HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use.
`RASUVO™ safely and effectively. See full prescribing information for
`RASUVO.
`RASUVO (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).
`
`• Adjust dose gradually to achieve an optimal response (2.2, 2.3)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Injection: Single-dose manually-triggered auto-injector delivering
`methotrexate in the following dosage strengths: 7.5 mg, 10 mg, 12.5 mg, 15
`mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 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 Rasuvo. 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,
`leukopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin
`lesions” (6).
`To report SUSPECTED ADVERSE REACTIONS, contact Medac at
`1-855-336-3322 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)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`•
`Pediatric use: Safety and efficacy of methotrexate, including Rasuvo,
`have not been established in pediatric patients with psoriasis. Safety and
`efficacy of Rasuvo 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.
`
`•
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Rasuvo 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
`Rasuvo is not indicated for the treatment of neoplastic diseases (
`1.3).
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`•
`Rasuvo is for once weekly subcutaneous use only.
`• Administer Rasuvo 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 30 mg per week, high-dose regimens,
`or dose adjustments of less than 2.5 mg increments (2.1)
`(cid:891) Starting doses of methotrexate:
`• RA: 7.5 mg once weekly of an oral or subcutaneous formulation
`(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)
`_______________________________________________________________________________________________________________________________________
`
`•
`•
`
`Revised: 07/2014
`
`FULL PRESCRIBING INFORMATION: CONTENTS(cid:13)(cid:13)
`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
`Reference ID: 3540287
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`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
`
`Medac Exhibit 2089
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
`
`

`

`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
`
` (cid:13)
`
` Sections or subsections omitted from the full prescribing information are not
`listed
`
`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
`7.2 Proton Pump Inhibitors (PPIs) and H2 Blockers
`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
`8.8 Hepatic Impairment
`
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`
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`

`

`FULL PRESCRIBING INFORMATION
`WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
`
`Rasuvo 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), Rasuvo 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, Rasuvo 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)]. Rasuvo 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 Rasuvo
`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 Rasuvo 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)].
`11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and
`osteonecrosis [see Warnings and Precautions (5.10)].
`
`Reference ID: 3540287
`
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`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`1.1
`Rasuvo 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
`Rasuvo 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
`Rasuvo is not indicated for the treatment of neoplastic diseases.
`
`2 DOSAGE AND ADMINISTRATION
`
`Important Dosing Information
`2.1
`Rasuvo is a single-dose manually-triggered auto-injector for once-weekly subcutaneous use only [see Warnings
`and Precautions (5.5)]. Administer Rasuvo in the abdomen or the thigh. Rasuvo is only available in doses
`between 7.5 to 30 mg in 2.5 mg increments. 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 30 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg
`increments.
`2.2
`Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
`Recommended starting dose of methotrexate:
`Adult RA: 7.5 mg as a single oral or subcutaneous dose once weekly.
`pJIA: 10 mg/m2 once weekly.
`For patients switching from oral methotrexate to Rasuvo, 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,
`physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Rasuvo
`therapy [see Warnings and Precautions (5.4)]. Females of childbearing potential should not be started on Rasuvo
`until pregnancy is excluded [see Contraindications (4) and Warnings and Precautions (5.2)].
`
`Reference ID: 3540287
`
`Page 00004
`
`

`

`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: 10-25 mg as a single oral, intramuscular, subcutaneous, or intravenous dose once weekly.
`For patients switching from oral methotrexate to Rasuvo, 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 Rasuvo may permit the return to conventional
`topical therapy, which should be encouraged.
`2.4
`Administration and Handling
`Rasuvo is a manually-triggered auto-injector intended for subcutaneous use under the guidance and supervision
`of a physician.
`Patients may self-inject with Rasuvo 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.
`Rasuvo is injected once weekly. The patient must be explicitly informed about the once weekly dosing schedule.
`It is advisable to determine an appropriate fixed day of the week for the injection.
`Visually inspect Rasuvo for particulate matter and discoloration prior to administration. Do not use Rasuvo if the
`seal is broken.
`Handle and dispose of Rasuvo consistent with recommendations for handling and disposal of cytotoxic drugs1.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Rasuvo is an injection containing methotrexate at a concentration of 50 mg/ml available as a manually-triggered
`auto-injector that administers a single dose of methotrexate solution in the following dosage strengths:
`7.5 mg
`(cid:120)
`10 mg
`(cid:120)
`12.5 mg
`(cid:120)
`15 mg
`(cid:120)
`17.5 mg
`(cid:120)
`20 mg
`(cid:120)
`22.5 mg
`(cid:120)
`25 mg
`(cid:120)
`27.5 mg
`(cid:120)
`30 mg
`(cid:120)
`
`4 CONTRAINDICATIONS
`
`Rasuvo is contraindicated in the following:
`Pregnancy
`(cid:120)
`Rasuvo can cause fetal death or teratogenic effects when administered to a pregnant woman. Rasuvo 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
`5.2) and Use in Specific Populations (8.1)].
`Precautions (
`Nursing Mothers
`(cid:120)
`Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Rasuvo is
`8.3)].
`contraindicated in nursing mothers [see Use in Specific Populations (
`
`Reference ID: 3540287
`
`Page 00005
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`

