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Onxol (Paclitaxel) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

Pooled Analysis of Adverse Events Experiences from Single-Agent Studies

Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy five patients were treated in eight Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared two doses (135 or 175 mg/m2) and two schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m2) administered over 3 hours in a controlled study.

TABLE 4: SUMMARYa OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL
Percent of Patients
(n=812)
a Based on worst course analysis
b All patients received premedication
c During first 3 hours of infusion
Severe events are defined as at least Grade III toxicity
Bone Marrow
- Neutropenia<2,000/mm390
<500/mm352
- Leukopenia<4,000/mm390
<1,000/mm317
- Thrombocytopenia<100,000/mm320
<50,000/mm37
- Anemia<11g/dL78
<8g/dL16
- Infections30
- Bleeding14
- Red Cell Transfusions25
- Platelet Transfusions2
Hypersensitivity Reaction b
- All41
- Severe 2
Cardiovascular
- Vital Sign Changes c
- Bradycardia (N=537)3
- Hypotension (N=532)12
- Significant Cardiovascular Events1
Abnormal ECG
- All Pts23
- Pts with normal baseline (N=559)14
Peripheral Neuropathy
- Any60
- Severe symptoms 3
Myalgia/Arthralgia
- Any60
- Severe symptoms 8
Gastrointestinal
- Nausea and vomiting52
- Diarrhea38
- Mucositis31
Alopecia 87
Hepatic (pts with normal baseline and on study data)
- Bilirubin elevations (N=765)7
- Alkaline phosphate elevations (N=575)22
- AST (SGOT) elevations (N=591)19
Injection Site Reaction 13

None of the observed toxicities were clearly influenced by age.

Disease Specific Adverse Event Experiences

Second-Line Ovary: For the 403 patients who received single-agent paclitaxel in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

TABLE 5: FREQUENCYa OF ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY
PERCENT OF PATIENTS
175/3 b 175/24 b 135/3 b 135/24 b
(n=95) (n=105) (n=98) (n=105)
a Based on worst course analysis
b Paclitaxel dose in mg/m2/infusion duration in hours
c All patients received premedication
Severe events are defined as at least Grade III toxicity
Bone Marrow
- Neutropenia<2,000/mm378987898
<500/mm327751467
- Thrombocytopenia<100,000/mm341886
<50,000/mm31721
- Anemia<11g/dL84906888
<8g/dL1112610
- Infections26292018
Hypersensitivity Reaction c
- All41453845
- Severe †2021
Peripheral Neuropathy
- Any symptoms63605542
- Severe symptoms 1200
Mucositis
- Any symptoms17352125
- Severe symptoms 0302

Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence.

Breast Cancer After Failure of Initial Chemotherapy: For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a-3 hour infusion).

TABLE 6: FREQUENCYa OF ADVERSE EVENTS IN THE PHASE 3 STUDY OF BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
PERCENT OF PATIENTS
175/3 b 135/3 b
(n=229) (n=229)
a Based on worst course analysis
b Paclitaxel dose in mg/m2/infusion duration in hours
c All patients received premedication
Severe events are defined as at least Grade III toxicity
Bone Marrow
- Neutropenia<2,000/mm39081
<500/mm32819
- Thrombocytopenia<100,000/mm3117
<50,000/mm332
- Anemia<11g/dL5547
<8g/dL42
- Infections2315
- Febrile Neutropenia22
Hypersensitivity Reaction c
- All3631
- Severe 0<1
Peripheral Neuropathy
- Any symptoms7046
- Severe symptoms 73
Mucositis
- Any symptoms2317
- Severe symptoms 3<1

Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.

Adverse Event Experiences By Body System

The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. The frequency and severity of important adverse events for the phase 3 ovarian carcinoma and breast carcinoma studies are presented above in tabular form by treatment arm. In addition, rare events have been reported from post-marketing experience or from other clinical studies. The frequency and severity of adverse events have been generally similar for patients receiving paclitaxel for the treatment of ovarian or breast carcinoma.

