daratumumab

REMS

Multiple myeloma in patients whose disease has relapsed or is refractory despite receiving ≥1 prior therapy (in combination with lenalidomide and dexamethasone).
Multiple myeloma in patients who have received ≥1 prior therapy (in combination with bortezomib and dexamethasone).
Multiple myeloma in patients whose disease has relapsed or is refractory despite receiving 1–3 previous drug therapies (in combination daratumumab and dexamethasone).
Multiple myeloma in patients who received ≥2 lines of therapy including lenalidomide and a proteasome inhibitor (in combination with pomalidomide and dexamethasone).
Multiple myeloma in patients who have received ≥3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Newly diagnosed multiple myeloma in patients who are ineligible for autologous stem cell transplant (in combination with bortezomib, melphalan, and prednisone).
Newly diagnosed multiple myeloma in patients who are ineligible for autologous stem cell transplant (in combination with lenalidomide and dexamethasone).Newly diagnosed multiple myeloma in patients who are eligible for autologous stem cell transplant (in combination with bortezomib, thalidomide, and dexamethasone).

Action ⬆ ⬇

Binds to CD38 on tumor cells causing apoptosis, thereby inhibiting growth of CD38-expressing tumor cells.

Therapeutic effects:

Improved survival and decreased progression of multiple myeloma.

Pharmacokinetics ⬆ ⬇

Absorption: IV administration results in complete bioavailability.

Distribution: Monoclonal antibodies cross the placenta.

Metabolism/Excretion: Unknown.

Half-Life: 18 days (as monotherapy); 23 days (when used as combination therapy).

Time/Action Profile ⬆ ⬇

(blood levels)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	end of infusion	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Severe hypersensitivity;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Chronic obstructive pulmonary disease;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension, peripheral edema

EENT: nasal congestion

GI: ↓appetite, diarrhea, nausea, vomiting

Hemat: anemia, lymphopenia, neutropenia, thrombocytopenia

MS: arthralgia, muscle spasms, pain

Neuro: headache, peripheral neuropathy

Resp: cough, dyspnea

Misc: fatigue, fever, INFUSION REACTIONS (INCLUDING ANAPHYLAXIS)

Interactions ⬆ ⬇

Drug-drug:

None known.

Route/Dosage ⬆ ⬇

Combination Therapy with Bortezomib, Melphalan, and Prednisone

Monotherapy and Combination Therapy with Lenalidomide or Pomalidomide and Dexamethasone

Combination Therapy with Bortezomib and Dexamethasone

Combination Therapy with Bortezomib, Thalidomide, and Dexamethasone

Combination Therapy with Carfilzomib and Dexamethasone

During Week 1 ONLY, the 16 mg/kg dose may administered in one dose or may be split into two doses (8 mg/kg) administered over 2 days (Days 1 and 2).
IV (Adults ): 16 mg/kg every wk starting at Week 1 through Week 6 (total of 6 doses), then 16 mg/kg every 3 wk starting at Week 7 until Week 54 (total of 16 doses), then 16 mg/kg every 4 wk starting at Week 55 and onward; continue until disease progression or unacceptable toxicity.
IV (Adults ): 16 mg/kg every wk starting at Week 1 through Week 8 (total of 8 doses), then 16 mg/kg every 2 wk starting at Week 9 until Week 24 (total of 8 doses), then 16 mg/kg every 4 wk starting at Week 25 and onward; continue until disease progression or unacceptable toxicity.
IV (Adults ): 16 mg/kg every wk starting at Week 1 through Week 9 (total of 9 doses), then 16 mg/kg every 3 wk starting at Week 10 until Week 24 (total of 5 doses), then 16 mg/kg every 4 wk starting at Week 25 and onward; continue until disease progression or unacceptable toxicity.
IV (Adults ): Induction treatment: 16 mg/kg every wk starting at Week 1 through Week 8 (total of 8 doses), then 16 mg/kg every 2 wk starting at Week 9 until Week 16 (total of 4 doses), then stop for high-dose chemotherapy and autologous stem cell transplant; Consolidation treatment (following autologous stem cell treatment): 16 mg/kg every 2 wk starting at Week 1 through Week 8 (total of 4 doses).
IV (Adults ): 8 mg/kg once daily for 2 days (Days 1 and 2 of Week 1), then 16 mg/kg every wk starting at Week 2 through Week 8 (total of 7 doses), then 16 mg/kg every 2 wk starting at Week 9 until Week 24 (total of 8 doses), then 16 mg/kg every 4 wk starting at Week 25 and onward; continue until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Solution for injection: 20 mg/mL
In combination with: hyaluronidase (Darzalex Faspro). See Appendix [not included in this PDA edition].

