Rituxan Hycela (Page 5 of 9)

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

RITUXAN HYCELA is a combination of rituximab and hyaluronidase human. Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension.

Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is produced by mammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). It is a glycosylated single-chain protein with an approximate molecular weight of 61 kD.

RITUXAN HYCELA (rituximab and hyaluronidase human) injection is a colorless to yellowish, clear to opalescent solution supplied in sterile, preservative-free, single-dose vials for subcutaneous use.

RITUXAN HYCELA is supplied as 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL in single-dose vials or 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL in single-dose vials. Each mL of solution contains rituximab (120 mg), hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), α,α-trehalose dihydrate (79.45 mg), and Water for Injection.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in RITUXAN HYCELA acts locally.

The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Hyaluronidase human has been shown to increase the absorption rate of a rituximab product into the systemic circulation when given in the subcutis of Göttingen Minipigs.

12.2 Pharmacodynamics

Peripheral B-cell counts declined to levels below normal following a dose of rituximab by intravenous infusion. In patients treated with rituximab for hematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer.

Follicular Lymphoma (FL)

Peripheral B-cell counts decline to levels below normal following the first cycle of rituximab and are maintained during treatment with RITUXAN HYCELA. After stopping RITUXAN HYCELA treatment, B-cell repletion followed similar kinetics to that of rituximab with B-cell repletion beginning after 6 months of stopping treatment, although in some patients this may take longer.

Chronic Lymphocytic Leukemia (CLL)

Following the first cycle of treatment of rituximab, B-cells begin to deplete, with 28% of patients B-cell depleted at pre-dose Cycle 2 in the SAWYER study. An increase in the proportion of B-cell depleted patients was observed with subsequent cycles of RITUXAN HYCELA and by Cycle 6, 96% of patients were depleted. Patients remained B-cell depleted until the month 9 follow-up visit, where signs of repletion were seen.

12.3 Pharmacokinetics

The geometric mean rituximab exposures are provided in Table 4. The pharmacokinetic properties of rituximab following the administration of RITUXAN HYCELA in the approved indications are provided in Table 5. The elimination of rituximab was characterized by a time-dependent process that occurred early in therapy and a time-independent process.

Table 4: Rituximab Exposure Values following Subcutaneous Administration of RITUXAN HYCELA *

		Study †	Cycle	Rituximab
* Pharmacokinetic parameters are presented as geometric mean unless otherwise specified. † For study design information, see Clinical Studies (14). ‡ RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) § Based on predicted values ¶ RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human)
FL ‡	Cmax , mcg/mL (CV%)	SABRINA	7	237 (29.4)
			18	156 (24.7)§
	Ctrough , mcg/mL (CV%)		7	122.2 (55.3)
			18	45.5 (53.6)§
	AUCTAU , mcg∙day/mL (CV%)		7	3779 (33.7)
			18	5000 (34.3)§
CLL ¶	Cmax , mcg/mL (CV%)	SAWYER	6	202 (36.1)
	Ctrough , mcg/mL (CV%)		5	97.5 (42.6)
	AUCTAU , mcg∙day/mL (CV%)		5	4088 (34.2)

In the SABRINA study, the geometric mean C_trough in the RITUXAN HYCELA arm was higher than in the rituximab arm with a geometric mean ratio (C_trough , RITUXAN HYCELA/C_trough , rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle 7 [see Clinical Studies (14.1)].

In the SAWYER study, the geometric mean C_trough in the RITUXAN HYCELA arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27–1.85) at Cycle 5 [see Clinical Studies (14.3)].

Table 5: Pharmacokinetic Parameters of Rituximab following Subcutaneous Administration of RITUXAN HYCELA *

	FL	CLL
* Parameters represented as geometric mean (%CV) unless otherwise specified † Compared to a rituximab product administered intravenously ‡ 95% CI § Volume of central compartment and peripheral compartment
Absorption
Absolute Bioavailability †	0.646 (0.634–0.659‡)	0.634 (0.602–0.665‡)
Distribution
Volume of Central compartment (L)	4.06 (26)	4.80 (18)
Apparent Volume of Distribution at steady state § (L)	8.09 (19)	8.52 (13)
Elimination
Terminal Half-life (days)	34.1 (27)	32 (24)
Clearance (L/day)	0.18 (34)	0.204 (31)

Specific Populations

The pharmacokinetics of rituximab and hyaluronidase human in children and adolescents is unknown. The effect of either renal or hepatic impairment on the pharmacokinetics of rituximab and hyaluronidase human is unknown.

Drug Interaction Studies

The drug interaction potential of rituximab and hyaluronidase human is unknown.