Hematologic: Bone marrow suppression was the major dose-limiting toxicity of paclitaxel. Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 ovarian study with a 3 hour infusion, neutrophil counts declined below 500 cells/mm3 in 14% of the patients treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05). In the same study, severe neutropenia (<500 cells/mm3) was more frequent with the 24-hour than the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously treated with radiation therapy.

Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes were reported in 20% and 26% of the patients treated with a dose of 135 or 175 mg/m2 given as a 3 hour infusion respectively. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications.

Thrombocytopenia was uncommon, and almost never severe (<50,000 cells/mm3). Twenty percent of the patients experienced a drop in their platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had a platelet count <50,000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4% of all courses and by 14% of all patients but most of the hemorrhagic episodes were localized and the frequency of these events was unrelated to the paclitaxel injection dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3 hour infusion received platelet transfusions.

Anemia (Hb<11 g/dL) was observed in 78% of all patients and was severe (Hb<8 g/dL) in 16% of the cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all the patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.

Hypersensitivity Reactions (HSRs): All patients received premedication prior to paclitaxel injection (See “ WARNINGS ” and “ PRECAUTIONS: Hypersensitivity Reactions ” sections). The frequency and severity of HSRs were not affected by the dose or schedule of paclitaxel administration. In the Phase 3 second-line ovarian study the 3 hour infusion was not associated with a greater increase in HSRs when compared to the 24 hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of paclitaxel infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain and tachycardia.

The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%) and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period. Rare reports of chills and reports of back pain in association with hypersensitivity reactions have been received as part of the continuing surveillance of paclitaxel safety.

Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all courses. In the Phase 3 second-line ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy.

Significant cardiovascular events possibly related to single-agent paclitaxel occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the patients with syncope treated with paclitaxel at 175 mg/m2 over 24 hours had progressive hypotension and died. The arrhythmias included asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia and premature beats. Among patients with normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.

Cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines. (See PRECAUTIONS: “ Drug Interactions ” section).

Rare reports of atrial fibrillation and supraventricular tachycardia have been received as part of the continuing surveillance of paclitaxel safety.

Respiratory: Rare reports of interstitial pneumonia, lung fibrosis and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel safety. Rare reports of radiation pneumonitis have been received in patients receiving concurrent radiotherapy.

Neurologic: The frequency and severity of neurologic manifestations were dose-dependent, but were not influenced by infusion duration. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy.

The frequency of peripheral neuropathy increased with cumulative dose. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34 to 51% from course 2 to 10.

Peripheral neuropathy was the cause of paclitaxel discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. The incidence of neurologic symptoms did not increase in the subset of patients previously treated with cisplatin. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.

Other than peripheral neuropathy, serious neurologic events following paclitaxel administration have been rare (<1%) and have included grand mal seizures, syncope, ataxia and neuroencephalopathy.

Rare reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel safety. Optic nerve and/or visual disturbances (scintillating scotomata) have also been reported, particularly in patients who have received higher doses than those recommended. These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period.

Hepatic: No relationship was observed between liver function abnormalities and either dose or schedule of paclitaxel administration. Among patients with normal baseline liver function 7%, 22% and 19% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. Prolonged exposure to paclitaxel was not associated with cumulative hepatic toxicity.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel safety.

Gastrointestinal (GI): Nausea/vomiting, diarrhea and mucositis were reported by 52%, 38% and 31% of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred more frequently with the 24 hour than with the 3 hour infusion.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration have been received as part of the continuing surveillance of paclitaxel safety. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel alone and in combination with other chemotherapeutic agents.

Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24 hour infusion than with the 3 hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and fibrosis have been received as part of the continuing surveillance of paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.

A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to paclitaxel related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with paclitaxel administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study.

Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash and pruritus 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.

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.

Drug label data at the top of this Page last updated: 2006-02-27

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