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Rheumatrex Dose Pack

Name: Rheumatrex Dose Pack drug & pharmaceuticals. Available Forms, Doses, Prices
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Published: 2021-11-11T10:10:10+00:00

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Rheumatrex Dose Pack uses

Rheumatrex Dose Pack consists of Methotrexate, Methotrexate Sodium.

Methotrexate:

Warning: severe toxic reactions, including embryo-fetal toxicity
Indications and usage
Dosage and administration
Dosage forms and strengths
Contraindications
Warnings and precautions
Adverse reactions
Drug interactions
Use in specific populations
Overdosage
Description
Rheumatrex Dose Pack (Methotrexate) reviews

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

Rheumatrex Dose Pack (Methotrexate) can cause the following severe or fatal adverse reactions.

Monitor closely and modify dose or discontinue Rheumatrex Dose Pack (Methotrexate) as appropriate.

Bone marrow suppression
Serious infections
Renal toxicity and increased toxicity with renal impairment
Gastrointestinal toxicity
Hepatic toxicity
Pulmonary toxicity
Hypersensitivity and dermatologic reactions
Rheumatrex Dose Pack (Methotrexate) can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate) to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with Rheumatrex Dose Pack (Methotrexate) .

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

Rheumatrex Dose Pack (Methotrexate) can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression (5.1), infection (5.2), renal (5.3), gastrointestinal (5.4), hepatic (5.5), pulmonary (5.6), hypersensitivity and dermatologic (5.7).
Rheumatrex Dose Pack (Methotrexate) can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate) to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with Rheumatrex Dose Pack (Methotrexate) (5.9, 8.1, 8.3).

1 INDICATIONS AND USAGE

Rheumatrex Dose Pack is a folate analog metabolic inhibitor indicated for the:

Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen (1.1)
Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy (1.2)

1.1 Acute Lymphoblastic Leukemia

Rheumatrex Dose Pack (Methotrexate) is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

1.2 Polyarticular Juvenile Idiopathic Arthritis

Rheumatrex Dose Pack (Methotrexate) is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

2 DOSAGE AND ADMINISTRATION

Use another formulation of Rheumatrex Dose Pack for patients requiring dosing via routes of administration other than oral (2.1).
Measure with an accurate measuring device (2.1).

Recommended

Dosage:

ALL: 20 mg/m² one time weekly (2.2)
pJIA: Starting dose of 10 mg/m² one time weekly (2.3)

2.1 Important Administration Information

Rheumatrex Dose Pack (Methotrexate) is intended for oral use only. Use another formulation of Rheumatrex Dose Pack (Methotrexate) for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

It is important that Rheumatrex Dose Pack (Methotrexate) be measured with an accurate measuring device . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

2.2 Acute Lymphoblastic Leukemia

The recommended starting dose of Rheumatrex Dose Pack, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m² given one time weekly. After initiating Rheumatrex Dose Pack (Methotrexate), continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.

2.3 Polyarticular Juvenile Idiopathic Arthritis

The recommended starting dose of Rheumatrex Dose Pack (Methotrexate) is 10 mg/m² given one time weekly.

Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m²/week in pediatric patients, doses greater than 20 mg/m²/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m²/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if Rheumatrex Dose Pack (Methotrexate) is administered by an alternative route using another formulation.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Certain side effects such as mouth sores may be reduced by folate supplementation with Rheumatrex Dose Pack (Methotrexate) in pJIA.

2.4 Evaluations Prior to Starting Rheumatrex Dose Pack

Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with Rheumatrex Dose Pack (Methotrexate) [see Warnings and Precautions (5.1, 5.3, 5.5, 5.7, 5.14 )]. Exclude pregnancy in females of reproductive potential before starting Rheumatrex Dose Pack (Methotrexate) .

2.5 Handling Information

Rheumatrex Dose Pack (Methotrexate) is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

3 DOSAGE FORMS AND STRENGTHS

Rheumatrex Dose Pack (Methotrexate) is a clear yellow to orange oral solution that contains 2.5 mg of Rheumatrex Dose Pack (Methotrexate) per milliliter.

Oral solution: 2.5 mg/mL (3)

4 CONTRAINDICATIONS

Rheumatrex Dose Pack (Methotrexate) is contraindicated in the following:

Pregnancy in patients with non-malignant diseases. Rheumatrex Dose Pack (Methotrexate) can cause embryo-fetal toxicity and fetal death when administered during pregnancy .
Patients with severe hypersensitivity to Rheumatrex Dose Pack (Methotrexate) .

