuangan.
Kekhawatiran terkait dengan efek samping:
Gagal ginjal akut: [AS Kotak Peringatan]: Dapat menyebabkan
kerusakan ginjal menyebabkan gagal ginjal akut, terutama dengan
metotreksat dosis tinggi; memantau fungsi ginjal dan tingkat
methotrexate erat, mempertahankan hidrasi yang memadai dan
alkalinisasi urin. Gunakan hati-hati pada pasien osteosarcoma diobati
dengan metotreksat dosis tinggi dalam kombinasi dengan kemoterapi

nefrotoksik (misalnya, cisplatin).


penekanan sumsum tulang: [AS Kotak Peringatan]: penekanan
sumsum tulang dapat terjadi, yang mengakibatkan anemia, anemia
aplastik, pansitopenia, leukopenia, neutropenia, dan / atau
trombositopenia. Gunakan hati-hati pada pasien dengan penekanan
sumsum tulang yang sudah ada. Menghentikan terapi di RA atau
psoriasis jika penurunan yang signifikan dalam komponen hematologi
dicatat.
reaksi Dermatologic: [AS Kotak Peringatan]: Setiap tingkat dosis
atau rute pemberian dapat menyebabkan reaksi dermatologi parah
dan berpotensi fatal, termasuk toksik beracun epidermal, sindrom
Stevens-Johnson, dermatitis eksfoliatif, nekrosis kulit, dan eritema
multiforme. dermatitis radiasi dan sengatan matahari dapat dipicu oleh
administrasi methotrexate. lesi psoriatik dapat diperburuk oleh
paparan bersamaan radiasi ultraviolet.
Diare / stomatitis: [AS Kotak Peringatan]: Diare dan stomatitis
ulseratif mungkin memerlukan penghentian terapi; kematian dari
hemoragik enteritis atau perforasi usus telah dilaporkan. Gunakan
dengan hati-hati pada pasien dengan penyakit ulkus peptikum, kolitis
ulserativa.
Kesuburan: Dapat menyebabkan penurunan kesuburan,
oligospermia, dan disfungsi menstruasi.
Hepatotoksisitas: [AS Kotak Peringatan]: Methotrexate telah
dikaitkan dengan akut (peningkatan transaminase) dan kronis
berpotensi fatal (fibrosis, sirosis) hepatotoksisitas. Risiko terkait
dengan dosis kumulatif dan kontak yang terlalu lama. Memonitor
(dengan tes fungsi hati, termasuk albumin serum) untuk toksisitas hati.
peningkatan enzim hati dapat dicatat, tetapi mungkin tidak prediktif
penyakit hati pada pengobatan jangka panjang untuk psoriasis (tetapi
umumnya adalah prediksi pada rheumatoid arthritis [RA] pengobatan).
Dengan penggunaan jangka panjang, biopsi hati dapat menunjukkan
perubahan histologis, fibrosis atau sirosis; periodik biopsi hati
dianjurkan dengan penggunaan jangka panjang untuk psoriasis dan
untuk tes fungsi hati yang abnormal terus-menerus dengan RA;
menghentikan methotrexate dengan perubahan moderat sampai berat
di biopsi hati. etanol penyalahgunaan, obesitas, usia lanjut, dan
diabetes dapat meningkatkan risiko reaksi hepatotoksik. Gunakan hatihati dengan yang sudah ada sebelumnya gangguan hati; mungkin
memerlukan pengurangan dosis. Gunakan hati-hati bila digunakan
dengan agen lainnya hepatotoksik (azathioprine, retinoid,
sulfasalazine).
Limfoma: [AS Kotak Peringatan]: Penggunaan metotreksat dosis
rendah telah dikaitkan dengan perkembangan limfoma ganas; mungkin
mundur setelah penghentian terapi; mengobati limfoma tepat jika
regresi tidak disebabkan oleh berhentinya methotrexate.
Neurotoksisitas: Dapat menyebabkan neurotoksisitas termasuk

