Monjuvi Injection, Powder, Lyophilized, For Solution
FDA Label NDC 73535-208

MONJUVI, in combination with lenalidomide, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT).

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The recommended dose of MONJUVI is 12 mg/kg based on actual body weight administered as an intravenous infusion according to the dosing schedule in Table 1.

Administer MONJUVI in combination with lenalidomide 25 mg for a maximum of 12 cycles, then continue MONJUVI as monotherapy until disease progression or unacceptable toxicity [see Clinical Studies (14)]. Refer to the lenalidomide prescribing information for lenalidomide dosage recommendations.

MONJUVI should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions (IRRs) [see Warnings and Precautions (5.1)].

Administer premedications 30 minutes to 2 hours prior to starting MONJUVI infusion to minimize infusion-related reactions [see Warning and Precautions (5.1)]. Premedications may include acetaminophen, histamine H₁ receptor antagonists, histamine H₂ receptor antagonists, and/or glucocorticosteroids.

For patients not experiencing infusion-related reactions during the first 3 infusions, premedication is optional for subsequent infusions.

If a patient experiences an infusion-related reaction, administer premedications before each subsequent infusion.

The recommended dosage modifications for adverse reactions are summarized in Table 2.

Reconstitute and dilute MONJUVI prior to infusion.

Reconstitution

• Calculate the dose (mg) and determine the number of vials needed.
• Reconstitute each 200 mg MONJUVI vial with 5 mL Sterile Water for Injection, USP with the stream directed toward the wall of each vial to obtain a final concentration of 40 mg/mL tafasitamab-cxix.
• Gently swirl the vial(s) until completely dissolved. Do not shake or swirl vigorously. Complete dissolution may take up to 5 minutes.
• Visually inspect the reconstituted solution for particulate matter or discoloration. The reconstituted solution should appear as a colorless to slightly yellow solution. Discard the vial(s) if the solution is cloudy, discolored, or contains visible particles.
• Use the reconstituted MONJUVI solution immediately. If needed, store the reconstituted solution in the vial for a maximum of 12 hours either refrigerated at 36°F to 46°F (2°C to 8°C) or room temperature at 68°F to 77°F (20°C to 25°C) before dilution. Protect from light during storage.

Dilution

• Determine the volume (mL) of the 40 mg/mL reconstituted MONJUVI solution needed based on the required dose.
• Remove a volume equal to the required MONJUVI solution from a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag and discard it.
• Withdraw the necessary amount of MONJUVI and slowly dilute in the infusion bag that contains the 0.9% Sodium Chloride Injection, USP to a final concentration of 2 mg/mL to 8 mg/mL. Discard any unused portion of MONJUVI remaining in the vial.
• Gently mix the intravenous bag by slowly inverting the bag. Do not shake. Visually inspect the infusion bag with the diluted MONJUVI infusion solution for particulate matter and discoloration prior to administration.
• If not used immediately, store the diluted MONJUVI infusion solution refrigerated for up to 18 hours at 36°F to 46°F (2°C to 8°C) and/or at room temperature for up to 12 hours at 68°F to 77°F (20°C to 25°C). The room temperature storage includes time for infusion. Protect from light during storage.

Do not shake or freeze the reconstituted or diluted infusion solutions.

Administration

• Administer MONJUVI as an intravenous infusion.
  • For the first infusion, use an infusion rate of 70 mL/h for the first 30 minutes, then, increase the rate so that the infusion is administered within 1.5 to 2.5 hours.
  • Administer all subsequent infusions within 1.5 to 2 hours.
  • Infuse the entire contents of the bag containing MONJUVI.
  • Do not co-administer other drugs through the same infusion line.
  • No incompatibilities have been observed between MONJUVI with infusion containers made of polypropylene (PP), polyvinylchloride (PVC), polyethylene (PE), polyethylenterephthalate (PET), or glass and infusion sets made of polyurethane (PUR) or PVC.