Pregnancy (patients with pJIA) (4)
Severe hypersensitivity to Rheumatrex Dose Pack (Methotrexate) (4)

5 WARNINGS AND PRECAUTIONS

Secondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue Rheumatrex Dose Pack before starting treatment for lymphoma (5.8).
Immunizations may be ineffective (5.10).
Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).

5.1 Bone Marrow Suppression

Rheumatrex Dose Pack (Methotrexate) suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.

Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of bone marrow suppression. Provide supportive care and modify dose or discontinue Rheumatrex Dose Pack (Methotrexate) as needed.

5.2 Serious Infections

Patients treated with Rheumatrex Dose Pack are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections.

Monitor patients for the signs and symptoms of infection during and after treatment with Rheumatrex Dose Pack (Methotrexate) and treat promptly. Consider dose modification or discontinuation of Rheumatrex Dose Pack (Methotrexate) in patients who develop serious infections .

5.3 Renal Toxicity and Increased Toxicity with Renal Impairment

Rheumatrex Dose Pack (Methotrexate) can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.

Consider administration of glucarpidase in patients with toxic plasma Rheumatrex Dose Pack (Methotrexate) concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function .

5.4 Gastrointestinal Toxicity

Rheumatrex Dose Pack can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.

Interrupt or discontinue Rheumatrex Dose Pack (Methotrexate) and institute appropriate supportive care as needed.

Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of Rheumatrex Dose Pack (Methotrexate) (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) .

5.5 Hepatic Toxicity

Rheumatrex Dose Pack (Methotrexate) can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of Rheumatrex Dose Pack (Methotrexate) in patients with chronic liver disease.

Assess liver function prior to initiating Rheumatrex Dose Pack (Methotrexate) and monitor liver function tests during treatment. Interrupt or discontinue Rheumatrex Dose Pack (Methotrexate) as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.

Other risk factors for hepatotoxicity include alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of inheritable liver disease, persistent abnormal liver chemistry findings, duration of therapy, and advanced age.

5.6 Pulmonary Toxicity

Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and interrupt or discontinue Rheumatrex Dose Pack as appropriate.

5.7 Hypersensitivity and Dermatologic Reactions

Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with Rheumatrex Dose Pack (Methotrexate). Discontinue Rheumatrex Dose Pack (Methotrexate) if severe dermatologic reactions occur.

Anaphylaxis can occur with Rheumatrex Dose Pack (Methotrexate). If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Rheumatrex Dose Pack (Methotrexate) and institute appropriate therapy. Rheumatrex Dose Pack (Methotrexate) is contraindicated for use in patients with a history of severe hypersensitivity.

Radiation dermatitis and sunburn may be “recalled” by the use of Rheumatrex Dose Pack (Methotrexate).

5.8 Secondary Malignancies

Secondary malignancies can occur at all dose levels of Rheumatrex Dose Pack.

There have been instances of lymphoproliferative disease associated with low-dose oral Rheumatrex Dose Pack (Methotrexate) which have regressed completely following withdrawal of Rheumatrex Dose Pack (Methotrexate) without institution of antineoplastic therapy. Discontinue Rheumatrex Dose Pack (Methotrexate) first and institute appropriate treatment if the lymphoma does not regress.

5.9 Embryo-Fetal Toxicity

Based on published reports and methotrexate’s mechanism of action, Rheumatrex Dose Pack (Methotrexate) can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, Rheumatrex Dose Pack (Methotrexate) is contraindicated. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate) to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final Rheumatrex Dose Pack (Methotrexate) dose .

5.10 Ineffective Immunization and Risks Associated with Live Vaccines

Immunization may be ineffective when given during Rheumatrex Dose Pack therapy.

Immunization with live virus vaccines is not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving Rheumatrex Dose Pack (Methotrexate) therapy.

5.11 Effects on Reproduction

Based on published reports, Rheumatrex Dose Pack (Methotrexate) can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients .

5.12 Increased Toxicity Due to ThirdSpace Accumulation

Rheumatrex Dose Pack can exit slowly from third‑space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Rheumatrex Dose Pack (Methotrexate) administration .

5.13 Soft Tissue and Bone Toxicity with Radiation Therapy

Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with Rheumatrex Dose Pack (Methotrexate).

