References: 1. US FDA/CDER/Office of Compliance. Guidance for Industry: Compounded drug products that are essentially copies of a commercially available drug product under section 503A of the FDCA. January 2018. 2. Sellers S, Utian WH. Pharmacy compounding primer for physicians. Drugs. 2012;72:2043-2050. 3. Xatmep® [prescribing information]. Greenwood Village, CO: Silvergate Pharmaceuticals, Inc.; 2018. 4. Data on file, Silvergate Pharmaceuticals, Inc.; 2018.
IMPORTANT SAFETY INFORMATION
IMPORTANT SAFETY INFORMATION
WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY
Methotrexate can cause the following severe or fatal adverse reactions.
- Bone marrow suppression [see Warnings and Precautions (5.1)]
- Serious infections [see Warnings and Precautions (5.2) ]
- Renal toxicity and increased toxicity with renal impairment [see Warnings and Precautions (5.3)]
- Gastrointestinal toxicity [see Warnings and Precautions (5.4)]
- Hepatic toxicity [see Warnings and Precautions (5.5)]
- Pulmonary toxicity [see Warnings and Precautions (5.6)]
- Hypersensitivity and dermatologic reactions [see Warnings and Precautions (5.7)]
- Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females and males of reproductive potential to use effective contraception during and after treatment with XATMEP [see Contraindications (4), Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3)].
Monitor closely and modify dose or discontinue methotrexate as appropriate.
INDICATIONXatmep is a folate analog metabolic inhibitor indicated for the:
- treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.
- 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).
ADDITIONAL IMPORTANT SAFETY INFORMATIONContraindications:
Xatmep is contraindicated in pregnant patients with non-malignant disease and in patients with severe hypersensitivity to methotrexate.
Warnings and Precautions: See full Prescribing Information for additional information.
- Xatmep suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia. Obtain blood counts at baseline and periodically; monitor patients for complications of bone marrow suppression.
- Patients treated with Xatmep are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections, including Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis (primary or reactivation), disseminated Herpes zoster and cytomegalovirus infections.
- Renal toxicity and increased toxicity with renal impairment, including acute renal failure. Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole/liter) and delayed clearance due to impaired renal function.
- Xatmep can cause diarrhea, stomatitis, vomiting, hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic ulcer disease and ulcerative colitis are at increased risk for severe gastrointestinal adverse reactions. Unexpected severe and fatal gastrointestinal toxicity can occur with concomitant use of NSAIDs.
- Hepatic toxicity: severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure can occur. Avoid use of Xatmep in patients with chronic liver disease.
- Pulmonary toxicity: acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels.
- Hypersensitivity: anaphylaxis or other serious hypersensitivity reactions. Discontinue methotrexate.
- Severe, including fatal, dermatologic reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme can occur. Radiation dermatitis and sunburn may be “recalled.”
- Secondary malignancies can occur at all dose levels. Lymphoproliferative disease has been reported with lowdose oral methotrexate which regressed when methotrexate was withdrawn.
- Methotrexate can cause embryo-fetal toxicity and fetal death when administered during pregnancy. Consider the risks and benefits of Xatmep and risks to the fetus when prescribing to a pregnant patient with a neoplastic disease. Effective contraception should be practiced by patients of reproductive potential while receiving Xatmep therapy, and for 3 and 6 months afterwards for males and females, respectively. Xatmep is contraindicated in pregnant women with non-malignant disease.
- Effects on reproduction: Methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is unknown if the infertility is reversible in affected patients.
- Increased toxicity in third-space accumulation. Evacuate significant third-space accumulation prior to methotrexate administration.
- Immunizations may be ineffective when given during Xatmep therapy.
- Immunization with live virus vaccines is not recommended during Xatmep therapy.
- Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate.
- Closely monitor laboratory parameters for hematology, renal function, and liver function. Increase monitoring during initial dosing, dose changes, and during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration).
- Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
- Risk of improper dosing: Once-weekly dosing is appropriate. Fatal toxicity has been reported with daily dosing. An accurate milliliter measuring device should be used. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage.
- Advise women not to breastfeed during Xatmep therapy.
- Most common adverse reactions are ulcerative stomatitis, leukopenia, nausea, abdominal distress, and elevated liver function tests.
- Other frequently reported reactions are malaise, fatigue, chills and fever, dizziness, and decreased resistance to infection.
- The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2week 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.
- Penicillins may reduce the clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Monitor patients accordingly.
- Trimethoprim/sulfamethoxazole has been reported to increase bone marrow suppression in patients receiving methotrexate. Monitor patients accordingly.
- Hepatotoxins: May increase hepatotoxicity. Monitor patients receiving concomitant hepatotoxins for signs of hepatotoxicity.
- Probenecid may reduce renal elimination of methotrexate; consider alternative drugs.
- Nitrous oxide as an anesthetic potentiates the effect of methotrexate resulting in the potential for increased toxicity.
- NSAIDs, Aspirin, and Steroids: Concomitant administration of Xatmep with NSAIDs, aspirin, or steroids may elevate and prolong methotrexate levels resulting in increased hematologic and gastrointestinal toxicity. Monitor patients accordingly.
- Theophylline: May decrease theophylline clearance. Monitor theophylline levels.
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.
Inform caregivers and patients of the need for proper storage and disposal of dispensing bottles and dosing devices.
Keep this and all medications out of reach of children.