kejang (biasanya di pediatrik ALL pasien), leukoencephalopathy


(biasanya dengan iradiasi kranial bersamaan) dan stroke-seperti
ensefalopati (biasanya dengan regimen dosis tinggi). arachnoiditis
kimia (sakit kepala, sakit punggung, kaku kuduk, demam), myelopathy
dan leukoencephalopathy kronis mungkin hasil dari administrasi
intratekal.
Infeksi oportunistik: [AS Kotak Peringatan]: Penekanan kekebalan
dapat menyebabkan infeksi oportunistik fatal.
Pneumonitis: [AS Kotak Peringatan]: Dapat menyebabkan
berpotensi mengancam jiwa pneumonitis (dapat terjadi setiap saat
selama terapi dan pada dosis ada); memonitor gejala paru, terutama
kering, batuk tidak produktif. Gejala potensial lainnya termasuk
demam, dyspnea, hipoksemia, atau infiltrate paru.
sindrom Tumor lisis: [AS Kotak Peringatan]: Tumor sindrom lisis
dapat terjadi pada pasien dengan beban tumor yang tinggi;
menggunakan pencegahan dan pengobatan yang tepat.
terkait penyakit keprihatinan:
Asites / efusi pleura: [AS Kotak Peringatan]: Penghapusan
berkurang pada pasien dengan asites dan / atau cairan pleura;
mungkin memerlukan pengurangan dosis atau penghentian.
Memonitor toksisitas.
Kerusakan Hati: Gunakan dengan hati-hati pada pasien dengan
gangguan hati yang sudah ada.
penyakit Ulkus peptikum: Gunakan dengan hati-hati pada pasien
dengan penyakit ulkus peptikum; diare dan stomatitis dapat terjadi.
Gangguan ginjal: [AS Kotak Peringatan]: eliminasi Metotreksat
berkurang pada pasien dengan gangguan ginjal; mungkin memerlukan
pengurangan dosis atau penghentian; memonitor toksisitas.
Kolitis ulseratif: Gunakan dengan hati-hati pada pasien dengan
kolitis ulserativa; diare dan stomatitis dapat terjadi.
masalah terapi obat bersamaan:
agen hepatotoksik: Gunakan hati-hati bila digunakan dengan
agen lainnya hepatotoksik (azathioprine, retinoid, sulfasalazine).
nefrotoksik kemoterapi: Gunakan hati-hati pada pasien
osteosarcoma diobati dengan metotreksat dosis tinggi dalam
kombinasi dengan kemoterapi nefrotoksik (misalnya, cisplatin).
NSAID: [AS Kotak Peringatan]: Pemberian bersama dengan NSAID
dapat menyebabkan penekanan parah sumsum tulang, anemia
aplastik, dan toksisitas GI. Jangan mengelola NSAID sebelum atau
selama terapi metotreksat dosis tinggi; dapat meningkatkan dan
memperpanjang tingkat methotrexate serum. Dosis yang digunakan
untuk psoriasis masih dapat menyebabkan toksisitas tak terduga;
menggunakan hati saat pemberian NSAID atau salisilat dengan dosis
yang lebih rendah dari methotrexate untuk RA. Metotreksat dapat
meningkatkan tingkat dan efek dari mercaptopurine; mungkin
memerlukan penyesuaian dosis. Vitamin yang mengandung folat dapat

