Zymfentra

ZYMFENTRA (infliximab-dyyb) is a clear, colorless to pale brown solution available as follow: 

• Injection: 120 mg/mL in a single-dose prefilled syringe.
• Injection: 120 mg/mL in a single-dose prefilled syringe with needle guard. 
• Injection: 120 mg/mL in a single-dose prefilled pen.

The following clinically significant adverse reactions are described elsewhere in the labeling: 

• Serious infections [
  see
  Warnings and Precautions (

  5.1 Serious Infections

  Patients treated with ZYMFENTRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.

  Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

  Treatment with ZYMFENTRA should not be initiated in patients with an active infection, including clinically important localized infections.Patients greater than 65 years of age, patients with comorbid-conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

  • with chronic or recurrent infection;
  • who have been exposed to tuberculosis;
  • with a history of an opportunistic infection;
  • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
  • with underlying conditions that may predispose them to infection.

  Tuberculosis

  Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating ZYMFENTRA and periodically during therapy.

  Treatment of latent tuberculosis infection prior to therapy with TNF blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating ZYMFENTRA even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).

  Consider anti-tuberculosis therapy prior to initiation of ZYMFENTRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

  Tuberculosis should be strongly considered in patients who develop a new infection during treatment with ZYMFENTRA especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

  Monitoring

  Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ZYMFENTRA including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with ZYMFENTRA.

  Discontinue ZYMFENTRA if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with ZYMFENTRA should undergo prompt and complete diagnostic workup appropriate for an immunocompromised patient; and appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

  Invasive Fungal Infections

  For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

  )
  ] 
• Malignancies [
  see
  Warnings and Precautions (

  5.2 Malignancies

  Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blockers (initiation of therapy ≤

  18 years of age), including infliximab products.

  AApproximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

  Lymphomas

  In the controlled portions of clinical trials of TNF blockers, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use, including infliximab products.

  Hepatosplenic T-cell Lymphoma (HSTCL)

  Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. TThese cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use ZYMFENTRA alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with TNF blocker monotherapy from the clinical trial data [

  see Warnings and Precautions

  ]

  Skin Cancer

  Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients during treatment with ZYMFENTRA, particularly those with risk factors for skin cancer.

  Cervical Cancer

  Cases of invasive cervical cancer have been reported postmarketing in women who received infliximab products for other conditions. A causal relationship between infliximab products and cervical cancer cannot be excluded. Routine cervical cancer screening is recommended during treatment with ZYMFENTRA.

  Other Malignancies

  In the controlled pportions of clinical trials of some TNF blockers, including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer) have been observed in patients receiving those TNF blockers compared with control patients. The most common malignancies were breast, colorectal, and melanoma in these controlled trials of TNF blockers.

  In controlled trials of TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater proportion of malignancies occurred in the TNF blocker group compared to the control group. Patients had a history of heavy smoking. Avoid ZYMFENTRA in patients with moderate to severe COPD.

  The potential role of TNF blockers in the development of malignancies is not known. Avoid ZYMFENTRA treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving ZYMFENTRA.

  )
  ]
• Hepatitis B virus reactivation [
  see
  Warnings and Precautions (

  5.3 Hepatitis B Virus Reactivation

  Use of TNF blockers has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.

  Test patients for HBV infection before initiating TNF blocker therapy, including ZYMFENTRA. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers, including ZYMFENTRA, should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.

  In patients who develop HBV reactivation, discontinue ZYMFENTRA and initiate antiviral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of ZYMFENTRA in this situation and monitor patients closely.

  )
  ]
• Hepatotoxicity [
  see
  Warning and Precautions (

  5.4 Hepatotoxicity

  Hepatobiliary disorders, including acute liver failure, jaundice abnormal hepatic function, hepatic steatosis, hepatitis, hepatotoxicity, hyperbilirubinemia and non-alcoholic fatty liver, have been reported in postmarketing data in patients receiving infliximab products. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between two weeks to more than one year after initiation of infliximab products administered intravenously; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation.

  In clinical trials, three subjects treated with ZYMFENTRA had drug induced liver injury based on hepatic transaminase elevations, including one subject with accompanying bilirubin elevation [

  see Adverse Reactions

  ].

  Monitor hepatic enzymes and liver function tests every 3 to 4 months during treatment with ZYMFENTRA. Prompt investigation of the cause of liver enzyme elevation should be undertaken to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfuction.