  Relapsed or Refractory Diffuse Large B-Cell Lymphoma

  The safety of MONJUVI was evaluated in L-MIND [see Clinical Studies (14)]. Patients (n=81) received MONJUVI 12 mg/kg intravenously in combination with lenalidomide for maximum of 12 cycles, followed by MONJUVI as monotherapy until disease progression or unacceptable toxicity as follows:

  • Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle;
  • Cycle 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle;
  • Cycles 4 and beyond: Days 1 and 15 of each 28-day cycle.

  Among patients who received MONJUVI, 57% were exposed for 6 months or longer, 42% were exposed for greater than one year, and 24% were exposed for greater than two years.

  Serious adverse reactions occurred in 52% of patients who received MONJUVI. Serious adverse reactions in ≥6% of patients included infections (26%) including pneumonia (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 5% of patients who received MONJUVI, including cerebrovascular accident (1.2%), respiratory failure (1.2%), progressive multifocal leukoencephalopathy (1.2%) and sudden death (1.2%).

  Permanent discontinuation of MONJUVI or lenalidomide due to an adverse reaction occurred in 25% of patients and permanent discontinuation of MONJUVI due to an adverse reaction occurred in 15%. The most frequent adverse reactions which resulted in permanent discontinuation of MONJUVI were infections (5%), nervous system disorders (2.5%), respiratory, thoracic and mediastinal disorders (2.5%).

  Dosage interruptions of MONJUVI or lenalidomide due to an adverse reaction occurred in 69% of patients and dosage interruption of MONJUVI due to an adverse reaction occurred in 65%. The most frequent adverse reactions which required a dosage interruption of MONJUVI were blood and lymphatic system disorders (41%), and infections (27%).

  The most common adverse reactions (≥ 20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.

  Table 3 summarizes the adverse reactions in L-MIND.

  Table 3: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Received MONJUVI in L-MIND

  Adverse Reaction	MONJUVI (N=81)
  	All Grades (%)	Grade 3 or 4 (%)
  Blood and lymphatic system disorders
  Neutropenia	51	49
  Anemia	36	7
  Thrombocytopenia	31	17
  Febrile neutropenia	12	12
  General disorders and administration site conditions
  Fatigue Fatigue includes asthenia and fatigue	38	3.7
  Pyrexia	24	1.2
  Peripheral edema	24	0
  Gastrointestinal disorders
  Diarrhea	36	1.2
  Constipation	17	0
  Nausea	15	0
  Vomiting	15	0
  Respiratory, thoracic and mediastinal disorders
  Cough	26	1.2
  Dyspnea	12	1.2
  Infections
  Respiratory tract infection Respiratory tract infection includes: lower respiratory tract infection, upper respiratory tract infection, respiratory tract infection	24	4.9
  Urinary tract infection Urinary tract infection includes: urinary tract infection, Escherichia urinary tract infection, urinary tract infection bacterial, urinary tract infection enterococcal	17	4.9
  Bronchitis	16	1.2
  Metabolism and nutrition disorders
  Decreased appetite	22	0
  Hypokalemia	19	6
  Musculoskeletal and connective tissue disorders
  Back pain	19	2.5
  Muscle spasms	15	0

  Clinically relevant adverse reactions in <10% of patients who received MONJUVI were:

  • Blood and lymphatic system disorders: lymphopenia (6%)
  • General disorders and administration site conditions: infusion-related reaction (6%)
  • Infections: sepsis (4.9%)
  • Investigations: weight decreased (4.9%)
  • Musculoskeletal and connective tissue disorders: arthralgia (9%), pain in extremity (9%), musculoskeletal pain (2.5%)
  • Neoplasms benign, malignant and unspecified: basal cell carcinoma (1.2%)
  • Nervous system disorders: headache (9%), paresthesia (7%), dysgeusia (6%)
  • Respiratory, thoracic and mediastinal disorders: nasal congestion (4.9%), exacerbation of chronic obstructive pulmonary disease (1.2%)
  • Skin and subcutaneous tissue disorders: erythema (4.9%), alopecia (2.5%), hyperhidrosis (2.5%)

  Table 4 summarizes the laboratory abnormalities in L-MIND.

