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Indications and Important Safety Information Including Boxed Warning

OTREXUP® (methotrexate) injection, for subcutaneous use

Indications:

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).
  • 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.

Limitations of Use:

OTREXUP is not indicated for the treatment of neoplastic diseases.

This product includes the following Boxed Warning:

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.

  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.
  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.
  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).
  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.
  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.
  6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
  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.
  8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  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.
  10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
  11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Contraindications:

OTREXUP is contraindicated in the following:

  • Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
  • Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
  • Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
  • Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
  • Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.

Warnings and Precautions:

  • Organ System Toxicity: 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. 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 OTREXUP closely.
    • Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
    • Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
    • Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
    • Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
  • Embryo-Fetal Toxicity: 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. In pregnant women OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
  • Effects on Reproduction: Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential.
  • Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
  • Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
  • Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
  • Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
  • Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
  • Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  • Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

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.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Drug Interactions:

  • Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids: Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate,. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
  • Proton Pump Inhibitors (PPIs): The concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
  • Oral Antibiotics: Certain oral antibiotics may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
  • Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
  • Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
  • Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
  • Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
  • Nitrous Oxide: The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate.
  • Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.

Use in Special Populations:

  • Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
  • Nursing Mothers: Because of the potential for serious adverse reactions 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: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. 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. 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. 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.
  • Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
  • 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: 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.

Dosage and Administration:

OTREXUP is for once weekly subcutaneous use only.

Administer OTREXUP in the abdomen or thigh.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

For full prescribing information including boxed warning, please click here.

Otrexup videoAbout Otrexup

Otrexup is easy to use for patients with RA

Otrexup has been designed to make it easy for patients to handle and inject their medicine.

What is Otrexup

Why use Otrexup?

More than 2 decades of scientific evidence have proven that oral methotrexate works.1 However, oral methotrexate may not work well enough or may not be tolerated well enough in some patients with RA.2 In these cases, doctors may switch patients from oral methotrexate to subcutaneous methotrexate.

Clinical evidence has shown the potential benefits of parenteral methotrexate compared with oral methotrexate.3-5 One recent study demonstrated no dose proportionality between oral and subcutaneous methotrexate above a dose of 15 mg.6

Indications

Otrexup is indicated in certain adults with severe, active rheumatoid arthritis, children with active polyarticular juvenile idiopathic arthritis (pJIA) and adults with severe, resistant, disabling psoriasis.7

 

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Designed for the rheumatoid arthritis patient.

References:

  1. Rezaei H, Saevarsdottir S, Forslind K, et al. In early rheumatoid arthritis, patients with a good clinical response to methotrexate have excellent 2-year clinical outcome, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial. Ann Rheum Dis. 2012;71:186-191.
  2. Yazici Y, Sokka T, Kautiainen H, et al. Long term safety of methotrexate in routine clinical care: discontinuation is usual and rarely the result of laboratory abnormalities. Ann Rheum Dis. 2005;64:207–211.
  3. Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58(1):73-8.
  4. Wegrzyn J, Adeleine P, Miossec P. “Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis.” Ann Rheum Dis. 2004;63;1232-1234.
  5. Mainman H, McClaren E, Heycock C, et al. When should we use parenteral methotrexate? Clin Rheumatol. 2010;29(10):1093-1098.
  6. Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study
of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73(8):1549-1551. 2
  7. Otrexup [prescribing information]. Ewing, NJ: Antares Pharma Inc.; 2016.

Indications and Important Safety Information Including Boxed Warning

OTREXUP® (methotrexate) injection, for subcutaneous use

Indications:

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).
  • 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.

Limitations of Use:

OTREXUP is not indicated for the treatment of neoplastic diseases.

This product includes the following Boxed Warning:

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.

  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.
  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.
  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).
  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.
  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.
  6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
  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.
  8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  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.
  10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
  11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Contraindications:

OTREXUP is contraindicated in the following:

  • Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
  • Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
  • Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
  • Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
  • Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.

Warnings and Precautions:

  • Organ System Toxicity: 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. 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 OTREXUP closely.
    • Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
    • Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
    • Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
    • Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
  • Embryo-Fetal Toxicity: 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. In pregnant women OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
  • Effects on Reproduction: Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential.
  • Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
  • Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
  • Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
  • Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
  • Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
  • Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  • Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

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.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Drug Interactions:

  • Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids: Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate,. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
  • Proton Pump Inhibitors (PPIs): The concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
  • Oral Antibiotics: Certain oral antibiotics may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
  • Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
  • Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
  • Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
  • Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
  • Nitrous Oxide: The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate.
  • Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.

