DECNUPAZ Powder for solution for injection Ref.[116689] Active ingredients: Pivekimab sunirine

5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

DECNUPAZ can cause hepatotoxicity, including VOD, a severe form of hepatotoxicity. In CADENZA, VOD occurred in 6% (7/116) of adult patients during treatment or following a subsequent hematopoietic stem cell transplantation (HSCT). Of the 7 total patients who developed VOD, 3 patients had treatment-naïve BPDCN and 4 patients had relapsed/refractory BPDCN. Among all 116 patients treated with DECNUPAZ at 0.045 mg/kg, VOD occurred in 2/116 (2%) during treatment, with onset up to 30 days after the last dose. Among 19 patients with BPDCN who proceeded to HSCT, VOD occurred in 5/19 patients (26%), including two fatal cases. The median time from subsequent HSCT to onset of VOD was 11 days (range: 7 – 25 days).

After receiving DECNUPAZ, patients should be closely monitored for signs and symptoms of VOD including elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitor liver tests, including ALT, AST, and total bilirubin, prior to each dose of DECNUPAZ. Based on elevations of liver tests, delay DECNUPAZ. In patients who experience VOD, discontinue DECNUPAZ and treat according to standard medical practice [see Dosage and Administration (2.4)].

5.2 Infusion-Related Reactions

DECNUPAZ can cause serious, life-threatening infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. In CADENZA, IRRs occurred in 26% (30/116) of patients during treatment with DECNUPAZ at 0.045 mg/kg once every three weeks, including Grade 1 in 4.3% (5/116), Grade 2 in 16% (19/116), and Grade 3 in 5% (6/116) of patients. IRR occurred in Cycle 1 in 25% (29/116) of patients with decreasing frequency in subsequent cycles. IRR led to discontinuation in one patient.

Premedicate with a corticosteroid the day before infusion, and premedicate with a corticosteroid, antihistamine, and antipyretic prior to dosing [see Dosage and Administration (2.3)]. Premedication the day before infusion and prior to dosing led to reduced frequency and severity of IRRs.

Monitor patients closely for potential IRR during the infusion and for at least four hours, or longer as clinically indicated, after the first infusion and for at least 1 hour after subsequent infusions.

Interrupt infusion of DECNUPAZ and institute appropriate medical management if an infusion-related reaction occurs. Depending on the severity of the infusion-related reaction, reduce infusion rate or permanently discontinue [see Dosage and Administration (2.4)].

5.3 Edema

DECNUPAZ can cause edema and fluid retention, including serious events. In CADENZA, Grade 3-4 edema occurred in 16% (18/116) of patients treated with DECNUPAZ, including Grade 3-4 generalized edema in 2.6% (3/116) of patients [see Adverse Reactions (6.1)].

Monitor patients for new or worsening edema. For Grade 2 or Grade 3 edema, delay further dosing of DECNUPAZ until edema has returned to Grade 0-1 or baseline. For Grade 3 edema or Grade 2 edema with dose delay for more than 2 weeks, consider resuming at a lower dose. For Grade 4 edema, permanently discontinue. Institute appropriate medical management for edema [see Dosage and Administration (2.4)].

5.4 Sulfite Allergic Reactions

DECNUPAZ contains sodium metabisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, DECNUPAZ can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

Advise patients of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DECNUPAZ, and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

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

• Hepatotoxicity, Including Hepatic VOD (also known as Sinusoidal Obstruction Syndrome) [see Warnings and Precautions (5.1)]
• Infusion-Related Reactions [see Warnings and Precautions (5.2)]
• Edema [see Warnings and Precautions (5.3)]

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

The safety of DECNUPAZ was evaluated in CADENZA, a single-arm, open-label study that included 116 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 84 with BPDCN, treated with DECNUPAZ 0.045 mg/kg once every three weeks.

The median number of cycles administered was 3 (range: 1 to 34) in the overall population, and 3.5 (range: 1 to 34) in patients with BPDCN.

Serious adverse reactions occurred in 55% of patients treated with DECNUPAZ. The most common (≥2%) serious adverse reactions were febrile neutropenia, pneumonia, edema, sepsis, hemorrhage, thrombosis, infusion-related reactions, viral infection, pneumonitis, infections without specified pathogens, pyrexia, and musculoskeletal pain. Fatal adverse reactions occurred in 4.3% of patients who received DECNUPAZ, including cardiac arrest (0.9%), clostridium difficile infection (0.9%), failure to thrive (0.9%), depressed level of consciousness (0.9%), and respiratory failure (0.9%).

Permanent discontinuation due to adverse reactions occurred in 10% of patients who received DECNUPAZ. Adverse reactions which resulted in permanent discontinuation of DECNUPAZ in ≥1% of patients included veno-occlusive disease and pneumonitis.

Dosage interruptions of DECNUPAZ due to adverse reactions occurred in 37% of patients. Adverse reactions which resulted in dosage interruptions in ≥2% of patients included edema, pneumonia, infusion-related reaction, bacterial infections, fatigue, hemorrhage, neutropenia, pneumonitis, and pyrexia.

Dose reductions of DECNUPAZ due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dose reductions in ≥2% of patients included edema.

The most common adverse reactions (≥20%) were edema, fatigue, musculoskeletal pain, hemorrhage, infusion-related reactions, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10%) were neutrophils decreased, platelets decreased, lymphocyte count decreased, white blood cells decreased, hemoglobin decreased, and glucose increased.

Table 3 summarizes the common adverse reactions (≥10%) in patients treated with DECNUPAZ in CADENZA.

