Zessly

Uses

Crohn’s Disease:

• Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
• Reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.

• Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

• Reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

• Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

• Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.

• Reducing signs and symptoms in patients with active disease.

• Reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.

• Treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

Zessly is also used to associated treatment for these conditions: Ankylosing Spondylitis (AS), Crohn's Disease (CD), Psoriasis Vulgaris (Plaque Psoriasis), Psoriatic Arthritis, Rheumatoid Arthritis, Ulcerative Colitis

How Zessly works

Zessly is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors. Zessly does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α . Blocked actions of TNF-α further leads to downregulation of local and systemic pro-inflammatory cytokines (i.e. IL-1, IL-6), reduction of lymphocyte and leukocyte migration to sites of inflammation, induction of apoptosis of TNF-producing cells (i.e. activated monocytes and T lymphocytes), increased levels of nuclear factor-κB inhibitor, and reduction of reduction of endothelial adhesion molecules and acute phase proteins . Its inhibitory actions on TNF-α was demonstrated in human fibroblasts, endothelial cells, neutrophils, B and Tlymphocytes and epithelial cells . Zessly also atteunates the production of tissue degrading enzymes synthesized by synoviocytes and/or chondrocytes. According to a transgenic mice study that developed polyarthritis due to consitutive levels of human TNF-α, infliximab decreased synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal .

Dosage

Zessly dosage

Crohn’s Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

Pediatric Crohn’s Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Ulcerative Colitis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Pediatric Ulcerative Colitis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Rheumatoid Arthritis: In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10
mg/kg or treating as often as every 4 weeks.

Ankylosing Spondylitis: 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.

Psoriatic Arthritis and Plaque Psoriasis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Zessly is administered by intravenous infusion over a period of not less than 2 hours.

Side Effects

Most common adverse reactions (>10%)- infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

Toxicity

In an acute toxicity animal study, the NOAEL of intravenous infliximab in rats was 50 mg/kg. In a repeated dose animal study, the NOAEL values of intravenous infliximab was 50 mg/kg in rats at 2 weeks following 3 doses and 40 mg/kg/day in mice at 6 months .

The toxicological potential of infliximab in humans has not yet been fully established. According to an analogous antibody study, infliximab is not predicted to induce tumorigenic, clastogenic or mutagenic effects. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study .

Precaution

Serious infections- do not give Zessly during an active infection. If an infection develops, monitor carefully and stop Zessly if infection becomes serious.

Invasive fungal infections- for patients who develop a systemic illness on Zessly, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic

Malignancies- the incidence of malignancies including lymphoma was greater in Zessly treated patients than in controls. Due to the risk of HSTCL carefully assess the risk/benefit especially if the patient has Crohn’s disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment.

Hepatitis B virus reactivation- test for HBV infection before starting Zessly. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop Zessly and begin anti-viral therapy.

Hepatotoxicity- rare severe hepatic reactions, some fatal or
necessitating liver transplantation. Stop Zessly in cases of jaundice and/or marked liver enzyme elevations.

Heart failure- new onset or worsening symptoms may occur.

Cytopenias- advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping Zessly.

Hypersensitivity- serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. 

Demyelinating disease- exacerbation or new onset may occur.

Lupus-like syndrome- stop Zessly if syndrome develops.

Live vaccines or therapeutic infectious agents- should not be given with Zessly. Bring pediatric patients

Interaction

Use with anakinra or abatacept- increased risk of serious infections

Food Interaction

Zessly Drug Interaction

Major: adalimumab, adalimumab, azathioprine, azathioprineModerate: atorvastatin, atorvastatinUnknown: sucralfate, sucralfate, celecoxib, celecoxib, sodium iodide, sodium iodide, acetaminophen, acetaminophen, mesalamine, mesalamine, cholecalciferol, cholecalciferol, cetirizine, cetirizine

Zessly Disease Interaction

Major: heart failure, liver disease, infections, malignancies, neurologic reactions, tuberculosisModerate: COPD, hematologic abnormalities, hepatitis B

Volume of Distribution

Based on a pharmacokinetic study of adult patients, the distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment .

In patients with Crohn's disease, the apparent volume of distribution at steady state (Vss) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 80 mL/kg and 65 mL/kg, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Vss of 70 mL/kg and 81 mL/kg , respectively .

In patients with rheumatoid arthritis, the Vss of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 4.3±2.5 L, 3.2±0.7 L, and 3.1±0.6 L, respectively .

Elimination Route

Following a single intravenous infusion, infliximab absorption displays a linear relationship between the dose administered and the maximum serum concentration .

In patients with Crohn's disease, the maximum plasma concentration (Cmax) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 75 µg/mL and 181 µg/mL, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Cmax of 120 µg/mL and 189 µg/mL , respectively .

In patients with rheumatoid arthritis, the Cmax of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 192±51 µg/mL, 427±106 µg/mL, and 907±183 µg/mL, respectively .

Half Life

The median terminal half-life of infliximab is 7.7 to 9.5 days. The data is based on a pharmacokinetic study in patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis receiving a single dose of infliximab .

Clearance

In patients with Crohn's disease, the total body clearance (CL) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 18.4 mL/h and 14.3 mL/h, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in CL of 15.2 mL/h and 15.2 mL/h, respectively .

In patients with rheumatoid arthritis, the CL of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 11±7.5 mL/h, 11.4±5 mL/h, and 11±8.9 mL/h, respectively .

Development of antibodies to infliximab increased infliximab clearance .

Elimination Route

Therapeutic monoclonal antibodies including infliximab are predicted to be nonspecifically metabolized to peptides and amino acids that can be re-used in the body for de novo synthesis of proteins or arc excreted by the kidney . The reticuloendothelial system (RES) are phagocytic cells of the immune system such as macrophages and monocytes that play a role in the elimination of endogenous IgG antibodies. Although administered infliximab accounts for a small fraction of total endogenous IgG and this route is not likely saturated by therapeutic mAbs, infliximab may be removed by opsonization via RES following binding of the Fc part of the antibody to Fcy-receptors expressed on the RES .

Pregnancy & Breastfeeding use

Pregnancy Category B. It is not known whether Zessly can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

It is not known whether Zessly is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from Zessly, women should not breast-feed their infants while taking Zessly.

Contraindication

Zessly doses >5 mg/kg in moderate to severe heart failure. Previous severe hypersensitivity reaction to Zessly or known hypersensitivity to inactive components of Zessly or to any murine proteins.

Storage Condition

Zessly must be refrigerated at 2ºC to 8ºC. Do not use Zessly beyond the expiration date (Exp) located on the carton and the vial. This product contains no preservative.

Innovators Monograph

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