  Table 4: Select Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Received MONJUVI in L-MIND

  Laboratory Abnormality	MONJUVI The denominator used to calculate the rate was 74 based on the number of patients with a baseline value and at least one post-treatment value.
  	All Grades (%)	Grade 3 or 4 (%)
  Chemistry
  Glucose increased	49	5
  Calcium decreased	47	1.4
  Gamma glutamyl transferase increased	34	5
  Albumin decreased	26	0
  Magnesium decreased	22	0
  Urate increased	20	7
  Phosphate decreased	20	5
  Creatinine increased	20	1.4
  Aspartate aminotransferase increased	20	0
  Coagulation
  Activated partial thromboplastin time increased	46	4.1

  Risk Summary

  Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on MONJUVI use in pregnant women to evaluate for a drug-associated risk. Animal reproductive toxicity studies have not been conducted with tafasitamab-cxix.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  MONJUVI is administered in combination with lenalidomide for up to 12 cycles. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide prescribing information for additional information. Lenalidomide is only available through a REMS program.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Immunoglobulin G (IgG) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, MONJUVI may cause depletion of fetal CD19 positive immune cells. Defer administering live vaccines to neonates and infants exposed to tafasitamab-cxix in utero until a hematology evaluation is completed.

  Data

  Animal Data

  Animal reproductive studies have not been conducted with tafasitamab-cxix. Tafasitamab-cxix is an IgG antibody and thus has the potential to cross the placental barrier permitting direct fetal exposure and depleting fetal B lymphocytes.

  Risk Summary

  There are no data on the presence of tafasitamab-cxix in human milk or the effects on the breastfed child or milk production. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to MONJUVI are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with MONJUVI and for at least 3 months after the last dose. Refer to lenalidomide prescribing information for additional information.

  Pregnancy Testing

  Refer to the prescribing information for lenalidomide for pregnancy testing requirements prior to initiating the combination of MONJUVI with lenalidomide.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose. Additionally, refer to the lenalidomide prescribing information for additional recommendations for contraception.

  Males

  Refer to the lenalidomide prescribing information for recommendations.

  Distribution

  The total volume of distribution for tafasitamab-cxix was 9.3 L (95% CI: 8.6, 10 L).

  Elimination

  The clearance of tafasitamab-cxix was 0.41 L/day (CV: 32%) and terminal elimination half-life was 17 days (95% CI: 15, 18 days).

  Specific Populations

  Body weight (40 to 163 kg) has a significant effect on the pharmacokinetics of tafasitamab-cxix, with higher clearance and volume of distribution expected with higher body weight. No clinically meaningful differences in the pharmacokinetics of tafasitamab-cxix were observed based on age (16 to 90 years), sex, mild to moderate renal impairment (CLcr 30-89 mL/min estimated by the Cockcroft-Gault equation), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST). The effect of severe renal impairment to end-stage renal disease (CLcr < 30 mL/min), moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST), and race/ethnicity on tafasitamab-cxix pharmacokinetics is unknown.

  Drug Interaction Studies

  No clinically meaningful differences in tafasitamab-cxix pharmacokinetics were observed when used concomitantly with lenalidomide.

  Infusion-Related Reactions

  Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion-related reactions [see Warnings and Precautions (5.1)].

  Myelosuppression

  Inform patients about the risk of myelosuppression. Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater or signs or symptoms of bruising or bleeding. Advise patients of the need for periodic monitoring of blood counts [see Warnings and Precautions (5.2)].

  Infections

  Inform patients about the risk of infections. Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater or signs or symptoms of infection [see Warnings and Precautions (5.3)].

  Embryo-Fetal Toxicity

  • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Population (8.1)].
  • Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose [see Use in Specific Populations (8.3)].
  • Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program [see Use in Specific Populations (8.1,8.3)].

  Lactation

  Advise women not to breastfeed during treatment with MONJUVI and for at least 3 months after the last dose [see Use in Specific Populations (8.2)].

  Manufactured by:
  MORPHOSYS US INC.
  Boston, MA 02210
  U.S. License No. 2152

  Marketed by:
  MORPHOSYS US INC. and INCYTE Corporation.
  MONJUVI is a registered trademark of MorphoSys AG

  Copyright © 2020 MorphoSys AG. All rights reserved.
  Product of Germany  

For injection: 200 mg of tafasitamab-cxix as white to slightly yellowish lyophilized powder in single-dose vial for reconstitution and further dilution.

