Adverse reactions : תופעות לוואי

4.8         Undesirable effects

Summary of the safety profile
The most serious reactions observed with temsirolimus in clinical trials are hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracranial haemorrhage, renal failure, intestinal perforation, wound healing complication, thrombocytopenia, neutropenia (including febrile neutropenia), pulmonary embolism.

The adverse reactions (all grades) experienced by at least 20% of the patients in RCC and MCL registration studies include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), decreased appetite, oedema asthenia, fatigue, thrombocytopenia, diarrhoea, pyrexia, epistaxis, mucosal inflammation, stomatitis, vomiting, hyperglycaemia, hypercholesterolemia, dysgeusia, pruritus, cough, infection, pneumonia, dyspnoea.

Cataracts have been observed in some patients who received the combination of temsirolimus and IFN-α.


Based on the results of the phase 3 studies, elderly patients may be more likely to experience certain adverse reactions, including face oedema, pneumonia, pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, ageusia, dizziness, upper respiratory infection, mucositis, and rhinitis.
Serious adverse reactions observed in clinical trials of temsirolimus for advanced RCC, but not in clinical trials of temsirolimus for MCL include: anaphylaxis, impaired wound healing, renal failure with fatal outcomes, and pulmonary embolism.
Serious adverse reactions observed in clinical trials of temsirolimus for MCL, but not in clinical trials of temsirolimus for advanced RCC include: thrombocytopenia, and neutropenia (including febrile neutropenia).

See section 4.4 for additional information concerning serious adverse reactions, including appropriate actions to be taken if specific reactions occur.

The occurrence of undesirable effects following the dose of 175 mg temsirolimus/week for MCL, e.g.
Grade 3 or 4 infections or thrombocytopenia, is associated with a higher incidence than that observed with either 75 mg temsirolimus/week or conventional chemotherapy.

Tabulated list of adverse reactions

Adverse reactions that were reported in RCC and MCL patients in the phase 3 studies are listed below (Table 1), by system organ class, frequency and grade of severity (NCI-CTCAE). Frequencies are defined as follows: 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.



Table 1: Adverse reactions from clinical trials in RCC (study 3066K1-304) and in MCL (study 3066K1-305)



System             Frequency            Adverse reactions           All grades   Grade organ class                                                             n (%)       3&4 n (%)
Infections and        Very common       Bacterial and viral infections    91 (28.3)    18 (5.6) infestations                            (including infection,viral infection, cellulitis, herpes zoster, oral herpes, influenza,
herpes simplex, herpes zoster ophthalmic, herpes virus infection, bacterial infection,
bronchitis*, abscess, wound infection, post-operative wound infections)
Pneumoniaa (including             35 (10.9)    16 (5.0) interstitial pneumonia)
Common            Sepsis* (including septic          5 (1.6)      5 (1.6) shock)
Candidiasis (including oral        16 (5.0)     0 (0.0) and anal candidiasis) and fungal infection/fungal skin infections
Urinary tract infection            29 (9.0)     6 (1.9)
(including cystitis)
Upper respiratory tract            26 (8.1)     0 (0.0) infection
Pharyngitis                         6 (1.9)     0 (0.0)
Sinusitis                          10 (3.1)     0 (0.0)
Rhinitis                            7 (2.2)     0 (0.0)
Folliculitis                        4 (1.2)      0 (0.0)
Uncommon          Laryngitis                          1 (0.3)      0 (0.0) Blood and             Very common       Neutropenia                       46 (14.3)     30 (9.3) lymphatic system                        Thrombocytopenia**                97 (30.2)    56 (17.4) disorders                               Anaemia                           132(41.1)     48 (15) Common            Leukopenia **                      29 (9.0)     10 (3.1) Lymphopenia                        25 (7.8)     16 (5.0)
Immune system         Common            Hypersensitivity reactions /       24 (7.5)      1 (0.3) disorders                               drug hypersensitivity
Metabolism and        Very common       Hyperglycaemia                    63 (19.6)    31 (9.7) nutrition disorders                     Hypercholesterolaemia             60 (18.7)     1 (0.3) Hypertriglyceridaemia             56 (17.4)     8 (2.5)
Decreased appetite                107 (33.3)    9 (2.8)
Hypokalaemia                      44 (13.7)    13 (4.0)
Common            Diabetes mellitus                  10 (3.1)     2 (0.6) Dehydration                        17 (5.3)     8 (2.5)
Hypocalcaemia                      21 (6.5)     5 (1.6)
Hypophosphataemia                  26 (8.1)    14 (4.4)
Hyperlipidaemia                     4 (1.2)     0 (0.0)
Psychiatric           Very common       Insomnia                          45 (14.0)     1 (0.3) disorders             Common            Depression                         16 (5.0)     0 (0.0) 

