ZYMFENTRA is indicated in adults for maintenance treatment of: 

• moderately to severely active ulcerative colitis following treatment with an infliximab product administered intravenously.
• moderately to severely active Crohn's disease following treatment with an infliximab product administered intravetnously. 

2.1 Important Dosage Information

• ZYMFENTRA is indicated as maintenance treatment only, starting at Week 10 and thereafter.▫ All patients mush coplete an intravenous induction regimen with an infliximab product before starting ZYMFENTRA. For induction dosing information, see the corresponding full prescribing information for the chosen infliximab product.
• ZYMFENTRA is for subtutaneous use only.

2.2 Recommeneded Dosage for Maintenance Treatment in Ulcerative Colitis Crohn's Disease

• Maintenance dosage starting at Week 10 and thereafter: 120 mg subcutaneously once every two weeks. To switch patients who are responding to maintenance therapy with an infliximab product administered intravenously, administer the first subcutaneous dose of ZYMFNETRA in place of the next scheuled intravenous infusion and every two weeks thereafter. 

2.3 Subcutaenous Administration Instructions

• ZYMFENTRA is intended for use under the guidance and supervision of a healthcare professional. 
• If a healthcare professional determines that it is appropriate, patients may self-injection ZYMFENTRA or caregivers may injection ZYMFENTRA using either the ZYMFENTRA prefilled syringe, ZYMFENTRA prefilled syringe with needle guard, or ZYMFENTRA prefilled pen after proper training in subcutaenous injection technique. 
• Parental drug products should be inspected visually for particulate matter and discoloration prior to administration, whether solution and container permit. ZYMFENTRA should be a clear, colorless to pale brwon solution. Do not use if particulates or discoloration is presnet. 
• Inject into the front of the tights, the abdomen excepts for the 2 inches around the navel, or the outer area of the upper arms (caregiver only). 
• Rotate the injectoin site each time an inejction is given. Allow at least 1.2 inches between the new injection site and the previous inejction site. Never inject into areas where the skin is red, bruised, tender, or indurated. 
• Do not use the syringe or pen of it has been dropped or is visibly damaged. A damaged syringe may not function proprely. 
• Do not resue or shake the syringe or pen at any time.

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.

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.

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. 

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 (6.2)]. 

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. 

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. 

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. 

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. 

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.

5.9 Risk of Infection with Concurrent Administration with Other Biological Products

Serious infections and neutropenia have been reported with concurrent use of TNF-blockers and other immunosuppressive biological products (e.g., anakinra and abatacept). The concurrent use of ZYMFENTRA with other immunosuppressive biological products used to treat ulcerative colitis and Crohn’s disease may increase the risk of infection and is not recommended [see Drug Interactions (7.1)].

5.10 Risk of Additive Immunosuppressive Effects from Prior Biological Products

Consider the half-life and mode of action of prior biological products to avoid unintended additive immunosuppressive effects when initiating ZYMFENTRA [see Drug Interactions (7.1)].

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.

5.12 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents

6.1 Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 
• The data described below reflect exposure to ZYMFENTRA in 518 adult subjects in two 54-weekrandomized, double-blind, placebo-controlled trials in subjects with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) (UC Trial I an CD Trial I). Subject who achieved clinical response following three induction doses of infliximab-dyyb administered as an intravenous infusion at Week 0, 2 and 6 were randomized 2:1 to ZYMFENTRA 120 mg or placebo as a subcutaneous injection every two weeks at Week 10 [see Clinical Studies (14.1 and 14.2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of outside of the U.S with a non-U.S approved infliximab product administered subcutaneously. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 

• Infections and infestations: cellulitis, disseminated tuberculosis, lower respiratory tract infection, pneumonia, sepsis
• Neoplasms benign, malignant and unspecified: breast cancer, gastric cancer, lung cancer
• Nervous system disorders: multiple sclerosis
• General disorders and administration site conditions: fatigue, malaise

The following additional adverse ractions have been identified during post-approval use of infliximab products administered intravenously. 

• Neutropenia, agranuloxytosis (including infants exposed in utero to infliximab products), idiopathis thrombocytopenic purpura, thrombotic thrombocytopenic purpura. 
• Interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progessive disease). 
• Pericardial effusion, systemic and cutaneous vasculitis. 
• Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid react. 
• Preipheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy) transverse myelitis, and neuropathies (additional neurologic reactions have also been observed). 
• Acute liver failure, jaundice, hepatitis, and cholestasis. 
• Serious infections and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab products. 
• Malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer. 
• Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure. 
• Transient visual loss has been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported. 

7.1 Other Biological Products Used to Treat UC and CD 

The concurrent use of ZYMFENTRA with other immunosuppressive biological products used to treat UC and CD may increase the risk of infection and is not recommended [seeWarnings and Precautions (5.9)].

Consier the half-life and mode of action of prior biologial products to avoid unintended additive immunosuppressive effects when initiating ZYMFENTRA [seeWarnings and Precautions (5.10)].

