CIMZIA

Certolizumab pegol is a pegylated monoclonal antibody against the tumor necrosis factor-alpha (TNF-alpha).

It is formed with a humanized

Fab fragment of 50 kDa, from an IgG 1 isotype, fused to a 40 kDa polyethylene glycol moiety replacing the Fc antibody region.

The absence of the

Fc region was ideated to prevent complement fixation and antibody-mediated cytotoxicity as well as to markedly increase its half-life.

Certolizumab does not require glycosylation for active function and hence, its production is significantly more affordable when compared to other existing TNF-alpha therapies as it can be done directly in bacterial hosts such as E. coli.

It was developed and.

Certolizumab pegol has been approved for several different conditions listed below: Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy.

Treatment of adult patients with moderate to severely active rheumatoid arthritis.

Treatment of adult patients with active psoriatic arthritis.

Treatment of adult patients with active ankylosing spondylitis.

Treatment of adult patients with moderate-to-severe plaque psoriasis that are candidates for systemic therapy or phototherapy.

Treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation.

In Canada, certolizumab pegol is additionally approved in combination with methotrexate for the symptomatic treatment, including major clinical response, and for the reduction of joint damage in adult patients with moderately to severely active rheumatoid arthritis and psoriatic arthritis.

Inflammation is a biological response against a potential threat.

This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation.

TNF-alpha has been identified as a key regulator of the inflammatory response.

The signaling cascades of this inflammatory mediator can produce a wide range of reactions including cell death, survival, differentiation, proliferation and migration.

As part of the mechanism of action and nature of the drug, certolizumab does not induce apoptosis in cultured lymphocytes and monocytes.

However, as a piece of the inhibition of inflammation, certolizumab pegol inhibits lipopolysaccharide-induced production of IL-1 beta and it induces nonapoptotic cell death via signaling transmembrane TNF-alpha.

In vitro studies with certolizumab pegol in human tissue did not show any unexpected binding at 3 mcg/ml nor at 10 mcg/ml. Due to the drug class, certolizumab pegol is not expected to present adverse effects on the major vital systems.

In phase

III clinical trials in psoriatic arthritis patients, certolizumab pegol was reported to generate improvements in skin disease, joint involvement, dactylitis, enthesitis and general life quality.

The clinical effect of certolizumab was paired to a comparable safety profile to other TNF-alpha inhibitors.

The clinical effectiveness of certolizumab pegol was mainly studied in six randomized controlled trials that compared its effect versus placebo.

In a comparative study, the efficacy for certolizumab pegol registered ranged from 30-65% while in placebo ranged from 4-25%.

However, in other additional trials, certolizumab was proven to present a similar clinical efficacy to other disease-modifying antirheumatic drugs in patients with inadequate response to TNF inhibitors.

After subcutaneous administration, the peak plasma concentration is reached between and 171 hours with a bioavailability of 80%.

Certolizumab presents a linear pharmacokinetic profile with a peak plasma concentration of 43-49 mcg/ml.

Certolizumab pegol volume of distribution is reported to be in the range of 4-8 L.

It is known to have a very good distribution in the joints when compared to other TNF-alpha inhibitors.

The presence of

PEG group in certolizumab pegol delays the metabolism and elimination of this drug.

However, once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling.

Later, it is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis.

On the other hand, the PEG section is processed normally by the action of the alcohol dehydrogenase to the formation of carboxylic acid.

As certolizumab is a monoclonal antibody, the elimination route is not widely studied.

However, it is known that the elimination of the PEG moiety is dependent on the renal function which links it directly with a high portion of renal elimination.

The circulatory half-life of certolizumab is of 14 days.

The clearance rate of certolizumab pegol ranged between 9-14 ml/h when administered Intravenous.

However, when administered Subcutaneous, the clearance rate is estimated to range between 14-21 ml/h depending on the patient condition.

