Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, the overall subject incidence of all adverse reactions for romiplostim-treated subjects was 91.5% (248/271). The mean duration of exposure to romiplostim in this study population was 50 weeks.

The most serious adverse reactions that may occur during Nplate treatment include: reoccurrence of thrombocytopenia and bleeding after cessation of treatment, increased bone marrow reticulin, thrombotic/thromboembolic complications, medication errors and progression of existing MDS to AML. The most common adverse reactions observed include hypersensitivity reactions (including cases of rash, urticaria and angioedema) and headache.

Tabulated list of adverse reactions

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each MedDRA system organ class and frequency grouping, undesirable effects are presented in order of decreasing incidence.

MedDRA system            Very common               Common               Uncommon organ class
Infections and           Upper respiratory         Gastroenteritis      Influenza infestations             tract infection           Pharyngitis***       Localized infection Rhinitis***               Conjunctivitis***    Nasopharyngitis
Ear infection***
Sinusitis***/****
Bronchitis****


MedDRA system          Very common              Common              Uncommon organ class
Neoplasms benign,                                                   Multiple myeloma malignant and                                                       Myelofibrosis unspecified
(including cysts and polyps)
Blood and                                       Bone marrow         Aplastic anemia lymphatic system                                disorder*           Bone marrow failure disorders                                       Thrombocytopenia*   Leukocytosis Anemia              Splenomegaly
Thrombocythemia
Platelet count increased
Platelet count abnormal
Immune system          Hypersensitivity**       Angioedema disorders
Metabolism and                                                      Alcohol intolerance nutrition disorders                                                 Anorexia Decreased appetite
Dehydration
Gout
Psychiatric                                     Insomnia            Depression disorders                                                           Abnormal dreams Nervous system         Headache                 Dizziness           Clonus disorders                                       Migraine            Dysgeusia Paresthesia         Hypoesthesia
Hypogeusia
Neuropathy peripheral
Transverse sinus thrombosis
Eye disorders                                                       Conjunctival hemorrhage
Accommodation disorder
Blindness
Eye disorder
Eye pruritus
Lacrimation increased
Papilloedema
Visual disturbances
Ear and labyrinth                                                   Vertigo disorders
Cardiac disorders                               Palpitations        Myocardial infarction
Heart rate increased


MedDRA system         Very common           Common           Uncommon organ class
Vascular disorders                          Flushing         Deep vein thrombosis
Hypotension
Peripheral embolism
Peripheral ischemia
Phlebitis
Thrombophlebitis superficial
Thrombosis
Erythromelalgia
Respiratory,          Oropharyngeal         Pulmonary        Cough thoracic and          pain***               embolism*        Rhinorrhea mediastinal                                                  Dry throat disorders                                                    Dyspnea
Nasal congestion
Painful respiration
Gastrointestinal      Upper abdominal       Nausea           Vomiting disorders             pain***               Diarrhea         Rectal hemorrhage Abdominal pain   Breath odor
Constipation     Dysphagia
Dyspepsia        Gastro-esophageal reflux disease
Hematochezia
Mouth hemorrhage
Stomach discomfort
Stomatitis
Tooth discoloration
Hepatobiliary                                                Portal vein disorders                                                    thrombosis Increase in transaminase
Skin and                                    Pruritus         Alopecia subcutaneous tissue                         Ecchymosis       Photosensitivity disorders                                   Rash             reaction Acne
Dermatitis contact
Dry skin
Eczema
Erythema
Exfoliative rash
Hair growth abnormal
Prurigo
Purpura
Rash papular
Rash pruritic
Skin nodule
Skin odor abnormal
Urticaria