5.14 Laboratory Tests

Closely monitor patients undergoing Rheumatrex Dose Pack therapy so that toxic effects are detected promptly. In general, monitoring of the following parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1, 5.3, 5.5)].

Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated Rheumatrex Dose Pack (Methotrexate) blood levels (e.g., dehydration).

Liver Function Tests

Transient liver function test abnormalities are observed frequently after Rheumatrex Dose Pack (Methotrexate) administration and are usually not cause for modification of Rheumatrex Dose Pack (Methotrexate) therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation .

Pulmonary Function Tests

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available .

5.15 Risk of Improper Dosing

Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

Advise patients to measure Rheumatrex Dose Pack (Methotrexate) with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

Bone Marrow Suppression
Serious Infections
Renal Toxicity and Increased Toxicity with Renal Impairment
Gastrointestinal Toxicity
Hepatic Toxicity
Pulmonary Toxicity
Hypersensitivity and Dermatologic Reactions
Secondary Malignancies
Ineffective Immunization and Risks Associated with Live Vaccines
Infertility
Increased Toxicity Due to Third‑Space Accumulation
Soft Tissue and Bone Toxicity with Radiation Therapy

Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests. Other frequently reported adverse reactions are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection (6).

To report SUSPECTED ADVERSE REACTIONS, contact Silvergate Pharmaceuticals at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials 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.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase Rheumatrex Dose Pack (Methotrexate) toxicity.

Polyarticular Juvenile Idiopathic Arthritis

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of Rheumatrex Dose Pack (Methotrexate) (5 to 20 mg/m²/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m²/week in JIA, the published data for doses above 20 mg/m²/week are too limited to provide reliable estimates of adverse reaction rates.

6.2 Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of Rheumatrex Dose Pack (Methotrexate) are listed below by organ system.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphaden-opathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia

Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of Rheumatrex Dose Pack (Methotrexate).

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens‑Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.

7 DRUG INTERACTIONS

Oral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly.
Hepatotoxins: May increase risk of hepatotoxicity. Monitor patients accordingly (7.1).
Probenecid: May increase Rheumatrex Dose Pack (Methotrexate) exposure. Consider alternative drugs (7.1).
Theophylline: May reduce theophylline clearance. Monitor theophylline levels (7.2).

7.1 Effect of Other Drugs on Rheumatrex Dose Pack (Methotrexate)

Oral Antibiotics

Penicillins may reduce the renal clearance of Rheumatrex Dose Pack (Methotrexate); increased serum concentrations of Rheumatrex Dose Pack (Methotrexate) with concomitant hematologic and gastrointestinal toxicity have been observed with Rheumatrex Dose Pack (Methotrexate). Monitor patients accordingly .

Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving Rheumatrex Dose Pack (Methotrexate). Monitor patients accordingly .

Hepatotoxins

The potential for increased hepatotoxicity when Rheumatrex Dose Pack (Methotrexate) is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving Rheumatrex Dose Pack (Methotrexate) with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.

Probenecid

Probenecid may reduce renal elimination of Rheumatrex Dose Pack (Methotrexate). Consider alternative drugs.

7.2 Effect of Rheumatrex Dose Pack on Other Drugs

Theophylline

Rheumatrex Dose Pack (Methotrexate) may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with Rheumatrex Dose Pack (Methotrexate).

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed.

8.1 Pregnancy

Risk Summary

Based on published reports and methotrexate’s mechanism of action, Rheumatrex Dose Pack is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman . In pregnant women with non-malignant disease, Rheumatrex Dose Pack (Methotrexate) is contraindicated. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate) to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Published data from cases, literature reviews, and observational studies report that Rheumatrex Dose Pack (Methotrexate) exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Rheumatrex Dose Pack (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 Rheumatrex Dose Pack (Methotrexate) is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception Rheumatrex Dose Pack (Methotrexate) exposure.

A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking Rheumatrex Dose Pack (Methotrexate) less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to Rheumatrex Dose Pack (Methotrexate) was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to Rheumatrex Dose Pack (Methotrexate) after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to Rheumatrex Dose Pack (Methotrexate) after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

Risk Summary

Limited published literature report the presence of Rheumatrex Dose Pack in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of Rheumatrex Dose Pack (Methotrexate) on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from Rheumatrex Dose Pack (Methotrexate) in breastfed infants, advise women not to breastfeed during Rheumatrex Dose Pack (Methotrexate) therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Test for pregnancy prior to initiating therapy with Rheumatrex Dose Pack.

