Adverse reactions : תופעות לוואי

ADVERSE REACTIONS
The incidence of adverse reactions in the table that follows are derived from ten clinical trials in carcinoma of the ovary and 2 of the breast involving 812 patients treated with paclitaxel at doses ranging from 135-300 mg/m /day and schedules of three 2 or twenty-four hours. Data from a subset of 181 patients treated with 175 mg/m and a three-hour infusion schedule are also included in the table.


SUMMARY OF ADVERSE REACTIONS
2                     2
135 to 300 mg/m               175 mg/m
% of Patients (N=812)         % of Patients
(N=181)

Bone Marrow
3
Neutropenia               < 2 000/mm                                    90                       87 3
< 500/mm                                      52                       27 3
Leukopenia                < 4 000/mm                                    90                       86 3
< 1 000/mm                                    17                        4 3
Thrombocytopenia          < 100 000 mm                                  20                        6 3
< 50 000 mm                                    7                        1 Anemia                    < 11 g/dL                                     78                       62 < 8 g/dL                                      16                        6 

Infections                                                              30                       18 Bleeding                                                                14                        9 Red Cell Transfusions                                                   25                       13 Red Cell Transfusions (normal baseline)                                 12                        6 Platelet Transfusions                                                    2                        0 

Hypersensitivity Reactions
All                                                                     41                       40 Severe                                                                   2                        1 
Cardiovascular
Bradycardia during first 3 hours of infusion                             3                        3 Hypotension during first 3 hours of infusion                            12                       11 Severe cardiovascular events                                             1                        2 

Abnormal ECG
All patients                                                             23                       13 Patients with normal baseline                                            14                        8 

Peripheral Neuropathy
Any symptoms                                                             60                       64 Severe symptoms                                                           3                        4 
Myalgia/Arthralgia
Any symptoms                                                             60                       54 Severe symptoms                                                           8                       12 
Gastrointestinal
Nausea and vomiting                                                      52                       44 Diarhhea                                                                 38                       25 Mucositis                                                                31                       20 
Alopecia                                                                 87                       93 
Hepatic (patients with normal baseline)
Bilirubin elevations                                                      7                        4 Alkaline phosphatase elevations                                          22                       18 AST elevations                                                           19                       18 
Injection site reactions                                                 13                        4 

The table below lists undesirable effects regardless of severity associated with the administration of single agent paclitaxel administered as a three hour infusion in the metastatic setting (286 patients treated in paclitaxel clinical studies and 812 patients treated in other clinical studies) .

The frequency of undesirable effects listed below is defined using the following convention: 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).
In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.


Infections and infestations:                          Very common: infection (mainly urinary tract and upper respiratory tract infections including herpes simplex, oral candidiasis, pharyngitis,
rhinitis), with reported cases of fatal outcome
Common: flu syndrome
Uncommon: severe infection, septic shock
Rare*: Sepsis pneumonia, peritonitis

Blood and the lymphatic system disorders:             Very common: myelosuppression, severe neutropenia, anaemia, thrombocytopenia,
severe leucopenia, bleeding
Common: neutropenic fever
Uncommon: severe anaemia
Rare*: febrile neutropenia
Very rare*: acute myeloid leukaemia,
myelodysplastic syndrome


Immune system disorders:              Very common: minor hypersensitivity reactions (mainly flushing and rash)
Uncommon: (delayed) hypersensitivity, significant hypersensitivity reactions requiring therapy (e.g.,
hypotension, angioneurotic oedema, respiratory distress, generalised urticaria, chills, back pain,
chest pain, tachycardia, abdominal pain, pain in extremities, diaphoresis and hypertension)
Rare*: anaphylactic reactions
Very rare*: anaphylactic shock (including fatal hypersensitivity)

Metabolism and nutrition disorders:   Very common: anorexia
Uncommon: weight gain, weight loss
Not known*: tumor lysis syndrome
Psychiatric disorders:                Very rare*: confusional state
Nervous system disorders:             Very common: neurotoxicity (mainly: peripheral neuropathy), paraesthesia,
somnolence
Common: depression, severe neuropathy (mainly peripheral), nervousness, insomnia, abnormal thinking, hypokinesia, abnormal gait, hypoaesthesia,
taste perversion
Rare*: motor neuropathy (with resultant minor distal weakness)
Very rare*: autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, acute encephalopathy,
dizziness, ataxia, headache.


