belimumab (Rx)

Listed adverse reactions of belimumab PLUS standard therapy

>10%

SC

• Nausea (15%)
• Diarrhea (12%)

1-10%

IV

• Pyrexia (10%)
• Nasopharyngitis (9%)
• Bronchitis (9%)
• Insomnia (7%)
• Pain in extremity (6%)
• Depression (5%)
• Migraine (5%)
• Pharyngitis (5%)
• Cystitis (4%)
• Leukopenia (4%)
• Gastroenteritis viral (3%)

SC

• Serious infections (4.1%)
• Depression-related events (2.7%)
• Suicidal ideation (1.3%)

<1%

SC

• Fatal infections (0.5%)
• Serious psychiatric events (0.2%)

Postmarketing Reports

Fatal anaphylaxis

Contraindications

Anaphylaxis to belimumab

Cautions

Serious and sometimes fatal infections reported in patients receiving immunosuppressive agents; consider risk and benefit before initiating treatment in patients with severe or chronic infections; consider interrupting therapy in patients who develop a new infection during therapy and monitor patients closely

Hypersensitivity reactions reported; delayed onset of acute hypersensitivity reactions observed; limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk; before IV dosing, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions

Impact on development of malignancies is unknown; as with other immunomodulating agents, mechanism of action of belimumab could increase the risk for developing malignancies

Cases of progressive multifocal leukoencephalopathy resulting in neurological deficits reported in patients with SLE receiving immunosuppressants, including belimumab; consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated; in patients with confirmed PML, consider stopping therapy

Infusion-related effects were associated with IV administration; serious infusion reactions (eg, bradycardia, myalgia, headache, rash, urticaria, hypotension) reported; monitor during and for an appropriate period of time after infusion; infusion rate may be slowed or interrupted if patient develops an infusion reaction; instruct patients to seek immediate medical care should a reaction occur

Depression and suicidality

• In clinical trials, psychiatric events were associated with IV administration in SLE patients
• Before treatment, assess risk of depression and suicide considering the patient’s medical history and current psychiatric status
• Continue to monitor during treatment
• Instruct patients to contact healthcare provider if new or worsening depression arises, suicidal thoughts or behavior, or other mood changes; assess risk and benefit of continued therapy for patients who develop such symptoms
• Consider risk and benefit of continued treatment for patients who develop symptoms of depression or suicidality

Drug interaction overview

• Immunizations

  • Do not administer live vaccines 30 days before or concurrently with belimumab
  • May decrease response to immunizations

• Other biologic therapies

  • Not studied in combination with other biologic therapies (eg, B-cell targeted therapies) and therefore not recommended

Pregnancy

Healthcare professionals are encouraged to register patients by calling the pregnancy registry: at 1- (877) 681-6296

Data are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage

There are risks to the mother and fetus associated with SLE, including worsening of the underlying disease, premature birth, spontaneous abortion, and intrauterine growth restriction

Clinical considerations

• Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia
• Passage of maternal antiphospholipid antibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block
• Monoclonal antibodies, such as belimumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero-exposed infant
• Use during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus

Contraception

• Following an assessment of benefit versus risk, if prevention of pregnancy is warranted, females of reproductive potential should use effective contraception during treatment and for at least 4 months after the final treatment

Lactation

Passage of maternal antiphospholipid antibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block

Monoclonal antibodies, such as belimumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero-exposed infant

Use during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus

Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits the biological activity of B-lymphocyte stimulator (BLyS); BLyS is a naturally occurring protein required for survival and development of B-lymphocyte cells into mature plasma B cells that produce antibodies

In autoimmune diseases, elevated BLyS levels are thought to contribute to production of autoantibodies

Belimumab specifically recognizes and binds to BLyS, inhibits BLyS’s stimulation of B-cell development, and finally, restores the potential for autoantibody-producing B cells to undergo the normal process of apoptosis (programmed cell death)

Absorption

Peak plasma concentration: 313 mcg/mL (IV); 108 mcg/mL (SC)

AUC: 3,083 days•mcg/mL (IV); 726 days•mcg/mL (SC)