Contraception

Females

Rheumatrex Dose Pack (Methotrexate) can cause fetal harm when administered to a pregnant woman .

Advise females of reproductive potential to use effective contraception during and for 6 months after the final Rheumatrex Dose Pack (Methotrexate) dose.

Males

Rheumatrex Dose Pack (Methotrexate) can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final Rheumatrex Dose Pack (Methotrexate) dose.

Infertility

Females

Based on published reports of female infertility after therapy with Rheumatrex Dose Pack, advise females of reproductive potential that Rheumatrex Dose Pack (Methotrexate) can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after therapy with Rheumatrex Dose Pack (Methotrexate), advise males of reproductive potential that Rheumatrex Dose Pack (Methotrexate) can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

8.4 Pediatric Use

Safety and effectiveness of Rheumatrex Dose Pack (Methotrexate) in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) .

8.6 Renal Impairment

Rheumatrex Dose Pack elimination is reduced in patients with impaired renal function. Monitor patients with renal impairment for an extended period of time. Consider a dose reduction or, in some cases, discontinue Rheumatrex Dose Pack (Methotrexate) administration .

8.7 Hepatic Impairment

The effect of hepatic impairment on Rheumatrex Dose Pack (Methotrexate) pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.

10 OVERDOSAGE

Manifestations

Fatal overdosage has occurred with Rheumatrex Dose Pack (Methotrexate). Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.

Management

Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of Rheumatrex Dose Pack (Methotrexate). Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum Rheumatrex Dose Pack (Methotrexate) concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum Rheumatrex Dose Pack (Methotrexate) concentrations may cause renal damage leading to acute renal failure.

Glucarpidase is indicated for the treatment of toxic Rheumatrex Dose Pack (Methotrexate) concentrations in patients with delayed Rheumatrex Dose Pack (Methotrexate) clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of Rheumatrex Dose Pack (Methotrexate) and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve Rheumatrex Dose Pack (Methotrexate) elimination. However, effective clearance of Rheumatrex Dose Pack (Methotrexate) has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION

Rheumatrex Dose Pack (Methotrexate) contains Rheumatrex Dose Pack (Methotrexate), a folate analog metabolic inhibitor.

Chemically Rheumatrex Dose Pack (Methotrexate) is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:

NDC 52652-2001-1

Rheumatrex Dose Pack (Methotrexate)

(methotrexate)

Oral Solution

2.5 mg/mL

For Oral Use Only

READY TO USE

120 mL

Silvergate

Pharmaceuticals Inc.

Rx Only

Each 1 mL contains 2.5 mg

Rheumatrex Dose Pack (Methotrexate) (equivalent to

2.74 mg Rheumatrex Dose Pack (Methotrexate) sodium).

Usual Dose:

See prescribing information.

Store refrigerated

2° - 8°C (36° - 46°F).

After dispensing, may be

stored at room temperature

15° - 30°C (59° - 86°F)

for 60 days.

KEEP THIS AND ALL

MEDICATIONS OUT OF THE

REACH OF CHILDREN

Manufactured for:

Silvergate Pharmaceuticals, Inc.

Greenwood Village, CO 80111

Lot:

EXp:

Methotrexate Sodium:

Warning: severe toxic reactions, including embryo-fetal toxicity
Indications and usage
Dosage and administration
Dosage forms and strengths
Contraindications
Warnings and precautions
Adverse reactions
Drug interactions
Use in specific populations
Overdosage
Description
Rheumatrex Dose Pack (Methotrexate Sodium) reviews

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

Rheumatrex Dose Pack (Methotrexate Sodium) can cause the following severe or fatal adverse reactions.

Monitor closely and modify dose or discontinue Rheumatrex Dose Pack (Methotrexate Sodium) as appropriate.

Bone marrow suppression
Serious infections
Renal toxicity and increased toxicity with renal impairment
Gastrointestinal toxicity
Hepatic toxicity
Pulmonary toxicity
Hypersensitivity and dermatologic reactions
Rheumatrex Dose Pack (Methotrexate Sodium) can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate Sodium) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with Rheumatrex Dose Pack (Methotrexate Sodium) .