Table 3. Adverse Reactions (≥10%) in Patients Who Received DECNUPAZ in CADENZA:

^§ Adverse reactions were graded based on CTCAE Version 4.03
^a Edema includes acute pulmonary edema, face edema, generalized edema, hypervolemia, edema, edema genital, edema peripheral, pericardial effusion, peripheral swelling, pleural effusion, pulmonary edema, swelling face, weight increased, ascites.
^b Consists of multiple related terms.
^c Rash includes erythema, erythema nodosum, guttate psoriasis, photosensitivity reaction, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, skin lesion, skin lesion inflammation, stasis dermatitis.
^d Neuropathy peripheral includes burning sensation, dysesthesia, facial nerve disorder, hypoesthesia, IIIrd nerve disorder, neuralgia, neuropathy peripheral, paresthesia, sciatica.
^e Viral infections includes COVID-19, cytomegalovirus infection, HCoV-229E infection, herpes simplex, herpes zoster, herpes zoster disseminated, influenza, ophthalmic herpes simplex, oral herpes.
^f Bacterial infections includes cellulitis, clostridium difficile infection, erysipelas, folliculitis, vulval abscess.
^g Pneumonia includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia viral.

Clinically relevant adverse reactions occurring in <10% of patients who received DECNUPAZ in CADENZA included:

Vascular disorders: capillary leak syndrome (9%)^a, hypotension^b (7%)

Gastrointestinal disorders: stomatitis^b (6%)

Infections and infestations: sepsis^c (7%), fungal infections^d (5%)

Respiratory, thoracic and mediastinal disorders: pneumonitis (5%)

Cardiac disorders: arrhythmia^e (6%)

Renal and urinary disorders: acute kidney injury^b (6%)

Hepatobiliary disorders: veno-occlusive disease (1.7%)

^a At least 2 of the following new onset signs and symptoms within 7 days of each other: hypoalbuminemia (including albumin <3.0 g/dL), edema (including weight increase >5 kg), hypotension (including systolic blood pressure <90 mmHg).
^b Consists of multiple related terms.
^c Includes bacteremia, klebsiella bacteremia, pulmonary sepsis, sepsis, and streptococcal bacteremia.
^d Includes candida infection, fungal balanitis, fungal foot infection, fungal skin infection.
^e Includes arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, tachyarrhythmia.

Table 4 summarizes laboratory abnormalities in CADENZA.

Table 4. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received DECNUPAZ in CADENZA:

^* Laboratory abnormalities were graded based on CTCAE Version 4.03.
^a The denominator used to calculate the rate varied from 78 to 114 based on the number of patients with at least one post-baseline value.

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the study described below with the incidence of ADA in other studies, including those of pivekimab sunirine-pvzy.

Following administration of pivekimab sunirine-pvzy in CADENZA in BPDCN patients, 19/80 (24%) of patients tested positive for treatment emergent antibodies against pivekimab sunirine-pvzy. Of those who tested positive for anti-drug antibody, neutralizing antibodies were detected in 14/18 (78%) of evaluable patients. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, safety, or effectiveness of pivekimab sunirine-pvzy.

7.1 Effect of Other Drugs on DECNUPAZ

Strong and moderate CYP3A inhibitors

Closely monitor patients for adverse reactions with DECNUPAZ when used concomitantly with strong and moderate CYP3A inhibitors.

FGN849 is a substrate of CYP3A [see Clinical Pharmacology (12.3)]. Concomitant use of DECNUPAZ with strong and moderate CYP3A inhibitors may increase unconjugated FGN849 exposure, which may increase the risk of DECNUPAZ adverse reactions.

Risk Summary

Based on its mechanism of action, DECNUPAZ can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (FGN849) and affects actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. There are no available data on the use of DECNUPAZ in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus.

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

Data

Animal Data

Animal reproductive or developmental toxicity studies were not conducted with pivekimab sunirine-pvzy. The cytotoxic component of DECNUPAZ, FGN849, is a DNA-alkylating agent that is toxic to rapidly dividing cells, indicating it has the potential to cause embryofetal lethality and teratogenicity.

Risk Summary

There are no data on the presence of pivekimab sunirine-pvzy or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with DECNUPAZ and for 1 month after the last dose.

DECNUPAZ can cause fetal harm when administered to a pregnant patient [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiation of DECNUPAZ.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 7 months after the last dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with DECNUPAZ and for 4 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on its mechanism of action, DECNUPAZ may impair male and female reproductive function and fertility.

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

Of the 116 patients who were treated in CADENZA, 70% of patients were ≥65 years of age and 28% were ≥75 years of age. No overall differences in safety or effectiveness of DECNUPAZ have been observed between patients 65 years of age and older and younger adult patients.

Age does not have a clinically meaningful effect on the pharmacokinetics of DECNUPAZ [see Clinical Pharmacology (12.3)].

Avoid use of DECNUPAZ in patients with moderate to severe renal impairment (CLcr <60 mL/min, estimated by Cockcroft-Gault) or patients with end stage renal disease. A higher incidence of Grade ≥3 adverse events, serious adverse events, and dose delays was observed in patients with moderate renal impairment (CLcr 30 to <60 mL/min). DECNUPAZ has not been studied in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease.

No dosage adjustment of DECNUPAZ is recommended for patients with mild renal impairment (CLcr 60 to <90 mL/min, estimated by Cockcroft-Gault) [see Clinical Pharmacology (12.3)].

Avoid use of DECNUPAZ in patients with moderate to severe hepatic impairment (total bilirubin >1.5 x ULN with any AST). Limited data are available in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). DECNUPAZ has not been studied in patients with severe hepatic impairment.

No dosage adjustment of DECNUPAZ is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin ≤1.5 times ULN and any AST) [see Clinical Pharmacology (12.3)].