menurunkan respon terhadap methotrexate sistemik; defisiensi folat


dapat meningkatkan toksisitas methotrexate.
populasi khusus:
Lansia: Gunakan hati-hati pada orang tua; peningkatan risiko
toksisitas.
Kehamilan: [AS Kotak Peringatan]: Dapat menyebabkan kematian
janin atau kelainan kongenital; tidak digunakan untuk psoriasis atau
pengobatan RA pada wanita hamil.
penerima Radioterapi: [AS Kotak Peringatan]: Seiring administrasi
methotrexate dengan radioterapi dapat meningkatkan risiko nekrosis
jaringan lunak dan osteonekrosis.
Dosis membentuk isu-isu spesifik:
Benzyl alcohol: Injection mungkin berisi benzyl alcohol yang telah
dikaitkan dengan "terengah sindrom" pada neonatus.
Pengawet mengandung formulasi / Pengencer: [AS Peringatan
kemas]: formulasi Methotrexate dan / atau pengencer yang
mengandung pengawet tidak boleh digunakan untuk terapi intratekal
atau dosis tinggi.
Lain peringatan / tindakan pencegahan:
dokter berpengalaman: [AS Peringatan kemas]: Harus diberikan
di bawah pengawasan seorang dokter berpengalaman dalam
penggunaan terapi antimetabolit; toksisitas serius dan fatal telah
terjadi di semua tingkatan dosis. Untuk rheumatoid arthritis dan
psoriasis, terapi imunosupresif seharusnya hanya digunakan ketika
penyakit aktif dan kurang toksik, terapi tradisional tidak efektif.
Pertimbangan Geriatric
Keracunan untuk methotrexate atau imunosupresif meningkat pada
orang tua. Harus memantau dengan seksama. Untuk rheumatoid
arthritis dan psoriasis, terapi imunosupresif seharusnya hanya
digunakan ketika penyakit aktif dan kurang toksik, terapi tradisional
tidak efektif. dosis yang dianjurkan harus dikurangi ketika memulai
terapi pada orang tua karena kemungkinan penurunan metabolisme,
penurunan fungsi ginjal, dan kehadiran berinteraksi penyakit dan obatobatan. Menyesuaikan dosis yang diperlukan untuk fungsi ginjal (ClCr).
Faktor Risiko Kehamilan
X (psoriasis, rheumatoid arthritis)
Pertimbangan kehamilan
[KAMI. Kotak Peringatan]: Dapat menyebabkan kematian janin atau
kelainan kongenital; tidak digunakan untuk psoriasis atau pengobatan
RA pada wanita hamil. Gunakan untuk pengobatan penyakit neoplastik
hanya ketika manfaat potensial untuk ibu melampaui risiko yang
mungkin untuk janin. Kehamilan harus dikeluarkan sebelum terapi
pada wanita usia subur. Kehamilan harus dihindari untuk 3
bulan setelah perawatan pada pasien laki-laki dan 1 siklus
ovulasi pada pasien wanita.
Laktasi

Memasuki ASI / kontraindikasi


Reaksi yang merugikan
Catatan: Efek samping bervariasi oleh rute dan dosis. Hematologi dan /
atau toksisitas gastrointestinal mungkin umum pada dosis yang
digunakan dalam kemoterapi; reaksi-reaksi ini jauh lebih jarang bila
digunakan pada dosis yang khas untuk penyakit rematik.
> 10%:
Sistem saraf pusat (dengan administrasi T.I. atau sangat terapi dosis
tinggi):
Arachnoiditis: Reaksi akut dimanifestasikan sebagai sakit kepala parah,
kaku kuduk, muntah, dan demam; dapat diatasi dengan mengurangi
dosis
toksisitas subakut: 10% dari pasien yang diobati dengan 12-15 mg /
m2 T.I. methotrexate dapat berkembang ini pada minggu kedua atau
ketiga terapi; terdiri motor kelumpuhan ekstremitas, kelumpuhan saraf
kranial, kejang, atau koma. Ini juga telah terlihat dalam kasus-kasus
pediatrik menerima sangat I.V. dosis tinggi methotrexate.
Demielinasi encephalopathy: Terlihat bulan atau tahun setelah
menerima metotreksat; biasanya berkaitan dengan iradiasi kranial
atau kemoterapi sistemik lainnya
Dermatologic: kemerahan kulit
Endokrin dan metabolik: Hyperuricemia, oogenesis rusak atau
spermatogenesis
Gastrointestinal: stomatitis ulseratif, glositis, gingivitis, mual, muntah,
diare, anoreksia, perforasi usus, mucositis (tergantung dosis; muncul
dalam 3-7 hari setelah terapi, menyelesaikan dalam waktu 2 minggu)
Hematologi: Leukopenia, trombositopenia
Ginjal: gagal ginjal, azotemia, nefropati
Pernafasan: Faringitis
1% sampai 10%:
Kardiovaskular: Vaskulitis
Sistem saraf pusat: Pusing, malaise, ensefalopati, kejang, demam,
menggigil
Dermatologic: Alopecia, ruam, fotosensitifitas, depigmentasi atau
hiperpigmentasi kulit
Endokrin dan metabolik: Diabetes
Genitourinari: Cystitis
Hematologi: Perdarahan
Myelosuppressive: Ini adalah faktor dosis yang membatasi utama
(bersama dengan mucositis) metotreksat; terjadi sekitar 5-7 hari
setelah terapi methotrexate, dan harus menyelesaikan dalam waktu 2
minggu
WBC: Ringan
Trombosit: Moderat
Onset: 7 hari
Nadir: 10 hari

