Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most common clinically significant adverse reactions associated with the use of Abraxane have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

Tabulated list of adverse reactions
Table 6 lists adverse reactions associated with Abraxane monotherapy at any dose in any indication during clinical trials (N = 789). Abraxane in combination with gemcitabine for pancreatic adenocarcinoma from the phase III clinical trial (N = 421), Abraxane in combination with carboplatin for non-small cell lung cancer from the phase III clinical trial (N = 514) and from post-marketing use.
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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 6: Adverse reactions reported with Abraxane
Monotherapy (N=789)                                                Combination Combination therapy therapy with with gemcitabine carboplatin
(N =421)
(N = 514)
Infections and infestations


Infection, urinary tract infection,     Sepsis, pneumonia, oral   Pneumonia, folliculitis, upper respiratory tract   candidiasis               bronchitis, upper Common:            infection, candidiasis, sinusitis                                 respiratory tract infection, urinary tract infection
Sepsis1, neutropenic sepsis1,                                      Sepsis, oral pneumonia, oral candidiasis,                                       candidiasis nasopharyngitis, cellulitis, herpes
Uncommon:         simplex, viral infection, herpes zoster, fungal infection,
catheter-related infection,
injection site infection
Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon:         Tumour necrosis, metastatic pain
Blood and lymphatic system disorders
Bone marrow suppression,            Neutropenia,                   Neutropenia3, neutropenia, thrombocytopenia,      thrombocytopenia,              thrombocytopenia3, anaemia, leukopenia,                anaemia                        anaemia3, leukopenia3 lymphopenia,
Very common:



Pancytopenia              Febrile neutropenia,
Common:            Febrile neutropenia lymphopenia
Thrombotic                Pancytopenia
Uncommon:                                                  thrombocytopenic purpura
Rare:            Pancytopenia
Immune system disorders
Hypersensitivity                                                    Drug hypersensitivity, Uncommon:                                                                           hypersensitivity 
Rare:            Severe hypersensitivity1
Metabolism and nutrition disorders
Anorexia                                  Dehydration, decreased    Decreased appetite appetite, hypokalaemia
Very common:

Common:            Dehydration, decreased appetite,                                  Dehydration hypokalaemia
Hypophosphataemia, fluid retention, hypoalbuminaemia,
Uncommon:          polydipsia, hyperglycaemia,
hypocalcaemia, hypoglycaemia,
hyponatraemia
Not known:         Tumour lysis syndrome1
Psychiatric disorders
Very common:                                                 Depression, insomnia Depression, insomnia, anxiety           Anxiety                Insomnia Common:

Uncommon:         Restlessness
Nervous system disorders
Peripheral neuropathy,                     Peripheral neuropathy,    Peripheral neuropathy neuropathy, hypoaesthesia,                 dizziness, headache,
paraesthesia                               dysgeusia
Very common:


Peripheral sensory neuropathy,                                    Dizziness, headache, dizziness, peripheral motor                                       dysgeusia neuropathy, ataxia, headache,
Common: sensory disturbance, somnolence dysgeusia

Polyneuropathy, areflexia,              VIIth nerve paralysis syncope, postural dizziness,
Uncommon:            dyskinesia, hyporeflexia,
neuralgia, neuropathic pain,
tremor, sensory loss
Not known:           Cranial nerve palsies multiple 1
Eye disorders
Vision blurred, lacrimation             Lacrimation increased     Vision blurred increased, dry eye,
keratoconjunctivitis sicca,
madarosis
Common:



Reduced visual acuity, abnormal           Cystoid macular vision, eye irritation, eye pain,         oedema
Uncommon: conjunctivitis, visual disturbance,
eye pruritus, keratitis
Rare:              Cystoid macular oedema1
Ear and labyrinth disorders
Vertigo
Common:

Uncommon:         Tinnitus, ear pain
Cardiac disorders
Arrhythmia, tachycardia,                   Cardiac failure supraventricular tachycardia               congestive, tachycardia
Common:
Cardiac arrest, cardiac failure congestive, left ventricular
Rare: dysfunction, atrioventricular block1 , bradycardia,
Vascular disorders


Hypertension, lymphoedema,            Hypotension,               Hypotension, flushing, hot flushes                 hypertension               hypertension Common:


Hypotension, orthostatic              Flushing                   Flushing Uncommon:            hypotension, peripheral coldness

Rare:              Thrombosis
Respiratory, thoracic and mediastinal disorders
Dyspnoea, epistaxis,       Dyspnoea
Very common: cough
Interstitial pneumonitis2,            Pneumonitis, nasal         Haemoptysis, dyspnoea, epistaxis,                  congestion                 epistaxis, cough pharyngolaryngeal pain, cough,
Common: rhinitis, rhinorrhoea