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

Rheumatrex Dose Pack (Methotrexate Sodium) can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression (5.1), infection (5.2), renal (5.3), gastrointestinal (5.4), hepatic (5.5), pulmonary (5.6), hypersensitivity and dermatologic (5.7).
Rheumatrex Dose Pack (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate Sodium) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with Rheumatrex Dose Pack (Methotrexate Sodium) (5.9, 8.1, 8.3).

1 INDICATIONS AND USAGE

Rheumatrex Dose Pack is a folate analog metabolic inhibitor indicated for the:

Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen (1.1)
Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy (1.2)

1.1 Acute Lymphoblastic Leukemia

Rheumatrex Dose Pack (Methotrexate Sodium) is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

1.2 Polyarticular Juvenile Idiopathic Arthritis

Rheumatrex Dose Pack (Methotrexate Sodium) is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).

2 DOSAGE AND ADMINISTRATION

Use another formulation of Rheumatrex Dose Pack for patients requiring dosing via routes of administration other than oral (2.1).
Measure with an accurate measuring device (2.1).

Recommended

Dosage:

ALL: 20 mg/m² one time weekly (2.2)
pJIA: Starting dose of 10 mg/m² one time weekly (2.3)

2.1 Important Administration Information

Rheumatrex Dose Pack (Methotrexate Sodium) is intended for oral use only. Use another formulation of Rheumatrex Dose Pack (Methotrexate Sodium) for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity .

It is important that Rheumatrex Dose Pack (Methotrexate Sodium) be measured with an accurate measuring device . A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

2.2 Acute Lymphoblastic Leukemia

The recommended starting dose of Rheumatrex Dose Pack, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m² given one time weekly. After initiating Rheumatrex Dose Pack (Methotrexate Sodium), continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.

2.3 Polyarticular Juvenile Idiopathic Arthritis

The recommended starting dose of Rheumatrex Dose Pack (Methotrexate Sodium) is 10 mg/m² given one time weekly.

Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m²/week in pediatric patients, doses greater than 20 mg/m²/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m²/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if Rheumatrex Dose Pack (Methotrexate Sodium) is administered by an alternative route using another formulation.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

Certain side effects such as mouth sores may be reduced by folate supplementation with Rheumatrex Dose Pack (Methotrexate Sodium) in pJIA.

2.4 Evaluations Prior to Starting Rheumatrex Dose Pack

Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with Rheumatrex Dose Pack (Methotrexate Sodium) [see Warnings and Precautions (5.1, 5.3, 5.5, 5.7, 5.14 )]. Exclude pregnancy in females of reproductive potential before starting Rheumatrex Dose Pack (Methotrexate Sodium) .

2.5 Handling Information

Rheumatrex Dose Pack (Methotrexate Sodium) is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

3 DOSAGE FORMS AND STRENGTHS

Rheumatrex Dose Pack (Methotrexate Sodium) is a clear yellow to orange oral solution that contains 2.5 mg of Rheumatrex Dose Pack (Methotrexate Sodium) per milliliter.

Oral solution: 2.5 mg/mL (3)

4 CONTRAINDICATIONS

Rheumatrex Dose Pack (Methotrexate Sodium) is contraindicated in the following:

Pregnancy in patients with non-malignant diseases. Rheumatrex Dose Pack (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death when administered during pregnancy .
Patients with severe hypersensitivity to Rheumatrex Dose Pack (Methotrexate Sodium) .

Pregnancy (patients with pJIA) (4)
Severe hypersensitivity to Rheumatrex Dose Pack (Methotrexate Sodium) (4)

5 WARNINGS AND PRECAUTIONS

Secondary malignancies can occur. In case of immunosuppression-associated lymphoma, discontinue Rheumatrex Dose Pack before starting treatment for lymphoma (5.8).
Immunizations may be ineffective (5.10).
Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).

5.1 Bone Marrow Suppression

Rheumatrex Dose Pack (Methotrexate Sodium) suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.

5.2 Serious Infections

Monitor patients for the signs and symptoms of infection during and after treatment with Rheumatrex Dose Pack (Methotrexate Sodium) and treat promptly. Consider dose modification or discontinuation of Rheumatrex Dose Pack (Methotrexate Sodium) in patients who develop serious infections .

5.3 Renal Toxicity and Increased Toxicity with Renal Impairment

Rheumatrex Dose Pack (Methotrexate Sodium) can cause renal damage including acute renal failure. Monitor renal function to decrease the risk of renal injury and mitigate renal toxicity.