7.2 Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, ZYMFENTRA, an antagonist of TNFα, could normalize the formation of CYP450 enzymes potentially resulting in a decrease in exposure of CYP450 substrates. 

Upon initiation or discontinuation of TNF blockers, including ZYMFENTRA, in patients being treated with CYP450 substrates requiring therapeutic drug monitoring, monitor therpeutic parameters (e.g., INR for warfarin) or drug concentration (e.g., cyclosporine or theophylline). Dosage adjustment may be needed to maintain drug concentrations or parameters within the therapeutic range. See prescribing information for specific drugs. 

7.3 Live Vaccines/Therapeutic Infectious Agents

It is recommended that live vaccines not be given concurrently with ZYMFENTRA. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab products for 6 months following birth [see Warnings and Precautions (5.12)]. 

It is recommended that therapeutic infectious agents not be given concurrently with ZYMFENTRA [see Warnings and Precautions (5.12)]. 

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established. 

8.5 Geriatirc Use

Clinical trials of ZYMFENTRA did not include sufficient numbers of sugjects aged 65 and over (8 subjects with UC and 6 subjects with CD) to determined whether they respond differently from younger subjects. 

12.1 Mechanism of Action

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 TNFα binding affinities, complement 1q (C1q) binding affinity and crystallizable fragment (Fc) receptor binding affinities in a wide variety of in vitro bioasays. The relationship of these biological response markers to the mechanism(s) by which infliximab-dyyb exerts its clinical effects is unknown.

12.2 Pharmacodynamics

No formal pharmacodynamic studies have been conducted. 

12.3 Phamacokinetics

Following single and multiple subcutaneous dosing of infliximab-dyyb, exposures to infliximab-dyyb (i.e., AUC) are proportionally increased over the dose range from 120 mg to 240 mg (2 times the recommended dosage). After a single subcutaneous dose of infliximab-dyyb 120 mg in healthy subjects, the median (SD) Cmax and AUCinf were 10.0 (3.2) mcg/mL and 6945.6 (2830.2) mcg·h/mL, respectively. Following recommended subcutaneous maintenance dose of ZYMFENTRA (120 mg every 2 weeks) in adult subjects with UC and CD from Week 10 after intravenous induction treatment with infliximab-dyyb, steady-state was achieved by Week 22, and the mean (SD) trough serum concentrations of infliximab-dyyb at steady-state were 14.6 (7.8) mcg/mL and 14.6 (8.9) mcg/mL in subjects with UC and CD, respectively. Pharmacokinetics are comparable between healthy subjects, and subjects with UC or CD.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Difference in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of infliximab-dyyb or of other infliximab products. 

In UC and CD clinical studies (UC Trial I and CD Trial I), approximately 64% subjects developed anti-drug antibodies to infliximab-dyyb following induction treatment with infliximab-dyyb intravenously and maintenance treatment with ZYMFENTRA by Week 54 [183/287 (64%) in subjects with UC, and 151/232 (65%) in subjects with CD] [see Clinical Studies (14)]. Among subjects with anti-drug antibodies, 92% had neutralizing antibodies [161/183 (88%) subjects with UC, and 147/151 (97%) subjects with CD]. Use of concomitant immunosuppressant agents (azathioprine, 6-mercaptopurine and methotrexate) appeared to reduce the frequency of ADA to infliximab-dyyb.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies of infliximab-dyyb have not been conducted to evaluate the carcinogenic potential or its effect on fertility. 

14.1 Adult Ulcerative Colitis

The safety and efficacy of ZYMFENTRA were assessed in a randomized, double-blind, placebo-controlled clinical trial (UC Trial I; NCT04205643) in adult subjects with moderately to severely active UC (defined as a modified Mayo score [mMS] between 5 to 9 with an endoscopic subscore [ES] of 2 or 3). The mMS is a 3-component Mayo score (0-9), which consists of following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration. 

Subjects had demonstrated an inadequate response or intolerance to treatment with corticosteroids alone or in combination with 6-mercaptopurine or azathioprine. Subjects were permitted to use stable doses of oral aminosalicylates, oral corticosteroids (prednisone ≤20 mg/day or equivalent, budesonide ≤9 mg/day), UC-related antibiotics, and/or immunomodulatory agents (azathioprine, 6-mercaptopurine, or methotrexate). Corticosteroid tapering was permitted after Week 10. 

All subjects received three intravenous induction doses of 5 mg/kg of infliximab-dyyb at Weeks 0, 2 and 6. In order to be randomized to treatment in UC Trial I, subjects had to be in clinical response at Week 10. Clinical response was defined as a decrease from baseline in the mMS of at least 2 points and at least 30%, with an accompanying decrease in the RBS of at least 1 point or an aabsolute RBS of 0 or 1 point. 

A total of 438 subjects were randomized at Week 10 in a double-blind fashion (2:1) to ZYMFENTRA 120 mg as a subcutaneous injection or placebo every two weeks. 

