METHOTREXATE- methotrexate tablet
Accord Healthcare Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use METHOTREXATE TABLETS safely and effectively. See full prescribing information for METHOTREXATE TABLETS.
METHOTREXATE tablets, for oral use
Initial U.S. Approval: 1953
FULL PRESCRIBING INFORMATION: CONTENTS*
Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed.
For patients prescribed a once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death.
The following clinically significant adverse reactions are described elsewhere in the labeling:
Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.
The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n=128) with rheumatoid arthritis are listed below. Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received corticosteroids. Hepatic histology was not examined in these short-term studies.
Incidence ≥10%: Elevated liver tests 15%, nausea/vomiting 10%
Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count < 100,000/mm 3)
Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count < 3000/mm 3), pancytopenia, dizziness
Two other controlled trials of patients (n=680) with rheumatoid arthritis who received methotrexate 7.5 mg to 15 mg orally once weekly showed the following serious adverse reaction:
Incidence 1%: Interstitial pneumonitis
Other less common adverse reactions were: anemia, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge.
Polyarticular Juvenile Idiopathic Arthritis (pJIA)
The most common adverse reactions reported in patients 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m 2 to 20 mg/m 2 orally once weekly or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver tests 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea) 11%; stomatitis 2%; leukopenia 2%; headache 1.2%; alopecia 0.5%; dizziness 0.2%; rash 0.2%. Most patients received concomitant NSAIDs and some also received corticosteroids.
In two published series of adults with psoriasis (n=204, 248) who received methotrexate up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with rheumatoid arthritis, except for alopecia, photosensitivity, and “burning of skin lesions” (3% to 10% each). Painful plaque erosions have been reported.
The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure
Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death
Eye: Optic neuropathy, blurred vision, ocular pain, conjunctivitis, xerophthalmia
Gastrointestinal: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration
Hematology: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia Hepatobiliary: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis Immune system: Anaphylaxis, anaphylactoid reactions, vasculitis Metabolism: Hyperglycemia
Musculoskeletal: Stress fracture, soft tissue and bone necrosis, arthralgia, myalgia, osteoporosis
Nervous system: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, and convulsions.
Renal: Azotemia, hematuria, proteinuria, cystitis
Reproductive: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction
Respiratory: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis
Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis
Drugs that Increase Methotrexate Exposure
Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.
If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with:
Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.
Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions ( 5.10)].
Methotrexate Tablets is contraindicated in pregnant women with non-neoplastic diseases [see Contraindications ( 4)] .
Based on published reports and its mechanism of action [see Clinical Pharmacology ( 12.1)] , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with non-autoimmune disease (17%; 95% CI: 13, 23). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI: 0.6, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
Limited published literature report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, instruct women not to breastfeed during treatment with Methotrexate Tablets and for 1 week after the final dose.
Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [Use in Specific Populations ( 8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Methotrexate Tablets and for 6 months after the final dose.
Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with Methotrexate Tablets and for
3 months after the final dose.
Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with Methotrexate Tablets and after the final dose. It is not known if the infertility may be reversed in all affected females.
Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with Methotrexate Tablets and after the final dose. It is not known if the infertility may be reversed in all affected males.
The safety and effectiveness of Methotrexate Tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage ( 1), Dosage and Administration ( 2)]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions ( 6.1)].
The safety and effectiveness of Methotrexate Tablets have not been established in pediatric patients for the other indications [see Indications and Usage ( 1)].
Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology ( 12.3)]. Patients with renal impairment are at increased risk for methotrexate adverse reactions. Closely monitor patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, Cockcroft-Gault] for adverse reactions. Reduce the dosage or discontinue Methotrexate Tablets as appropriate [see Warnings and Precautions ( 5.8)].
The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reactions based on the elimination characteristics of methotrexate [see Clinical Pharmacology ( 12.3)]. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue Methotrexate Tablets as appropriate [see Warnings and Precautions ( 5.5)].
Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions ( 5.9)].
Manifestations of methotrexate overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported.
Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy. Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information.
Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional dosage information.
Administer concomitant hydration and urinary alkalinization.
Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, methotrexate has been effectively cleared with acute, intermittent hemodialysis using a high-flux dialyzer.
Methotrexate is dihydrofolate reductase inhibitor with the chemical name of N-[4-[[(2,4 diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L glutamic acid. The molecular formula is C
5 and the molecular weight is 454.4 g/mol. The structural formula is:
Methotrexate Tablets, USP for oral use is available in bottles of 36 and 100 tablets. Each methotrexate tablet contains 2.5 mg methotrexate equivalent to 2.74 mg methotrexate sodium and the following inactive ingredients: Lactose Anhydrous, Magnesium Stearate and Pregelatinized Starch.
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.
The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.
At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized.
Effect of Food
Food has been shown to delay absorption and reduce peak concentration.
Methotrexate in serum is approximately 50% protein bound.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.
The elimination half-life of methotrexate is approximately 3 to 10 hours.
Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors.
Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg.
Methotrexate is partially metabolized by intestinal flora after oral administration.
Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate.
Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration.
Biliary excretion accounts for ≤10% of the methotrexate dose.
The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown.
In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (C max 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) was 20-fold. The time to peak concentration (T max 0.67 to 4 hours after a 15 mg/m 2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses.
In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m
2/week to 11.2 mg/m
2/week, mean serum concentrations were
0.59 micromolar (0.03 to 1.40) at 1 hour, 0.44 micromolar (0.01 to 1.00) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours.
In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2) or for JIA (3.75 mg/m 2 to 26.2 mg/m 2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively.
Patients with Renal impairment
The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.
