---------------------DOSAGE FORMS AND STRENGTHS---------------­
`
`Injection: Single-dose auto-injector delivering 0.4 mL of methotrexate in the
`
`
`following dosage strengths: 7.5 mg, 10 mg, 15 mg, 20mg, and 25 mg (3).
`
`
`
`
`
`-------------------------CONTRAINDICATIONS------------------------------­
`• Pregnancy (4)
`
`
`• Nursing mothers (4)
`
`
`• Alcoholism or liver disease (4)
`
`
`• Immunodeficiency syndromes (4)
`
`
`• Preexisting blood dyscrasias (4)
`
`
`
`• Hypersensitivity to methotrexate (4)
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------­
`• Organ system toxicity: Potential for serious toxicity. Only for use by
`
`
`physicians experienced in antimetabolite therapy (5.1).
`
`
`
`• Embryo-fetal toxicity: Exclude pregnancy before treatment. Avoid
`
`
`
`pregnancy if either partner is receiving Otrexup. Advise males to avoid
`
`
`pregnancy for a minimum of three months after therapy and females to
`
`
`avoid pregnancy for at least one ovulatory cycle after therapy (5.2).
`
`
`
`• Effects on reproduction: May cause impairment of fertility, oligospermia
`
`
`and menstrual dysfunction (5.3)
`
`• Laboratory tests: Monitor complete blood counts, renal function and liver
`
`
`
`
`function tests (5.4).
`
`
`• Risks from improper dosing: Mistaken daily use has led to fatal toxicity
`
`
`
`
`
`(5.5)
`
`• Patients with impaired renal function, ascites, or pleural effusions:
`
`
`
`Elimination is reduced (5.6).
`
`• Dizziness and fatigue: May impair ability to drive or operate machinery
`
`
`
`(5.7)
`
`
`
`-----------------------------ADVERSE REACTIONS---------------------------­
`
`Common adverse reactions are: nausea, abdominal pain, dyspepsia,
`
`
`
`
`
`
`
`
`stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test
`
`
`
`
`
`
`
`
`abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia,
`
`
`
`
`
`
`leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin
`
`
`
`
`
`
`
`
`lesions” (6).
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Antares at
`
`
`
`
`
`
`
`1-855-Otrexup (1-855-687-3987) or FDA at 1-800-FDA-1088 or
`
`
`
`
`
`
`www.fda.gov/medwatch.
`
`
`-----------------------------DRUG INTERACTIONS---------------------------­
`
`• Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong
`
`
`
`
`
`
`
`
`
`
`serum methotrexate levels and cause increased toxicity (7.1)
`
`
`
`
`
`
`
`
`• Proton pump inhibitors: concomitant use may elevate and prolong serum
`
`
`
`
`
`
`
`
`
`
`methotrexate levels and cause increased toxicity (7.2)
`
`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` OTREXUP™ safely and effectively. See full prescribing information for
`
` OTREXUP.
`
`
` OTREXUP (methotrexate) injection, for subcutaneous use
`
` Initial U.S. Approval: 1953
`
`
`
`
`
`
`
`
`
`
`
`
`
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO­
`
`FETAL TOXICITY AND DEATH
`See full prescribing information for complete boxed warning.
`
`
`
`• Serious toxic reactions and death have been reported with the use of
`
`methotrexate. Patients should be closely monitored for bone marrow,
`liver, lung, skin, and kidney toxicities (5.1).
`
`
`• Methotrexate has been reported to cause fetal death and/or congenital
`
`
`
`
`anomalies and is contraindicated in pregnancy (4, 5.2).
`
`
`• Unexpectedly severe (sometimes fatal) bone marrow suppression,
`
`
`aplastic anemia, and gastrointestinal toxicity have been reported with
`
`
`
`concomitant administration of methotrexate (usually in high dosage)
`
`
`along with some nonsteroidal anti-inflammatory drugs (NSAIDs) (5.1).
`
`
`• Hepatotoxicity, fibrosis, and cirrhosis may occur after prolonged use
`(5.1).
