OPDIVO Solution for injection Ref.[116349] Active ingredients:

Nivolumab solution for injection pharmacokinetics (PK) were assessed using a population PK approach. The PK was studied at a dose of 1200 mg administered as multiple doses every 4 weeks.

Nivolumab time-averaged serum concentration over 28 days (C_avgd28) showed non-inferiority of subcutaneous nivolumab (77.4 mcg/mL) to intravenous nivolumab (36.9 mcg/mL), with a geometric mean ratio of 2.098 (90% CI: 2.001, 2.200). Nivolumab minimum serum concentration at steady state (C_minss) showed non-inferiority of subcutaneous nivolumab (122.2 mcg/mL) to intravenous nivolumab (68.9 mcg/mL), with a geometric mean ratio of 1.774 (90% CI: 1.633, 1.927).

Absorption

The mean absorption rate constant (Ka) and bioavailability (F) of nivolumab solution for injection are 0.0123 hr-1 (or 0.295 Day-1) and 78.8%, respectively. Peak concentrations occurred by around 6 days.

Distribution

The geometric mean (CV%) volume of distribution at steady state (V_ss) is 6.32 L (21.3%).

Elimination

Nivolumab solution for injection human clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.6% (15.8%) resulting in a geometric mean (CV%) steady-state clearance (CL_ss) of 7.18 mL/h (52.3%) in patients with RCC; the decrease in CL_ss is not considered clinically relevant.

The geometric mean (CV%) elimination half-life (t1/2) is 26.5 days (32.1%).

Special populations

The following factors had no clinically important effect on the bioavailability of nivolumab solution for injection: sex and performance status. The following factors had no clinically important effect on the clearance of nivolumab solution for injection: body weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m²), or performance status.

Renal impairment

In population PK analyses for intravenous nivolumab, the effect of renal impairment on the CL of nivolumab was evaluated in patients with mild (GFR <90 and ≥60 mL/min/1.73 m²; n=379), moderate (GFR <60 and ≥30 mL/min/1.73 m²; n=179), or severe (GFR <30 and ≥15 mL/min/1.73 m²; n=2) renal impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m²; n=342). No clinically important differences in the CL of nivolumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Data from patients with severe renal impairment are too limited to draw conclusions on this population (see section 4.2).

Hepatic impairment

In population PK analyses for intravenous nivolumab, the effect of hepatic impairment on the CL of nivolumab was evaluated in patients with different tumour types (NSCLC, SCLC, melanoma, RCC, SCCHN, UC, GC, and cHL) with mild hepatic impairment (total bilirubin 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=351) and in patients with moderate hepatic impairment (total bilirubin >1.5 × to 3 × ULN and any AST; n=10) compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN; n=3096). No clinically important differences in the CL of nivolumab were found between patients with mild or moderate hepatic impairment and normal hepatic function. Similar results were observed in patients with HCC (mild hepatic impairment: n=152; moderate hepatic impairment: n=13). Nivolumab has not been studied in patients with severe hepatic impairment (total bilirubin >3 × ULN and any AST) (see section 4.2).

Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was a dose-dependent increase in foetal losses and increased neonatal mortality beginning in the third trimester.

The remaining offspring of nivolumab-treated females survived to scheduled termination, with no treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, immunological, and clinical pathology parameters throughout the 6-month postnatal period were comparable to the control group. However, based on its mechanism of action, foetal exposure to nivolumab may increase the risk of developing immune-related disorders or altering the normal immune response and immune-related disorders have been reported in PD-1 knockout mice.

Fertility studies have not been performed with nivolumab.

Subcutaneous formulation

Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant human hyaluronidase reveal no special hazard for humans based on conventional studies of repeated dose toxicity including safety pharmacology endpoints. Reproductive toxicology studies with rHuPH20 revealed embryofoetal toxicity in mice at high systemic exposure but did not show teratogenic potential.