  )
  ]
• Congestive heart failure [
  see
  Warnings and Precautions (

  5.5 Congestive Heart Failure

  Cases of worsening congestive heart failure (CHF) and new onset CHF, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), have been reported with TNF blockers, including infliximab products. Some of these patients have been under 50 years of age, and some cases had a fatal outcome. In several exploratory trials of other TNF blockers in the treatment of CHF, there were greater proportions of TNF-blocker-treated patients who had CHF exacerbations requiring hospitalization or increased mortality. ZYMFENTRA has not been studied in patients with a history of CHF. Avoid ZYMFENTRA in patients with CHF.

  If a decision is made to administer ZYMFENTRA to patients with CHF, closely monitor patients during therapy for new or worsening symptoms of heart failure and discontinue ZYMFENTRA if symptoms appear

  .

  )
  ]
• Hematologic reactions [
  see
  Warnings and Precautions (

  5.6 Hematologic Reactions

  Report of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab products. Clinically significant events of neutropenia were noted in the clinical trials of ZYMFENTRA. The causal relationship to infliximab product therapy remains unclear. Although no high-risk group(s) has been identified, avoid ZYMFENTRA in patients who have ongoing or a history of significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) during treatment with ZYMFENTRA. Consider discontinuation of ZYMFENTRA therapy in patients who develop significant hematologic

  abnormalities.

  )
  ]
• Hypersensitivity and other administration reactions [
  see
  Warnings and Precautions (

  5.7 Hypersensitivity and Other Administration Reactions

  In clinical trials of ZYMFENTRA, symptoms compatible with hypersensitivity reactions have been reported including bronchospasm, dyspnea, rash, and edema. In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylaxis, hypotension, and serum sickness) have been reported following administration of infliximab products. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA. There are no data on the risks of using ZYMFENTRA in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients, caution is

  needed.

  )
  ] 
• Neruologic reactions [
  see
  Warnings and Precautions (

  5.8 Neurologic Reactions

  Agents that inhibit TNF have been associated with central nervous system (CNS) manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Avoid the use of ZYMFENTRA in patients with these neurologic disorders and consider discontinuation of ZYMFENTRA if these disorders develop.

  )
  ]
• Autoimmunity [
  see
  Warnings and Precautions (

  5.11 Autoimmunity

  Treatment with TNF blockers, iincluding ZYMFENTRA may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with ZYMFENTRA, discontinue treatment.

  )
  ]

Infliximab-dyyb, a tumor necrosis factor (TNF) blocker, is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions). It has a molecular weight of approximately 145.9 kDa. Infliximab-dyyb is produced by a recombinant murine myeloma cell line, SP2/0. 

ZYMFENTRA (inifliximab-dyyb) injection for subcutaneous use is a sterile, preservative-free, clear to opalescent, colorless to pale brown solution. 

ZYMFENTRA is supplied in a single-dose prefilled syringe with 29 gauge fixed 1/2 inch needle, prefilled syringe with 29 gauge fixed 1/2 inch needle with needle guard, or prefilled pen with 27 gauge fixed 1/2 inch needle. 

Read and follow the Instructions for Use that come with your ZYMFENTRA Prefilled Syringe before you start using it and each time you get a refill. There may be new information. This information dose not take the place of talking to your healthcare provider about your medical condition or treatment.

• Use the Prefilled Syringe 
  only if
   your healthcare provider has trained you on the right way to prepare for and to give an injection.
• Ask your healthcare provider how often you will need to give an injection.
• Rotate the injection site each time you give an injection. Each new injection site should be at least 1.2 inches away from the previous injection site.
• Do not
  use Prefilled Syringe if it has been dropped or is visibly damaged.
• Do not
  reuse the Prefilled Syringe.
• Do not
   shake the Prefilled Syringe at any time.
• Do not
   share the Prefilled Syringe with anyone.
• Do not
  pull back on the plunger rod at any time.
• Only use each Prefilled Syringe for one injection.

• Store the Prefilled Syringe in a refrigerator between 36°F to 46°F (2°C to 8°C).
• Keep the Prefilled Syringe in the original carton until use to protect it from light.
• Do not
  use the Prefilled Syringe that has been left in direct sunlight.
• Do not
   freeze the Prefilled Syringe. If the Prefilled Pen has been frozen, 
  do not
   use the Prefilled Syringe even if it is thawed.
• Do not
  warm the Prefilled Syringe using heat sources such as hot water or a microwave. Let the Prefilled Syringe naturally warm at room temperature between 68°F to 77°F (20°C to 25°C) for 30 minutes before giving an injection.
• When the Prefilled Syringe has reached room temperature,
  do not
  put it back in the refrigerator. The Prefilled Syringe must be thrown away (discarded) if not used within the 14 days. 
• Keep the Prefilled Syringe and all medicines out of the reach of children.

