methotrexate

[methotre- (probably shortening and alteration of methylaminopterin, one of its chemical names : METHYL + AMINOPTERIN) + perhaps (O)X(Y)- + -ATE².]

Key Terms: Antimetabolite, Antineoplastic, BCD, Cytotoxic, Hodgkin's lymphoma, Immunosupressant, Leucovorin, Lymphocytic leukemia, Metastatic.

Definition

Methotrexate is a folic acid derivative that interferes with folic acid metabolism (folate antagonist). It is a cytotoxic agent (a chemical that is directly toxic to cells) with multiple characteristics and may be described as an antimetabolite, antineoplastic, and immunosuppressant. In the United States, methotrexate is also recognized by the trade names Folex and Mexate, or the generic name amethopterin.

Purpose

Methotrexate is administered to cancer patients diagnosed with various malignancies. These conditions may include breast cancer, lung cancer, non-metastatic bone cancer, cancers associated with the head and neck, acute lymphocytic leukemia, meningeal leukemia, advanced non-Hodgkin's lymphomas, and uterine tumors. Certain other cancers may be treated with methotrexate as prescribed by the oncologist.

Description

Methotrexate was granted FDA approval in 1986. Methotrexate is a highly effective chemical compound that targets a specific enzyme required by cells for normal function. When this enzyme activity is blocked by methotrexate, certain processes within the cell are shut down and cell death results. The growth of some normal cells may be affected by methotrexate. However, because this is a process associated with actively dividing cells, the accelerated rate at which cancer cells grow and divide make them more susceptible to the effects of methotrexate. Methotrexate may be given as a single agent, often followed by leucovorin rescue. Methotrexate may also be administered in a combination regimen with steroids to produce and maintain rapid remission of certain cancers or as part of an adjuvant therapy regimen with doxorubicin, cisplatin, or the BCD combination of bleomycin, cyclophosphamide, and dactinomycin.

Recommended Dosage

Methotrexate is available is both injectable and tablet form. The injectable form may be given intravenously (IV), intramuscularly (IM), or intrathecal (directly into the spinal fluid). The dose amount varies over a wide range for patients receiving methotrexate. The final dose and treatment cycle will be determined by the oncologist based on what the medication is being used for, what cancer type is being treated, whether methotrexate is being used as a single agent or in concert with other anticancer drugs, and the method by which the medication is being administered. It is extremely important to take methotrexate in the correct timetable prescribed by the oncologist. If a dose is missed, the patient should not take the missed dose at a later time, or double the next prescribed dose. Rather, the patient should maintain the schedule prescribed and notify the oncologist about the missed dose.

Precautions

To maximize treatment effects, patients receiving methotrexate should observe certain guidelines. Including any modifications given by the oncologist, these guidelines should include regular visits with the oncologist and laboratory testing for white blood cell count, kidney, liver, and bone marrow function. Avoid any immunizations not approved or prescribed by the oncologist. Avoid contact with individuals taking or that have recently taken oral polio vaccine, or individuals that have an active infection. When necessary wear a protective facemask. Avoid prolonged or direct exposure to sunlight, as some patients experience an increased sensitivity. Ask for specific instructions on oral hygiene procedures to reduce the risk of gum abrasion, and avoid touching the eye and nasal areas unless hands have been properly washed immediately prior to contact. To reduce bleeding and bruising complications, patients should exercise extreme caution when handling sharp instruments and decline participation in contact sports. Prior to treatment, the patient's medical history should be thoroughly reviewed to avoid complications that might arise from previous conditions such as gout, kidney stones or kidney disease, liver disease, chickenpox, shingles, intestinal blockage, colitis, immunosupression, stomach ulcers, mouth sores, or a history of allergic reactions to various drugs. The oncologist should also be made aware if the patient is pregnant or if there is the possibility the patient might be pregnant, or if the patient is a breast-feeding mother. Only prescribed medications or over the counter (OTC) drugs approved by the oncologist should be taken by a patient receiving methotrexate.