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The oral ld50 observed in mice is determined to be of 300 mg/kg. MSDS To this date, there have not been reports of overdosage, however, in case of accidental overexposure close monitoring is recommended.

Certolizumab pegol does not present mutagenic potential nor presents effects in fertility and reproductive performance.

On the other hand, carcinogenicity studies have not been performed.

is contraindicated in patients with a history of hypersensitivity reaction to certolizumab pegol or to any of the excipients.

Reactions have included angioedema, anaphylaxis, serum sickness, and urticaria.

Serious hypersensitivity reaction to certolizumab pegol or to any of the excipients.

is administered by subcutaneous injection.

Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard.

When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen.

The solution should be carefully inspected visually for particulate matter and discoloration prior to administration.

The solution should be a clear to opalescent, colorless to yellow liquid, essentially free from particulates and should not be used if cloudy or if foreign particulate matter is present.

CIMZIA does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded.

CIMZIA is administered by subcutaneous injection.

Crohn's Disease 400 mg initially and at Weeks and 4.

If response occurs, follow with 400 mg every four weeks Rheumatoid Arthritis 400 mg initially and at Weeks and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered Polyarticular Juvenile Idiopathic Arthritis 10 kg (22 lbs) to less than 20 kg (44 lbs): 100 mg initially and at Weeks and 4, followed by 50 mg every other week 20 kg (44 lbs) to less than 40 kg (88 lbs): 200 mg initially and at Weeks and 4, followed by 100 mg every other week Greater than or equal to 40 kg (88 lbs): 400 mg initially and at Weeks and 4, followed by 200 mg every other week Psoriatic Arthritis 400 mg initially and at week and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered.

Spondylitis 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks and 4, followed by 200 mg every other week or 400 mg every 4 weeks.

Spondyloarthritis 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks and 4, followed by 200 mg every other week or 400 mg every 4 weeks.

Psoriasis 400 mg (given as 2 subcutaneous injections of 200 mg each) every other week.

For some patients (with body weight less than or equal to 90 kg), a dose of 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at Weeks and 4, followed by 200 mg every other week may be considered. 2.1 Crohn's Disease The recommended initial adult dose of CIMZIA is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks and 4.

In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks. 2.2 Rheumatoid Arthritis The recommended dose of CIMZIA for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks and 4, followed by 200 mg every other week.

For maintenance dosing, CIMZIA 400 mg every 4 weeks can be considered. 2.3 Polyarticular Juvenile Idiopathic Arthritis The recommended dose of CIMZIA for patients 2 years of age and older with pJIA is based on weight as shown below.

Weight range (2 years of age and older) Loading dose Maintenance dose (beginning at Week 6) 10 kg (22 lbs) to less than 20 kg (44 lbs) 100 mg at Week and 4 50 mg every 2 weeks 20 kg (44 lbs) to less than 40 kg (88 lbs) 200 mg at Week and 4 100 mg every 2 weeks Greater than or equal to 40 kg (88 lbs) 400 mg at Week and 4 200 mg every 2 weeks There is no dosage form for Cimzia that allows for patient self-administration for doses below 200 mg. Doses less than 200 mg require administration by a health care professional using the vial kit. 2.4 Psoriatic Arthritis The recommended dose of CIMZIA for adult patients with psoriatic arthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at week and 4, followed by 200 mg every other week.

For maintenance dosing, CIMZIA 400 mg every 4 weeks can be considered. 2.5 Ankylosing Spondylitis The recommended dose of CIMZIA for adult patients with ankylosing spondylitis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks. 2.6 Non-radiographic Axial Spondyloarthritis The recommended dose of CIMZIA for adult patients with non-radiographic axial spondyloarthritis is 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at weeks and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks. 2.7 Plaque Psoriasis The recommended dose of CIMZIA for adults with moderate-to-severe plaque psoriasis is 400 mg (given as 2 subcutaneous injections of 200 mg each) every other week.