Pulmonary emboli, pulmonary            Dry throat, nasal          Pneumonitis thromboembolism, pleural               dryness effusion, exertional dyspnoea,
sinus congestion, decreased
Uncommon: breath sounds, productive cough,
allergic rhinitis, hoarseness, nasal congestion, nasal dryness,
wheezing,
Not known:          Vocal cord paresis1
Gastrointestinal disorders
Diarrhoea, vomiting, nausea,           Diarrhoea, vomiting,       Diarrhoea, vomiting, constipation, stomatitis               nausea, constipation,      nausea, constipation Very common:                                               abdominal pain, abdominal pain upper

Gastrooesophageal reflux              Intestinal obstruction,    Stomatitis, dyspepsia, disease, dyspepsia, abdominal         colitis, stomatitis, dry   dysphagia, abdominal pain, abdominal distension,           mouth                      pain Common: abdominal pain upper, oral hypoaesthesia

Rectal haemorrhage, dysphagia,
flatulence, glossodynia, dry mouth, gingival pain, loose
Uncommon: stools, oesophagitis, abdominal pain lower, mouth ulceration,
oral pain,
Hepatobiliary disorders
Common:                                                    Cholangitis                Hyperbilirubinaemia Uncommon:          Hepatomegaly
Skin and subcutaneous tissue disorders


Alopecia, rash                       Alopecia, rash             Alopecia, rash 
Very common:

Pruritus, dry skin, nail disorder,   Pruritus, dry skin, nail   Pruritus, nail disorder erythema, nail                       disorder pigmentation/discolouration, skin
Common: hyperpigmentation, onycholysis,
nail changes

Photosensitivity reaction,                                      Skin exfoliation, urticaria, skin pain, generalised                               dermatitis allergic, pruritus, pruritic rash, skin                                   urticaria disorder, pigmentation disorder,
hyperhidrosis, onychomadesis,
erythematous rash, generalised
Uncommon:          rash, dermatitis, night sweats,
maculo-papular rash, vitiligo,
hypotrichosis, nail bed tenderness, nail discomfort,
macular rash, papular rash, skin lesion, swollen face

Stevens-Johnson syndrome1,
Very rare: toxic epidermal necrolysis1
Palmar-plantar
Not known:        erythrodysaesthesiae syndrome1,
4
, scleroderma1
Musculoskeletal and connective tissue disorders
Arthralgia, myalgia.                  Arthralgia, myalgia,       Arthralgia, myalgia pain in extremity
Very common:

Back pain, pain in extremity,        Muscular weakness,         Back pain, pain in bone pain, muscle cramps, limb       bone pain                  extremity, Common: pain                                                            musculoskeletal pain 
Chest wall pain, muscular weakness, neck pain, groin pain,
Uncommon:         muscle spasms, musculoskeletal pain, flank pain, limb discomfort,
muscle weakness
Renal and urinary disorders
Common:                                                 Acute renal failure Haemolytic uraemic
Haematuria, dysuria, pollakiuria,
syndrome
Uncommon:          nocturia, polyuria, urinary incontinence
Reproductive system and breast disorders
Uncommon:          Breast pain
General disorders and administration site conditions

Fatigue, asthenia, pyrexia            Fatigue, asthenia,        Fatigue, asthenia, pyrexia, oedema           oedema peripheral
Very common: peripheral, chills

Malaise, lethargy, weakness,          Infusion site reaction    Pyrexia, chest pain peripheral oedema, mucosal inflammation, pain, rigors,
oedema, decreased performance
Common: status, chest pain, influenza-like illness, hyperpyrexia


Mucosal inflammation, infusion
Chest discomfort, abnormal gait,
site extravasation,
Uncommon:            swelling, injection site reaction infusion site inflammation, infusion site rash
Rare:                Extravasation
Investigations
Weight decreased,
alanine
Very common: aminotransferase increased
Decreased weight, increased           Aspartate                 Weight decreased, alanine aminotransferase,             aminotransferase          alanine increased aspartate                   increased, blood          aminotransferase aminotransferase, decreased           bilirubin increased,      increased, aspartate haematocrit, decreased red blood      blood creatinine          aminotransferase cell count, increased body            increased                 increased, blood Common: temperature, increased                                          alkaline phosphatase gamma-glutamyltransferase,                                      increased increased blood alkaline phosphatase


Increased blood pressure,
increased weight, increased blood lactate dehydrogenase, increased
Uncommon:          blood creatinine, increased blood glucose, increased blood phosphorus, decreased blood potassium, increased bilirubin
Injury, poisoning and procedural complications
Uncommon:          Contusion
Rare:               Radiation recall phenomenon,
radiation pneumonitis
.
1
As reported in the post-marketing surveillance of Abraxane.
2
The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breast cancer and for other indications 3
Based on laboratory assessments: maximal degree of myelosuppression (treated population).
4
In some patients previously exposed to capecitabine.


