Besponsa: Package Insert and Label Information (Page 3 of 4)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. 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 to inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.

7. DRUG INTERACTIONS

Drugs That Prolong the QT Interval

Concomitant use of BESPONSA with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc interval prolongation [see Clinical Pharmacology (12.2)]. Discontinue or use alternative concomitant drugs that do not prolong QT/QTc interval while the patient is using BESPONSA. When it is not feasible to avoid concomitant use of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Warnings and Precautions (5.5)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)], BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively.

Data

Animal Data

In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m² during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m² (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m² (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).

In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m² (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m² , slight maternal toxicity was observed in the absence of any effects on embryo-fetal development.

8.2 Lactation

Risk Summary

There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with BESPONSA and for at least 2 months after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.

Contraception

Females

Advise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA. Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 8 months after the last dose [see Nonclinical Toxicology (13.1)].

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 5 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

Males

Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were ≥ 65 years of age. No differences in responses were identified between older and younger patients.

Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology (12.3)].

No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration (2.3)]. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

11. DESCRIPTION

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) consisting of 3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (IgG4) kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the condensation product of 4-(4′-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab.

Inotuzumab ozogamicin has an approximate molecular weight of 160 kDa. The average number of calicheamicin derivative molecules conjugated to each inotuzumab molecule is approximately 6 with a distribution from 2–8. Inotuzumab ozogamicin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the semisynthetic calicheamicin derivative is produced by microbial fermentation followed by synthetic modification.

BESPONSA (inotuzumab ozogamicin) for Injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous administration. Each single-dose vial delivers 0.9 mg inotuzumab ozogamicin. Inactive ingredients are polysorbate 80 (0.36 mg), sodium chloride (2.16 mg), sucrose (180 mg), and tromethamine (8.64 mg). After reconstitution with 4 mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with a deliverable volume of 3.6 mL (0.9 mg) and a pH of approximately 8.0.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

12.2 Pharmacodynamics

During the treatment period, the pharmacodynamic response to BESPONSA was characterized by the depletion of CD22-positive leukemic blasts.

Cardiac Electrophysiology

In a randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of ≥ 60 msec from baseline were measured in 4/162 patients (3%) in the BESPONSA arm and 3/124 patients (2%) in the Investigator’s choice of chemotherapy arm. Increases in QTcF of > 500 msec were observed in none of the patients in the BESPONSA arm and 1/124 patients (1%) in the Investigator’s choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the BESPONSA arm [see Warnings and Precautions (5.5)].

12.3 Pharmacokinetics

The mean C_max of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ng∙h/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.

Distribution

N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.

Elimination

The pharmacokinetics of inotuzumab ozogamicin was well characterized by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t_½ ) was 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.

Metabolism

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.

Specific Populations

The effect of intrinsic factors on inotuzumab ozogamicin pharmacokinetics was assessed using a population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race (Asian versus non-Asian [Caucasian, Black, and Unspecified]) had no clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. Body surface area was found to significantly affect inotuzumab ozogamicin disposition. BESPONSA is dosed based on body surface area [see Dosage and Administration (2.1)].

Patients with Renal Impairment

The clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CL_cr; based on the Cockcroft-Gault formula] 60–89 mL/min; n=237), moderate renal impairment (CL_cr 30–59 mL/min; n=122), or severe renal impairment (CL_cr 15–29 mL/min; n=4) was similar to patients with normal renal function (CL_cr ≥90 mL/min; n=402). The safety and efficacy of inotuzumab ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.

Patients with Hepatic Impairment

The clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin ≤ULN and AST > ULN, or total bilirubin >1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST ≤ULN; n=611). There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).

Drug Interactions

In vitro

Effect of Metabolic Pathways and Transporter Systems on BESPONSA

N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp).

Effect of BESPONSA on Metabolic Pathways and Transporter Systems

At clinically relevant concentrations, N-acetyl-gamma-calicheamicin dimethylhydrazide had a low potential to:

• Inhibit cytochrome P450 (CYP 450) Enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
• Inhibit UGT Enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.
• Inhibit Drug Transporters: P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.

At clinically relevant concentrations, inotuzumab ozogamicin had a low potential to:

• Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity studies, rats were dosed weekly for 4 or 26 weeks with inotuzumab ozogamicin at doses up to 4.1 mg/m² and 0.73 mg/m² , respectively. After 26 weeks of dosing, rats developed hepatocellular adenomas in the liver at 0.73 mg/m² (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC).

Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single doses ≥1.1 mg/m². This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

In a female fertility and early embryonic development study, female rats were administered daily intravenous doses of inotuzumab ozogamicin up to 0.11 mg/m² for 2 weeks before mating through Day 7 of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos and gravid uterine weights were observed at the 0.11 mg/m² dose level (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were nonreversible following a 4-week nondosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at ≥0.07 mg/m² in male rats and at 0.73 mg/m² in female monkeys [see Use in Specific Populations (8.3)].