For some patients (with body weight less than or equal to 90 kg), CIMZIA 400 mg (given as 2 subcutaneous injections of 200 mg each) initially and at Weeks and 4, followed by 200 mg every other week can be considered. 2.8 Preparation and Administration of CIMZIA Using the Lyophilized Powder for Injection CIMZIA Lyophilized powder should be prepared and administered by a health care professional.

CIMZIA is provided in a package that contains everything required to reconstitute and inject the drug.

Step-by-step preparation and administration instructions are provided below.

If refrigerated, remove CIMZIA from the refrigerator and allow the vial(s) to sit at room temperature for 30 minutes before reconstituting.

Do not warm the vial in any other way.

Use appropriate aseptic technique when preparing and administering CIMZIA.

Reconstitute the vial(s) of CIMZIA with 1 mL of Sterile Water for Injection, USP using the 20-gauge needle provided.

The sterile water for injection should be directed at the vial wall rather than directly on CIMZIA.

Gently swirl each vial of

CIMZIA for about one minute without shaking, assuring that all of the powder comes in contact with the Sterile Water for Injection.

The swirling should be as gentle as possible in order to avoid creating a foaming effect.

Continue swirling every 5 minutes as long as non-dissolved particles are observed.

Full reconstitution may take as long as 30 minutes.

The final reconstituted solution contains 200 mg/mL and should be clear to opalescent, colorless to yellow liquid essentially free from particulates.

Once reconstituted, CIMZIA can be stored in the vials for up to 24 hours between 2° to 8° C (36° to 46° F) prior to injection.

Do not freeze.

Prior to injecting, reconstituted CIMZIA should be at room temperature but do not leave reconstituted CIMZIA at room temperature for more than two hours prior to administration.

Withdraw the reconstituted solution into a separate syringe for each vial using a new 20-gauge needle for each vial so that each syringe contains the required volume of CIMZIA.

Replace the 20-gauge needle(s) on the syringes with a 23-gauge(s) for administration.

Inject the full contents of the syringe(s) subcutaneously, by pinching the skin of the thigh or abdomen.

Where a 400 mg dose is required, two injections are required, therefore, separate sites should be used for each 200 mg injection. 2.9 Preparation and Administration of CIMZIA Using the Prefilled Syringe After proper training in subcutaneous injection technique, a patient may self-inject with the CIMZIA Prefilled Syringe if a physician determines that it is appropriate.

If refrigerated, remove the prefilled syringe from the carton and let it warm to room temperature.

Inspect the liquid in the prefilled syringe.

It should be clear to opalescent and colorless to yellow and free from particulates.

Discard the syringe if cloudy, discolored or contains particulates.

Suitable sites for injection include the thigh or abdomen at least 2 inches away from the navel.

Inject at least 1 inch from the previous site.

Do not inject into areas where the skin is tender, bruised, red or hard, or where there are scars or stretch marks.

The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause allergic reactions and should be handled with caution by latex-sensitive individuals. 2.10 Monitoring to Assess Safety Before initiation of therapy with CIMZIA, all patients must be evaluated for both active and inactive (latent) tuberculosis infection.

The possibility of undetected latent tuberculosis should be considered in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis.

Appropriate screening tests (e.g. tuberculin skin test and chest x-ray) should be performed in all patients. 2.11 Concomitant Medications CIMZIA may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs).

The use of CIMZIA in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy is not recommended.

CIMZIA (certolizumab pegol) for injection is a sterile white, lyophilized powder for subcutaneous use after reconstitution in the following packaging configuration.

Package size NDC Pack Contents

Carton of two 200 mg vials NDC 50474-700-62 Two 200 mg/vial glass vials with rubber stopper Two 1 mL Sterile Water for Injection, USP glass vials Two 3 mL plastic syringes Four 20-gauge needles (1 inch) Two 23-gauge needles (1 inch) Eight alcohol swabs CIMZIA (certolizumab pegol) injection is a sterile, clear to opalescent, colorless to yellow solution for subcutaneous use in the following packaging configurations.