MedDRA system           Very common            Common                   Uncommon organ class
Musculoskeletal and                            Arthralgia               Muscle tightness connective tissue                              Myalgia                  Muscular weakness disorders                                      Muscle spasms            Shoulder pain Pain in extremity        Muscle twitching
Back pain
Bone pain
Renal and urinary                                                       Protein urine present disorders
Reproductive                                                            Vaginal hemorrhage system and breast disorders
General disorders                              Fatigue                  Injection site and administration                             Edema peripheral         hemorrhage site conditions                                Influenza like illness   Chest pain Pain                     Irritability
Asthenia                 Malaise
Pyrexia                  Face edema
Chills                   Feeling hot
Injection site           Feeling jittery reaction
Peripheral swelling***
Investigations                                                          Blood pressure increased
Blood lactate dehydrogenase increased
Body temperature increased
Weight decreased
Weight increased
Injury, poisoning                              Contusion and procedural complications
* see section 4.4
** Hypersensitivity reactions including cases of rash, urticaria, and angioedema *** Additional adverse reactions observed in pediatric studies
**** Additional adverse reactions observed in adult patients with ITP duration up to 12 months

Adult population with ITP duration up to 12 months

The safety profile of romiplostim was similar across adult patients, regardless of ITP duration.
Specifically in the integrated analysis of ITP ≤ 12 months duration (n = 311), 277 adult patients with ITP ≤ 12 months duration and who received at least one dose of romiplostim from among those patients in 9 ITP studies were included (see section 5.1). In this integrated analysis, the following adverse reactions (at least 5% incidence and at least 5% more frequent with Nplate compared with placebo or standard of care) occurred in romiplostim patients with ITP duration up to 12 months, but were not observed in those adult patients with ITP duration > 12 months: bronchitis, sinusitis (reported commonly (≥ 1/100 to < 1/10)).


Pediatric population

In the pediatric studies, 282 pediatric ITP subjects were treated with romiplostim in 2 controlled and 3 uncontrolled clinical trials. The median duration of exposure was 65.4 weeks. The overall safety profile was similar to that seen in adults.

The pediatric adverse reactions are derived from each of the pediatric ITP randomized safety set (2 controlled clinical trials) and pediatric ITP safety set (2 controlled and 3 uncontrolled clinical trials) where the subject incidence was at least 5% higher in the romiplostim arm compared to placebo and at least a 5% subject incidence in romiplostim-treated subjects.

The most common adverse reactions in pediatric ITP patients 1 year and older were upper respiratory tract infection, rhinitis, cough, oropharyngeal pain, upper abdominal pain, diarrhea, rash, pyrexia, contusion (reported very commonly (≥ 1/10)), and pharyngitis, conjunctivitis, ear infection, gastroenteritis, sinusitis, purpura, urticaria and peripheral swelling (reported commonly (≥ 1/100 to < 1/10)).

Oropharyngeal pain, upper abdominal pain, rhinitis, pharyngitis, conjunctivitis, ear infection, sinusitis and peripheral swelling were additional adverse reactions observed in pediatric studies compared to those seen in adult studies.

Some of the adverse reactions seen in adults were reported more frequently in pediatric subjects such as cough, diarrhea, rash, pyrexia and contusion reported very commonly (≥ 1/10) in pediatric subjects and purpura and urticaria were reported commonly (≥ 1/100 to < 1/10) in pediatric subjects.

Description of selected adverse reactions

In addition, the reactions listed below have been deemed to be related to romiplostim treatment.

Bleeding events

Across the entire adult ITP clinical program an inverse relationship between bleeding events and platelet counts was observed. All clinically significant (≥ grade 3) bleeding events occurred at platelet counts < 30 × 109/L. All bleeding events ≥ grade 2 occurred at platelet counts < 50 × 109/L. No statistically significant differences in the overall incidence of bleeding events were observed between Nplate and placebo treated patients.

In the two adult placebo-controlled studies, 9 patients reported a bleeding event that was considered serious (5 [6.0%] romiplostim, 4 [9.8%] placebo; Odds Ratio [romiplostim/placebo] = 0.59; 95% CI = (0.15, 2.31)). Bleeding events that were grade 2 or higher were reported by 15% of patients treated with romiplostim and 34% of patients treated with placebo (Odds Ratio; [romiplostim/placebo] = 0.35; 95% CI = (0.14, 0.85)).

In the phase 3 pediatric study, the mean (SD) number of composite bleeding episodes (see section 5.1) was 1.9 (4.2) for the romiplostim arm and 4.0 (6.9) for the placebo arm.