Assessment ⬆ ⬇

Frequently monitor for signs and symptoms of infusion reactions (bronchospasm, hypoxia, dyspnea, hypertension, cough, wheezing, larynx and throat tightness, laryngeal edema, pulmonary edema, nasal congestion, allergic rhinitis, hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, chills) during therapy; occur frequently, usually during or within 4 hrs of infusion. Premedicate with antihistamines, antipyretics, and corticosteroids and medicate post-infusion to prevent delayed infusion reactions.
Monitor for ocular adverse reactions (acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure, glaucoma). If ocular symptoms occur, interrupt infusion and seek immediate ophthalmologic evaluation prior to restarting therapy.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
- Type and screen before starting therapy. Therapy results in a positive Indirect Antiglobulin Test (Coombs test) which interferes with antibody screening and cross matching for blood transfusions; may persist for up to 6 mo.
- Monitor CBC periodically during therapy. May cause anemia, thrombocytopenia, neutropenia, and lymphopenia. Monitor patient with neutropenia for signs and symptoms of infection. Consider holding daratumumab until neutrophil recovery or recovery of platelets.

Implementation ⬆ ⬇

Administer by a health care professional with immediate access to emergency equipment and medical support.
Monotherapy: Pre-infusion: Administer methylprednisolone 100 mg or equivalent intermediate-acting or long-acting corticosteroid plus PO antipyretics (acetaminophen 650–1000 mg) plus PO or IV antihistamine (diphenhydramine 25–50 mg or equivalent) 1–3 hrs prior to each infusion. Following second infusion, methylprednisolone dose may be ↓ to 60 mg IV. Post-infusion:Following infusion, administer methylprednisolone 20 mg PO or equivalent on 1st and 2nd day after all infusions to ↓ risk of infusion reactions.
Combination Therapy: Pre-infusion: Administer dexamethasone 20 mg (or equivalent) PO or IV plus PO antipyretics (acetaminophen 650–1000 mg) plus PO or IV antihistamine (diphenhydramine 25–50 mg or equivalent) 1–3 hrs prior to each infusion. When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on days of infusion. Do not administer background regimen-specific corticosteroids (e.g. prednisone) on infusion days when patients have received dexamethasone (or equivalent) as a pre-medication. Post-infusion: Consider administering PO methylprednisolone at a dose ≤20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) starting the day after administration of daratumumab infusion. If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the infusion, additional corticosteroids may not be needed.
For patients with a history of COPD, consider post-infusion short and long-acting bronchodilators, and inhaled corticosteroids. After first 4 infusions, if no major infusion reactions occurred, may be discontinued.
Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 wk of starting therapy and continue for 3 mo following therapy with daratumumab. May also result in hepatitis B virus (HBV) reactivation.
If a planned dose is missed, administer as soon as possible and adjust dosing to maintain same treatment interval.

IV Administration:

Intermittent Infusion: Diluent: Calculate volume of dose of daratumumab solution required based on patient body weight. Remove volume from polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin bag of 0.9% NaCl equal to required volume. Withdraw required amount of daratumumab solution and add to 0.9% NaCl. For Single Dose Infusion: Dilute first infusion in 1000 mL, second and third infusions in 500 mL of 0.9% NaCl. For Split Dose Infusion: Dilute all infusions in 500 mL of 0.9% NaCl. Discard unused portion. Invert gently to mix; do not shake. Stable for up to 24 hrs if refrigerated and protected from light; do not freeze. Allow to come to room temperature before administration. Solution is colorless to pale yellow and may develop very small, translucent to white proteinaceous particles; do not administer solution if discolored or contains opaque particulate matter.
Rate: Infuse first and second infusion at an initial rate of 50 mL/hr through an infusion set fitted with a flow regulator and in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone filter (pore size 0.22 or 0.2 micrometer). Administration sets must be either polyurethane, polybutadiene, PVC, PP or PE. If no infusion reactions ≥Grade 1 during first 3 hrs of first infusion, ↑ rate by 50 mL/hr for a maximum rate of 200 mL/hr. Infuse subsequent infusions at an initial rate of 100 mL/hr. If no infusion reactions ≥Grade 1 during first 3 hrs of first infusion, ↑ rate by 50 mL/hr for a maximum rate of 200 mL/hr. Complete infusion within 15 hrs.
- Grade 1–2 (mild to moderate) infusion reactions: Once reaction symptoms resolve, resume infusion at ≤ half the rate at which reaction occurred. If no further reactions experienced, resume at increments and intervals as appropriate.
- Grade 3 (severe) infusion reactions: If intensity of reaction ↓ to ≤Grade 2, consider restarting infusion at ≤ half rate at which reaction occurred. If no further reactions experienced, resume infusion rate escalation at appropriate increments and intervals. Repeat procedure if Grade 3 reaction recurs. If third ≥Grade 3 reaction occurs, permanently discontinue daratumumab.
- Grade 4 (life threatening infusion reactions: Permanently discontinue therapy.
Y-Site Incompatibility: Do not administer in same IV line with other agents.

Patient/Family Teaching ⬆ ⬇

Instruct patient to read the Patient Information sheet prior to therapy.
Advise patient to notify health care professional immediately if signs and symptoms of infusion reactions (itchy, runny, or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath, difficulty breathing), bleeding, bruising, or fever occur.
Advise patient to inform blood transfusion centers/personnel they are taking daratumumab in the event of a planned transfusion.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 3 mo after completion of therapy and to avoid breastfeeding during therapy. Immunoglobulin G1 monoclonal antibodies are transferred across the placenta. May cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