Package size NDC Pack Contents Prefilled Syringe Starter Kit: each unit carton contains three cartons of two 200 mg/mL prefilled syringes per individual carton NDC 50474-710-81 Six 200 mg/mL prefilled syringes with a fixed 25 ½ gauge thin-wall needle 6 alcohol swabs Carton of two 200 mg/mL prefilled syringes NDC 50474-710-79 Two 200 mg/mL prefilled syringe with a fixed 25 ½ gauge thin-wall needle Two alcohol swabs Carton of one 200 mg/mL prefilled syringe NDC 50474-750-10 One 200 mg/mL prefilled syringe with a fixed 25 ½ gauge thin-wall needle One alcohol swab The needle shield inside the removable cap of the CIMZIA prefilled syringe contains a derivative of natural rubber latex which may cause allergic reactions and should be handled with caution by latex-sensitive individuals.

CIMZIA vials and prefilled syringes between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Do not separate contents of carton prior to use.

Do not use beyond expiration date, which is located on the drug label and carton.

CIMZIA lyophilized vials may also be stored at room temperature up to a maximum of 25°C (77°F) for 6 months, but not exceeding the original expiration date.

If stored at room temperature, do not place back in refrigerator and write the new expiration date on the carton in the space provided.

When necessary, CIMZIA prefilled syringes may be stored at room temperature up to 77 ° F (25 ° C) in the original carton to protect from light for a single period of up to 7 days.

Once stored at room temperature, do not place back in refrigerator.

Write the date removed from the refrigerator in the space provided on the carton and discard if not used within the 7-day period.

CIMZIA vials and prefilled syringes between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Do not separate contents of carton prior to use.

Do not use beyond expiration date, which is located on the drug label and carton.

CIMZIA lyophilized vials may also be stored at room temperature up to a maximum of 25°C (77°F) for 6 months, but not exceeding the original expiration date.

If stored at room temperature, do not place back in refrigerator and write the new expiration date on the carton in the space provided.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMZIA during pregnancy.

For more information, healthcare providers or patients can contact: MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS).

Study at 1-877-311-8972 or visit Risk Summary Limited data from an ongoing pregnancy exposure registry on use of CIMZIA in pregnant women are not sufficient to inform a risk of major birth defects or other adverse pregnancy outcomes.

However, certolizumab pegol plasma concentrations obtained from two studies of CIMZIA use during the third trimester of pregnancy demonstrated that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth.

There are risks to the mother and fetus associated with active rheumatoid arthritis or Crohn's disease.

The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to CIMZIA should be weighed against the benefits of vaccinations.

No adverse developmental effects were observed in animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol during organogenesis at up to 2.4 times the recommended human dose of 400 mg every four weeks.

The background risk of major birth defects and miscarriage for the indicated population(s) are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and to 20%, respectively.

Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn's disease is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth.

Fetal/Neonatal Adverse Reaction Due to its inhibition of TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero -exposed newborn and infant.

The clinical significance of

BLQ or low levels is unknown for in utero -exposed infants.

Additional data available from one exposed infant suggest that CIMZIA may be eliminated at a slower rate in infants than in adults.

The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

Dosing During Pregnancy and the Postpartum Period Based on a pharmacokinetic study in pregnant women with psoriasis or rheumatological diseases who were administered certolizumab pegol during pregnancy until at least 12 weeks postpartum, plasma certolizumab pegol concentrations throughout pregnancy were within the range observed in non-pregnant women with the same chronic inflammatory diseases.

No dosage adjustment is required for pregnant women.

A limited number of pregnancies have been reported in an ongoing pregnancy exposure registry.

Due to the small number of

CIMZIA-exposed pregnancies with known outcomes (n=217), no meaningful comparisons between the exposed group and control groups may be conducted to determine an association with CIMZIA and major birth defects or adverse pregnancy outcomes.