Use in Special Populations:

  • Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
  • Nursing Mothers: Because of the potential for serious adverse reactions 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: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. 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. 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. 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.
  • Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
  • 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: 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.

Dosage and Administration:

OTREXUP is for once weekly subcutaneous use only.

Administer OTREXUP in the abdomen or thigh.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

For full prescribing information including boxed warning, please click here.

For more information, call 1-855-Otrexup (1-855-687-3987).    

Indications and Important Safety Information Including Boxed Warning

OTREXUP® (methotrexate) injection, for subcutaneous use

Indications:

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).
  • 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.

Limitations of Use:

OTREXUP is not indicated for the treatment of neoplastic diseases.

This product includes the following Boxed Warning:

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.

  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.
  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.
  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).
  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.
  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.
  6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
  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.
  8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  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.
  10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
  11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Contraindications:

OTREXUP is contraindicated in the following:

  • Pregnancy: OTREXUP can cause embryo-fetal toxicity and fetal death when administered during pregnancy.
  • Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
  • Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
  • Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
  • Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.

Warnings and Precautions:

  • Organ System Toxicity: 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. 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 OTREXUP closely.
    • Hematologic: OTREXUP can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. OTREXUP should be stopped immediately if there is a significant drop in blood counts.
    • Infection or Immunologic States: OTREXUP should be used with extreme caution in the presence of active infection.
    • Renal: OTREXUP may cause renal damage that may lead to acute renal failure.
    • Other Precautions: OTREXUP should be used with extreme caution in the presence of debility.
  • Embryo-Fetal Toxicity: 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. In pregnant women OTREXUP is contraindicated. Verify pregnancy status in females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during treatment with OTREXUP and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during OTREXUP treatment and for at least 3 months after the final dose.
  • Effects on Reproduction: Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential.
  • Laboratory Tests: Patients undergoing OTREXUP therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray.
  • Risks from Improper Dosing: Both the physician and pharmacist should emphasize to the patient that OTREXUP is administered weekly and that mistaken daily use has led to fatal toxicity.
  • Patients with Impaired Renal Function, Ascites, or Pleural Effusions: Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of OTREXUP administration.
  • Dizziness and Fatigue: Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.
  • Malignant Lymphomas: Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti- lymphoma treatment. Discontinue OTREXUP first and, if the lymphoma does not regress, appropriate treatment should be instituted.
  • Tumor Lysis Syndrome: Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
  • Concomitant Radiation Therapy: Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

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.” The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Drug Interactions:

  • Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids: Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate,. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including OTREXUP.
  • Proton Pump Inhibitors (PPIs): The concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
  • Oral Antibiotics: Certain oral antibiotics may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate. Use of OTREXUP with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate.
  • Hepatotoxins: Patients receiving concomitant therapy with OTREXUP and other potential hepatotoxins should be closely monitored for possible increased risk of hepatotoxicity.
  • Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with OTREXUP.
  • Folic Acid and Antifolates: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Folate deficiency states may increase methotrexate toxicity.
  • Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. The combination of OTREXUP and mercaptopurine may therefore require dose adjustment.
  • Nitrous Oxide: The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate.
  • Other Drugs: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs. Renal tubular transport is also diminished by probenecid; use of OTREXUP with this drug should be carefully monitored.

Use in Special Populations:

  • Pregnancy: Methotrexate has been reported to cause embryo-fetal toxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
  • Nursing Mothers: Because of the potential for serious adverse reactions 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: Verify the pregnancy status of females of reproductive potential prior to initiating OTREXUP. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of OTREXUP. 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. 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. 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.
  • Geriatric Use: Use caution in dose selection. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.
  • 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: 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.

Dosage and Administration:

OTREXUP is for once weekly subcutaneous use only.

Administer OTREXUP in the abdomen or thigh.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

For full prescribing information including boxed warning, please click here.

For more information, call 1-855-Otrexup (1-855-687-3987).    

Register now to receive updates about Otrexup.

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Privacy Policy Statement

I. Information We Collect

We may have access to the following categories of information regarding you and your visit to our website. Only some of these categories of information identify you directly, but each category offers some information about your interests and activities that could be used to make inferences about you. The next section of this Statement describes how Antares Pharma, Inc. (“Antares”) uses the information we collect.