Description of selected adverse reactions
This section contains the most common and clinically relevant adverse reactions related to Abraxane.
Adverse reactions were assessed in 229 patients with metastatic breast cancer who were treated with 260 mg/m2 Abraxane once every three weeks in the pivotal phase III clinical study(Abraxane monotherapy).

Adverse reactions were assessed in 421 patients with metastatic pancreatic cancer who were treated with Abraxane in combination with gemcitabine (125 mg/m2 Abraxane in combination with gemcitabine at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle) and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas (Abraxane/gemcitabine).

Adverse reactions were assessed in 514 patients with non-small cell lung cancer who were treated with Abraxane in combination with carboplatin (100mg/m2 Abraxane given on Days 1, 8 and 15 of each 21-day cycle in combination with carboplatin given on Day 1 of each cycle) in the phase III randomized, controlled clinical trial (Abraxane/carboplatin). Patient-reported taxane toxicity was assessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet, and hearing) favored Abraxane and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

Infections and infestations
Abraxane/gemcitabine
Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Of the 22 cases of sepsis reported in patients treated with Abraxane in combination with gemcitabine, 5 had a fatal outcome. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2).

Blood and lymphatic system disorders
Abraxane monotherapy-metastatic breast cancer
In patients with metastatic breast cancer, neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm3) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Abraxane and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.

Abraxane/gemcitabine
Table 7 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Abraxane in combination with gemcitabine or with gemcitabine.

Table 7: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial 

Abraxane (125 mg/m2)/
Gemcitabine
Gemcitabine
Grades 1-4           Grade 3-4       Grades 1-4         Grade 3-4
(%)                 (%)              (%)               (%)
Anaemiaa,b                             97                  13                96                 12 Neutropenia a,b                        73                  38                58                 27 Thrombocytopeniab,c                     74               13                 70                 9 a
405 patients assessed in Abraxane/gemcitabine-treated group b
388 patients assessed in gemcitabine-treated group c
404 patients assessed in Abraxane/gemcitabine-treated group

Abraxane/carboplatin
Anaemia and thrombocytopenia were more commonly reported in the Abraxane and carboplatin arm than in the Taxol and carboplatin arm (54% versus 28% and 45% versus 27% respectively).

Nervous system disorders
Abraxane monotherapy-metastatic breast cancer
In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Abraxane with 10% being Grade 3, and no cases of Grade 4.

Abraxane/gemcitabine
For patients treated with Abraxane in combination with gemcitabine, the median time to first occurrence of Grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was 21 days, and the median time to improvement from Grade 3 peripheral neuropathy to Grade 0 or 1 was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination with gemcitabine had Grade 4 peripheral neuropathy.

Abraxane/carboplatin
For non-small cell lung cancer patients treated with Abraxane and carboplatin, the median time to first occurrence of Grade 3 treatment related peripheral neuropathy was 121 days, and the median time to improvement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patients treated with Abraxane and carboplatin experienced Grade 4 peripheral neuropathy.

Eye disorders
There have been rare reports during post-marketing surveillance of reduced visual acuity due to cystoid macular oedema during treatment with Abraxane (see section 4.4).

Respiratory, thoracic and mediastinal disorders
Abraxane/gemcitabine
Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine.
Of the 17 cases of pneumonitis reported in patients treated with Abraxane in combination with gemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis.
After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).

Gastrointestinal disorders
Abraxane monotherapy-metastatic breast cancer
Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.

Skin and subcutaneous tissue disorders
Abraxane monotherapy-metastatic breast cancer
Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia events occurred less than one month after initiation of Abraxane. Pronounced hair loss ≥50% is expected for the majority of patients who experience alopecia.

Musculoskeletal and connective tissue disorders
Abraxane monotherapy-metastatic breast cancer
Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in 7% of cases. The symptoms were usually transient,
typically occurred three days after Abraxane administration and resolved within a week.

General disorders and administration site conditions
Abraxane monotherapy-metastatic breast cancer
Asthenia/Fatigue was reported in 40% of the patients.

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.
Side effects can be reported to the Ministry of Health by clicking on the link “Report Side Effects of Drug Treatment” that appears on the homepage of the Ministry of Health’s website (www.health.gov.il) which links to an online form for reporting side effects, or by following this link: https://sideeffects.health.gov.il and by emailing the Registration Holder's Patient Safety Unit at :drugsafety@neopharmgroup.com