`

`Alcoholism or Liver Disease
`(cid:120)
`Patients with alcoholism, alcoholic liver disease or other chronic liver disease [see Warnings and Precautions
`(
`5.1)].
`Immunodeficiency Syndromes
`(cid:120)
`Patients who have overt or laboratory evidence of immunodeficiency syndromes [see Warnings and
`Precautions (
`5.1)].
`Preexisting Blood Dyscrasias
`(cid:120)
`Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia,
`5.1)].
`or significant anemia [see Warnings and Precautions (
`Hypersensitivity
`(cid:120)
`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)].
`
`5 WARNINGS AND PRECAUTIONS
`
`Organ System Toxicity
`5.1
`Rasuvo 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), Rasuvo 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 and kidney toxicities.
`Rasuvo has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or
`frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it
`is necessary to follow patients on Rasuvo closely. Most adverse reactions are reversible if 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 calcium and/or acute,
`intermittent hemodialysis with a high-flux dialyzer [see Overdosage (10)]. If Rasuvo therapy is reinstituted, it
`should be carried out with caution, with adequate consideration of further need for the drug and increased
`alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well
`studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in
`this population, relatively low doses should be considered, and these patients should be closely monitored for
`early signs of toxicity [see Use in Specific Populations (8.5)].
`Gastrointestinal:
`Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death
`from intestinal perforation may occur.
`If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, Rasuvo should be discontinued until
`recovery occurs. Rasuvo should be used with extreme caution in the presence of peptic ulcer disease or ulcerative
`colitis.
`Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant
`administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs
`(NSAIDs) [see Drug Interactions (7.1)].
`Hematologic:
`Rasuvo can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia,
`and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Rasuvo should be used with
`caution, if at all. In controlled clinical trials conducted with another formulation of 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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`
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`

`

`Rasuvo 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
`antibiotic therapy.
`Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with
`concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-
`inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)].
`Hepatic:
`Rasuvo 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 two years or more)
`and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a
`function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced
`age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not
`known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function.
`In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but
`are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy.
`The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4
`months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis
`or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in
`6 months.
`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 Rasuvo therapy, the
`drug should be used with caution.
`In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk 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 precede
`appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid
`arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g)
`and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of
`cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis
`and its use may increase these figures. It is unknown whether even longer use will increase these risks.
`Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving Rasuvo for
`rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive
`alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C
`infection. During therapy, liver biopsy should be performed if there are persistent liver function test
`abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled
`rheumatoid arthritis).
`If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), Rasuvo may be continued and the
`patient monitored as per recommendations listed above. Rasuvo should be discontinued in any patient who
`displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy
`shows moderate to severe changes (Roenigk grade IIIb or IV).
`Infection or Immunologic States:
`Rasuvo should be used with extreme caution in the presence of active infection, and is contraindicated in patients
`with overt or laboratory evidence of immunodeficiency syndromes.
`Immunization may be ineffective when given during Rasuvo therapy. Immunization with live virus vaccines is
`generally not recommended. There have been reports of disseminated vaccinia infections after smallpox
`immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely.
`Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with Rasuvo
`therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia
`should be considered.
`
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`
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`

`

`Neurologic:
`There have been reports of leukoencephalopathy following intravenous administration of methotrexate to
`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
`lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2).
`Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications
`on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received
`repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation.
`Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic
`syndrome has been observed in patients treated with high dose regimens. Manifestations of this stroke-like
`encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is
`unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be
`classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal
`rigidity, and fever; sub- acute myelopathy characterized by paraparesis/paraplegia associated with involvement
`with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability,
`somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal.
`Pulmonary:
`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) or a non-specific pneumonitis occurring during
`Rasuvo therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and
`careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease
`presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including
`pneumonia) needs to be excluded. This lesion can occur at all dosages.
`Renal:
`Rasuvo may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the
`treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily
`to the precipitation of methotrexate and 7- hydroxymethotrexate in the renal tubules. Close attention to renal
`function including adequate hydration, urine alkalinization and measurement of serum methotrexate and
`creatinine levels are essential for safe administration.
`Skin:
`Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens- Johnson
`syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and
`adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions
`were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic
`and non-neoplastic diseases.
`Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
`Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.
`Other precautions:
`Rasuvo should be used with extreme caution in the presence of debility.
`Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a
`prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space
`accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
`5.2
`Embryo-Fetal Toxicity
`Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, Rasuvo 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. Rasuvo is contraindicated in pregnant women with psoriasis or
`rheumatoid arthritis.
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`Females of childbearing potential should not be started on Rasuvo until pregnancy is excluded and should be
`fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment.
`Appropriate steps should be taken to avoid conception during Rasuvo therapy. Pregnancy should be avoided if
`either partner is receiving Rasuvo; during and for a minimum of three months after therapy for male patients, and
`during and for at least one ovulatory cycle after therapy for female patients.
`5.3
`Effects on Reproduction
`Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in
`humans, during a