Eye disorders                         Uncommon: dry eyes, amblyopia, visual field defect
Very rare*: optic nerve and/or visual disturbances
(scintillating scotomata), particularly in patients who have received higher doses than recommended.
Not known*: macular oedema, photopsia, vitreous floaters

Ear and labyrinth disorders:          Very rare*: ototoxicity, sensorineuronal hearing loss, tinnitus, vertigo



Cardiac disorders:                        Common: bradycardia, tachycardia, palpitation, syncope
Uncommon: congestive heart failure, myocardial infarction, AV block and syncope,
cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy,
Rare: cardiac failure
Vary rare*: atrial fibrillation supraventicular tachycardia.
Vascular disorders:                       Very common: hypotension
Common: vasodilatation (flushing)
Uncommon: hypertension, thrombosis,
thrombophlebitis
Very rare*: shock
Not known: phlebitis

Respiratory, thoracic and mediastinal     Common: epistaxis disorders:                                Rare*: respiratory failure. pulmonary embolism, lung fibrosis, interstitial pneumonia, dyspnoea pleural effusion,
Very rare*: cough, pulmonary hypertension

Gastrointestinal disorders:               Very common: diarrhoea, vomiting, nausea, mucosal inflammation, stomatitis,
abdominal pain
Common: dry mouth, mouth ulceration,
melaena, dyspepsia
Rare*: bowel obstruction, bowel perforation,
ischemic colitis, acute pancreatitis
Very rare*: mesenteric thrombosis,
pseudomembranous colitis, neutropenic colitis, necrotising enterocolitis,
ascites,oesophagitis, constipation.


Hepato-biliary disorders:                 Very rare*: hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome)

Skin and subcutaneous tissue disorders:   Very common: alopecia
Common: transient and mild nail and skin change,
dry skin, acne
Uncommon: changes in nail pigmentation or discoloration of nail bed
Rare*: pruritus, rash, erythema
Very rare*: Stevens-Johnson syndrome, exfoliative dermatitis, epidermal necrolysis, erythema multiforme, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet), folliculitis
Not known: scleroderma

Musculoskeletal, connective tissue and bone           Very common: Arthralgia, myalgia disorders:                                            Common: bone pain, leg cramps, myasthenia, back pain
Not known: systemic lupus erythematosis

Renal and urinary disorders                           Common: dysuria General disorders and administration site             Very common: asthenia, pain, oedema conditions:                                           including peripheral and face Common: mild injection site reaction (including localised oedema, pain, erythema, induration,
tenderness, skin discoloration or swelling, on occasion extravasation, can result in cellulitis and skin fibrosis and skin necrosis), chest pain, chills
Rare*: pyrexia, dehydration, asthenia, oedema,
malaise.


Investigations:                                       Common: severe elevation in transaminases, AST (SGOT), severe elevation in alkaline phosphatase
Uncommon: severe elevation in bilirubin
Rare*: increase in blood creatinine


2
The safety profile has been evaluated from a large randomized trial (paclitaxel 135 mg/m over 24 hours with cisplatin 75 2 mg/m versus cyclophosphamide/cisplatin) which included 410 patients, 196 of whom received paclitaxel. Use of paclitaxel with platinum agents has not resulted in any clinically significant changes to the safety profile of the product when used at the recommended dosage.
2
Summary of Three Hour Infusion Data at a Dose of 175 mg/m

Unless otherwise stated, the following safety data relate to sixty-two patients with ovarian cancer and 119 patients with 2 breast cancer treated at a dose of 175 mg/m and a three hour infusion schedule, in phase III clinical trials. All patients were premedicated to minimize hypersensitivity reactions. Bone marrow suppression and peripheral neuropathy were the principal dose-related adverse reactions. Further, as compared to a 24 hour infusion schedule, the incidence of neutropenia was less common when paclitaxel was administered as a three-hour infusion. Neutropenia was generally rapidly reversible and did not become worse with cumulative exposure. Repeated exposure increases the frequency of neurologic symptoms. None of the observed toxicities were influenced by age.

Hematologic

The most frequent notable undesirable effect of paclitaxel was bone marrow suppression. Severe neutropenia (< 500 3 cells/mm ) occurred in 27% of patients, but was not associated with febrile episodes. Only one percent of patients experienced severe neutropenia for seven days or more. Neutropenia was not more frequent or severe in patients who received prior radiation therapy, nor did it appear to be affected by treatment duration or cumulative exposure. Eighteen percent of patients had an infectious episode, all non-fatal. Although severe septic episodes associated with severe neutropenia attributable to paclitaxel were reported in early clinical trials, no severe infections or septic episodes were seen at the recommended dose and infusion schedule. There were five fatal septic episodes associated with severe neutropenia attributable to paclitaxel in the overall 812 patient database.
3
Thrombocytopenia with platelet counts <100,000 cells/mm was reported in six percent of patients. Thrombocytopenia with 3                                                                                      3 platelet counts <50,000 cells/mm was reported in one percent of patients. Severe thrombocytopenia (<50,000 cells/mm ) was observed during the first two courses only. Bleeding episodes occurred in nine percent of patients; no patient needed platelet transfusion.

Anemia was seen in 62% of patients, but was severe (Hb<8 g/dL) in only 6% of patients. Incidence and severity of anemia are associated with baseline hemoglobin status. Red cell transfusions were required in 13% of patients (6% of those with normal baseline hemoglobin levels).

Hypersensitivity Reactions

Severe hypersensitivity reactions occurred in 1% of patients even with premedication. These reactions occurred generally in early treatment courses and within the first hour of infusion. Dyspnea, flushing, chest pain and tachycardia were the most frequent signs and symptoms.