Thrombocytosis

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 3 events of thrombocytosis were reported, n = 271. No clinical sequelae were reported in association with the elevated platelet counts in any of the 3 subjects.

Thrombocytosis in pediatric subjects occurred uncommonly (≥ 1/1,000 to < 1/100), with a subject incidence of 1 (0.4%). Subject incidence was 1 (0.4%) for either grade ≥ 3 or serious thrombocytosis.

Thrombocytopenia after cessation of treatment

Based on an analysis of all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 4 events of thrombocytopenia after cessation of treatment were reported, n = 271 (see section 4.4).

Progression of existing Myelodysplastic Syndromes (MDS)

In a randomized placebo-controlled trial in MDS adult subjects treatment with romiplostim was prematurely stopped due to a numerical increase in cases of MDS disease progression to AML and transient increases in blast cell counts in patients treated with romiplostim compared to placebo. Of the cases of MDS disease progression to AML that were observed, patients with RAEB-1 classification of MDS at baseline were more likely to have disease progression to AML (see section 4.4). Overall survival was similar to placebo.

Increased bone marrow reticulin

In adult clinical trials, romiplostim treatment was discontinued in 4 of the 271 patients because of bone marrow reticulin deposition. In 6 additional patients reticulin was observed upon bone marrow biopsy (see section 4.4).

In a pediatric clinical trial (see section 5.1), of the subjects with an evaluable on-study bone marrow biopsy, 5 out of 27 subjects (18.5%) developed increased reticulin at year 1 after exposure to romiplostim (cohort 1) and 17 out of 36 subjects (47.2%) developed increased reticulin at year 2 after exposure to romiplostim (cohort 2). However, no subject showed any bone marrow abnormalities that were inconsistent with an underlying diagnosis of ITP at baseline or on-treatment.

Immunogenicity

Clinical trials in adult ITP patients examined antibodies to romiplostim and TPO. While 5.7% (60/1,046) and 3.2% (33/1,046) of the subjects were positive for developing binding antibodies to romiplostim and TPO respectively, only 4 subjects were positive for neutralizing antibodies to romiplostim but these antibodies did not cross react with endogenous TPO. Of the 4 subjects, 2 subjects tested negative for neutralizing antibodies to romiplostim at the subject’s last timepoint (transient positive) and 2 subjects remained positive at the subject’s last timepoint (persistent antibodies). The incidence of pre-existing antibodies to romiplostim and TPO was 3.3% (35/1,046) and 3.0% (31/1,046), respectively.

In pediatric studies, the incidence of binding antibodies to romiplostim at any time was 9.6% (27/282). Of the 27 subjects, 2 subjects had pre-existing binding non-neutralizing romiplostim antibodies at baseline. Additionally, 2.8% (8/282) developed neutralizing antibodies to romiplostim. A total of 3.9% (11/282) subjects had binding antibodies to TPO at any time during romiplostim treatment. Of these 11 subjects, 2 subjects had pre-existing binding non-neutralizing antibodies to TPO. One subject (0.35%) had a weakly positive postbaseline result for neutralizing antibodies against TPO while on-study (consistently negative for anti-romiplostim antibodies) with a negative result at baseline. The subject showed a transient antibody response for neutralizing antibodies against TPO, with a negative result at the subject’s last timepoint tested within the study period.


In the post-marketing registry study, 19 confirmed pediatric patients were included. The incidence of binding antibody post-treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positive for neutralizing antibodies to romiplostim. There were no antibodies detected to TPO. A total of 184 confirmed adult patients were included in this study; for these patients, the incidence of binding antibody post-treatment was 3.8% (7/184) to romiplostim, of which 0.5% (1/184) was positive for neutralizing antibodies to romiplostim. A total of 2.2% (4/184) adult patients developed binding, non-neutralizing antibody against TPO.

As with all therapeutic proteins, there is a potential for immunogenicity. If formation of neutralizing antibodies is suspected, contact the local representative of the Marketing Authorization Holder for antibody testing.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il