Information That You Voluntarily Provide
Information That Is Routinely Collected By Our Site Technology:

II. How We Use Your Information

Whether you are a consumer or a health care professional, we use the information about your use of the services and activities on our website to monitor user traffic patterns and try to analyze what our users prefer so that we can design better services. The personally identifying information and health-related information that you provide may be used to create customized offers, information, and services tailored to your interests and preferences.

Personally Identifying Information. You do not have to register to use certain information and services available for consumers on our website. If you choose to register, we may use the personally identifying information you give us to send you an e-mail confirming your registration with our site and to respond to questions from you. Upon your request, we may also, from time-to-time, send you e-mail with special promotions or newsletters with information that we think may be of interest to you.

Health-Related Information. If you choose to participate in our interactive services, we will collect the information you choose to disclose and analyze it to discover new facts that could help us better understand how our products are used in coping with the diseases for which they are marketed.

We may offer interactive services such as health questionnaires and care management tools that ask you to furnish health-related information about you, your family members, or, if you are a health care provider, your patients. The information you disclose and provide in interactive services may be linked (pursuant to all applicable laws) with the personally identifying information you may choose to provide elsewhere on our site and together this may provide us with personally identifying information about your health and health care. We may combine your health-related information with that from other site users to create summary data that we will use for our business purposes, including research to improve our products and analyses that may help us better market our products.

If you submit health-related personal information through our website to participate in a clinical trial, we may use that information to assess whether you qualify for enrollment in the trial, to contact you about potential participation in the trial, and to provide you with additional information about the trial. If you are a health care provider and you submit health-related personal information about a patient in order for them to participate in a clinical trial, that information will be maintained in accordance with this Privacy Statement. If we determine that your patient is eligible for the trial, we will use the information you submit to contact you about your patient’s potential participation in the trial and to provide you with additional information.

Product Reports. If you contact Antares regarding your experience in using one of our products, we may use the information you provide in submitting reports to the U.S. Food and Drug Administration, and as otherwise required of us by law. We also may use the information to contact the prescribing physician to follow up regarding an unexpected event involving use of our product. IP Address. In addition to using the IP address of your computer to maintain communications with your computer as you move about our site, we also may use your IP address to personalize content provided on the website. We retain IP addresses, and we retain them together with personally identifying information.

Cookies. We use the data we obtain through the use of cookies to customize your site experience by anticipating the information and services that may be of interest to you. We also analyze the information collected with cookie technology to help us improve the functioning of our site by monitoring traffic in popular areas and to modify the services and information we provide to meet customer demand. We will link the clickstream data available to us through the use of cookies to the personally identifiable information and health-related information that you may choose to provide elsewhere on our site. We use the information we collect through the use of cookies for our business purposes, including operation of our site, as well as research and product analyses to help us better market our products.

Law Enforcement. In certain limited circumstances, Antares may be called upon to release your personal information in response to a court order, subpoena, search warrant, law, or regulation. We plan to cooperate in responding to such requests, taking appropriate measures to ensure that the requester understands the sensitive nature of the personally identifiable information or health-related personal information that the requester may receive. We also reserve the right to cooperate with law enforcement authorities in investigating and prosecuting users who violate our rules or engage in behavior that is illegal or harmful to other websites or their property.

III. Our Relationship To Third Parties

We may use third parties to provide services and information on our site and we may provide some co-branded services in partnership with others. We also may use third parties to analyze data collected on our site. We will not disclose your personally identifying information or health-related personal information to anyone other than Antares employees and those third parties with whom we have a business relationship. If we allow a third party contractor to have access to your personally identifying information or health-related personal information, we will not authorize them to take it or use it for any purpose that is not consistent with this Privacy Statement.

We pledge that we will not sell or disclose any personally identifying information or health-related personal information you provide on our site to an unrelated third party without your express permission, except as explained in this Privacy Statement.

Other Important Information About Our Relationship With Third Parties

IV. Our Children’s Policy

Antares’s website content and services are intended for users over the age of 13. Our site is not designed to attract child users. If we learn that an under-13 user has volunteered personal or health-related information on our site, or that a provider has volunteered information about a patient who is identified as younger than 13, we will delete such information from our active databases in accordance with our deletion policy, which is described in the section below on Your Privacy Choices.

V. Your Privacy Choices

When you access any interactive tool or service on an Antares website, you will be asked to affirmatively choose (“opt-in”) to provide the requested information. You may always choose not to provide the requested information.