`
`• Methotrexate may cause interstitial pneumonitis at any time during
`
`
`therapy and has been reported at low doses. Pulmonary symptoms
`
`
`(especially a dry, nonproductive cough) may require interruption of
`
`
`
`
`
`treatment and careful investigation (5.1).
`
`
`
`• Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from
`
`
`intestinal perforation may occur (5.1).
`
`
`• Severe, occasionally fatal, skin reactions have been reported (5.1).
`
`
`• Potentially fatal opportunistic infections may occur (5.1).
`
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Dosage and Administration (2)
`11/2014
`
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Otrexup is a folate analog metabolic inhibitor indicated for the:
`
`
`
`• Management of patients with severe, active rheumatoid arthritis (RA) and
`
`
`
`
`polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or
`
`had an inadequate response to first-line therapy (1.1)
`
`
`
`• Symptomatic control of severe, recalcitrant, disabling psoriasis in adults
`
`
`
`
`who are not adequately responsive to other forms of therapy (1.2)
`
`
`Limitation of Use
`
`Otrexup is not indicated for the treatment of neoplastic diseases (1.3).
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------­
`• Otrexup is for once weekly subcutaneous use only. Administer Otrexup in
`
`
`
`
`the abdomen or thigh. (2.1)
`
`• Use another formulation of methotrexate for patients requiring oral,
`
`
`intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less
`
`
`than 7.5 mg per week, doses above 25 mg per week, high-dose regimens, or
`
`
`
`dose adjustments of less than 5 mg increments (2.1)
`
`• Starting doses of methotrexate:
`
`
`
`• RA: 7.5 mg once weekly (2.2)
`
`
`• pJIA: 10 mg/m2 once weekly (2.2)
`
`
`
`
`
`
`
`• Psoriasis: 10 to 25 mg once weekly of an oral, intramuscular,
`
`
`
`subcutaneous, or intravenous formulation (2.3)
`
`
`
`
`• Adjust dose gradually to achieve an optimal response (2.2, 2.3)
`_______________________________________________________________________________________________________________________________________
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-------------------­
`
`
`
`
`
`
`
`
`
`
` • Pediatric use: Safety and efficacy of methotrexate, including Otrexup,
` have not been established in pediatric patients with psoriasis. Safety and
`
`
`
`
`
`
`
`
`
`
` efficacy of Otrexup have not been established in pediatric patients with
`
`
`
`
`
`
`
`
`
`
`
` malignancy (8.4)
`
`
`• Geriatric use: Use caution in dose selection (8.5)
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 11/2014
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO­
`
`FETAL TOXICITY AND DEATH
`
`
`1 INDICATIONS AND USAGE
`
`1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic
`
`
`
`
`Arthritis
`
`
`1.2 Psoriasis
`
`1.3 Limitation of Use
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Dosing Information
`
`2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic
`
`
`
`
`
`Arthritis
`
`
`2.3 Psoriasis
`
`2.4 Administration and Handling
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`
`
`
`Reference ID: 3655450
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Organ System Toxicity
`
`5.2 Embryo-Fetal Toxicity
`
`5.3 Effects on Reproduction
`
`
`5.4 Laboratory Tests
`
`
`5.5 Risks from Improper Dosing
`
`
`5.6 Patients with Impaired Renal Function, Ascites, or Pleural Effusions
`
`
`5.7 Dizziness and Fatigue
`
`
`5.8 Malignant Lymphomas
`
`
`5.9 Tumor Lysis Syndrome
`
`
`5.10 Concomitant Radiation Therapy
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Other Adverse Reactions
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids
`
`
`
`
`
` 1
`
`Medac Exhibit 2074
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`

`
`
`
`
`
`8.8 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Rheumatoid Arthritis
`
`
`14.2 Polyarticular Juvenile Idiopathic Arthritis
`
`
`
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed
`
`__________________________________________________________________________________________________________________________
`
`
`7.2 Proton Pump Inhibitors (PPIs)
`
`
`
`7.3 Oral Antibiotics
`
`
`7.4 Hepatotoxins
`
`7.5 Theophylline
`
`7.6 Folic Acid and Antifolates
`
`
`
`7.7 Mercaptopurine
`
`
`7.8 Other Drugs
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Females and Males of Reproductive Potential
`
`
`
`8.7 Renal Impairment
`
`
`
`
`
`
`
`
`Reference ID: 3655450
`
`
`
` 2
`
`Page 00002
`
`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
`
`
`
`
`
`
`Otrexup should be used only by physicians whose knowledge and experience include the use of
`
`
`
`
`antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup
`should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling
`
`
`
`
`
`disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the
`
`
`
`
`
`use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be
`
`
`
`
`
`closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by
`
`
`
`their physician of the risks involved and be under a physician’s care throughout therapy [see Warnings and
`
`
`
`
`Precautions (5.1)].