System             Frequency           Adverse reactions           All grades   Grade organ class                                                            n (%)      3&4 n (%)
Anxiety                           28 (8.7)    0 (0.0)
Nervous system        Very common       Dysgeusia                        55 (17.1)    0 (0.0) disorders                               Headache                         55 (17.1)    2 (0.6) Common            Dizziness                         30 (9.3)    1 (0.3) Paresthaesia                      21 (6.5)    1 (0.3)
Somnolence                         8 (2.5)    1 (0.3)
Ageusia                            6 (1.9)    0 (0.0)
Uncommon                                             1 (0.3)    1 (0.3) Intracranial haemorrhage
Eye disorders         Common            Conjunctivitis (including         16 (5.0)    1 (0.3) conjunctivitis, lacrimal disorder)
Uncommon          Eye haemorrhage***                3 (0.9)     0 (0.0) Cardiac disorders     Uncommon          Pericardial effusion              3 (0.9)     1 (0.3) Vascular disorders    Common            Venous thromboembolism            7 (2.2)     4 (1.2) (including deep vein thrombosis, venous thrombosis)
Thrombophlebitis                   4 (1.2)     0 (0.0)
Hypertension                      20 (6.2)     3 (0.9)
Respiratory,          Very common       Dyspnoeaa                        79 (24.6)    27 (8.4) thoracic and                            Epistaxis **                     69 (21.5)     1 (0.3) mediastinal                             Cough                            93 (29.0)     3 (0.9) disorders
Common
Interstitial lung diseasea****    16 ( 5.0)    6(1.9)
Pleural effusiona,b                19 (5.9)    9 (2.8)
Uncommon          Pulmonary embolism a                2 (0.6)    1 (0.3) Gastrointestinal      Very common       Nausea                           109 (34.0)    5 (1.6) disorders                               Diarrhoea                        109(34.0)    16 (5.0) Stomatitis                        67 (20.9)    3 (0.9)
Vomiting                          57 (17.8)    4 (1.2)
Constipation                      56 (17.4)    0 (0.0)
Abdominal pain                    56 (17.4)   10 (3.1)
Common            Gastrointestinal haemorrhage       16 (5.0)    4 (1.2) (including anal, rectal,
haemorrhoidal, lip, and mouth haemorrhage, gingival bleeding)
7 (2.1)     2 (0.6)
Gastritis **
Dysphagia                         13 (4.0)    0 (0.0)
Abdominal distension              14 (4.4)    1 (0.3)
Aphthous stomatitis               15 (4.7)    1 (0.3)
Oral pain                          9 (2.8)    1 (0.3)
Gingivitis                         6 (1.9)    0 (0.0)
Intestinala/duodenal              2 ( 0.6)    1 (0.3)
Uncommon perforation