Side Effects

The beneficial effects of methotrexate are usually accompanied by less desirable side effects. Side effects correlate in severity with dose amount and length of treatment. It is important to encourage the patient to discuss any presenting side effects. Some side effects do not require medical attention, but still cause the patient concern. Side effects that fall into this category may include loss of hair (alopecia) and appetite (anorexia), nausea or vomiting, skin rash with itching, pale skin tone, and the appearance of boils or acne. These side effects tend to diminish as the body adjusts to the therapy, or if they become bothersome, the oncologist may prescribe interventions. Side effects that should be reported immediately to the oncologist include mouth sores; back, lower side, joint or stomach pain; fever or chills; headaches; bloody or dark urine; drowsiness; dizziness; black tarry stools; bloody stools or vomit; diarrhea; redness or pinpoint red spots on the skin; swelling of the feet or lower legs; the development of a cough or hoarseness; and shortness of breath.

Interactions

Anti-inflammatory medications should be avoided while the patient is receiving methotrexate. These drugs elevate the effects of methotrexate to potentially harmful levels. Vaccines should be avoided due to the immunosuppression action of methotrexate, and alcohol should be avoided to reduce the risk of liver complications.

—Jane Taylor-Jones, Research Associate, M.S.

Brand names: Rheumatrex®Trexall®

Chemical formula:

Drug Forms:
• Methotrexate injection (below)
• Methotrexate Sodium Oral tablet
• Methotrexate Sodium Solution for injection

Español:
• Inyección de metotrexato
• Metotrexato Sódico, Tableta oral
• MetotrexatoSódico, Solución para inyección

Methotrexate injection

What is methotrexate injection?

METHOTREXATE is a type of chemotherapy that is used to treat certain kinds of cancer and other diseases. Methotrexate affects cells that are rapidly growing such as cancer cells, cells of psoriasis, and cells in your mouth and stomach. Methotrexate is used to treat many different types of cancers including leukemias, lymphoma, breast cancer, and others. Lower dose of methotrexate injections may be given to patients with psoriasis or rheumatoid arthritis. Generic methotrexate injection is available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• If you are HIV-positive or have acquired immunodeficiency syndrome (AIDS)
• If you frequently drink alcohol-containing beverages
• bleeding or blood disorders
• cold sores or previous chickenpox or shingles infection
• gout
• an active infection
• kidney disease, including a history of kidney stones
• liver disease
• lung disease
• recent radiation therapy or sunburn
• stomach or intestinal disease or obstruction
• ulcerative colitis
• an unusual or allergic reaction to methotrexate, other chemotherapy, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

Methotrexate is for injection into a muscle, vein, artery, or the spinal cord. It is usually administered in a hospital or clinic setting by a health care professional. The dose of methotrexate, how often it will be given, and how it will be given may be different depending upon your disease and other medicines you are taking. If you have questions about the proper dose of your medicine, ask your prescriber or other health care professional.

What if I miss a dose?

What drug(s) may interact with methotrexate?

• anti-inflammatory drugs (NSAIDs, such as ibuprofen)
• antibiotics and other medicines for infections
• aspirin and aspirin-like medicines including bismuth subsalicylate (e.g. Pepto-Bismol®)
• cholestyramine
• dapsone
• leucovorin
• medicines for diabetes
• pemetrexed
• phenytoin or fosphenytoin
• probenecid
• pyrimethamine
• trimetrexate
• vaccines

Tell your prescriber or health care professional about all other medicines that you are taking, including nonprescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking methotrexate injection?

Visit your prescriber or health care professional for checks on your progress. You will need to have regular blood checks. The side effects of methotrexate can continue after you finish your treatment; report side effects promptly. It may take several weeks before you see an improvement in your rheumatoid arthritis or psoriasis.

Avoid alcohol-containing beverages while taking methotrexate. Methotrexate therapy for rheumatoid arthritis and psoriasis may cause damage to your liver. Your prescriber or health care professional will closely monitor your liver function while you are taking methotrexate. You may need to have a liver sample (a biopsy) taken before you receive methotrexate and during your therapy for rheumatoid arthritis or psoriasis.