Pemulihan: 21 hari
Hati: Sirosis dan fibrosis portal telah dikaitkan dengan terapi
methotrexate kronis; elevasi akut enzim hati yang umum setelah
metotreksat dosis tinggi, dan biasanya diselesaikan dalam waktu 10
hari.
Neuromuskular & skeletal: Artralgia
Okular: Penglihatan kabur
Ginjal: Disfungsi ginjal: Diwujudkan oleh kenaikan mendadak kreatinin
serum dan BUN dan penurunan output urin; lebih umum dengan
metotreksat dosis tinggi, dan mungkin karena pengendapan obat.
Pernapasan: Pneumonitis: Terkait dengan demam, batuk, dan infiltrat
paru interstitial; pengobatan adalah untuk menahan metotreksat
selama reaksi akut; pneumonitis interstitial telah dilaporkan terjadi
dengan kejadian 1% pada pasien dengan RA (dosis 7,5-15 mg /
minggu)
<1% (terbatas untuk penting atau mengancam jiwa): sindrom
neurologis akut (pada dosis tinggi - gejala termasuk kebingungan,
hemiparesis, kebutaan sementara, dan koma); anafilaksis, alveolitis,
disfungsi kognitif (telah dilaporkan pada dosis rendah), penurunan
resistensi terhadap infeksi, eritema multiforme, gagal hati,
leukoencephalopathy (terutama setelah iradiasi craniospinal atau
terapi dosis tinggi berulang), gangguan limfoproliferatif, osteonekrosis
dan nekrosis jaringan lunak (dengan radioterapi), perikarditis, erosi
plak (psoriasis), kejang (lebih sering pada pasien anak dengan ALL),
sindrom Stevens-Johnson, tromboemboli
Onkologi: yg menyebabkan bengkak
Tidak
Onkologi: Emetik Potensi
Rendah (10% sampai 30%): <250 mg / m2
Sedang (30% sampai 90%): 250 mg / m2
Methotrexate (oral): Sangat rendah (<10%)
Interaksi obat
Acitretin: Semoga meningkatkan efek hepatotoksik dari Methotrexate.
Risiko X: Hindari kombinasi
Bile Acid sequestrants: Semoga menurunkan penyerapan
Methotrexate. Risiko C: Terapi Memantau
Glikosida jantung: Agen antineoplastik dapat menurunkan penyerapan
jantung Glikosida. Hal ini hanya dapat mempengaruhi tablet digoxin.
Pengecualian: digitoksin. Risiko C: Terapi Memantau
Ciprofloxacin: Dapat meningkatkan konsentrasi serum Methotrexate.
Risiko C: Terapi Memantau
Siklosporin: Methotrexate dapat meningkatkan konsentrasi serum
siklosporin. Hal ini dapat mengakibatkan nefrotoksisitas. Siklosporin
dapat meningkatkan konsentrasi serum Methotrexate. Hal ini dapat
mengakibatkan mual, muntah, ulkus oral, hepatotoksisitas dan / atau
nefrotoksisitas. Risiko D: Pertimbangkan modifikasi terapi