Consider administration of glucarpidase in patients with toxic plasma Rheumatrex Dose Pack (Methotrexate Sodium) concentrations (> 1 micromole per liter) and delayed clearance due to impaired renal function .

5.4 Gastrointestinal Toxicity

Interrupt or discontinue Rheumatrex Dose Pack (Methotrexate Sodium) and institute appropriate supportive care as needed.

Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of Rheumatrex Dose Pack (Methotrexate Sodium) (primarily at high dosage) and nonsteroidal anti-inflammatory drugs (NSAIDs) .

5.5 Hepatic Toxicity

Rheumatrex Dose Pack (Methotrexate Sodium) can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid use of Rheumatrex Dose Pack (Methotrexate Sodium) in patients with chronic liver disease.

Assess liver function prior to initiating Rheumatrex Dose Pack (Methotrexate Sodium) and monitor liver function tests during treatment. Interrupt or discontinue Rheumatrex Dose Pack (Methotrexate Sodium) as appropriate. Transient asymptomatic acute liver enzyme elevations are common and are not predictive of subsequent hepatic disease. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis.

5.6 Pulmonary Toxicity

5.7 Hypersensitivity and Dermatologic Reactions

Severe, including fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, can occur with Rheumatrex Dose Pack (Methotrexate Sodium). Discontinue Rheumatrex Dose Pack (Methotrexate Sodium) if severe dermatologic reactions occur.

Anaphylaxis can occur with Rheumatrex Dose Pack (Methotrexate Sodium). If anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Rheumatrex Dose Pack (Methotrexate Sodium) and institute appropriate therapy. Rheumatrex Dose Pack (Methotrexate Sodium) is contraindicated for use in patients with a history of severe hypersensitivity.

Radiation dermatitis and sunburn may be “recalled” by the use of Rheumatrex Dose Pack (Methotrexate Sodium).

5.8 Secondary Malignancies

Secondary malignancies can occur at all dose levels of Rheumatrex Dose Pack.

There have been instances of lymphoproliferative disease associated with low-dose oral Rheumatrex Dose Pack (Methotrexate Sodium) which have regressed completely following withdrawal of Rheumatrex Dose Pack (Methotrexate Sodium) without institution of antineoplastic therapy. Discontinue Rheumatrex Dose Pack (Methotrexate Sodium) first and institute appropriate treatment if the lymphoma does not regress.

5.9 Embryo-Fetal Toxicity

Based on published reports and methotrexate’s mechanism of action, Rheumatrex Dose Pack (Methotrexate Sodium) can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, Rheumatrex Dose Pack (Methotrexate Sodium) is contraindicated. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate Sodium) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final Rheumatrex Dose Pack (Methotrexate Sodium) dose .

5.10 Ineffective Immunization and Risks Associated with Live Vaccines

Immunization may be ineffective when given during Rheumatrex Dose Pack therapy.

5.11 Effects on Reproduction

Based on published reports, Rheumatrex Dose Pack (Methotrexate Sodium) can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients .

5.12 Increased Toxicity Due to ThirdSpace Accumulation

5.13 Soft Tissue and Bone Toxicity with Radiation Therapy

Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with Rheumatrex Dose Pack (Methotrexate Sodium).

5.14 Laboratory Tests

Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated Rheumatrex Dose Pack (Methotrexate Sodium) blood levels (e.g., dehydration).

Liver Function Tests

Transient liver function test abnormalities are observed frequently after Rheumatrex Dose Pack (Methotrexate Sodium) administration and are usually not cause for modification of Rheumatrex Dose Pack (Methotrexate Sodium) therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation .

Pulmonary Function Tests

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available .

5.15 Risk of Improper Dosing

Advise patients to measure Rheumatrex Dose Pack (Methotrexate Sodium) with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

Bone Marrow Suppression
Serious Infections
Renal Toxicity and Increased Toxicity with Renal Impairment
Gastrointestinal Toxicity
Hepatic Toxicity
Pulmonary Toxicity
Hypersensitivity and Dermatologic Reactions
Secondary Malignancies
Ineffective Immunization and Risks Associated with Live Vaccines
Infertility
Increased Toxicity Due to Third‑Space Accumulation
Soft Tissue and Bone Toxicity with Radiation Therapy

To report SUSPECTED ADVERSE REACTIONS, contact Silvergate Pharmaceuticals at 1-855-379-0383 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Polyarticular Juvenile Idiopathic Arthritis

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of Rheumatrex Dose Pack (Methotrexate Sodium) (5 to 20 mg/m²/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m²/week in JIA, the published data for doses above 20 mg/m²/week are too limited to provide reliable estimates of adverse reaction rates.