System           Frequency              Adverse reactions               All grades         Grade organ class                                                                 n (%)             3&4 n (%)
Skin and               Very common        Rash (including rash, pruritic         138 (43.0)        16 (5.0) subcutaneous                              rash, maculo-papular rash, rash, tissue disorders                          generalised rash, macular rash, papular rash)
Pruritus (including pruritus           69 (21.5)          4 (1.2) generalised)
Dry skin                               32 (10.0)          1 (0.3)
Common             Dermatitis                               6 (1.9)          0 (0.0) Exfoliative rash                         5 (1.6)          0 (0.0)
Acne                                    15 (4.7)          0(0.0)
Nail disorder                           26 (8.1)          0 (0.0)
Ecchymosis***                            5 (1.6)          0 (0.0)
Petechiae***                             4 (1.2)          0 (0.0)
Musculoskeletal        Very common        Arthralgia                             50 (15.6)          2 (0.6) and connective                            Back pain                              53 (16.5)          8 (2.5) tissue disorders       Common             Myalgia                                19 ( 5.9)          0 (0.0) Renal and urinary      Common             Renal failurea                           5 (1.6)          0 (0.0) disorders
General disorders      Very common        Fatigue                                133 (41.4)        31 (9.7) and administration                        Oedema (including                      122 (38.0)        11 (3.4) site conditions                           generalised oedema, facial oedema, peripheral oedema,
scrotal oedema, genital oedema)
Astheniaa                              67 (20.9)         16 (5.0)
Mucosal inflammation                   66 (20.6)          7 (2.2)
Pyrexia                                91 (28.3)          5 (1.6)
Pain                                   36 (11.2)          7 (2.2)
Chills                                 32 (10.0)          1 (0.3)
Chest pain                             32 (10.0)          1 (0.3)
Uncommon           Impaired wound healing                   2 (0.6)          0 (0.0) Investigations         Very common        Blood creatinine increased             35 (10.9)          4 (1.2) Common             Increased aspartate                     27 (8.4)          5 (1.6) aminotransferase
Common             Increased alanine                       17 (5.3)          2 (0.6) aminotransferase a one fatal case .
b
One pleural effusion fatal event occurred in the low-dose (175/25 mg) arm of the MCL study.
*Most NCI-CTC Grade 3 and above reactions observed in clinical trials of temsirolimus for MCL ** Most NCI-CTC all grades reactions observed in clinical trials of temsirolimus for MCL.
*** All NCI-CTC Grade 1 and 2 reactions observed in clinical trials of temsirolimus MCL.
****Interstitial lung disease is defined by a cluster of related Preferred Terms: interstitial lung disease (n = 6), pneumonitisa (n = 7), alveolitis (n = 1), alveolitis allergic (n = 1), pulmonary fibrosis (n = 1) and eosinophilic pneumonia (n = 0).

Adverse reactions that were reported in post-marketing experience are listed below (Table 2).
Table 2: Adverse reactions reported in post-marketing setting

System Organ class                  Frequency                            Adverse reactions Infections and infestations           Rare                              Pneumocystis jiroveci pneumonia
Immune system disorders               Not known                         Angioneurotic oedema-type reactions
Skin and subcutaneous tissue          Not known                         Stevens-Johnson syndrome disorders
Musculoskeletal and                   Not known                         Rhabdomyolysis connective tissue disorders

Description of selected adverse reactions

Post-marketing experience
Angioneurotic oedema-type reactions have been reported in some patients who received temsirolimus and ACE-inhibitors concomitantly.

Cases of PCP, some with fatal outcomes, have been reported (see section 4.4).

Paediatric population
In a Phase 1/2 study, 71 patients (59 patients, aged from 1 to 17 years old, and 12 patients, aged 18 to 21 years) were administered temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2 (see section 5.1).
The adverse reactions reported by the highest percentage of patients were haematologic (anaemia, leukopenia , neutropenia, and thrombocytopenia), metabolic (hypercholesterolemia, hyperlipaemia, hyperglycaemia, increase of serum aspartate amino transferase (AST) and serum alanine aminotransferase (ALT) plasma levels), and digestive (mucositis, stomatitis, nausea, and vomiting).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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/