Fatalities

Summary of Fatalities

  • In ocrelizumab clinical trials and their open-label extensions, there was no increase in fatalities in ocrelizumab-treated patients compared with controls1,2
  • From the post-marketing experience there was no pattern observed in the causes of fatalities as reported to the regulatory authorities.1 Causes of fatalities in the post-marketing setting are outlined below

Background Rates in the MS Populationa

  • Estimated mortality rates in the MS population ranged from 0.37 per 100 patient-years3 to 0.9 per 100 patient-years4
  • These estimates were based on an observational study in France (27,603 MS patients)3 and a retrospective study in the US (30,402 MS patients from the OptumInsight Research database)4

a The incidence rates of fatalities are derived from varied sources, and intended to provide context. Confounding factors which may influence mortality have not been accounted for, and therefore, no direct comparisons should be made. Such factors may include, but are not limited to: type of MS, age, gender, disease duration, geographical region, population size, drug exposure, comorbid conditions, treatment history, and duration of follow-up.

Clinical Trials (Controlled Treatment Period and Open-Label Extension)

Incidence rate in phase 3 clinical trials (controlled treatment period only):2

  OPERA (Pooled)
Incidence Rate per 100 Patient-Years (95% CI)
ORATORIO
Incidence Rate per 100 Patient-Years (95% CI)
IFN β-1a Ocrelizumab Placebo Ocrelizumab
Phase 3  Controlled Treatment Period 0.14 (0.02, 0.52) 0.07 (0, 0.38) 0.41 (0.08, 1.20) 0.25 (0.07, 0.64)

a Two identical phase 3, global, randomised, double-blind, double-dummy studies with a 96-week controlled period during which 1656 patients with relapsing forms of MS received either intravenous ocrelizumab (600 mg) every 24 weeks or subcutaneous interferon beta-1a (44 μg) three times weekly.5

b A phase 3, global, randomised, double-blind study with a ≥120-week controlled period during which 732 patients with primary progressive MS received either intravenous ocrelizumab (600 mg) or placebo every 24 weeks.6

Incidence rate by exposure in clinical trials (controlled treatment period and open-label extension):1a

  Data Cutoff Date Patients on Ocrelizumab (N) Patient-Years Fatalities (n)c Incidence Rate per 100 Patient-Years 95% CIs

Ocrelizumab All-Exposure
Populationb

JUL 2015 2147 4484.5 8 0.178 0.077, 0.352
JAN 2016 2279 5710.7 8 0.140 0.060, 0.276
SEP 2016 2300 6940.9 11 0.158 0.079, 0.284
FEB 2017 2301 7747.8 13 0.168 0.089, 0.287
SEP 2017 3778 9473.5 16 0.169 0.097, 0.274
FEB 2018 3811 10,918.5 17 0.156 0.091, 0.249
JUL 2018
4501
12,558.9
19 0.151
0.091, 0.236

a Data cuts are cumulative; each data cut includes the previous cut and fatalities are included from both the DBP and OLE.

b Includes all patients exposed to ocrelizumab in the global and US MS clinical trials except Ensemble; excludes patients in compassionate use program.

c The causes of the fatalities in the all-exposure population are as follows: Cardiac arrest (n=2), metastatic pancreatic cancer (n=2), suicide (n=2), acute coronary insufficiency (n=1), adenocarcinoma of esophagus (n=1), aspiration pneumonia (n=1), bladder cancer (n=1), epileptic seizure (n=1), injury (n=1), MS disease progression (n=1), pneumonia (n=1), pulmonary embolism (n=1), systemic inflammatory response syndrome of undetermined origin (n=1), unknown (n=1), urinary infection/urosepsis (n=1), and fall (n=1)

Post-Marketing Experience1

  Market Period Patientes on Ocrelizumaba Patient-Years Fatalities (n)b Incidence Rate per 100 Patient-Years
Ocrelizumab Post-Marketing APR 2017–DEC 2017
~27,678
~8899
24 0.27
APR 2017–MAR 2018
~37,171
~15,682
45 0.29
APR 2017–MAY 2018
~48,780
~23,776
64 0.27
APR 2017–JULY 2018
~58,667
~33,526
87 0.26
APR 2017–SEP 2018
~66,662
~43,560
114 0.26
APR 2017–DEC 2018
~78,554
~60,710
149 0.25
APR 2017–MAY 2019
~103,290 ~94,964 250 0.26

a The number of post-marketing patients exposed to ocrelizumab is based on estimated total number of vials sold, as well as US claims data.

b Based on reported fatalities in the Roche safety database with patients suffering from relapsing or progressive multiple sclerosis treated with ocrelizumab reported within the designated post-marketing period.