Echinacea: Semoga mengurangi efek terapi imunosupresan. Risiko D:


Pertimbangkan modifikasi terapi
Eltrombopag: Dapat meningkatkan konsentrasi serum Substrat
OATP1B1 / SLCO1B1. Manajemen: Menurut informasi eltrombopag
resep, pertimbangan pengurangan dosis pencegahan dapat
dibenarkan. Risiko D: Pertimbangkan modifikasi terapi
Leflunomide: Methotrexate dapat meningkatkan efek myelosuppressive
dari leflunomide. Risiko C: Terapi Memantau
Natalizumab: imunosupresan dapat meningkatkan / efek toksik yang
merugikan dari natalizumab. Secara khusus, risiko infeksi bersamaan
dapat ditingkatkan. Risiko X: Hindari kombinasi
Agen Anti-inflamasi nonsteroid: Semoga menurunkan ekskresi
Methotrexate. Risiko D: Pertimbangkan modifikasi terapi
Penisilin: Semoga menurunkan ekskresi Methotrexate. Risiko C: Terapi
Memantau
P-Glycoprotein Reagen: Semoga menurunkan konsentrasi serum PGlycoprotein Substrat. P-glikoprotein induser juga dapat lebih
membatasi distribusi substrat p-glikoprotein ke spesifik sel / jaringan /
organ mana p-glikoprotein hadir dalam jumlah besar (misalnya, otak, Tlimfosit, testis, dll). Risiko C: Terapi Memantau
P-Glycoprotein Inhibitor: Dapat meningkatkan konsentrasi serum PGlycoprotein Substrat. inhibitor P-glikoprotein juga dapat meningkatkan
distribusi substrat p-glikoprotein ke spesifik sel / jaringan / organ mana
p-glikoprotein hadir dalam jumlah besar (misalnya, otak, T-limfosit,
testis, dll). Risiko C: Terapi Memantau
Proton Pump Inhibitor: Semoga menurunkan ekskresi Methotrexate.
dosis antirematik metotreksat mungkin terus risiko minimal. Risiko C:
Terapi Memantau
Salisilat: Dapat meningkatkan konsentrasi serum Methotrexate. dosis
salisilat digunakan untuk profilaksis kejadian kardiovaskular tidak
mungkin untuk menjadi perhatian. Risiko D: Pertimbangkan modifikasi
terapi
Sapropterin: Methotrexate dapat menurunkan konsentrasi serum
Sapropterin. Secara khusus, methotrexate dapat menurunkan
konsentrasi jaringan tetrahydrobiopterin. Risiko C: Terapi Memantau
Derivatif sulfonamide: Semoga meningkatkan efek merugikan /
beracun dari Methotrexate. Risiko D: Pertimbangkan modifikasi terapi
Trastuzumab: Semoga meningkatkan efek neutropenia dari
Imunosupresan. Risiko C: Terapi Memantau
Trimetoprim: Semoga meningkatkan / efek toksik yang merugikan dari
Methotrexate. Risiko D: Pertimbangkan modifikasi terapi
Agen uricosuric: Semoga menurunkan ekskresi Methotrexate. Risiko D:
Pertimbangkan modifikasi terapi
Vaksin (dilemahkan): imunosupresan dapat mengurangi efek terapi
vaksin (dilemahkan). Risiko C: Terapi Memantau
Vaksin (Hidup): imunosupresan dapat meningkatkan efek merugikan /

beracun dari vaksin (Hidup). Infeksi Vaccinal dapat berkembang.