Distribution

Vd (steady-state): 5 L

Half-life, distribution: 1.8 days (IV); 1.1 days (SC)

Elimination

Half-life, terminal: 19.4 days (IV); 18.3 days (SC)

Clearance: 215 mL/day (IV); 204 mL/day (SC)

IV Compatibilities

0.9% NaCl

0.45% NaCl

Lactated Ringer solution

IV Incompatibilities

Dextrose solutions

IV Preparation

Lyophilized powder in a single-use vial for intravenous infusion only and should be reconstituted and diluted using aseptic technique

Remove vial from refrigerator; let stand for 10-15 minutes to reach room temperature

Reconstitution

• Remove vial from refrigerator; allow vial to reach room temperature for 10-15 min
• Reconstitute with 1.5 mL (120-mg vial) and 4.8 mL (400-mg vial) of sterile water for injection to final concentration of 80 mg/mL
• Direct stream of sterile water toward side of vial to minimize foaming
• DO NOT SHAKE; gently swirl vial for 60 seconds every 5 minutes until powder is dissolved
• Reconstitution is typically complete within 10-15 minutes, but may take up to 30 minutes
• Note: If mechanical reconstitution device is used, it should not exceed 500 rpm and vial swirled for no longer than 30 minutes
• Once reconstituted, solution should be opalescent and colorless to pale yellow, and without particles; small air bubbles are expected and acceptable

Dilution

• Dilute reconstituted solution in 250-mL infusion bag (ie, 0.9% NaCl, 0.45% NaCl, LR) OR in 100-mL infusion bag if patient weighs <40 kg
• Withdraw and discard volume equal to volume of the reconstituted solution required for dose
• Add required volume of reconstituted solution to infusion bag/bottle (final concentration should not exceed 4 mg/mL)
• Gently invert bag/bottle to mix the solution
• Visually inspect for particulate matter and discoloration before administration, whenever solution and container permits
• Discard any unused portion
• Total time from reconstitution to completion of infusion should not exceed 8 hours

IV Administration

Administer diluted solution IV over 1 hour

Administer by health care providers prepared to manage anaphylaxis

Do not infuse concomitantly in same IV line with other drugs

Consider administering premedication (ie, antihistamines, corticosteroids) for prophylaxis against infusion reactions and hypersensitivity

SC Preparation

Instruct patient to remove the autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for 30 minutes prior to the SC injection; do not warm drug in any other way

Visually inspect the window of the autoinjector or the prefilled syringe for particulate matter or discoloration; solution should be clear to opalescent and colorless to pale yellow

Do not use if the product exhibits discoloration or particulate matter

Instruct the patient not to use autoinjector or prefilled syringe if dropped on a hard surface

SC Administration

Administer SC once weekly, preferably on the same day each week

Administer SC in abdomen or thigh

When injecting in the same body region, advise to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard

When a 400-mg dose is administered at same site, it is recommended that the 2 individual 200-mg injections be administered at least 5 cm (~2 inches) apart

Missed dose

• Administer missed dose as soon as the patient remembers
• Thereafter, the patient can resume dosing on their usual day of administration or start a new weekly schedule from the day that the missed dose was administered
• Not recommended to administer 2 doses on the same day

Storage

Unopened IV vials

• Store refrigerated 2-8ºC (36-46ºF); do not freeze
• Store vials in original carton and protect from light until use
• Avoid exposure to heat

Reconstituted IV vials

• If not used immediately, may be stored refrigerated 2-8ºC (36-46ºF)
• For single use only; discard any unused portion

Diluted IV solution

• Refrigerate at 2-8ºC (36-46ºF) or at room temperature
• Total time from reconstitution to completion of infusion should not exceed 8 hours

SC prefilled syringes or autoinjector

• Refrigerated

  • Refrigerate prefilled syringe or autoinjectors at 2-8°C (36-46°F)
  • Keep product in the original carton to protect from light until the time of use
  • Do not freeze, shake, or expose to heat

• Nonrefrigerated

  • May be stored outside of the refrigerator up to 86°F (30°C) for up to 12 hr in the original container
  • Do not use and do not place back in refrigerator if left out for >12 hr