Dosage & Administration
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Otrexup Prescribing Information
Otrexupshould 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),Otrexupshould 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 can cause embryo-fetal toxicity, including fetal death.
Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Otrexup [see Contraindications ( 4), Warnings and Precautions ( 5.2), and Use in Specific Populations ( 8.1, 8.3)].
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 ofOtrexupadministration [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 somenonsteroidalanti-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 underlong-termtreatment. 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. DiscontinueOtrexupfirst 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 “tumorlysissyndrome” 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, orintrathecalmethotrexate administration. Recovery has been reported with discontinuation of therapy [see Warnings and Precautions ( 5.1)] .
10. Potentially fatal opportunistic infections, especially Pneumocystisjirovecipneumonia, 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)] .
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).
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.
Limitation of Use
Otrexup is not indicated for the treatment of neoplastic diseases.
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: 10, 12.5, 15, 17.5, 20, 22.5 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 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments between the available doses.
Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis
Recommended starting dose of methotrexate:
Adult RA:7.5 mg once weekly.
pJIA:10 mg/m 2once 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/m 2/wk in children, there are too few published data to assess how doses over 20 mg/m 2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m 2/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 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.
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.
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 drugs 1.
Pregnancy testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with Otrexup [see Use in Specific Populations ( 8.1, 8.3)] .
Otrexup is an injection available as an autoinjector that administers a single 0.4 mL dose of methotrexate solution in the following dosage strengths:
- 10 mg/0.4 mL methotrexate
- 12.5 mg/0.4 mL methotrexate
- 15 mg/0.4 mL methotrexate
- 17.5 mg/0.4 mL methotrexate
- 20 mg/0.4 mL methotrexate
- 22.5 mg/0.4 mL methotrexate
- 25 mg/0.4 mL methotrexate
Pregnancy
Risk Summary
Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1)] . In pregnant women with non-malignant disease, Otrexup is contraindicated. Consider the benefits and risks of Otrexup and risks to the fetus when prescribing Otrexup to a pregnant patient. 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
Lactation
Risk Summary
Limited published literature report the presence of methotrexate in human milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Otrexup and for one week after the final dose.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating Otrexup.
Contraception
Females
Otrexup can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .
Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Otrexup.
Males
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 dose of Otrexup.
Infertility
Females
Based on published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Otrexup 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 treatment with methotrexate, advise males of reproductive potential that Otrexup 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.
Pediatric Use
The safety and effectiveness of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis.
The safety and effectiveness of Otrexup have not been established in pediatric patients with neoplastic diseases.
The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies ( 14.2)] .
Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [ see Adverse Reactions ( 6.1) ].
Otrexup does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.
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/m 2) [see Warnings and Precautions ( 5.1)] .
Geriatric Use
Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population [see Warnings and Precautions ( 5.1), Drug Interactions ( 7.7) and Use in Specific Populations ( 8.6)]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see Warnings and Precautions ( 5.1)].
Renal Impairment
Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Otrexup administration.
Hepatic Impairment
The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Otrexup is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely [see Warnings and Precautions ( 5.1)] .
Otrexup is contraindicated in the following:
• Pregnancy
Otrexup can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions ( 5.2) and Use in Specific Populations ( 8.1)].
• 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 BloodDyscrasias
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 ( 6.1and 6.2)].