Receive E-mail. When you register with our site, you will be given the option of requesting to receive e-mail with information we think you might find useful, including promotions, announcements of new services and products, and newsletters on particular health topics.

Accept Cookies. Your browser software can be set to reject all cookies, but if you reject our cookies, certain aspects of the functions and conveniences of our site may not work properly. Cookies and similar technologies are how we ensure that we can promptly retrieve and deliver the information to you when you use our site.

Deletion Practices. The information that you provide Antares is stored in servers that are operated and maintained by Antares and third parties under contract with Antares. Website users should be aware that it is not technologically possible to remove from our servers each and every record of the information you have provided to Antares. The need to back-up our systems to protect information from inadvertent loss means that a copy of information about you or your health-related interests may exist in non-erasable forms that will be difficult or impossible for us to locate. Nevertheless, we promise that upon receiving your request, Antares will delete all personal and/or health-related personal information stored in the databases Antares actively uses for research and daily business activities, or otherwise stored in readily searchable media. In addition, we will use commercially reasonable efforts not to disclose any personal information stored in a non-erasable format after receiving your request for removal, except as required by law.

Please be aware that Antares may not comply with a consumer’s request to amend or remove information that was provided to Antares by a health care professional or a consumer regarding an adverse drug event.

Communicate With Antares By E-mail. At our website, consumers and providers may communicate with our staff to learn more about our products and services. We also offer interactive tools that enable consumers and health care professionals to submit customized e-mail requests for information about diseases and therapies. Please be aware of the limits on the confidentiality of these e-mail communications. We will not disclose personally identifiable information that we receive in e-mail, but all e-mail transmissions are vulnerable to unauthorized interception. In addition, we remind you that e-mail sent or received through an employer’s computer or computer system is not confidential and may be the legal property of the employer.

VI. Our Security Measures

We want your and your patient’s, if you are a health care professional, personal information to remain as secure as reasonably possible. Our success at improving our products and services depends upon your or your patients’ willingness to share information about patient health and health care with Antares.

Data Security. We use encryption practices to help insure the integrity and privacy of some of the personal and health-related personal information you provide to us. All personal and/or health-related personal information is kept physically behind firewalls that prevent intruders from gaining access. As an added security precaution, we deploy various methods of protection such as host intrusion prevention and detection systems to maintain the integrity and confidentiality of data. Although we will make reasonable efforts to protect personal and/or health-related personal information from loss, misuse, or alteration by third parties, you should be aware that there is always some risk that an unauthorized third party could intercept an Internet transmission, or that someone will find a way to thwart our security systems.

VII. Changes In Our Privacy Statement

We will only use personal information in the manner described in the Privacy Statement in effect when the information was collected from you. However, we reserve the right to change the terms of this Privacy Statement at any time by posting revisions to our site. If at any point, we decide to use personally identifiable information or health-related personal information in a manner different from that stated at the time it was collected, you will be given a choice to allow or disallow any additional uses or disclosures of your personally identifiable information or health-related personal information.

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This Terms of Use Agreement (this “Agreement”) describes the terms and conditions applicable to your use of any and all of Antares Pharma, Inc.’s and/or its affiliates (collectively “Antares”) or Antares co-branded websites. If you do not agree to the terms and conditions of this Agreement, please do not use this website. Your use of certain pages or services within this website may be subject to additional terms and conditions. Before being given access to these pages or services, you will be asked to indicate whether you agree to be bound by the additional terms and conditions. If you agree to be bound, you will be given access to the page or service. If you do not agree to be bound, you will not be given access to the page or service.

Antares may at any time revise or modify this Agreement or impose new conditions for use of this website. Such changes, revisions or modifications shall be effective immediately upon notice to you, which may be given by any means including, without limitation, posting on the website or by e-mail. Any use of the website by you after such notice shall be deemed to constitute acceptance of such changes, revisions or modifications. Antares may modify its services at any time.

THIS WEBSITE DOES NOT PROVIDE MEDICAL OR PROFESSIONAL SERVICES ADVICE.

The content on this website is intended to be a general information resource in regard to the subject matter covered, and is provided solely on an “AS IS” and “AS AVAILABLE” basis. You are encouraged to confirm the information contained herein with other sources, and to review the information carefully with your professional health care provider. Antares is not engaged in rendering medical or similar professional services or advice via this website, and the information provided is not intended to replace medical advice offered by a physician. If you desire or need such services or advice, you should consult a professional health care provider. You should not construe Antares’s publication of this content as an endorsement by Antares of the views expressed herein, or any warranty or guarantee of any strategy, recommendation, treatment, action, or application of medication or preparation made by the author of the content.