`
`1. Methotrexate has been reported to cause fetal death and/or congenital anomalies.
`
`
`
`Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical
`
`
`
`
`evidence that the benefits can be expected to outweigh the considered risks [see Warnings and Precautions
`
`
`
`(5.2)]. Otrexup is contraindicated in pregnant women [see Contraindications (4)].
`
`
`
`
`
`2. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural
`
`
`
`
`
`effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in
`
`
`
`
`some cases, discontinuation of Otrexup administration [see Warnings and Precautions (5.6)].
`
`
`
`
`3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal
`
`
`toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along
`
`
`
`with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions (5.1) and Drug
`
`
`
`Interactions (7.1)].
`
`
`4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use.
`
`
`Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and
`
`
`
`also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows
`
`
`
`histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded
`
`
`
`
`by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver
`
`
`
`
`biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent
`
`
`abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid
`
`
`
`arthritis population [see Warnings and Precautions (5.1)].
`
`
`
`5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially
`
`
`
`
`
`dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses.
`
`
`
`
`
`
`
`
`
`
`It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry,
`
`
`
`
`
`nonproductive cough) may require interruption of treatment and careful investigation [see Warnings and
`
`
`
`
`
`
`Precautions (5.1)].
`
`
`6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and
`
`
`death from intestinal perforation may occur [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients
`
`
`
`receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue Otrexup first
`
`
`
`
`and, if the lymphoma does not regress, appropriate treatment should be instituted [see Warnings and
`
`
`
`
`
`Precautions (5.8)].
`
`
`8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly
`
`
`
`
`
`growing tumors [see Warnings and Precautions (5.9)].
`
`
`
`9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of
`
`
`
`
`methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal
`
`
`
`
`methotrexate administration. Recovery has been reported with discontinuation of therapy [see Warnings
`
`
`
`and Precautions (5.1)].
`
`
`10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with
`
`
`
`methotrexate therapy [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`Reference ID: 3655450
`
`
`
` 3
`
`Page 00003
`
`

`
`
`
`
`
` 11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and
`osteonecrosis [see Warnings and Precautions (5.10)].
`
`
`
`
`
`
`
`
`
`1 INDICATIONS AND USAGE
`
`1.1 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`
`Otrexup is indicated in the management of selected adults with severe, active rheumatoid arthritis (RA)
`(ACR criteria), or children 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).
`
`1.2 Psoriasis
`
`Otrexup is indicated in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is
`
`
`not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by
`
`
`biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an
`
`
`undiagnosed concomitant disease affecting immune responses.
`
`1.3 Limitation of Use
`
`
`Otrexup is not indicated for the treatment of neoplastic diseases.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Dosing Information
`Otrexup is a single-dose auto-injector for once-weekly subcutaneous use only [see Warnings and
`
`
`
`
`Precautions (5.5)]. Administer Otrexup in the abdomen or the thigh. Otrexup is available in the following
`
`
`
`
`dosage strengths: 7.5, 10, 15, 20 and 25 mg. Use another formulation of methotrexate for alternative dosing
`
`
`
`
`
`in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than
`
`7.5 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments between the
`
`
`available doses.
`2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`
`Recommended starting dose of methotrexate:
`
`
`Adult RA: 7.5 mg once weekly.
`
`
`
`
` pJIA: 10 mg/m2 once weekly.