Imunosupresan juga dapat menurunkan respon terapi untuk vaksin.
Risiko X: Hindari kombinasi
Vitamin K Antagonis (misalnya, warfarin): Agen antineoplastik dapat
meningkatkan efek antikoagulan dari vitamin K antagonis. Agen
antineoplastik dapat mengurangi efek antikoagulan dari Vitamin K
antagonis. Risiko C: Terapi Memantau
Etanol / Nutrisi / Herb Interaksi
Etanol: Hindari etanol (mungkin berhubungan dengan peningkatan
kerusakan hati).
Makanan: kadar serum puncak Methotrexate dapat menurun jika
diambil dengan makanan. makanan-susu yang kaya dapat menurunkan
penyerapan methotrexate. Folat dapat menurunkan respon obat.
Ramuan / Nutraceutical: Hindari echinacea (memiliki sifat
imunostimulan).
Parameter pemantauan
Untuk penggunaan jangka panjang (terutama rheumatoid arthritis,
psoriasis) biopsi hati dasar, diulang pada setiap interval dosis kumulatif
1-1,5 g, harus dilakukan; WBC dan platelet menghitung setiap 4
minggu; CBC dan kreatinin, LFT setiap 3-4 bulan; dada x-ray
referensi Rentang
tingkat terapeutik: Variable; Konsentrasi toksik: Variable; Kisaran terapi
tergantung pada pendekatan terapi.
rejimen dosis tinggi menghasilkan tingkat obat yang antara 0,1-1
mikromol / L 24-72 jam setelah infus obat
Beracun: Terapi dosis rendah:> 0,2 mikromol / L; Terapi dosis tinggi:> 1
mikromol / L
Keperawatan: Pengkajian Fisik / Monitoring
Memonitor jika digunakan di hadapan kondisi yang sudah ada
sebelumnya yang meningkatkan potensi toksisitas (misalnya,
gangguan ginjal, penyakit ulkus peptikum, kolitis ulserativa, gangguan
hati, tulang penekanan sumsum). Menilai potensi interaksi dengan
obat lain farmakologi dan produk herbal pasien dapat menggunakan
(misalnya, NSAIDs dan salisilat atau agen hepatotoksik lainnya, atau
obat yang dapat mempengaruhi tingkat / efek methotrexate).
Mengevaluasi hasil tes laboratorium sebelum terapi dan pada sering
interval selama terapi. Pasien harus dimonitor untuk efek samping
(misalnya, hiper- atau hipotiroidisme, pneumonitis [kering, batuk tidak
produktif], gangguan pencernaan [stomatitis ulseratif, nyeri, perforasi
usus], gagal ginjal [penurunan output urin]). Menilai efektivitas secara
berkala (sesuai dengan tujuan untuk digunakan). Ajarkan penggunaan
pasien yang tepat, efek samping yang mungkin / intervensi yang tepat,
dan gejala yang merugikan melaporkan. Kehamilan faktor risiko X:
Tentukan pasien yang tidak hamil sebelum memulai pengobatan.
Anjurkan pasien usia subur (atau laki-laki yang mungkin memiliki
hubungan dengan wanita usia subur) digunakan sesuai dengan