None.

MONJUVI can cause infusion-related reactions [see Adverse Reactions (6.1)]. In L-MIND, infusion-related reactions occurred in 6% of the 81 patients. Eighty percent of infusion-related reactions occurred during cycle 1 or 2. Signs and symptoms included chills, flushing, dyspnea, and hypertension. These reactions were managed with temporary interruption of the infusion and/or with supportive medication.

Premedicate patients prior to starting MONJUVI infusion [see Dosage and Administration (2.2)]. Monitor patients frequently during infusion. Based on the severity of the infusion-related reaction, interrupt or discontinue MONJUVI [see Dosage and Administration (2.3)]. Institute appropriate medical management.

MONJUVI can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)]. In L-MIND, Grade 3 neutropenia occurred in 25% of patients, thrombocytopenia in 12% and anemia in 7%. Grade 4 neutropenia occurred in 25% and thrombocytopenia in 6%. Neutropenia led to treatment discontinuation in 3.7% of patients.

Monitor CBC prior to administration of each treatment cycle and throughout treatment. Monitor patients with neutropenia for signs of infection. Consider granulocyte colony stimulating factor administration. Withhold MONJUVI based on the severity of the adverse reaction [see Dosage and Administration (2.3)]. Refer to the lenalidomide prescribing information for dosage modifications.

Fatal and serious infections, including opportunistic infections, occurred in patients during treatment with MONJUVI and following the last dose [see Adverse Reactions (6.1)].

In L-MIND, 73% of the 81 patients developed an infection. The most frequent infections were respiratory tract infection (24%), urinary tract infection (17%), bronchitis (16%), nasopharyngitis (10%) and pneumonia (10%). Grade 3 or higher infection occurred in 30% of the 81 patients. The most frequent grade 3 or higher infection was pneumonia (7%). Infection-related deaths were reported in 2.5% of the 81 patients.

Monitor patients for signs and symptoms of infection and manage infections as appropriate.

Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

MONJUVI is initially administered in combination with lenalidomide. The combination of MONJUVI with lenalidomide is contraindicated in pregnant women, because lenalidomide can cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion-related reactions [see Warning and Precautions (5.1)]
• Myelosuppression [see Warning and Precautions (5.2)]
• Infections [see Warning and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in practice.

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other tafasitamab products may be misleading.

Overall, no treatment-emergent or treatment-boosted anti-tafasitamab antibodies were observed. No clinically meaningful differences in the pharmacokinetics, efficacy, or safety profile of tafasitamab-cxix were observed in 2.5% of 81 patients with relapsed or refractory DLBCL with pre-existing anti-tafasitamab antibodies in L-MIND.

MONJUVI can cause fetal B-cell depletion when administered to a pregnant woman [see Use in Specific Populations (8.1)].

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

Among 81 patients who received MONJUVI and lenalidomide in L-MIND, 72% were 65 years and older, while 38% were 75 years and older. Clinical studies of MONJUVI did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs compared to that of younger subjects. Patients 65 years and older had more serious adverse reactions (57%) than younger patients (39%).

Tafasitamab-cxix is a humanized CD19-directed cytolytic monoclonal antibody that contains a IgG1/2 hybrid Fc-domain with 2 amino acid substitutions to modify the Fc-mediated functions of the antibody. It is produced by recombinant DNA technology in mammalian cells (Chinese hamster ovary). Tafasitamab-cxix has a molecular weight of approximately 150 kDa.

MONJUVI (tafasitamab-cxix) for injection is supplied as a sterile, preservative-free, white to slightly yellowish lyophilized powder in a single-dose vial for intravenous use after reconstitution and further dilution. After reconstitution with 5 mL of Sterile Water for Injection, USP, the resulting concentration is 40 mg/mL with a pH of 6.0. Each single-dose vial contains 200 mg tafasitamab-cxix, citric acid monohydrate (3.7 mg), polysorbate 20 (1 mg), sodium citrate dihydrate (31.6 mg) and trehalose dihydrate (378.3 mg).