`
`
`
` For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between
`
` oral and subcutaneously administered methotrexate [see Clinical Pharmacology (12.3)].
`
`
`
`
`
` Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant
`
` increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at
`
`
`
`
` doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in
`
`
`children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of
`
`
`serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk
`
`
`
`
`
`(0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is
`
`administered either intramuscularly or subcutaneously.
`
`
`
`Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another
`
`
`12 weeks or more.
`
`
`The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate
`
`
`
`
`that the initial clinical improvement is maintained for at least two years with continued therapy. When
`
`
`methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.
`
`
`
`The patient should be fully informed of the risks involved and should be under constant supervision of the
`
`physician. Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history,
`
`
`
`
`
`
`Reference ID: 3655450
`
`
`
` 4
`
`Page 00004
`
`

`
`
`
` physical examination, and laboratory tests before beginning, periodically during, and before reinstituting
`
` Otrexup therapy [see Warnings and Precautions (5.4)]. Females of childbearing potential should not be
`
` started on Otrexup until pregnancy is excluded [see Contraindications (4) and Warnings and Precautions
`
`
` (5.2)]
` All schedules should be continually tailored to the individual patient. An initial test dose may be given prior
`
`
`
` to the regular dosing schedule to detect any extreme sensitivity to adverse effects.
` Maximal myelosuppression usually occurs in seven to ten days.
`
`
` 2.3 Psoriasis
`
` Recommended starting dose of methotrexate:
`
` Psoriasis: single weekly oral, intramuscular, subcutaneous, or intravenous doses of 10-25 mg.
`
`
`
`
` For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between
`
` oral and subcutaneously administered methotrexate [see Clinical Pharmacology (12.3)].
`
`
`
`
`
` Dosage may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be
`
` exceeded. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest
`
`
`
`
` possible amount of drug and to the longest possible rest period. The use of Otrexup may permit the return to
`
`
` conventional topical therapy, which should be encouraged.
`
`
`
`
` 2.4 Administration and Handling
`
`
` Otrexup is an auto-injector intended for subcutaneous use under the guidance and supervision of a physician.
`
`
`Patients may self-inject with Otrexup if a physician determines that it is appropriate, if they have received
`
` proper training in how to prepare and administer the correct dose, and if they receive medical follow-up, as
`
`
`
`necessary. A trainer device is available for training purposes.
`
`Visually inspect Otrexup for particulate matter and discoloration prior to administration. Do not use Otrexup
`
`
`
`
` if the seal is broken.
`
` Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic
`
`
`
`drugs1 .
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`Otrexup is an injection available as an autoinjector that administers a single 0.4 mL dose of methotrexate
`
`solution in the following dosage strengths:
`
`
`• 7.5 mg/0.4 mL methotrexate
`• 10 mg/0.4 mL methotrexate
`• 15 mg/0.4 mL methotrexate
`• 20 mg/0.4 mL methotrexate
`• 25 mg/0.4 mL methotrexate
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`Otrexup is contraindicated in the following:
`
`• Pregnancy
`
`
`
`Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman.
`
`
`
`Otrexup is contraindicated in pregnant women. If this drug is used during pregnancy, or if the patient
`
`
`
`becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
`
`
`[see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].
`
`•Nursing Mothers
`
`
`Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is
`
`contraindicated in nursing mothers [see Use in Specific Populations (8.3)].
`
`
`
`
`
`Reference ID: 3655450
`
`
`
` 5
`
`Page 00005
`
`

`
`
`
` •Alcoholism or Liver Disease
`
`Patients with alcoholism, alcoholic liver disease or other chronic liver disease [see Warnings and
`
`
`
`Precautions (5.1)].
`
`• Immunodeficiency Syndromes
`Patients who have overt or laboratory evidence of immunodeficiency syndromes [see Warnings and
`
`Precautions (5.1)].
`
`• Preexisting Blood Dyscrasias
`
`Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia,
`
`thrombocytopenia, or significant anemia [see Warnings and Precautions (5.1)].
`
`
`
`•Hypersensitivity
`
`Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been
`
`observed with methotrexate use [see Warnings and Precautions (5.1) and Adverse Reactions (6.1 and 6.2)].