tindakan kontrasepsi selama terapi dan selama 3 bulan setelah


pengobatan laki-laki atau 1 siklus ovulasi pada wanita.
Monitoring: Tes Lab
Untuk penggunaan jangka panjang (terutama rheumatoid arthritis,
psoriasis) biopsi hati dasar, diulang pada setiap interval dosis kumulatif
1-1,5 g, harus dilakukan; WBC dan platelet menghitung setiap 4
minggu; CBC dan kreatinin, LFT setiap 3-4 bulan; dada x-ray
Pendidikan pasien
Jangan mengambil obat baru selama terapi kecuali disetujui oleh
prescriber. Infus / injeksi: Laporkan segera setiap kemerahan,
pembengkakan, nyeri, atau terbakar di situs infus / injeksi. Hal ini
sangat penting untuk mempertahankan hidrasi yang memadai (2-3 L /
hari cairan) kecuali diperintahkan untuk membatasi asupan cairan dan
nutrisi (sering makan kecil dapat membantu). Hindari alkohol untuk
mencegah efek samping yang serius. Anda akan lebih rentan terhadap
infeksi (menghindari orang banyak dan paparan infeksi dan tidak
memiliki vaksinasi tanpa prescriber konsultasi). Dapat menyebabkan
sensitivitas terhadap sinar matahari (penggunaan tabir surya,
memakai pakaian pelindung, dan kacamata); mual atau muntah
(makanan kecil sering, perawatan mulut sering, mengisap lozenges,
atau mengunyah permen karet dapat membantu, jika belum
terselesaikan, kontak prescriber); mengantuk, pusing, mati rasa, atau
penglihatan kabur (menggunakan hati saat mengemudi atau terlibat
dalam tugas-tugas yang membutuhkan kewaspadaan sampai respon
terhadap obat yang diketahui); kehilangan rambut (mungkin
reversibel); perubahan warna kulit; kemandulan permanen; atau
sariawan (perawatan mulut yang sering dengan lembut sikat gigi atau
kapas penyeka dan sering bilasan dapat membantu). Laporan segera
ruam, kelelahan yang berlebihan atau tidak biasa, atau kesulitan
pernapasan. Laporkan denyut jantung yang cepat atau palpitasi, tinja
berwarna hitam atau ter, demam, menggigil, perdarahan yang tidak
biasa atau memar, sesak napas, gangguan GI yang persisten, diare,
sembelit, nyeri saat buang air kecil atau perubahan pola kemih, atau
efek samping persisten lainnya. Kehamilan / menyusui tindakan
pencegahan: Jangan hamil saat mengambil obat ini. obat ini tidak
boleh digunakan pada trimester 2 atau 3 kehamilan. Konsultasikan
prescriber untuk langkah-langkah kontrasepsi yang tepat jika
diperlukan atau jika Anda mencurigai Anda mungkin hamil. Obat ini
dapat menyebabkan cacat lahir. Jangan menyusui.
Bentuk sediaan
Informasi eksipien disajikan bila tersedia (terbatas, terutama untuk
obat generik); berkonsultasi pelabelan produk tertentu.
Injeksi, bubuk untuk pemulihan [bebas pengawet]: 20 mg, 1 g
Injection, solusi: 25 mg / mL (2 mL, 10 mL) [mengandung benzyl
alcohol]
Injection, solusi [pengawet gratis]: 25 mg / mL (2 mL, 4 mL, 8 mL, 10

mL, 40 mL)
Tablet: 2.5 mg
Trexall ": 5 mg, 7,5 mg, 10 mg, 15 mg
Tablet, natrium [pack dosis] (Rheumatrex Dosis Pack): 2,5 mg (4
kartu dengan 2, 3, 4, 5, atau 6 tablet masing-masing)
generik Tersedia
iya nih
Harga: AS (www.drugstore.com)
Solusi (Methotrexate Sodium)
25 mg / mL (2): $ 8,99
25 mg / mL (2): $ 14,99
25 mg / mL (10): $ 24,99
25 mg / mL (40): $ 58,99
Solusi (Methotrexate Sodium LPF)
25 mg / mL (2): $ 7,99
Tablet (Rheumatrex)
2,5 mg (8): $ 49,99
Tablet (Trexall)
10 mg (30): $ 426,29
Mekanisme aksi
Metotreksat adalah antimetabolit folat yang menghambat sintesis DNA.
Methotrexate ireversibel mengikat dihidrofolat reduktase, menghambat
pembentukan berkurang folat, dan timidilat sintetase, yang
mengakibatkan penghambatan purin dan timidilat sintesis asam.
Metotreksat adalah siklus sel spesifik untuk fase S dari siklus.
MOA dalam pengobatan rheumatoid arthritis tidak diketahui, tetapi
dapat mempengaruhi fungsi kekebalan tubuh. Pada psoriasis,
methotrexate diduga menargetkan cepat berkembang biak sel epitel di
kulit.
Farmakodinamik / Kinetics

melintasi plasenta;