Methotrexate may decrease your body's ability to fight infections. Call your prescriber or health care professional if you have a fever, chills, sore throat or other symptoms of a cold or flu. Do not treat these symptoms yourself. Try to avoid being around people who are sick. Methotrexate may increase your risk to bruise or bleed at higher doses used to treat cancer. Call your prescriber or health care professional if you notice any unusual bleeding. Be careful not to cut, bruise or injure yourself because you may get an infection and bleed more than usual.

Methotrexate may harm your unborn baby. You should contact your prescriber immediately if you believe or suspect you or your partner have become pregnant while you are taking methotrexate. Both men and women must use effective birth control continuously while taking methotrexate. It is recommended that you use 2 reliable forms of contraception together. Men should continue to use contraception for at least 3 months after stopping methotrexate therapy. Women should continue to use contraception until after their first normal menstrual cycle after stopping methotrexate therapy.

Call your prescriber or health care professional if you get diarrhea or mouth sores. Do not treat yourself.

Be careful brushing and flossing your teeth or using a toothpick while receiving methotrexate because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are received methotrexate.

Drink several glasses of water a day. This will help to reduce possible kidney problems.

If you are going to have surgery, tell your prescriber or health care professional that you are taking methotrexate.

Methotrexate may cause you to more sensitive to the sun. Also methotrexate may cause a previous sunburn or radiation therapy reaction to reappear. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.

What side effects may I notice from receiving methotrexate injection?

Side effects will vary depending on the condition for which you are being treated, the dose, how the dose was given, and the length of time you are taking methotrexate. If you want more information on possible side effects ask your prescriber or health care professional to discuss this with you.

Side effects that you should report to your prescriber or health care professional as soon as possible:
• changes in vision
• confusion
• diarrhea
• difficulty breathing, a non-productive cough
• difficulty walking
• headache
• mouth or throat sores or ulcers
• redness, blistering, peeling or loosening of the skin, including inside the mouth
• seizures
• skin rash, hives, or itching
• symptoms of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• symptoms of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
• symptoms of decreased red blood cells (anemia) - unusual weakness or tiredness, fainting spells, lightheadedness
• vomiting
• yellow coloring of skin or eyes

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• eye irritation
• hair loss
• increased sensitivity to sun and ultraviolet light
• loss of appetite
• nausea

Where can I keep my medicine?

Methotrexate injection will be given in a hospital or clinic setting. You will not need to take or store this medicine at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

A folic acid antagonist used as an antineoplastic agent.

"Amethopterin" redirects here. Not to be confused with aminopterin.

This article needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (October 2008)

Methotrexate
Systematic (IUPAC) name
(2S)-2-[(4-{[(2,4-diamino-7,8-dihydropteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
Identifiers
CAS number	59-05-2
ATC code	L01BA01 L04AX03
PubChem	126941
DrugBank	APRD00353
ChemSpider	112728
Chemical data
Formula	C20H22N8O5
Mol. mass	454.44 g/mol
Pharmacokinetic data
Bioavailability	17–90%
Metabolism	hepatic
Half life	3–15 hours (dose dependent)
Excretion	renal 48–100%
Therapeutic considerations
Pregnancy cat.	D(AU) X(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	oral, IV, IM, SC, intrathecal
Y(what is this?)  (verify)

Methotrexate (rINN) (pronounced /mɛθɵˈtrɛkseɪt/), abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other.

Contents 1 Mode of action 2 Uses 2.1 In cancer chemotherapy 2.2 Medical termination of pregnancy 2.3 Other uses 3 Pharmacokinetics 4 Administration 5 Adverse effects 5.1 Most frequent 5.2 Other frequent 5.3 Other rarer reactions 5.4 Alimentary System 5.5 Blood/Lymphatic System 5.6 Cardiovascular System 5.7 Central Nervous System 5.8 Hepatobiliary System 5.9 Immune System (Infections) 5.10 Musculoskeletal System 5.11 Ophthalmic 5.12 Respiratory System 5.13 Dermatologic 5.14 Urogenital System 6 References 7 External links

Mode of action

Methotrexate competitively and irreversibly inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

The similar structure of folic acid and methotrexate indicates methotrexate as a competitive inhibitor

Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well as causing the side effects listed above.

Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis, Crohn's disease, and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.^[1]

Uses

In cancer chemotherapy

Methotrexate was originally used as part of combination chemotherapy regimens to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia.

Medical termination of pregnancy

Methotrexate is commonly used (generally in combination with misoprostol) to terminate early pregnancies (i.e. as an abortifacient). It is also used to treat ectopic pregnancies. In the case of early missed miscarriage (particularly a blighted ovum), in which fetal demise has occurred but the body has not expelled the fetus, methotrexate may be used to help the body begin the miscarriage process.

Other uses

It has come into use as a treatment for some autoimmune diseases, including Myasthenia Gravis, polymyositis, dermatomyositis, inclusion body myositis, ankylosing spondylitis, Crohn's disease, psoriasis, pustular psoriasis, psoriatic arthritis, rheumatoid arthritis, Wegener's granulomatosis, and scleroderma (see disease-modifying antirheumatic drugs). A parallel use with TNFα blockers such as infliximab or etanercept has been shown to markedly improve symptoms.^[2]

It is also sometimes used to treat a rare condition called Behçet's disease where it is taken weekly, along with folic acid daily. In the case of immune disorders, such as Behçet's disease and rheumatoid disorders, the clinical goal of the low dose methotrexate regimen is to inhibit AICAR transformylase, which leads to increased AICA ribose (AICAR transformylase's substrate). The AICA ribose inhibits adenosine deaminase, resulting in a build-up of extracellular adenosine. Extracellular adenosine inhibits the expression of IL-2 receptors on circulating T-lymphocytes, causing a suppression of the immune system, and thus ameliorating the effects of the immune disorder.

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with pKa 4.8 and 5.5, and thus it is mostly ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/M2 having 42% bioavailability and doses greater than 40 mg/M2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.

Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) and accounts for less than 5% loss of the oral dose.

Factors that decrease absorption include food, oral non-absorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the gastrointestinal tract (GI) tract such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption. Methotrexate is also administered in the placenta accreta, inhibiting the blood circulation to the target site.

Administration

It can be taken orally or administered by injection (subcutaneous, intramuscular, intravenous or intrathecal). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects. (People taking this medicine must get appropriate tests done every 6 weeks in hospital, especially (older people) to make sure no potentially fatal damage is being done to blood cells and immune system)

Adverse effects

Possible side effects can include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea. A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign.

The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used).

Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate. There have also been some reports of central nervous system reactions to methotrexate especially when given via the intrathecal route which include myelopathies and leucoencephalopathies.

Generally, the more "non-specific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has like all "cell toxic" substances a broad array of possible adverse effects. Care shall always be taken to read the manufacturer's original instructions for the preparation in question.

Here is a more thorough list of potential side effects for Methotrexate:

Most frequent

Ulcerative stomatitis, leukopenia, nausea, abdominal distress.

Other frequent

Malaise, undue fatigue, chills and fever, dizziness and lowered resistance to infection.

Other rarer reactions

(related to or attributed to Methotrexate) nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, osteonecrosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, anaphylactoid reactions.

By organ system:

Alimentary System

Anorexia, nausea, vomiting, diarrhea; Gingivitis, pharyngitis, stomatitis, hematemesis, melena, gastrointestinal ulceration/bleeding, enteritis, pancreatitis.

Blood/Lymphatic System

Anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy and lymphoproliferative disorders. Hypogammaglobulinemia.

Cardiovascular System

Pericarditis, pericardial effusion, hypotension, thromboembolic events (cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus.

Central Nervous System

Headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions. Occasional reports of transient subtle cognitive dysfunction, mood alteration (depression), unusual cranial sensations, leukoencephalopathy, encephalopathy.

Hepatobiliary System

Hepatotoxicity, acute hepatitis, chronic fibrosis/cirrhosis, decrease in serum albumin, liver enzyme elevations.

