Adverse reactions : תופעות לוואי

4.8   Undesirable effects
The overall reported frequency of undesirable effects was determined from clinical studies in 316 patients (132 patients with non-small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of NAVELBINE(first three administrations at 60mg/m²/week followed by 80mg/m²/week).

Adverse reactions reported are listed below, by system organ and by frequency.

Additional Adverse reactions pooled from Post Marketing experience and clinical trials have been added according to the MedDRA classification with the frequency Not known.


Very common                  ≥1/10

Common                       ≥1/100,   <1/10
Uncommon                     ≥1/1,000,   <1/100
Rare                         ≥1/10,000,   <1/1,000
Very rare                    <1/10,000
Not known                    Cannot be estimated from the available data 

Undesirable effects reported with NAVELBINE soft capsule:
Pre-marketing experience:
The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly.
Post-marketing experience:
The most common system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’ and ‘General disorders and administration site conditions’. This information is consistent with the pre- marketing experience.
Infections and infestations
Very common:        Bacterial, viral or fungal infections without neutropenia at different sites: G1-4: 12.7%; G3-4: 4.4%,


Common:             Bacterial, viral or fungal infections resulting from bone marrow depression and/or immune system compromise
(neutropenic infections) are usually reversible with an appropriate treatment. Neutropenic infection: G3-4:
3.5%.

Not known:          Neutropenic sepsis.
Complicated septicaemia and sometimes fatal Severe sepsis sometimes with other organ failure
Septicaemia
Blood and lymphatic disorders
Very common: Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; G3: 21.8%; G4: 25.9%, is reversible and is the dose limiting toxicity.
Leucopenia: G1-4: 70.6 %; G3: 24.7 %; G4: 6%.
Anaemia: G1-4: 67.4 %; G3-4: 3.8%.
Thrombocytopenia: G1-2: 10.8%.

Common:         G4 Neutropenia associated with fever over 38°C including febrile neutropenia 2.8%.

Not known:      Thrombocytopenia G3-4
Pancytopenia
Endocrine disorders

Not known:      Inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders
Very common:     Anorexia G 1-2: 34.5%; G 3-4: 4.1%.

Not known:       Severe hyponatraemia.

Psychiatric disorders

Common:         Insomnia: G1-2: 2.8%.
Nervous system disorders
Very common:     Neurosensory disorders: G1-2: 11.1%, generally limited to loss of tendon reflexes and infrequently severe.

Common:         Neuromotor disorders: G1-4: 9.2%; G3-4:1.3%.
Headache: G1-4: 4.1%, G3-4: 0.6%.
Dizziness: G1-4: 6%; G3-4: 0.6%.
Taste disorders: G1-2:3.8%.
Uncommon:       Ataxia grade 3: 0.3%.

Not known:      Posterior reversible encephalopathy syndrome.

Eye disorders

Common:         Visual impairment: G1-2: 1.3%.
Cardiac disorders

Uncommon:       Heart failure and cardiac dysrhythmia

Not known:      Myocardial infarction in patients with cardiac medical history or cardiac risk factors.
Vascular disorders

Common:         Arterial hypertension: G1-4: 2.5%; G3-4: 0.3%.
Arterial hypotension: G1-4: 2.2%; G3-4: 0.6%.

Respiratory system, thoracic and mediastinal disorders

Common:           Dyspnoea: G1-4: 2.8%; G3-4: 0.3%.
Cough: G1-2: 2.8%.

Not known:        Pulmonary embolism
Gastrointestinal disorders

Very Common:      Nausea: G1-4: 74.7%; G3-4: 7.3%;
Vomiting: G1-4: 54.7%; G 3-4: 6.3%; supportive treatment
(such as oral setrons) may reduce the occurrence of nausea and vomiting:
Diarrhoea: G1-4: 49.7%; G3-4: 5.7%.
Stomatitis: G1-4:10.4%; G3-4: 0.9%,
Abdominal pain: G1-4: 14.2%,
Constipation: G1-4: 19%; G3-4: 0.9%, Prescription of laxatives may be appropriate in patients with prior history of constipation and/or who receive concomitant treatment with morphine or morphine-mimetics,
Gastric disorders: G1-4: 11.7%.

Common:           Oesophagitis: G1-3: 3.8%; G3: 0.3%,
Dysphagia: G1-2: 2.3%.
Uncommon:         Paralytic ileus: G3-4: 0.9% [exceptionally fatal], treatment may be resumed after recovery of normal bowel mobility.

Not known:        Gastro-intestinal bleeding.

Hepatobiliary disorders
Common:           Hepatic disorders: G1-2: 1.3%.

Not known:        Transient elevations of liver function tests

Skin and subcutaneous tissue disorders
Very common:      Alopecia usually mild in nature G1-2: 29.4%, may occur.

Common:           Skin reactions: G1-2: 5.7%.

Musculoskeletal and connective tissue disorders

Common:           Arthralgia including jaw pain,
Myalgia: G1-4: 7 %, G3-4: 0.3%.
Renal and urinary disorders

Common:            Dysuria: G1-2: 1.6%.
Other genitourinary symptom G1-2: 1.9%.
General disorders and administration site conditions

Very common:       Fatigue/malaise: G1-4: 36.7%; G3-4: 8.5%.
Fever: G1-4: 13.0%, G3-4: 12.1%.

Common:            Pain including pain at the tumour site: G1-4: 3.8%, G3-4: 0.6%.
Chills: G1-2: 3.8%.
Investigations

Very common:       Weight loss: G1-4: 25%, G3-4: 0.3%.

Common:            Weight gain: G1-2: 1.3%.
For the intravenous formulation of NAVELBINE, the following additional Adverse Drug Reactions were reported: systemic allergic reactions, severe paresthesias, weakness of lower extremities, heart rhythm disorders, flushing, peripheral coldness, collapse, angina pectoris, bronchospasm, interstitial pneumopathy, pancreatitis, palmar-plantar erythrodysesthesia syndrome, acute respiratory distress syndrome.

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 at http://sideeffects.health.gov.il In addition, you can report to Padagis via the following address: Padagis.co.il