At the time of randomization into the double-blind phase (Week 10), 92% were receiving aminosalicylates, 41% were receiving oral corticosteroids, and 22% were receiving immunomodulators including AZA, 6-MP or MTX. 

A total of 10% of randomized subjects had prior exposure to biological poucts or JAK inhibitors. 

Subjects in the boule-blind phase had a mean age of 39 years (range 18 to 75 years); 44% were female; and 98% identified as White, and 2% as American Indian or Alaska Native. 

The primary endpoint was the proportion of subjects in clinical remission at Week 54. Wecondary endpoints included the proportion of subjects achieving histologic-endoscopic mucosal improvement and corticosteroid-fee remission at Week 54 (see Table 3). 

14.2 Adult Crohn's Disease

The safety and efficacy of ZYMFENTRA were assessed in a randomized, double-blind, placebo-controlled clinical studies (CD Trial I; NCT03945019) in adult subjects with moderately to severely active CD, defined as Crohn's Disease Activity Index (CDAI) score of 220 to 450 points, and a centrally-reveiwed Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD) of ≥6 points for ileal-colonic CD (or ≥4 points for isolated ileal disease). 

Subjects had demonstrated an inadequate response or intolerance to treatment with corticosteroids and/or immunosuppressants. Subjects were permitted to use stable doses of oral amisosalicylates, oral corticosteroids (prednisone ≤20 mg/day or equivalent, budesonide ≤9 mg/day), CD-related antibiotics and/or immunomodulatory agents (azathioprine, 6-mercaptopurine, or methotrexate). Corticosteroid dose was tapered after Week 10. 

All subjects received three intravenous induction doses of 5 mg/kg infliximab-dyyb at Week 0, 2 and 6. In order to be ranomized to treatment in CD Trial I, subjects had to be in clinical response at Week 10. Clinical response was defined as a decrease from baseline in CDAI of at least 100 points (i.e., CDAI-100 responders). 

A total of 323 subjects were randomized at Week 10 in a double-blind fashion (2:1) to ZYMFENTRA 120 mg as a subcutaneous injection or placebo every 2 weeks. 

At the time of randomization into thd double-blind phase (Week 10), 61% were receiving aminosalicylates, 40 % were receiving oral corticosteroids, and 32% were receiving immunomodulators including azathioprine, 6-mercaptopurine, or methotrexate. 

A total of 11% of randomized subjects had prior exposure to biological products. 

Subjects in the double-blind phase had a mean age of 35 years (range 18 to 75 years); 40% were female; and 91% identified as White, 4% identified as American Indian or Alaska Native, 4% identified as Asian, 0.3% as Black or African American, and 1% identified as another racial group. 

The co-primary endopoints were clinical remission (based on CDAI) and endoscopic response at Week 54. Secondary endpoints included endoscopic remission, and corticosteroid-free remission at Week 54 (see Table 4). 

How Supplied

ZYMFENTRA (Infliximab-dyyb) injection for subcutaneous use is supplied as a sterile, preservative-free, clear to opalescent, colorless to pale brown solution in a single-use prefilled syringe, prefilled syringe with needle guard or prefilled pen. The syringe is fitted with a needle shield which are not made with natural rubber latex or any derivatives from natural rubber latex in any ingredient. 

Storage and Handling

Store in refrigerator at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE. Keep the product in its outer carton until time of administration in order to protect from light. 

If needed, the product may be stored at room temperature at 20°C to 25°C (68°F to 77°F) for up to 14 days with protection from light. Once the product has been stored at room temperature, it should not be placed back into the refrigerator. The product must be discarded if not used within the 14 days.

Infections

Inform patients that ZYMFENTRA increases the risk for developing serious infections. Instruct patients of the importance of contacting their healthcare provider if they develop any symptoms of an infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections [see Warnings and Precautions (5.1, 5.3)]. 

Malignancies

Malignancies have been reported among children, adolescents and young adults who received treatment with TNF blockers. Patients should be counseled about the risk of lymphoma and other malignancies while receiving ZYMFENTRA [see Warnings and Precautions (5.2)].

Hepatotoxicity

Instruct patients to seek medical attention if they develop signs or symptoms of hepatotoxicity (e.g., jaundice) [see Warnings and Precautions (5.4)]. 

Congestive Heart Failure

Instruct patients to seek medical attention and consult their prescriber if they develop signs or symptoms of heart failure [see Warnings and Precautions (5.5)]. 

Hematologic Reactions

Instruct patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on ZYMFENTRA [seeWarnings and Precautions (5.6)]. 

Hypersensitivity

Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.7)]. 

Neurologic Reactions

Advise patients to seek medical attention if they develop signs or symptoms of neurologic reactions [seeWarnings and Precautions (5.8)]. 

Live Vaccines/Therapeutic Infectious Agents

Instruct ZYMFENTRA-treated patients to avoid receiving live vaccines or therapeutic infectious agents [seeWarnings and Precautions (5.12)]

Administration

Instruct patients to follow sharp disposal recommendations, as described in the Instructions for Use.