A multicenter clinical study was conducted in 16 women treated with CIMZIA at a maintenance dose of 200 mg every 2 weeks or 400 mg every 4 weeks during the third trimester of pregnancy for rheumatological diseases or Crohn's disease.

The last dose of

CIMZIA was given on average 11 days prior to delivery (range to 27 days).

Certolizumab pegol plasma concentrations were measured in samples from mothers and infants using an assay that can measure certolizumab pegol concentrations at or above 0.032 mcg/mL.

Certolizumab pegol plasma concentrations measured in the mothers at delivery (range: 4.96 to 49.4 mcg/mL) were consistent with non-pregnant women's plasma concentrations in Study RA-I.

Certolizumab pegol plasma concentrations were not measurable in 13 out of 15 infants at birth.

The concentration of certolizumab pegol in one infant was 0.0422 mcg/mL at birth (infant/mother plasma ratio of 0.09%).

In a second infant, delivered by emergency Caesarean section, the concentration was 0.485 mcg/mL (infant/mother plasma ratio of 4.49%).

At Week and

Week 8, all 15 infants had no measurable concentrations.

Among 16 exposed infants, one serious adverse reaction was reported in a neonate who was treated empirically with intravenous antibiotics due to an increased white blood cell count; blood cultures were negative.

The certolizumab pegol plasma concentrations for this infant were not measurable at birth, Week 4, or Week 8.

In another clinical study conducted in 10 pregnant women with Crohn´s disease treated with CIMZIA (400 mg every 4 weeks for every mother), certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood at the day of birth with an assay that can measure concentrations at or above 0.41 mcg/mL.

CIMZIA was given on average 19 days prior to delivery (range to 42 days).

Plasma certolizumab pegol concentrations ranged from not measurable to 1.66 mcg/mL in cord blood and 1.58 mcg/mL in infant blood; and ranged from 1.87 to 59.57 mcg/mL in maternal blood.

Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol.

In one infant, the plasma certolizumab pegol concentration declined from 1.02 to 0.84 mcg/mL over 4 weeks suggesting that certolizumab pegol may be eliminated at a slower rate in infants than adults.

Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol.

Animal reproduction studies have been performed in rats during organogenesis at intravenous doses up to 100 mg/kg (about 2.4 times the recommended human dose of 400 mg, based on the surface area) and have revealed no evidence of harm to the fetus due to cTN3 PF.

The safety and effectiveness of

CIMZIA for active polyarticular juvenile idiopathic arthritis has been established in pediatric patients 2 years of age and older.

The use of

CIMZIA in this is supported by evidence from adequate and well-controlled studies of CIMZIA in adults with RA, pharmacokinetic data from adults with RA and pediatric patients with JIA with active polyarthritis, and safety data from an open-label clinical study in 193 pediatric patients to < 18 years of age with JIA with active polyarthritis.

The observed pre-dose (trough) concentrations are generally comparable between adults with RA and pediatric patients with JIA with active polyarthritis.

The safety and effectiveness for

CIMZIA in pediatric patients less than 2 years of age with pJIA have not been established.

CIMZIA have not been established in pediatric patients for other indications.

CIMZIA was evaluated for the treatment of pediatric patients with moderately to severely active Crohn's disease.

Effectiveness was not demonstrated in an open-label, randomized, parallel-group, multiple dose study for a period of up to 62 weeks in 99 subjects aged to 17 years.

The study was ended prematurely because of a high number of patient discontinuations.

Due to its inhibition of

TNFα, CIMZIA administered during pregnancy could affect immune responses in the in utero -exposed newborn and infant.

Clinical studies of

CIMZIA did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

Population pharmacokinetic analyses of patients enrolled in CIMZIA clinical studies concluded that there was no apparent difference in drug concentration regardless of age.

Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with CIMZIA.