OTREXUP- methotrexate injection, solution
Antares Pharma, Inc.
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)].
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, 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 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, 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
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
4 CONTRAINDICATIONS
Otrexup is contraindicated in the following:
� Pregnancy
Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman.
OVERDOSAGE
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996).
Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion.
In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported.
Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported.
There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.
Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported.
There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.
11 DESCRIPTION
Otrexup contains methotrexate, a folate analog metabolic inhibitor.
Chemically, methotrexate is [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-Lglutamic acid.
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function.
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use)
Risk of Organ Toxicity
Inform patients of the risks of organ toxicity, including gastrointestinal, hematologic, hepatic, infections, neurologic, pulmonary, renal and skin as well as possible signs and symptoms for which they should contact their healthcare provider. Advise patients of the need for close follow-up, including periodic laboratory tests to monitor toxicity [see Warnings and Precautions (5.1 and 5.4)].
Importance of Proper Dosing and Administration
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly and that mistaken daily use of the recommended dose has led to fatal toxicity [see Dosing and Administration (2)].
Otrexup is intended for use under the guidance and supervision of a physician. Patients should not self-administer until they receive training from a healthcare professional. The patient's or caregiver's ability to administer Otrexup should be assessed. A trainer device is available for training purposes.
Patients should be instructed to use administration sites on the abdomen or the thigh. Administration should not be made within 2 inches of the navel. Instruct patients not to administer Otrexup to the arms or any other areas of the body, as delineated in the Otrexup Instructions for Use [see Instructions for Use].
Risks of Pregnancy and Reproduction
Advise patients that Otrexup can cause fetal harm and is contraindicated in pregnancy. Advise women of childbearing potential that Otrexup should not be started until pregnancy is excluded. Women should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Inform patients to contact their physician if they suspect that they are pregnant.
Advise patients that pregnancy should be avoided if either partner is receiving Otrexup; 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 [see Warnings and Precautions (5.2)].
Discuss the risk of effects on reproduction with both male and female patients taking Otrexup.
Inform patients that methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction, during and for a short period after cessation of therapy [see Use in Specific Populations (8.6)].
Nursing Mothers
Inform patients that Otrexup is contraindicated in nursing mothers [see Use in Specific Populations (8.3)].
Ability to Drive or Operate Machinery
Inform patients that adverse reactions such as dizziness and fatigue may affect their ability to drive or operate machinery.
Proper Storage and Disposal
Advise patients to store Otrexup at room temperature (68 to 77�F or 20 to 25�C). Inform patients and caregivers of the need for proper disposal after use, including the use of a sharps disposal container.
Address Medical Inquiries to:
Antares Pharma, Inc.
Medical Communications
100 Princeton South, Suite 300
Ewing, NJ 08628
1-855-Otrexup (1-855-687-3987)
Manufactured for:
Antares Pharma, Inc.
100 Princeton South, Suite 300
Ewing, NJ 08628 USAOtrexup� is the subject of US Patent Nos. RE44,846, 8,021,335, 6,746,429, RE44,847, 8,480,631, 8,562,564, 8,579,865 and 8,945,063.
�2016 Antares Pharma, Inc., Ewing, NJ 08628