The causes of the post-marketing fatalities are as follows: Unknown cause (n=127), symptoms reported as a cause of death (asthenia, chest pain, pyrexia and decreased appetite) (n=1), myocardial infarction (n=12), completed suicide (n=9), pneumonia (n=8), sepsis (n=7), pulmonary embolism (n=6), infection (n=3), pancreatic carcinoma (n=3), sudden death (n=3), urosepsis (n=2), cardiac disorder (n=2), urinary tract infection (n=2), multiple sclerosis (n=2), tumefactive multiple sclerosis (n=1); subdural haematoma (n=2), fall (n=2), multiple sclerosis relapse with infection (n=1), opioid overdose (n=1), aspiration pneumonia (n=1), acute kidney injury (n=1), cerebral haemorrhage (n=1), influenza (n=1), influenza-like illness (n=1), brain herniation with toxic leukoencephalopathy (n=1), cardiogenic shock with circulatory collapse and urinary tract infection (n=1), epilepsy with status epilepticus (n=1), cellulitis with pneumonia, sepsis and urinary tract infection (n=1), aspiration pneumonia with respiratory failure (n=1), lung cancer with metastases to bone and CNS (n=1), metastatic lung adenocarcinoma (n=1), acute respiratory failure with urosepsis (n=1), dyspnoea, hyperhidrosis, and circulatory collapse (n=1), cardiopulmonary arrest with pulmonary embolism and deep vein thrombosis (n=1), sepsis with aspiration pneumonia, intestinal sepsis, cardiac arrest, and intestinal obstruction (n=1), lung infection with osteomyelitis (n=1), urinary tract infection with sepsis (n=1), choking (n=1), stroke (n=1), cardiac failure congestive (n=1), respiratory failure (n=1), encephalopathy, asthenia, seizure, and respiratory failure (n=1), cardiorespiratory arrest (n=1), adenocarcinoma (n=1), renal failure (n=1), aspiration and septic shock (n=1), lung infection (n=1), cardiac failure (n=1), victim of homicide (n=1), lung disorder (n=1), fracture (n=1), peritonitis (n=1), aortic aneurysm (n=1), acute myocardial infarction with nasopharyngitis, cardiac failure, and cardiac disorder (n=1), cardiac arrest with pulmonary embolism (n=1), haemorrhage (n=1), hepatic and renal failure (n=1), kidney infection (n=1), metastatic neoplasm (n=1), colon cancer (n=1), metastatic liver cancer (n=1), metastatic renal cell carcinoma (n=1), breast cancer with metastasis to lung (n=1), malignant lung neoplasm (n=1), sudden death and metastatic neoplasm (n=1), respiratory disorder (n=1), sepsis with liver disorder, malignant neoplasm and general physical health deterioration (n=1), respiratory failure, multiple organ dysfunction syndrome, and circulatory collapse (n=1), generalised oedema (n=1), thrombosis (n=1), cardiac arrest (n=1), sarcoma (n=1), angiosarcoma (n=1), septic shock (n=1), and intentional product use issue, off label use (n=1).

Prescribing information

Indications vary in different countries. The local prescribing information from your country is the primary source of information on the known and potential risks associated with ocrelizumab.
References
 
  1. Roche data on file.
  2. Hauser SL, et al. Presented at: ECTRIMS-ACTRIMS 2017 (Poster P676);
  3. Leray E, et al. PLoS One. 2015;10(7):e0132033;
  4. Goodin DS, et al. PLoS One. 2014;9(8):e105207;
  5. Hauser SL, et al. N Engl J Med. 2017; 376:221–234;
  6. Montalban X, et al. N Engl J Med. 2017; doi: 10.1056/NEJMoa1606468 [suppl];

Information current as of May 2019. Existence of a safety report does not establish causation. By regulation, all cases where causality is unknown or not captured are reported as related to ocrelizumab. The causes of fatalities are recorded as reported to the company; while the company follows up on all reports to identify the cause, an exact diagnosis is not always possible. Some of the investigations remain ongoing and, therefore, the information may be subject to change.

Date of preparation: June 2019

Fatalities