Immune System (Infections)

Fatal opportunistic infections (Pneumocystis carinii pneumonia, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis and disseminated Herpes simplex).

Musculoskeletal System

Stress fracture.

Ophthalmic

Conjunctivitis, serious visual changes (without known cause).

Respiratory System

Respiratory fibrosis, respiratory failure, interstitial pneumonitis, and chronic interstitial obstructive pulmonary disease. Dry cough possibly being a symptom of these aforementioned conditions.

Dermatologic

Acne, rashes (Erythematous rashes), pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration and exfoliative dermatitis.

Urogenital System

Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.^[3]

References

1. ^ Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H; (2005). "The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules". Clin Immunol. 114 (Feb.): 154–163. doi:10.1016/j.clim.2004.09.001. PMID 15639649. 
2. ^ Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M (2004). "Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial". Lancet 363 (9410): 675–81. doi:10.1016/S0140-6736(04)15640-7. PMID 15001324. 
3. ^ http://www.drugs.com/sfx/methotrexate-side-effects.html

External links

• National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
• Chembank entry on methotrexate
• Methotrexate general article from NIH
• Methotrexate Injection MedlinePlus article from NIH
• High Dose Methorexate as a potential treatment for Glioblastoma
• Patient Education - Methotrexate from American College of Rheumatology
• Methotrexate-resistant mutants of human dihydrofolate reductase for use as a selection marker in gene therapyas seen on Flintbox

v • d • e Intracellular chemotherapeutic agents/antineoplastic agents (L01) SPs/MIs (M phase) Block microtubule assembly Vinca alkaloids (Vinblastine, Vincristine, Vinflunine, Vindesine, Vinorelbine) Block microtubule disassembly Taxanes (Docetaxel, Larotaxel, Ortataxel, Paclitaxel, Tesetaxel) · Epothilones (Ixabepilone) DNA replication inhibitor DNA precursors/ antimetabolites (S phase) Folic acid dihydrofolate reductase inhibitor (Aminopterin, Methotrexate, Pemetrexed) · thymidylate synthase inhibitor (Raltitrexed, Pemetrexed) Purine adenosine deaminase inhibitor (Pentostatin) halogenated/ribonucleotide reductase inhibitors (Cladribine, Clofarabine, Fludarabine) thiopurine (Thioguanine, Mercaptopurine) Pyrimidine thymidylate synthase inhibitor (Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine) DNA polymerase inhibitor (Cytarabine) ribonucleotide reductase inhibitor (Gemcitabine) hypomethylating agent (Azacitidine, Decitabine) Deoxyribonucleotide ribonucleotide reductase inhibitor (Hydroxyurea) Topoisomerase inhibitors (S phase) I Camptotheca (Camptothecin, Topotecan, Irinotecan, Rubitecan, Belotecan) II Podophyllum (Etoposide, Teniposide) II+Intercalation Anthracyclines (Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin) · Anthracenediones (Mitoxantrone, Pixantrone) Crosslinking of DNA (CCNS) Alkylating Nitrogen mustards: Mechlorethamine · Cyclophosphamide (Ifosfamide, Trofosfamide) · Chlorambucil (Melphalan, Prednimustine) · Bendamustine · Uramustine · Estramustine Nitrosoureas: Carmustine · Lomustine (Semustine) · Fotemustine · Nimustine · Ranimustine · Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan, Treosulfan) Aziridines: Carboquone · ThioTEPA · Triaziquone · Triethylenemelamine Alkylating-like Platinum (Carboplatin, Cisplatin, Nedaplatin, Oxaliplatin, Triplatin tetranitrate, Satraplatin) Nonclassical Hydrazines (Procarbazine) · Triazenes (Dacarbazine, Temozolomide) · Altretamine · Mitobronitol Intercalation Streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin) Photosensitizers/PDT Aminolevulinic acid/Methyl aminolevulinate · Efaproxiral · Porphyrin derivatives (Porfimer sodium, Talaporfin, Temoporfin, Verteporfin) Other Enzyme inhibitors FI (Tipifarnib)  · CDK inhibitors (Alvocidib, Seliciclib) · PrI (Bortezomib) · PhI (Anagrelide) · IMPDI (Tiazofurine) · LI (Masoprocol) · PARP inhibitor (Olaparib) Receptor antagonists ERA (Atrasentan) · retinoid X receptor (Bexarotene) · sex steroid (Testolactone) Other/ungrouped Amsacrine · Trabectedin · retinoids (Alitretinoin, Tretinoin) · Arsenic trioxide · asparagine depleter (Asparaginase/Pegaspargase) · Celecoxib · Demecolcine · Elesclomol · Elsamitrucin · Etoglucid · Lonidamine · Lucanthone · Mitoguazone · Mitotane · Oblimersen · Temsirolimus · Vorinostat