6.2 Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of Rheumatrex Dose Pack (Methotrexate Sodium) are listed below by organ system.

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

7 DRUG INTERACTIONS

Oral Antibiotics: May increase hematologic and gastrointestinal toxicity. Monitor patients accordingly.
Hepatotoxins: May increase risk of hepatotoxicity. Monitor patients accordingly (7.1).
Probenecid: May increase Rheumatrex Dose Pack (Methotrexate Sodium) exposure. Consider alternative drugs (7.1).
Theophylline: May reduce theophylline clearance. Monitor theophylline levels (7.2).

7.1 Effect of Other Drugs on Rheumatrex Dose Pack (Methotrexate Sodium)

Oral Antibiotics

Penicillins may reduce the renal clearance of Rheumatrex Dose Pack (Methotrexate Sodium); increased serum concentrations of Rheumatrex Dose Pack (Methotrexate Sodium) with concomitant hematologic and gastrointestinal toxicity have been observed with Rheumatrex Dose Pack (Methotrexate Sodium). Monitor patients accordingly .

Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving Rheumatrex Dose Pack (Methotrexate Sodium). Monitor patients accordingly .

Hepatotoxins

The potential for increased hepatotoxicity when Rheumatrex Dose Pack (Methotrexate Sodium) is administered with other hepatotoxic agents has not been evaluated; however, hepatotoxicity has been reported in such cases. Monitor patients receiving Rheumatrex Dose Pack (Methotrexate Sodium) with other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) for possible signs of hepatotoxicity.

Probenecid

Probenecid may reduce renal elimination of Rheumatrex Dose Pack (Methotrexate Sodium). Consider alternative drugs.

7.2 Effect of Rheumatrex Dose Pack on Other Drugs

Theophylline

Rheumatrex Dose Pack (Methotrexate Sodium) may decrease the clearance of theophylline. Monitor theophylline levels when coadministered with Rheumatrex Dose Pack (Methotrexate Sodium).

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed.

8.1 Pregnancy

Risk Summary

Based on published reports and methotrexate’s mechanism of action, Rheumatrex Dose Pack is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman . In pregnant women with non-malignant disease, Rheumatrex Dose Pack (Methotrexate Sodium) is contraindicated. Consider the benefits and risks of Rheumatrex Dose Pack (Methotrexate Sodium) and risks to the fetus when prescribing Rheumatrex Dose Pack (Methotrexate Sodium) to a pregnant patient with a neoplastic disease. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

Data

Human Data

Published data from cases, literature reviews, and observational studies report that Rheumatrex Dose Pack (Methotrexate Sodium) exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Rheumatrex Dose Pack (Methotrexate Sodium) 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 Rheumatrex Dose Pack (Methotrexate Sodium) is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception Rheumatrex Dose Pack (Methotrexate Sodium) exposure.

A prospective multicenter study by U.S. and European teratology information services evaluated pregnancy outcomes in women taking Rheumatrex Dose Pack (Methotrexate Sodium) less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to Rheumatrex Dose Pack (Methotrexate Sodium) was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to Rheumatrex Dose Pack (Methotrexate Sodium) after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to Rheumatrex Dose Pack (Methotrexate Sodium) after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

Risk Summary

Limited published literature report the presence of Rheumatrex Dose Pack in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of Rheumatrex Dose Pack (Methotrexate Sodium) on a breastfed infant or on milk production. Because of the potential for serious adverse reactions, including myelosuppression, from Rheumatrex Dose Pack (Methotrexate Sodium) in breastfed infants, advise women not to breastfeed during Rheumatrex Dose Pack (Methotrexate Sodium) therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Test for pregnancy prior to initiating therapy with Rheumatrex Dose Pack.

Contraception

Females

Rheumatrex Dose Pack (Methotrexate Sodium) can cause fetal harm when administered to a pregnant woman .

Advise females of reproductive potential to use effective contraception during and for 6 months after the final Rheumatrex Dose Pack (Methotrexate Sodium) dose.