Methotrexate Tablets, USP contain an amount of methotrexate sodium equivalent to 2.5 mg of methotrexate, USP and are pale yellow to yellow, round shaped, biconvex, uncoated tablets, debossed on one side HZ” and “1” on either side of the score line and plain on other side.
36 count bottle NDC 16729-486-36
100 count bottle NDC 16729-486-01
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
Methotrexate Tablets is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise patients and their caregivers of the potential risk of hypersensitivity and that Methotrexate Tablets is contraindicated in patients with a history of hypersensitivity reactions to methotrexate. Instruct patients to seek immediate medical attention for signs of a hypersensitivity reaction [see Warnings and Precautions ( 5.2)].
Myelosuppression and Serious Infections
Inform patients and their caregivers that Methotrexate Tablets can cause myelosuppression and the need for frequent monitoring of blood cell counts. Advise patients and their caregivers to immediately report new onset fever, symptoms of infection, easy bruising or persistent bleeding to their healthcare provider [see Warnings and Precautions ( 5.3, 5.11)].
Advise patients and their caregivers to report new or worsening diarrhea, vomiting, or stomatitis to their healthcare provider. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions ( 5.4)].
Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions ( 5.5)].
Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see Warnings and Precautions ( 5.6)].
Advise patients and their caregivers that Methotrexate Tablets can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients and their caregivers to avoid excessive sun exposure and use sun protection measures [see Warnings and Precautions ( 5.7)].
Advise patients and their caregivers to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions ( 5.8)].
Risk of Serious Adverse Reactions with Medication Error
For patients who are prescribed a once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as a single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see Warnings and Precautions ( 5.9)].
Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions ( 5.12)].
Advise patients on the risk of second primary malignancies during treatment with Methotrexate Tablets [see Warnings and Precautions ( 5.13)].
Instruct women not to breastfeed during treatment with Methotrexate Tablets and for 1 week after the final dose [see Use in Specific Populations ( 8.2)].
Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions ( 7)].
For more information, go to www.accordhealthcare.us or call Accord Healthcare Inc. at 1-866-941-7875.
Accord Healthcare, Inc.,
1009 Slater Road,
Durham, NC 27703,
Intas Pharmaceuticals Limited,
Plot No 5 to 14 Pharmez,
Sarkhej-Bavla, National Highway No 8-A,
Near Village Matoda, Tal Sanand,
Ahmedabad – 382 213, Gujarat,
51 3344 1 726884
Issued August 2021
Methotrexate (meth oh trex ate)
|What is the most important information I should know about Methotrexate?
Methotrexate can cause serious side effects that may be severe and lead to death, including:
Harm to an unborn baby, including birth defects or death of an unborn baby.
Females who can become pregnant:
o Use effective birth control during treatment and for 3 months after your final dose of Methotrexate.
Tell your healthcare provider right away if your female partner becomes pregnant during treatment with Methotrexate.
Severe allergic reactions. Severe allergic reactions can happen with Methotrexate. Signs and symptoms of a severe allergic reaction may include:
|Do not take Methotrexate if you have had a severe allergic reaction to Methotrexate in the past.
Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction listed above.
Decreased blood cell counts. Methotrexate can affect your bone marrow and cause decreases in red blood counts, white blood cell counts, and platelets that can be severe and life-threatening.
Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools.
Liver problems. Methotrexate can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death.
|Lung problems. Lung problems can happen suddenly (acute) with Methotrexate or they can develop over a long period- of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death.
Tell your healthcare provider if you have any new or worsening symptoms including: cough (especially a dry cough), fever, or trouble breathing.
Severe skin reactions. Severe skin reactions can happen with Methotrexate and can lead to death.
Tell your healthcare provider right away about any new or worsening skin rash during treatment with Methotrexate.
Kidney problems. Kidney problems can happen with Methotrexate, including kidney failure which can happen suddenly (acute) and may not go away (irreversible).
Your healthcare provider will check your kidney function before you start and during treatment with Methotrexate.
Tell your healthcare provider right away if you have any signs or symptoms of kidney problems, including:
See “What are the possible side effects of Methotrexate” for more information about side effects.
|What is Methotrexate?
Methotrexate is a prescription medicine used:
It is not known if Methotrexate is safe in people with liver problems.
|Do not take Methotrexate if you:
|Before taking Methotrexate tell your healthcare provider about all of your medical conditions, including if you:
How should I take Methotrexate?
|What are the possible side effects of Methotrexate?
Methotrexate can cause serious side effects that may be severe and lead to death including:
|How should I store Methotrexate tablets?
|General information about the safe and effective use of Methotrexate.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use methotrexate for a condition for which it was not prescribed. Do not give methotrexate to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about methotrexate. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about methotrexate that is written for healthcare professionals.
For additional information, please contact www.accordhealthcare.us or call Accord Healthcare Inc. at 1-866-941-7875.
|What are the ingredients in Methotrexate?
Active Ingredient: methotrexate sodium
Inactive Ingredients: lactose anhydrous, magnesium stearate and pregelatinized starch.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Accord Healthcare, Inc.,
1009 Slater Road,
Durham, NC 27703,
Intas Pharmaceuticals Limited,
Plot No 5 to 14 Pharmez,
Sarkhej-Bavla, National Highway No 8-A,
Near Village Matoda, Tal Sanand,
Ahmedabad – 382 213, Gujarat,
51 3344 1 726884
Issued August 2021
|Labeler - Accord Healthcare Inc. (604222237)|
|Intas Pharmaceuticals Limited||915837971||manufacture(16729-486) , analysis(16729-486)|