Intaxel Adverse Reactions

Myelosuppression: Neutropenia is the principle dose limiting toxicity of Paclitaxel on all administration schedules evaluated to date. The onset of neutropenia has usually occurred by day 8 and the nadir neutrophil counts have generally occurred on day 8-11 with rapid recovery by days 15-21. McGuire et al have reported that 213 of 281 courses of Paclitaxel in heavily pretreated patients with ovarian cancer were associated with grades 3 or 4 neutropenia (neutrophil count <1000 cell/µl). However, only 14 patients (21 out of 281 courses) required hospitalization for fever associated with neutropenia, but neutropenia is not cumulative and neutrophil count nadirs have generally remained unchange during successive courses indicating that Paclitaxel may not be irreversibly toxic to hematopoietic cells. Published reports on Paclitaxel given as a 3 hr. infusion indicate that shorter drug infusions may induce less severe neutropenia. The extent of prior myelosuppressive therapy is another predisposing factor for severe neutropenia. Hematopoietic colony stimulating factors have been demonstrated to ameliorate Paclitaxel induced neutropenia. More specify, absolute neutrophil count (ANC) nadirs are generally higher and the duration of severe grade 4 neutropenia (ANC <500 µl) was usually short (<5 days). Day 8 or 9 was consistently the median day of nadir for platelets.
The nursing management of hematological reactions should include a complete blood count (CBC) before each course of treatment. The White Blood Count (WBC) and platelet count should be >1500 cells/mm³ and 1,000,000 cells/mm² respectively, before re-treatment.
Frequent monitoring of blood is uncommon and almost never severe. Bleeding episodes are reported but most of the hemorrhagic episodes are localized. Anemia is also observed in 78% of patients and is severe in 16% of cases. Red cell transfusion is required in 25% of patients.
Hypersensitivity Reactions: A review of early phase I experience has identified reports of hypersensitivity in 25 of 159 patients (16%), 12 of which were classified as major reactions. The majority (53%) of HSRs occurred within 2 to 3 min. of beginning the Paclitaxel infusion and 78% began within 10 minutes. Although it is unclear whether Paclitaxel itself or Polyoxyl 35 castor oil vehicle induces the hypersensitivity reactions (HSRs), Polyoxyl 35 castor oil more likely to be responsible since other drugs formulated in Polyoxyl 35 castor oil have also been associated with HSRs. However following adoption of longer infusion schedules (primarily 24 hrs.) and use of prophylactic antiallergic premedication, incidence of severe hypersensitivity reactions fell substantially.
Severe symptoms manifest most frequently as dyspnea, hypotension and chest pains. In some patients, interruptions of the infusion are the only treatment requires. Other patients require therapy with bronchodilators, epinephrine, antihistamines and corticosteroids as single agents or in combination. Minor signs and symptoms such as flushing (36%) and rash (11%) have not been associated with subsequent development of major HSRs. None if these minor reactions require interruption of Paclitaxel for injection concentrate infusion or prevented completion of treatment.
Infections: Infections episodes in 30% of patients and 9% of courses; these episodes were fatal in 1% of patients and include sepsis, pneumonia and peritonitis. Infections episodes were reported in 19% of the patients given either 135 or 175 mg/m² dose by a 3 hour infusion. Urinary tract infections and upper respiratory tract infections were the most frequently reported infections complications.
Cardiovascular Adverse Effects: The most common cardiac rhythm disturbance noted during Paclitaxel administration is a transient asymptomatic bradycardia with heart rates occasionally decreasing to less than 40 beats/minute. It has been noted in 13 out of 45 patients (29%) in phase II trials. However, bradycardia alone is not an indication for discounting treatment, since the vast majority of these cases are totally asymptomatic. Instead, Paclitaxel should be continued unless bradycardia is associated with progressive atrioventricular (AV) conduction disturbances, and/or clinically significant hemodynamic effects, e.g. symptomatic hypotension.
Additionally, one case of progressive AV block, a fatal myocardial infarction and episodes of cheat discomfort have occurred in several patients at the time of Paclitaxel treatment in early trials.
Cardiac disturbances in recent trials have principally occurred in patients with cardiac risk factors. Since severe cardiac disturbances have been rare and inconsequential, routine cardiac monitoring during Paclitaxel infusion is not required for patients without cardiac risk factors.
In addition, the relative contributions of Paclitaxel, its Polyoxyl 35 castor oil formulation vehicle and H₁ & H₂ histamine antagonist premedication used to prevent HSRs, in inducing these cardiac disturbances is not clear.
Neurotoxicity: The neurotoxic manifestations of Paclitaxel can be categorized into those resulting from: Sensory neuropathy; Motor neuropathy; Autonomic neuropathy; Myopathy.
Sensory Neuropathy: It is most common neurotoxic effect of Paclitaxel. It invariably occurs when the Paclitaxel dose approaches 250 mg/m² (24 hr. infusion). The most common initial symptoms include numbness, tingling and/or burning pain in a glove and stocking distribution. The distal lower extremely are usually affected first. Mild sensory symptoms have usually improved or resolved completely within several months after discontinuation of Paclitaxel. However, some symptoms and deficits may persist for long periods after therapy in patients who develop more severe neuropathic symptoms.
Motor Neuropathy: Unlike sensory neuropathy, motor neuropathy is not well recognized. This is due to the fact that mild distal weakness rarely affects function.
Autonomic Neuropathy: Paralytic ileus and symptomatic orthostatic manifestation have been observed in patients receiving high doses of Paclitaxel - (250-275 mg/m²) and in those patients with diabetic mellitus who may be more predisposed to developing toxic neuropathies.
Myopathy and Myopathic Effects: Transient myalgia and/or arthralgia is commonly observed after treatment with moderate to high doses of Paclitaxel administered over 6 to 24 hrs. Symptoms generally occur 2 to 3 days after treatment and resolve within 5-6 days. While these symptoms are usually mild and infrequent at Paclitaxel doses less than 170 mg/m², they become more frequent and severe at Paclitaxel doses greater than 200 mg/m². Dose appears to be the most important risk factor for the development of significant neurotoxicity. Other factors that may predispose patients to developing severe peripheral neurotoxicity during Paclitaxel treatment are prior exposure to know neurotoxic agent and antecedent medical disorder (e.g. diabetes mellitus)
Gastrointestinal Toxicities: Paclitaxel relates gastrointestinal toxic effects include anorexia, nausea, vomiting and diarrhea. Although anorexia may frequently occur especially at high dosage, it is generally brief and rarely severe. Nausea, vomiting and diarrhea are also rarely severe and do not usually require symptomatic treatment. In phase II studies of Paclitaxel (24 hr. infusions) have experienced severe NCI (National Cancer Institute) grade 3 and 4 elevation of SGPT, SGOT, alkaline phosphate and bilirubin.
Other Toxicities: Alopecia has been reported in almost all patients treated with 24 hr. infusions of Paclitaxel at dose equal or greater than 135 mg/m². Like alopecia caused by other antineoplastic agents, Paclitaxel induced alopecia is also reversible. Transient skin changes caused by paclitaxel related hypersensitivity reactions have been observed, but no other skin toxicities have significantly been associated with administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%).
Arthralgia/Myalgia usually consisting of pain in the large joints of the arms and legs have been reported in about 50% of the patients and were usually mild. These symptoms were usually transient occurring two or three days after Paclitaxel administration and resolving within a few days.