1a. Prepare a clean, flat surface, such as a table or countertop, in a well-lit area.

1b. Remove 1 Prefilled Syringe from the carton by holding the middle of the Prefilled Syringe Body.

• Do not
  touch the plunger rod.

Note: Return the carton with any unused Prefilled Syringe to the refrigerator immediately after taking out one Prefilled Syringe.

1c. Make sure you have the following supplies:

- Prefilled Syringe

- Alcohol swab

2. Inspect the Prefilled Syringe. 2a. Make sure you have the correct medicine (ZYMFENTRA). 2b. Check the expiration (EXP) date on the label of the Prefilled Syringe (See Figure B). 2c. Look at the Prefilled Syringe and make sure it is not cracked or damaged. Do not  use the Prefilled Syringe if: - it is cracked or damaged. - the expiration (EXP) date has passed.	Figure B
3. Inspect the Medicine. 3a. Look through the Viewing Window and check that the liquid is clear and colorless to pale brown, and free of particles (see Figure C). Do not  use the Prefilled Syringe if the liquid is wrong color, cloudy, or contains particles in it. You may see air bubbles in the liquid. This is normal.	Figure C
4. Wait 30 minutes. 4a. Leave the Prefilled Syringe at room temperature 68°F to 77°F (20°C to 25°C) for 30 minutes to allow it to warm up (see Figure D). Do not  warm the Prefilled Syringe using heat sources such as hot water or a microwave.	Figure D
5. Choose an injection site (see Figure E). 5a. You may inject into: - the front of your thighs. - the stomach area (abdomen) except for the 2 inches around the belly button (navel). - the outer area of the upper arm ( caregiver only ). Do not  inject into skin that is within 2 inches of your belly button (navel), or is red, hard, tender, damaged, bruised, or scarred. Do not  inject through your clothes. 5b. Rotate the injection site each time you give an injection. Do not injection the same injection site each time you five an injection. Each new injection site should be at least 1.2 inches away from the previous injection site.	Figure E
6. Wash your hands. 6a. Wash your hands with soap and water and dry them thoroughly (see Figure F).	Figure F
7. Clean the injection site. 7a. Clean the injection site with an alcohol swab (see Figure G). 7b. Let the skin dry before injecting. Do not  blow on or touch the injection site again before giving the injection.	Figure G
Give the injection
8. Remove the Cap. 8a. Hold the Prefilled Syringe by the injector body with the Cap on top using one hand. Gently pull the Cap straight off with the other hand. Do not  pull back on plunger rod at any time. Do not  remove the Cap until you are ready to inject. Do not try to put the Cap back onto the Prefilled Syringe. Do not  touch the Needle. 8b. Throw away (dispose of) the Cap in an FDA cleared sharps container (see Step 12 and Figure H).	Figure H
9. Insert the Prefilled Syringe into the injection site. 9a. Hold the Prefilled Syringe by its body in one hand between your thumb and index finger. 9b. Gently pinch a fold of skin at the injection site with one hand. 9c. Witha quick and “dart-like” motion, insert the Needle completely into the fold of the skin at a 45-defree angle (see Figure I). Ÿ   Do not change the position of the Prefilled Syringe after the injection has started.	Figure I
10. Give the injection. 10a. After the Needle is inserted, release the pinched skin. 10b. Push the Plunger down slowly and as far as it will go until the Prefilled Syringe is empty (See Figure J). Note: The Needle Guard will not activate unless all the Medicines is injected.	Figure J
11. Remove the Prefilled Syringe from the injection site. 11a. After the Prefilled Syringe is empty, slowly lift your thumb from the Plunger until Needle is completely covered by the Neeld Guard (see Figure K). Do not  reuse the Prefilled Syringe. Do not touch the Needle. Some bleeding may occur. Do not  rub the injection site.	Figure K
After the injection
12. Throw away (dispose of) the Prefilled Syringe. 12a. Put the used Prefilled Syringe in an FDA-cleared sharps disposal container immediately after use (see Figure L). Do not try to put the Cap back onto the Prefilled Syringe. Do not  throw away (dispose of) the Prefilled Syringe in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - able to closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to disposal of it. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.	Figure L
13. Care for the injection site. 13a. Treat the injection site by gently pressing a cotton ball or gauze to the site and apply an adhesive bandage, if necessary.
Manufactured by: CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea US License Number 1996 Distributed by: CELLTRION USA, Inc., 1 Evertrust Plaza Suite 1207, Jersey City, NJ 07302

Infliximab-dyyb neutralize the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibit binding of TNFα with its receptors. Infliximab-dyyb has shown biological activities, such as TNFα neutralization activity and