Tafasitamab-cxix is an Fc-modified monoclonal antibody that binds to CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL).

Upon binding to CD19, tafasitamab-cxix mediates B-cell lysis through apoptosis and immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

In studies conducted in vitro in DLBCL tumor cells, tafasitamab-cxix in combination with lenalidomide resulted in increased ADCC activity compared to tafasitamab-cxix or lenalidomide alone.

Tafasitamab-cxix reduced peripheral blood B cell counts by 97% after eight days of treatment in patients with relapsed or refractory DLBCL. Nadir with a reduction of 100% was reached within 16 weeks of treatment.

Mean trough concentrations (± standard deviation) were 179 (± 53) μg/mL following administration of MONJUVI at 12 mg/kg on Days 1, 8, 15, and 22 in Cycle 1-3 (plus an additional dose on Cycle 1 Day 4), and 153 (± 68) μg/mL following administration of MONJUVI at 12 mg/kg on Days 1 and 15 from Cycle 4 onwards. Overall maximum tafasitamab-cxix serum concentrations were 483 (±109) μg/mL.

Carcinogenicity and genotoxicity studies have not been conducted with tafasitamab-cxix.

Fertility studies have not been conducted with tafasitamab-cxix.

In the 13-week repeat-dose general toxicity study in cynomolgus monkeys, no adverse effects on male and female reproductive organs were observed up to the highest dose tested, 100 mg/kg/week (approximately 9 times the human exposure based on AUC at the clinical dose of 12 mg/kg/week).

The efficacy of MONJUVI in combination with lenalidomide followed by MONJUVI as monotherapy was evaluated in L-MIND, an open label, multicenter single arm trial (NCT02399085). Eligible patients had relapsed or refractory DLBCL after 1 to 3 prior systemic therapies, including a CD20-directed cytolytic antibody, and were not candidates for high dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Patients received MONJUVI 12 mg/kg intravenously in combination with lenalidomide (25 mg orally on Days 1 to 21 of each 28-day cycle) for maximum of 12 cycles, followed by MONJUVI as monotherapy until disease progression or unacceptable toxicity as follows:

• Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle;
• Cycle 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle;
• Cycles 4 and beyond: Days 1 and 15 of each 28-day cycle.

Of the 71 patients with DLBCL confirmed by central laboratory who received the combination therapy, the median age was 71 years (range: 41 to 86 years); 55% were males, and 100% had received a prior CD20-containing therapy. Race was collected in 92% of patients; of these, 95% were White and 3% were Asian. The median number of prior therapies was two; 49% had one prior line of treatment, and 51% had 2 to 4 prior lines. Thirty two patients (45%) were refractory to their last prior therapy and 30 (42%) were refractory to rituximab. Nine patients (13%) had received prior ASCT. The primary reasons patients were not candidates for ASCT included age (47%), refractoriness to salvage chemotherapy (27%), comorbidities (13%) and refusal of high dose chemotherapy/ASCT (13%).

Efficacy was established based on best overall response rate, defined as the proportion of complete and partial responders, and duration of response, as assessed by an Independent Review Committee using the International Working Group Response Criteria (Cheson 2007). Results are summarized in Table 5.

Table 5: Efficacy Results in L-MIND

	N = 71
Best overall response rate, n (%)	39 (55%)
(95% CI)	(43%, 67%)
Complete response rate	37%
Partial response rate	18%
Duration of Response
Median (range) in months Kaplan Meier estimates	21.7 (0, 24)

MONJUVI (tafasitamab-cxix) for injection is a sterile, preservative-free, white to slightly yellowish lyophilized powder for reconstitution supplied as a 200 mg single-dose vial.

Each 200 mg vial is individually packaged in a carton (NDC 73535–208–01).

Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not shake. Do not freeze.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

NDC 73535–208–01

MONJUVI_™
(tafasitamab-cxix)

For Injection

200 mg/vial

For Intravenous
Infusion Only.
Reconstitute and
dilute prior to
administration.

Single-dose vial
Discard unused portion

1 Vial
Rx only

morphosys | Incyte

Principal Display Panel (5 mL Vial Carton)