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Antares invites you to view, use and download a single copy of this website for your informational, personal, non-commercial use. Except as otherwise provided on this page, no part of any content or software on this website may be copied, downloaded or stored in a retrieval system for any other purpose, nor may it be redistributed for any purpose, without the express written permission of Antares. You understand that Antares may discontinue, change, or restrict your use of this website for any reason without notice.

This website is for use by U.S. residents only. By using this website, you represent that you are at least eighteen (18) years old and a United States resident.

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The above exclusions may not apply in jurisdictions that do not allow the exclusion of certain implied warranties.

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The website may contain information, news and/or press releases about Antares. While this information was believed to be accurate as of the date it was prepared, Antares disclaims any duty or obligation to update this information, news or any press releases. Information about companies other than Antares contained in the news, press releases or otherwise, should not be relied upon as being provided or endorsed by Antares.

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This Antares website may contain links to websites operated by other parties. The linked sites are not under the control of Antares, and Antares is not responsible for the content available on any other Internet sites linked to this website. Such links do not imply Antares’s endorsement of material on any other site and Antares disclaims all liability with regard to your access to such linked websites. Antares provides links to other Internet sites as a convenience to users, and access to any other Internet sites linked to this website is at your own risk.

Unless otherwise set forth in a written agreement between you and Antares, you must adhere to Antares’s linking policy as follows: (i) any link to an Antares website must be a text only link clearly marked “Antares WEBSITE,” (ii) the appearance, position and other aspects of the link may not be such as to damage or dilute the goodwill associated with Antares’s names and trademarks, (iii) the link must “point” to the root domain name of the Antares website and not to other pages within the website, (iv) the appearance, position and other attributes of the link may not create the false appearance that your organization or entity is sponsored by, affiliated with, or associated with Antares, (v) when selected by a user, the link must display the website on full-screen and not within a “frame” on the linking website, and (vi) Antares reserves the right to revoke its consent to the link at any time and in its sole discretion.

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This website may require you to register or obtain a password prior to permitting access to the website or certain services available on this site. You are responsible for maintaining the confidentiality of your registration information and password, and for all uses of your password, whether or not authorized by you.

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This website is operated by Antares. The law of the State of Delaware shall govern these terms and conditions, without reference to its choice of law rules. Antares makes no representation that the information in the website is appropriate or available for use in other locations, and access to this website from territories where the content of this website may be illegal is prohibited. Those who choose to access this website from other locations do so on their own initiative and are responsible for compliance with applicable local laws.

Any controversy or claim arising under or related to this User Agreement or Antares’s products and/or services shall be settled by binding arbitration in accordance with the commercial rules of arbitration of the American Arbitration Association. Any such controversy or claim shall be arbitrated on an individual basis, and shall not be consolidated in any arbitration with any claim or controversy of any other party. The arbitration shall be conducted in the State of Delaware, and judgment on the arbitration award may be entered by any court of competent jurisdiction. Either you or Antares may seek any interim or preliminary relief from a court of competent jurisdiction in the state of Delaware, necessary to protect the rights or property of you or Antares pending the completion of arbitration.

Violations and Additional Policies

Antares reserves the right to seek all remedies available at law and in equity for violations of these Terms of Use, including the right to block access from a particular Internet address to the website.

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This website may include statements concerning Antares’s operations, prospects, strategies, financial condition, future economic performance and demand for Antares’s products or services, as well as its intentions, plans and objectives, that are forward-looking statements. These statements are based upon a number of assumptions and estimates which are subject to significant uncertainties, many of which are beyond our control. When used on the website, words like “anticipates,” “expects,” “believes,” “estimates,” “seeks,” “plans,” “intends” and similar expressions are intended to identify forward-looking statements designed to fall within securities law safe harbors for forward looking statements. The website and the information contained herein does not constitute an offer or a solicitation of an offer for sale of any securities. None of the information contained herein is intended to be, and shall not be deemed to be, incorporated into any of Antares’s securities-related filings or documents.

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If you have any questions about these Terms of Use, please contact Antares at +1 (609) 359 3020. For all other inquiries, please contact us through the relevant product, support or Antares website.