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Organ System Toxicity
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`Otrexup should be used only by physicians whose knowledge and experience include the use of
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`antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup
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`should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling
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`disease which is not adequately responsive to other forms of therapy.
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`Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and
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`rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.
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`Otrexup has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose
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`or frequency of administration but have been seen at all doses. Because they can occur at any time during
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`therapy, it is necessary to follow patients on Otrexup closely. Most adverse reactions are reversible if
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`detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and
`appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin
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`calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see Overdosage (10)]. If Otrexup
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`therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for
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`the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of
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`methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as
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`well as decreased folate stores in this population, relatively low doses should be considered, and these
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`patients should be closely monitored for early signs of toxicity [see Use in Specific Populations (8.5)].
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`Gastrointestinal:
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`Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death
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`from intestinal perforation may occur.
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`If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, Otrexup should be discontinued
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`until recovery occurs. Otrexup should be used with extreme caution in the presence of peptic ulcer disease or
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`ulcerative colitis.
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`Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant
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`administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory
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`drugs (NSAIDs) [see Drug Interactions (7.1)].
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`Hematologic:
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`Otrexup can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia,
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`neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Otrexup
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`should be used with caution, if at all. In controlled clinical trials conducted with another formulation of
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`methotrexate in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients,
`thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients.
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`Reference ID: 3655450
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`Otrexup should be stopped immediately if there is a significant drop in blood counts. Patients with profound
`granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum
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`antibiotic therapy.
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`Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported
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`with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-
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`inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)].
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`Hepatic:
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`Otrexup has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis)
`hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally
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`two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity
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`appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity,
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`diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and
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`reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage
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`or impaired hepatic function.
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`In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing
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`but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by
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`biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of
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`therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5
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`grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis
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`normally suggests a repeat biopsy in 6 months.
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`Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common
`pretherapy. Although these mild changes are usually not a reason to avoid or discontinue Otrexup therapy,
`the drug should be used with caution.
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`In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk
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`factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in
`rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may
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`precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217
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`rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of
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`at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis
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`and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more
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`sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will
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`increase these risks.
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`Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving Otrexup for
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`rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive
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`alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C
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`infection. During therapy, liver biopsy should be performed if there are persistent liver function test
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`abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well
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`controlled rheumatoid arthritis).
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`If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), Otrexup may be continued and
`the patient monitored as per recommendations listed above. Otrexup should be discontinued in any patient
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`who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver
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`biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
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`Infection or Immunologic States:
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`Otrexup should be used with extreme caution in the presence of active infection, and is contraindicated in
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`patients with overt or laboratory evidence of immunodeficiency syndromes.
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`Immunization may be ineffective when given during Otrexup therapy. Immunization with live virus vaccines
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`is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox
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`Reference ID: 3655450
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`immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported
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`rarely.
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`Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with
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`Otrexup therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis
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`jiroveci pneumonia should be considered.
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`Neurologic:
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`There have been reports of leukoencephalopathy following intravenous administration of methotrexate to
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`patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or
`focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute
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`lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2).
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`Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic
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`calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients
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`who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial
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`irradiation.
`Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic
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`syndrome has been observed in patients treated with high dose regimens. Manifestations of this stroke-like
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`encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause
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`is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur
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`can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back
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`pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated
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`with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by
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`confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive
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`and even fatal.
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`Pulmonary:
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`Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially
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`dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It
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`is not always fully reversible and fatalities have been reported.
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`Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during
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`Otrexup therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and
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`careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease
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`presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including
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`pneumonia) needs to be excluded. This lesion can occur at all dosages.
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`Renal:
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`Otrexup may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the
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`treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due
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`primarily to the precipitation of methotrexate and 7- hydroxymethotrexate in the renal tubules. Close
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`attention to renal function including adequate hydration, urine alkalinization and measurement of serum
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`methotrexate and creatinine levels are essential for safe administration.
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`Skin:
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`Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-
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`Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been rep