The dosage and schedule had no effect on the frequency of hypersensitivity reactions which occurred in 21% of courses where patients were given the recommended dose at the recommended schedule. The majority of reactions were minor.
The most frequent were flushing (28%), rash (14%), and hypotension (3%).

Cardiovascular

During infusion of paclitaxel, hypotension and bradycardia were experienced by 24% and 4% of patients, respectively, and did not usually occur during the same course; the majority of episodes were asymptomatic and did not require treatment.

One patient experienced transient hypertension during the second paclitaxel cycle. In addition, two patients experienced severe cardiovascular events (tachycardia and thrombophlebitis), possibly related to paclitaxel. None of these patients required discontinuation of treatment. In the same studies at a lower dose or longer infusion, three severe cardiovascular events (atrioventricular (AV) block, syncope and hypotension associated with coronary stenosis resulting in death) possibly related to paclitaxel administration were reported. Ten severe cardiovascular events occurred which included cardiac rhythm disturbance and syncope among the 812 patients (see WARNINGS).
2
An abnormal ECG occurred in 13% of patients during the clinical trials at a dosage of 175 mg/m and a three-hour infusion schedule. Some patients (8%) with a normal ECG prior to study entry developed an abnormal tracing during the study. Of the 812 patients, the most frequently reported ECG changes were non-specific repolarization abnormalities, sinus tachycardia and premature beats. In most cases, there was no clear relationship between the administration of paclitaxel and ECG changes; these changes were of no, or minimal, clinical relevance.

Since the above summary, cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported typically in patients who have received other prior chemotherapy especially anthracyclines.


Neurologic
Peripheral neuropathy, mainly manifested by paresthesia, affected 64% of patients, but was severe in only 4% of patients.
Neurologic symptoms can occur following the first course and can worsen with increased exposure to paclitaxel. Peripheral neuropathy was the cause of drug discontinuation in three cases. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy. Rare neurologic events include grand mal seizures and encephalopathy. Reports of motor neuropathy with resultant minor distal weakness and autonomic neuropathy resulting in paralytic ileus and orthostatic hypotension have also been observed. Optic nerve and/or visual disturbances (scintillation scotomata) have also been reported, especially in patients who have received higher doses than recommended. These effects have generally been reversible.

Arthralgia/Myalgia

Arthralgia or myalgia affected 54% of patients and was severe in 12% of patients. The symptoms usually were pain in the large joints of the arms and legs and were transient occurring two to three days after administration and resolving within a few days.


Alopecia
Alopecia was observed in nearly all patients.

Gastrointestinal

Gastrointestinal side effects were usually mild to moderate: nausea/vomiting (44%), diarrhea (25%) and mucositis (20%) were reported. Other gastrointestinal events included anorexia (25%), constipation (18%) and intestinal obstruction (4%).
Neutropenic enterocolitis, bowel obstruction/perforation and ischemic colitis and pancreatitis have occurred.

Hepatic

In patients with normal baseline liver function, four percent had elevated bilirubin, 18% had elevated alkaline phosphatase, and 18% had elevated AST (SGOT). Severe elevations (>5x normal values) of bilirubin, alkaline phosphatase or AST were seen in 1%, 5%, and 5% of patients, respectively. There have been rare reports of hepatic necrosis and hepatic encephalopathy leading to death.

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression. Dose adjustment is recommended. Patients should be monitored closely for the development of profound myelosuppression.

Injection Site Reactions

Phlebitis can occur following the intravenous administration of paclitaxel. Extravasation during intravenous infusion can lead to edema, pain, erythema and induration. Occasionally extravasation can result in cellulitis.
Skin discoloration can also occur. Recurrence of skin reactions at a site of previous extravasation following administration at a different site, so called "recall", has been reported rarely. A specific treatment of extravasation reactions is unknown, however treatment with a subcutaneous injection of hyaluronidase diluted in saline has been shown to be effective in a mouse skin model.

Other

Mild and transient nail and skin changes have been observed. Radiation pneumonitis has been reported in patients who have received concurrent radiotherapy.

Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash, pruritus, Stevens-Johnson syndrome and toxic epidermal necrolysis have been received as part of the continuing surveillance of paclitaxel safety.
Reports of asthenia and malaise have been received as part of the continuing surveillance of paclitaxel safety. In the phase 3 trial of paclitaxel 135 mg/m2 over 24 hours in combination with cisplatin as first-line therapy of ovarian cancer, asthenia was reported in 17% of patients, significantly greater than the 10% incidence observed in the control arm of cyclophosphamide/cisplatin.
Accidental Exposure:
Upon inhalation, dyspnea, chest pain, burning eyes, sore throat and nausea have been reported. Following topical exposure, events have included tingling, burning and redness.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
The carcinogenic potential of paclitaxel has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity.



SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is no known antidote for PACLIAVENIR SOLUTION FOR INJECTION (paclitaxel) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.