v • d • e Immunomodulators: Immunosuppressive drugs / Immunosuppressants (L04) Intracellular (signal initiation) Antimetabolites purine synthesis inhibitor: Azathioprine · Mycophenolic acid pyrimidine synthesis inhibitor: Leflunomide · Teriflunomide antifolate: Methotrexate Macrolides/ other IL-2 inhibitors FKBP/Cyclophilin/Calcineurin: Tacrolimus · Ciclosporin · Pimecrolimus Abetimus · Gusperimus TNF-α inhibitor Thalidomide · Lenalidomide Intracellular (signal reception) IL-1 receptor antagonists Anakinra mTOR Sirolimus · Deforolimus · Everolimus · Temsirolimus · Zotarolimus Extracellular Antibodies Monoclonal Serum target (noncellular) Complement component 5 (Eculizumab) · TNFs (Infliximab, Adalimumab, Certolizumab pegol, Afelimomab, Golimumab) · Interleukin 5 (Mepolizumab) · Immunoglobulin E (Omalizumab)  · BAYX (Nerelimomab) Interferon (Faralimomab) IL-6 (Elsilimomab) IL-12 and IL-13 (Lebrikizumab, Ustekinumab) Cellular target CD3 (Muromonab-CD3, Otelixizumab, Teplizumab, Visilizumab) · CD4 (Clenoliximab, Keliximab, Zanolimumab) · CD11a (Efalizumab) · CD18 (Erlizumab) · CD20 (Afutuzumab, Ocrelizumab, Pascolizumab) · CD23 (Lumiliximab) · CD40 (Teneliximab, Toralizumab) · CD62L/L-selectin (Aselizumab) · CD80 (Galiximab) · CD147/Basigin (Gavilimomab, Ziralimumab) · CD154 (Ruplizumab) BLyS (Belimumab)  · CTLA-4 (Ipilimumab, Tremelimumab) · CAT (Bertilimumab, Lerdelimumab, Metelimumab) · Integrin (Natalizumab) · Interleukin-6 receptor (Tocilizumab) · LFA-1 (Odulimomab) IL-2 receptor/CD25 (Basiliximab, Daclizumab, Inolimomab) T-lymphocyte (Zolimomab aritox) Unsorted Atorolimumab, Cedelizumab, Dorlimomab aritox, Dorlixizumab, Fontolizumab, Gantenerumab, Gomiliximab, Maslimomab, Morolimumab, Pexelizumab, Reslizumab, Rovelizumab, Siplizumab, Talizumab, Telimomab aritox, Vapaliximab, Vepalimomab Polyclonal Anti-thymocyte globulin · Anti-lymphocyte globulin -cept (Fusion protein) CTLA-4 (Abatacept, Belatacept) · Aflibercept · Alefacept · Rilonacept · TNF inhibitor (Etanercept)

v • d • e Specific antirheumatic products / DMARDs (M01C) Quinolines Oxycinchophen Gold preparations Sodium aurothiomalate · Sodium aurothiosulfate · Auranofin · Aurothioglucose · Aurotioprol Other Penicillamine #/Bucillamine · Chloroquine #/Hydroxychloroquine · Leflunomide · Sulfasalazine #  · antifolate (Methotrexate #)  · thiopurine (Azathioprine) # #WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III

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