Males

Rheumatrex Dose Pack (Methotrexate Sodium) can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final Rheumatrex Dose Pack (Methotrexate Sodium) dose.

Infertility

Females

Based on published reports of female infertility after therapy with Rheumatrex Dose Pack, advise females of reproductive potential that Rheumatrex Dose Pack (Methotrexate Sodium) can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after therapy with Rheumatrex Dose Pack (Methotrexate Sodium), advise males of reproductive potential that Rheumatrex Dose Pack (Methotrexate Sodium) can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

8.4 Pediatric Use

Safety and effectiveness of Rheumatrex Dose Pack (Methotrexate Sodium) in pediatric patients have been established for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen and for the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) .

8.6 Renal Impairment

8.7 Hepatic Impairment

The effect of hepatic impairment on Rheumatrex Dose Pack (Methotrexate Sodium) pharmacokinetics has not been studied. Patients with hepatic impairment may be more susceptible to hepatotoxicity . Consider dose adjustments or alternative treatments in patients with baseline hepatic impairment.

10 OVERDOSAGE

Manifestations

Fatal overdosage has occurred with Rheumatrex Dose Pack (Methotrexate Sodium). Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported.

Management

Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of Rheumatrex Dose Pack (Methotrexate Sodium). Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin Prescribing Information). Monitor serum Rheumatrex Dose Pack (Methotrexate Sodium) concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum Rheumatrex Dose Pack (Methotrexate Sodium) concentrations may cause renal damage leading to acute renal failure.

Glucarpidase is indicated for the treatment of toxic Rheumatrex Dose Pack (Methotrexate Sodium) concentrations in patients with delayed Rheumatrex Dose Pack (Methotrexate Sodium) clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of Rheumatrex Dose Pack (Methotrexate Sodium) and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve Rheumatrex Dose Pack (Methotrexate Sodium) elimination. However, effective clearance of Rheumatrex Dose Pack (Methotrexate Sodium) has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION

Rheumatrex Dose Pack (Methotrexate Sodium) contains Rheumatrex Dose Pack (Methotrexate Sodium), a folate analog metabolic inhibitor.

Chemically Rheumatrex Dose Pack (Methotrexate Sodium) is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-benzoyl]-L-glutamic acid. The structural formula is:

NDC 52652-2001-1

Rheumatrex Dose Pack (Methotrexate Sodium)

(methotrexate)

Oral Solution

2.5 mg/mL

For Oral Use Only

READY TO USE

120 mL

Silvergate

Pharmaceuticals Inc.

Rx Only

Each 1 mL contains 2.5 mg

Rheumatrex Dose Pack (Methotrexate Sodium) (equivalent to

2.74 mg Rheumatrex Dose Pack (Methotrexate Sodium) sodium).

Usual Dose:

See prescribing information.

Store refrigerated

2° - 8°C (36° - 46°F).

After dispensing, may be

stored at room temperature

15° - 30°C (59° - 86°F)

for 60 days.

KEEP THIS AND ALL

MEDICATIONS OUT OF THE

REACH OF CHILDREN

Manufactured for:

Silvergate Pharmaceuticals, Inc.

Greenwood Village, CO 80111

Lot:

EXp:

Rheumatrex Dose Pack pharmaceutical active ingredients containing related brand and generic drugs:

Rheumatrex Dose Pack available forms, composition, doses:

Rheumatrex Dose Pack destination | category:

Human:
Antineoplastic agents
Cytotoxic chemotherapy
Disease-modifying anti-rheumatic drugs (DMARDs)
Immunosuppressants

Rheumatrex Dose Pack Anatomical Therapeutic Chemical codes:

L01BA01 - Methotrexate
L04AX03 - Methotrexate

Rheumatrex Dose Pack pharmaceutical companies:

References

Dailymed."METHOTREXATE (METHOTREXATE SODIUM) INJECTION, SOLUTION [FRESENIUS KABI USA, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Dailymed."XATMEP (METHOTREXATE) SOLUTION [SILVERGATE PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Dailymed."METHOTREXATE SODIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Rheumatrex Dose Pack?

Depending on the reaction of the Rheumatrex Dose Pack after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Rheumatrex Dose Pack not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Rheumatrex Dose Pack addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Rheumatrex Dose Pack, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Rheumatrex Dose Pack consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.